Section 25. Skin Manifestations of Bone Marrow or Blood Chemistry Disorders

Hematology includes the study of blood and blood-forming tissues. Given the number and variety of hematologic disorders, it is not surprising that mucocutaneous manifestations of hematologic disorders are common. Many hematologic malignancies and pseudomalignancies can involve the skin through atypical cell infiltration (specific lesions), and some of these may present preferentially in the skin. These conditions, such as leukemias and lymphomas, plasma cell dyscrasias including myeloma, and Langerhans and non-Langerhans histiocytoses, are discussed in other chapters. Likewise, complications of chemotherapy, radiotherapy, cytokine use, or marrow transplantation are discussed elsewhere.

The first section of this chapter is directed toward the differential diagnosis of purpura with an emphasis on those subsets of purpura with important underlying hematologic abnormalities. The second major section of this chapter is directed toward nonspecific (nontumor-containing) findings that may be associated with hematologic disorders. Although the ready availability of laboratory testing has made early recognition of such conditions as anemia and polycythemia much less dependent on physical findings, cutaneous associations still may aid in the diagnosis of a hematologic condition or complicate its management. A comprehensive listing of these associations is presented in Table 144-1.

Selected associations are covered in more detail in the text.

Hemostasis

Hemostasis can be defined as the arrest of bleeding, and has two phases, primary and secondary, though research findings are blurring the compartmentalization of this process.65 Primary hemostasis depends both on the vasoconstriction of the injured vessel and on formation of a platelet plug at the injury site. It is usually sufficient for focal microcirculatory injury repair. Larger defects or injury in larger cutaneous vessels require secondary hemostasis to reinforce the platelet plug.

Primary hemostasis is characterized by vascular contraction, platelet adhesion and activation, and subsequent development of a plug at the site of vessel injury. Vascular contraction leads to slowing of the blood flow, so the platelets can adhere to the injured site and diminish blood loss.66 Secondary hemostasis promotes vascular integrity when primary hemostasis is insufficient and when larger vessels are involved. This phase maintains vasoconstriction through the secretion of prostaglandins, thromboxane, and serotonin. It also solidifies the platelet plug formed during primary hemostasis, through a series of clotting cascade pathways.

Because of the rich and highly visible nature of the skin microcirculation, and because of the very dynamic alterations of cutaneous blood flow (e.g., increasing to promote heat exchange, decreasing dramatically in shock states) as well as hydrostatic pressure variations by anatomic site and body position, the skin can be a very early and sensitive locale for signs of hemostatic alterations and coagulopathy. In nondisease states, the blood participates in an ongoing homeostatic balance between site-specific hemostasis or clot formation, clot extension inhibition, and clot lysis at the appropriate stage of injury repair. The platelet and coagulation cascade participate in clot formation, the antithrombin III and thrombomodulin/protein C/protein S systems in clot inhibition, and the plasminogen/plasmin system in clot lysis.

Differential Diagnosis of Purpura

The bedside dissection of the likely differential diagnosis of purpura can be summarized by five Ps: are lesions purpuric, primary, palpable, and what is their pattern and placement? For a lesion to qualify as purpuric, it must have a color that is compatible with hemorrhage—usually some shade of red, blue, or purple, but sometimes yellow–brown, green, or black—and at least some of this color must persist on compression of the skin. If the vessels are compressible, and if the color is due to mobile red cells within the vessels, then the skin color should completely blanch on compression, and no hemorrhage is clinically evident. False-positive results occur if the lesions contain tortuous vessels that kink on compression, or if compression is incomplete. Extravasated cells are not free to move, and therefore color persists on compression. It is important not only to determine the persistence of some color on compression, but also to assess in early lesions the proportion of erythema to hemorrhage. Complete blanching is a nonpurpuric lesion, but may be the physical presentation of mild urticarial vasculitis with clinically nonevident hemorrhage. Significant partial blanching of early lesions suggests an inflammatory etiology of the purpuric process. No detectable color change suggests no inflammatory component, and is characteristic of simple hemorrhage and most microvascular occlusive lesions.

Purpura may be primary or secondary in etiology. Hemorrhage may occur in inflammatory syndromes such as cellulitis, psoriasis, stasis dermatitis, or eczema, and these should be considered secondary purpura syndromes. In these and similar settings, the hemorrhage is generally secondary to nonvessel-directed inflammation increasing vascular permeability, and usually hydrostatic pressure increasing the likelihood of incidental red cell extravasation in areas of dependency.

Palpability rarely reflects the amount of cutaneous hemorrhage except for very large and deep focal cutaneous hemorrhage, resulting in a hematoma typically localizing in or below the fat layer of skin. Upward movement of the hemorrhage may occasionally result in an overlying ecchymosis. Most simple hemorrhage in the skin is nonpalpable. Instead, palpability typically results from protein-rich edema secondary to inflammation or microvascular ischemia with vascular and tissue injury. While the presence of palpability should exclude simple hemorrhage as a pathogenesis, the absence of palpability does not exclude inflammatory or occlusive hemorrhagic etiologies.

Many approaches to the differential diagnosis of purpura begin with pathophysiologic mechanisms. However, pathophysiology is usually what the physician is attempting to ascertain, and the diagnostic process begins with clinical clues. Some of the most important clinical information available from the bedside examination is lesional number, distribution, and morphology. Exploration of the differential diagnosis can begin with helpful patterns of lesional number and distribution are listed in Table 144-2.

The initial diagnostic considerations based on these patterns should then be combined with information gleaned from the lesional morphologic differential diagnosis (Tables 144-3, 144-4, and 144-5; Fig. 144-1).

The goal of the history and examination is to develop a narrow differential diagnosis or testable clinical hypothesis as to the etiology of purpura in a particular patient, and to order or review the appropriate laboratory studies that may prove or disprove suspected pathophysiologies. While the differential diagnosis of purpura could easily include hundreds of possible etiologies, the diagnostic process can be powerfully refined if one is able to determine clinically whether the early primary purpuric lesions is likely due to simple hemorrhage, inflammatory hemorrhage, or ischemia/occlusion.67,68,73 In concert with the number and distribution, lesional morphology is critical in facilitating this determination. Simple hemorrhage not severe enough to produce hematoma presents as nonpalpable (macular), nonblanchable purpura, and usually is either primarily petechial or ecchymotic, each pattern having its own differential composition (Tables 144-3, Figs. 144-2 and 144-3). Partially blanchable purpura, often palpable, is the expected clinical manifestation of inflammatory hemorrhage, including but not limited to necrotizing vasculitis (Table 143-4). If early lesions are both partially blanchable and retiform, the differential diagnosis is further narrowed (Fig. 144-4). Finally, if early lesions are retiform with minimal to no blanchable component, microvascular occlusion becomes the likely differential category, always with the caveat that some occlusive syndromes may be accompanied by inflammation when lesions are large and deep, and two vasculitides in particular [granulomatosis with polyangiitis (Wegener's) and microscopic polyangiitis] may present with purpura lesions which show no clinical evidence of inflammation. The differential diagnosis of minimal inflammatory retiform purpura, with these caveats, is listed in Table 143-5.

Nonpalpable, Nonblanchable Petechiae (<4 mm)

Palpable or partially blanching petechiae do not fit in this category; such lesions should instead prompt consideration of the differential diagnosis of classical palpable purpura. Nonpalpable petechial hemorrhage is typically the dominant type of hemorrhage resulting from problems in platelet number, always below 50,000/mm, and almost always below 10,000/mm (Table 144-3). In patients with immune thrombocytopenia, either idiopathic or alloimmune, the marrow is healthy, and platelet production is increased, leading to larger and more effective platelets. In such instances, spontaneous formation of petechiae is often minimal, even when platelet numbers are below 5,000. However, when thrombocytopenia is due to marrow failure (medications, especially chemotherapy, radiation exposure, marrow infiltration from leukemia, lymphoma, or other neoplasms), the platelets in circulation are often small, old, and poorly functional, and hemorrhage may occur despite platelet counts many thousands higher than in the immune thrombocytopenias. Drug-related thrombocytopenia can be due to several different mechanisms, including immune, destructive, and cytotoxic.69

Immune Thrombocytopenias

Idiopathic thrombocytopenic purpura (ITP) is a common bleeding disorder in children caused by autoantibodies against platelet surface antigens, especially glycoproteins IIb/IIIa and Ib. It presents with increased immunoglobulin (Ig) M, IgG, and IgA autoantibodies with decreased platelet surface antigens (CD41, CD61, and CD42b).74,75 Patients are usually asymptomatic with mostly petechiae and a few ecchymoses found on their physical examination. Oral blood blisters with gastrointestinal or mucocutaneous bleeding can also occur and are referred to as wet purpura. As in ITP, immunothrombocytopenic purpura can be associated with recent viral illness and vaccination.76 Alloimmune thrombocytopenic purpura occurs when alloantibodies against human platelets form during blood or platelet transfusion, or maternal–fetal blood exchange, leading to posttransfusion purpura and fetal and neonatal alloimmune thrombocytopenia, respectively.46 CD109 is a protein expressed on platelets, T lymphocytes, and endothelial cells. Antibodies against HPA-1, HPA-5, and HPA-15 on CD109+ cells should be sought.

Unique localization of petechial hemorrhage may result from intravascular pressure spikes. For example, vigorous Valsalva maneuver-like actions from crying in children, vigorous retching, or bearing down during childbirth may result in petechial hemorrhage above the clavicles. A ligature, blood pressure cuff, or attempted strangulation may result in hemorrhage in the affected venous drainage area.

Chronic pigmented purpuras, especially Schamberg type, may mimic simple petechial hemorrhage in the legs, despite histologic evidence of mild nonvasculitic hemorrhage such lesions. Clinically, the inflammation may not be evident, but clues to this diagnosis consist of a tendency of pigmented purpura and petechiae to cluster, leaving an orange–brown pigmentation in affected areas. The pigmented purpuric dermatoses are discussed in detail in Chapter 168.

Thrombotic Thrombocytopenic Purpura/Thrombotic Microangiopathies

Thrombotic thrombocytopenic purpura (TTP) is most commonly seen in adults, whereas hemolytic-uremic syndrome (HUS) is more frequent in children.77 TTP can result from pregnancy, cancer, drugs (chemotherapeutic-bevacizumab, and immunosuppressives—cyclosporine/tacrolimus, oral contraceptives, ticlopidine, and quinine), bone marrow transplantation, and autoimmune diseases. The most common pathogenesis is from antibodies, which interfere with the function of ADAMTS13. The result is improper cleavage of von Willebrand factor (VWF) and platelet-fibrin thrombotic microangiopathy.78,79 Patients have increased levels of LDH with associated schistocytes, helmet cells, and megakaryocytes; clinical signs include fever, renal (especially in HUS), and central nervous system (headache, seizures, hemiparesis, disorientation) abnormalities. Despite clear evidence of visceral vessel occlusion from platelet plugging, the mechanism of petechial hemorrhage in TTP is far from clear. Occlusive disease was reported in a small series of mucous membrane lesions, but biopsies of cutaneous lesions are not reported, and the morphology of these lesions is more in keeping with simple hemorrhage. Deficiency of ADAMTS13 has been shown in familial TTP (congenital TTP, Upshaw–Schulman syndrome). The treatment of choice is fresh frozen plasma/plasmapheresis. Acquired functional deficiency of ADAMTS13 is known to occur in several other settings, most commonly with lupus and other autoimmune diseases.80 HUS is commonly caused by Shiga toxin, producing Gram-negative bacilli, especially Escherichia coli O157:H7 infection. It presents with bloody diarrhea and hemorrhagic colitis, and usually causes oliguric or anuric renal failure. Cutaneous lesions are not seen. Diarrhea-negative or atypical HUS is not associated with Shiga toxin-producing organisms, and occurs without an obvious predisposing condition. Preeclampsia-HELLP (hemolysis, elevated liver enzymes, low platelets) is another thrombotic microangiopathy that can mimic TTP/HUS syndromes.

TTP typically presents as round nonpalpable petechial hemorrhage, in contrast to the typical cutaneous presentation of heparin-induced thrombocytopenia (HIT), in which the retiform morphology of purpura is consistent with platelet-related occlusion of the cutaneous microvasculature. The platelet aggregation is triggered by an antibody, which recognizes antigenic sites on both heparin and platelet factor 4 on the platelet surface. Treatment of heparin necrosis typically involved anticoagulation with coumarin, but this treatment may worsen the vascular occlusion, leading to limb necrosis.81 Worldwide, three accepted drugs are used in the treatment of patients with HIT: (1) danaparoid (not available in the United States), (2) recombinant hirudin (lepirudin), and (3) argatroban.79

Nonpalpable, Nonblanchable Ecchymoses (>1 cm)

The cutaneous lesions associated with scurvy are characterized by purpura that surrounds corkscrew hairs on the lower extremities (see Chapter 130), but nonspecific hemorrhage is more typical. True senile purpura is uncommon, and is usually the misdiagnosis for solar damage in poorly pigmented, often elderly individuals. Solar purpura usually occurs on the extensor surfaces of the forearms and results from the photo-induced loss of cutaneous elasticity and weakened dermal capillary support. Erythrocyte (RBC) extravasation occurs with minor trauma to the hands and other sites (see Chapter 109). Ecchymotic hemorrhage after minor trauma generally results from procoagulant defects, poor dermal vessel support, or Waldenstrom hypergammaglobulinemic purpura (on the legs) (Table 144-3, Fig. 144-2).

Partially Blanching Round Purpura (Classical Palpable Purpura) and Partially Blanching Retiform Purpura

Lesions of inflammatory hemorrhage are round, partially blanching, and palpable, and most commonly represent leukocytoclastic or necrotizing vasculitis. The differential diagnosis of this morphologic presentation is listed in Table 144-4 (Fig. 144-3).

When purpura is retiform in configuration, but also associated with prominent early partial blanching, the potential causes of the inflammatory hemorrhage are more limited (Table 144-4, Figs. 144-4 and 144-5, inflammatory retiform purpura). Given the lesional number and distribution, a highly probable clinical hypothesis can be formulated. However, four occlusive syndromes may occasionally present with a few, large, indurated plaques of early inflammation of the dermis and subcutaneous tissue surrounding retiform purpura or eschar. These include: (1) antiphospholipid antibody syndrome; (2) warfarin necrosis; (3) heparin necrosis; and (4) cutaneous calciphylaxis. Among inflammatory causes of hemorrhage/vasculitis, only benign cutaneous polyarteritis nodosa is likely to cause such large necrotic thick plaques with early inflammation.

Nonblanching Retiform Purpura

The differential diagnosis of cutaneous microvascular occlusion is extensive, and differs considerably from the usual list of causes of venous thrombosis and pulmonary emboli. Underlying causes can be organized by pathophysiology into eight categories, as shown in Table 144-5 (Figs. 144-6, 144-7, and 144-8, nonblanching retiform purpura). Of note, although early lesions of cutaneous vasculitis typically blanch partially, occasionally patients with granulomatosis with polyangiitis (Wegener's) and microscopic polyangiitis may present with necrotic or retiform lesions without discernible erythema. Discussion of all occlusive syndromes is beyond the space limitations of this chapter, but two syndromes merit discussion because of frequent confusion in their use and definition: (1) disseminated intravascular coagulation (DIC) and (2) purpura fulminans. A newly recognized vasculopathy thought secondary to levamisole used to cut illicit cocaine typically presents with nonblanching retiform purpura and necrosis, typically involving ears and trunk or extremities (Fig. 144-8).82,83 Though associated with both antineutrophil cytoplasmic antibodies and antiphospholipid antibodies, and both vasculitic and thrombotic histologic findings are reported, early lesional findings seem most consistent with thrombotic vasculopathy, with secondary vasculitic changes (personal observation, author).

Disseminated Intravascular Coagulation

DIC is not a disease, but rather always secondary to an underlying disorder. The disorders most commonly associated with DIC are listed in Table 144-6.

DIC is characterized by systemic activation of coagulation, insufficiently controlled by natural anticoagulant mechanisms, in concert with clot lysis, leading to the intravascular deposition of fibrin in the (micro) vasculature and the simultaneous consumption of coagulation factors and platelets.84 In addition to evidence of clot formation, DIC is also defined by prolonged prothrombin and partial thromboplastin times (PT and PTT) as well as depleted fibrinogen. Elevated fibrin degradation products or d-dimers typically provide evidence of active clot lysis, although increased plasma soluble fibrin may be more specific. This combination can result in three clinical scenarios: (1) no clinical evidence of thrombosis or hemorrhage; (2) clinically evident thrombosis; or (3) simple bleeding into skin or tissues, including at from puncture sites. The pathogenetic pathways that play a role in the development of thrombosis include tissue factor-dependent activation of coagulation, defective physiologic anticoagulant pathways (such as the antithrombin system and the protein C system), and impaired fibrinolysis, caused by elevated levels of plasminogen activator inhibitor type 1.85 Therapeutic strategies are based on the pathogenesis of DIC (trauma, burns, postsurgical, sepsis). These include administration of anticoagulants and strategies to restore physiologic anticoagulant pathways (such as activated protein C concentrate or antithrombin III.84)

Purpura Fulminans

Purpura fulminans is a severe skin disorder typically associated with DIC that was first reported in children and infants.86 This term has been used by some to describe widespread cutaneous hemorrhage of any type in seriously ill patients. However, use of the term is best limited to neonatal, sepsis-related, and postinfectious syndromes associated with histologic evidence of small vessel thrombi, typically with clinical lesions of nonblanching retiform purpura or eschar.68,73

Purpura fulminans occurs in three clinical settings: (1) in relation to acute sepsis, (2) after infection, and (3) in neonates. Catastrophic antiphospholipid antibody syndrome is a mimic. In acute sepsis-associated or secondary purpura fulminans, the related overwhelming infection is most commonly meningococcal (see Chapter 181), but may be caused by many other Gram-positive and Gram-negative organisms. Patients are hypotensive with reduced peripheral perfusion, contributing to the skin necrosis on distal extremities and elsewhere (Fig. 144-6). Sometimes, skin necrosis occurs in a patchy distribution. Postinfectious purpura fulminans can manifest within 10 days of an antecedent illness, most commonly following streptococcal and/or varicella infections in children. Neonatal purpura fulminans is most often seen in association with homozygous protein C deficiency, in which massive intravascular thrombosis and abdominal wall gangrene can also develop.87

Pallor

Pallor of the mucocutaneous tissue is observed most readily in the palms, nail beds, face, and conjunctivae. In these areas, the microvascular bed is visible through the skin. Pallor is the result of lowered hemoglobin content. Among the multiple causes for pallor are acute and chronic hemorrhage, emotion, drugs (i.e., vasopressors), cold, shock, and pathophysiologic adjustments that lead to anemia. Cutaneous edema can also produce pallor. Successful treatment of the underlying etiology corrects the pallor as well.

Anemia

The definition of anemia depends on the patient's age and sex. The palmar creases are a good indicator of the severity of anemia. Unless the hemoglobin level drops below 7 g/dL, palmar creases appear pink.88 Constitutional signs and symptoms of anemia include malaise, fatigue, dizziness, postural hypotension, dyspnea on exertion, and tachycardia.

Anemias may be classified based on RBC volume as microcytic, normocytic, and macrocytic.89 Review of the blood smear may also reveal distinctive morphologic red cell changes, such as targeting, spherocytosis, red cell fragmentation, or poikilocytosis, which narrow the diagnostic possibilities. Laboratory evaluation should be based on the suspicion of the underlying cause of anemia. In addition to complete blood count with white blood cell differential and red cell morphology, iron studies (iron, total iron blood count, percent saturation of iron), ferritin, B12, lactate dehydrogenase (LDH), haptoglobin, folate levels, platelet and reticulocyte counts may be warranted based on initial laboratory evaluation.

Microcytic Anemias

Microcytic anemias are most often due to (1) iron deficiency, (2) anemia of chronic disease, (3) autoimmune hemolytic anemias, or (4) thalassemias. Of these, the first two are by far the most common.

Iron Deficiency

Sixty percent to 70% of the body stores of iron are in the RBCs in the form of hemoglobin.90 Heme-containing proteins are essential for metabolic processes in virtually all cells.91 Hemoglobin, myoglobin, and the cytochromes are heme-containing proteins and enzymes. The average life of an erythrocyte is 120 days, after which it is phagocytized by macrophages of the liver, spleen, and bone marrow. The iron is then stored in the form of ferritin to be recycled.

Iron deficiency anemia can result from increased iron demand in the setting of inadequate iron stores. This is most commonly seen during pregnancy, because increased blood volume is necessary for fetal growth and development.

Symptoms of iron deficiency include fatigue, headache, tinnitus, irritability, paresthesias, burning sensations of the tongue, akathisia (restless leg syndrome), and pica (the craving to eat substances such as dirt, clay, ice, laundry starch, salt, or cardboard).90 The physical findings of anemia in their approximate order of frequency include: pallor, glossitis (smooth red tongue), stomatitis, and angular cheilitis.68 Skin dryness and coarsening, brittle nails, and fine, dry hair may also occur. Blue sclerae and koilonychias (spooning of nails) are rare. Retinal hemorrhages or exudates may develop with severe anemia (hemoglobin <5 g/dL), and iron deficiency may accelerate proliferative retinopathy in diabetics. Generalized fatigue often disrupts the patient's ability to focus on daily activities at work, home, and school, resulting in poor performance.92

Anemia of chronic disease is a common finding in chronically ill patients. Associated laboratory features somewhat mimic those of iron deficiency anemia with mild microcytosis and low serum iron, but with normal (i.e., not elevated) serum iron-binding capacity and transferrin. In some cases, bone marrow biopsy to stain for iron stores may be required to assess iron status.91 This form of anemia appears to result from altered recycling of iron in chronic diseases states, and is not repaired by iron replacement. Appropriate diagnosis is important before beginning iron supplementation for microcytic anemia, since iron supplementation may worsen iron storage overload in patients with thalassemia.

Treatment of iron deficiency anemia requires replacing lost iron and maintaining the daily iron dietary requirement. The recommended daily dose for treatment of iron deficiency is between 150 to 200 mg/day of elemental iron (325 mg ferrous sulfate = 65 mg of elemental iron), usually continued until the hemoglobin reaches a normal value.52

Macrocytic Anemia

Megaloblastic anemia is classified as a macrocytic anemia characterized by enlarged erythroid precursor cells. There are numerous etiologies for macrocytic anemia; folate and cobalamin (vitamin B12) deficiency are the most common. Folate and vitamin B12 deficiencies are distinguishable by their noncutaneous clinical presentations (see below), but not by hematologic findings. Their deficiency leads to impaired purine and pyrimidine synthesis, preventing normal DNA replication. The macrocytic cells are a result of nuclear-cytoplasmic asynchronization.

Vitamin B12 is found only in meat and dairy products, making vegetarians prone to deficiency.93 In nonvegetarian populations (especially of Scandinavia, Turkey, and Israel), vitamin B12 deficiency is caused by a rare genetic disorder of malabsorption, the Imerslund–Grasbeck syndrome. Pernicious anemia (PA) is the most common cause of vitamin B12 deficiency. It is an autoimmune disorder that attacks intrinsic factor in the ileum, which is essential to absorb vitamin B12. The second cause of PA, chronic atrophic gastritis, results in autoantibodies against gastric parietal cells, which produce intrinsic factor.

Folate is found in animal products and in green leafy vegetables. Its deficiency is usually attributed to dietary inadequacy, alcohol abuse, malabsorption, and drugs that interfere with folate metabolism, i.e., methotrexate, phenytoin, trimethoprim. The demand for folate by the placenta and fetus usually doubles. Therefore, it is now standard care to give prophylactic folic acid supplements to all pregnant women to reduce the risk of neural tube defects in newborns.94 Exfoliative skin disease and hemolysis can also lead to folate deficiency due to increased demand. Hereditary folate malabsorption results in impaired folate transport in the gastrointestinal tract and the blood–brain barrier.

Clinical findings of megaloblastic anemia develop slowly and vary, depending on the level of hemoglobin concentration and the etiology. The commonly shared signs and symptoms are malaise, fatigue, palpitation, glossitis, shortness of breath, and light-headedness. Mild jaundice can also be seen when ineffective erythropoiesis leads to hyperbilirubinemia and this, combined with anemic pallor, may lead to a characteristic lemon-yellow skin color. Hyperpigmentation is common in vitamin B12- and folate-deficient patients, especially skin types III–VI. Patients with PA may also develop vitiligo or Hashimoto thyroiditis.95 Hyperpigmentation is a common cutaneous manifestation of vitamin B12 deficiency.96 The hyperpigmentation is usually prominent on the knuckles of the hands and feet, especially in darkly pigmented individuals.97

Neurologic findings in vitamin B12 deficiency, but not folate deficiency, help to clinically distinguish between the two causes of megaloblastic anemia.93,94 Memory loss, dementia, tremor, Lhermitte's sign, irritability, atrophic glossitis, and neuropathy may occur. Specifically, patients with vitamin B12 deficiency develop subacute combined degeneration of the dorsal and lateral spinal columns—paresthesia (initial presentation), loss of vibration and position sense, shuffling gait, ataxia, spasticity, and paraplegia. The signs are symmetric in presentation and affect the lower extremities more than the upper extremities.

Typically, patients with folate deficiency are malnourished and often have diarrhea. Patients with alcoholism are prone to folate deficiency. Another distinguishing marker is that vitamin B12 deficiency takes many years to occur, given the large liver stores. Folate deficiency, on the other hand, can occur in a few months.

Correcting the underlying etiology usually resolves the anemia and reverses the signs and symptoms. Vitamin B12 is best administered parenterally. Prophylactic folic acid supplementation of 400 μg/day is recommended for all women of childbearing age. In folate-deficient patients, 1–5 mg/day of oral folic acid is recommended with subsequent maintenance therapy.

Anemia of Endocrine Disorders

Panhypopituitarism, hypothyroidism, and Addison disease are the most common endocrine disorders in association with anemia, although anemia may occur in hyperthyroidism and gonadal disease as well (see Chapter 151).

Flushing

Differential Diagnosis

Flushing occurs as a result of cutaneous vasodilation, and when associated with sweating is mediated through the sympathetic cholinergic fibers (Box 144-1; see Chapter 151).

Polycythemia Vera

The hallmark cutaneous finding of polycythemia vera (PV) is ruddy cyanosis and plethora. Other skin findings are aquagenic pruritus, neutrophilic dermatosis, pyoderma gangrenosum, and purpura. Acrocyanosis is seen in conditions with elevated hemoglobin levels, but deoxygenated blood through the dilated vessels in the skin. Increased red cell mass is either a direct result of compensation for hypoxia or from primary disorders such as PV. These changes lead to an increase in blood viscosity and vascular volume, resulting in a hypercoagulable state, especially when associated with thrombocytosis, and occasionally paradoxical hemorrhage from platelet dysfunction.98

Other symptoms are headache, paresthesia, and erythromelalgia. Erythromelalgia is a syndrome of altered acral responses, resulting in erythema and burning pain, especially when triggered by touching a warm object.99 In myeloproliferative diseases, this syndrome is most probably secondary to platelet abnormalities, and may result in microvascular occlusion and necrotic lesions in affected areas. The catastrophic symptoms include large vessel arterial cerebrovascular (stroke) or cardiovascular (myocardial infarction) events, and peripheral arterial occlusion. PV has an unusually high incidence of portal and hepatic vein thrombosis (Budd–Chiari syndrome), lower extremity deep venous thrombosis, leg ulcers, Raynaud phenomenon, and pulmonary emboli. Bleeding manifestation is assumed to be a direct cause of dysfunctional platelets or von Willebrand disease. Defective primary hemostasis manifests with ecchymosis, menorrhagia, epistaxis, gingival hemorrhage, and, less frequently, gastrointestinal hemorrhage. Risk factors for PV are age (more than 60 years of age), history of thrombosis, cardiovascular risk factors (hypertension, smoking, hypercholesterolemia, diabetes), hereditary and acquired thrombophilic states (congenital deficiency of anticoagulants: antithrombin III, protein C and S; genetic mutation in factor V Leiden, prothrombin G20210A, or methylenetetrahydrofolate reductase), and acquired conditions (anticardiolipin antibodies and/or lupus anticoagulants).98

Diagnosis of PV has been greatly simplified in most cases by the ability to test for the JAK2617F mutation present in 95% of all patients.100

There is no specific therapy for PV. Treatment is directed toward preventing thrombohemorrhagic episodes and progression to myelofibrosis or leukemia. Aspirin may be of minor help in preventing thrombosis. Those not benefiting symptomatically from aspirin usually require platelet cytoreduction, (hydroxyurea, busulfan, radioactive phosphorus, chlorambucil, interferon) or anagrelide to inhibit platelet function. Phlebotomy is useful in controlling red cell mass, but may exacerbate thrombocytosis or leukocytosis.100

Cyanosis

Cyanosis refers to discoloration of the mucocutaneous tissue that results in a blue or purple tinge, particularly in the peripheral tissues such as lips, ears, and nail beds. Central cyanosis refers specifically to the lingual and sublingual regions, and is more reflective of reduced hemoglobin in the blood; in peripheral cyanosis (skin, hands, feet, earlobes, etc.), the cause is often vasoconstriction. Cyanosis may be difficult to detect and is often missed on physical examination. Many factors, including natural skin pigment, thickness of the skin, and blood flowing through the cutaneous capillaries, determine the degree of cyanosis.

Cyanosis is detectable when at least 5 g of deoxygenated hemoglobin are circulating in the capillary blood, which correlates with an arterial concentration of deoxygenated hemoglobin of 3.4 g/dL. A patient with severe anemia of less than 7 g/dL Hg may never manifest cyanosis because they may become fatally hypoxic long before they reach 5 g/dL of desaturated hemoglobin, whereas a patient with PV frequently manifests ruddy cyanosis because the total increased hemoglobin content of their blood allows adequate oxygenation of tissue despite reaching the 5g/dL level at which the cyanosis becomes clinically evident (Box 144-2). Fluorescent light is best for detecting cyanosis. The diagnostic workup for a complete assessment of cyanosis includes complete blood cell count, arterial blood gas, pulse oximetry, partial arterial pressure of oxygen (PaO2) level, and arterial oxygen saturation. If cyanosis is positional, an intracardiac mass must be considered.24

The causes of cyanosis are broad, but best if characterized into two groups: (1) disorders involving deoxygenated hemoglobin and (2) disorders of abnormal hemoglobin.101,102 The latter includes acquired and inherited methemoglobinemia, sulfhemoglobinemia, and low oxygen-affinity hemoglobin. Methemoglobinemia causes clinically discernible cyanosis when the absolute level of methemoglobin exceeds 1.5 g/dL; this correlates with approximately 10%–15% methemoglobin. Offending agents are nitrates (found in drinking water, drugs, and food), topical anesthetic agents (lidocaine, benzocaine, and prilocaine), drugs (i.e., dapsone, phenazopyridine, sulfamethoxazole), and aniline dyes. Congenital methemoglobinemia is caused by deficiency in nicotinamide adenine dinucleotide (reduced form)–cytochrome b5 reductase.103 Treatment of choice for methemoglobinemia is intravenous methylene blue. Methylene blue should not be administered to patients with glucose-6-phosphate dehydrogenase deficiency. 104 If methylene blue is contraindicated, ascorbic acid can be given. RBC exchange transfusion has also been reported to be an effective treatment in symptomatic methemoglobinemic patients with coexistent glucose-6-phosphate dehydrogenase deficiency (see Chapter 225).

Sulfhemoglobin in concentrations greater than 0.5 g/dL in capillary blood also causes cyanosis, and cannot be reversed. Medications (especially sulfonamides, phenacetin, acetanilide, and phenazopyridine are the usual causes, but this condition has occurred independent of drug use in association with chronic constipation and purging. Offending agents in cases of acquired methemoglobinemia should be discontinued. No other therapy may be required. But if the patient is symptomatic, methylene blue, 1–2 mg/kg over 5 minutes, provides an artificial electron acceptor for the reduction of methemoglobin via the NADPH-dependent pathway. Response is usually rapid; the dose can be repeated in 1 hour, but frequently this is unnecessary. Caution should be exercised to avoid an overdose because large (more than 7 mg/kg) cumulative doses have been reported to cause dyspnea, chest pain, and hemolysis. Because co-oximetry detects methylene blue as methemoglobin, it cannot be used to monitor methemoglobin levels after treatment with methylene blue; however, the specific Evelyn-Malloy method allows for the discrimination of methemoglobin from methylene blue. Sulfhemoglobinemia occurs as sulfur binds to hemoglobin, resulting in irreversible deoxyhemogobinemia. It produces cyanosis at levels of only 0.5-g/dL capillary blood. Etiologies are drugs (sulfonamides, phenacetin, acetanilide, and phenazopyridine), constipation, and purging.

Low oxygen hemoglobin affinity occurs at altitude of 5,000 m (16,000 ft) or higher and can cause hypoxemia severe enough to result in cyanosis. Emotion, cold exposure, Raynaud phenomenon, and cryoglobulins (cold agglutinins) are some nonhematologic causes of peripheral cyanosis.

Disorders involving deoxygenated hemoglobin include congenital heart defects in the newborn (i.e., transposition of the great vessels, tetralogy of Fallot, and Ebstein's anomaly). X-linked dyskeratosis congenita presents with abnormal pigmentation, telangiectasias, nail dystrophy, leukoplakia; rarely, arteriovenous fistulas with central cyanosis occur. Arteriovenous fistulas are a feature of Osler–Weber–Rendu syndrome as well. Other disorders of the central nervous system, respiratory tract, and musculoskeletal and circulatory systems can also disrupt the oxygen supply to the tissues.

Jaundice

Jaundice (icterus) refers to the yellowish discoloration of the skin, caused by elevated bilirubin levels. The discoloration is a direct result of the bile pigment that stains the skin, suggesting an abnormality in bilirubin clearance or increased production due to hepatobiliary disease (see Chapter 150) or a hemolytic disorder. Kernicterus or permanent damage to the neonatal brain associated with hyperbilirubinemia is a serious risk.

Infiltrative Lesions

Extramedullary Hematopoiesis

Synthesis of blood elements outside the bone marrow usually takes place in the spleen and liver but can also affect the skin. The dermis is a normal site of hematopoiesis during early fetal development. Cutaneous lesions of extramedullary hematopoiesis include nodules (can be sclerosing), ulcers, erythematous papules, violaceous plaques, and diffusely erythematous induration. Neonates with dermal hematopoiesis present as blueberry muffin babies with dark blue-colored to violaceous nodules. In neonates, the causes are erythroblastosis fetalis, chromosomal abnormalities, infections, congenital hemolytic anemia, thalassemia, and twin-to-twin transfusion.105 Older individuals may show dermal hematopoiesis from hemolytic anemias, myeloproliferative syndromes such as chronic idiopathic myelofibrosis and PV, thalassemia, and osteoporosis. The histologic findings are intradermal proliferation of immature granulocytes, megakaryocytes, and erythroid and myeloid precursor cells.

Leukemia Cutis

Leukemia cutis (LC) is a localized or disseminated skin infiltration by leukemic cells. It is usually a sign of dissemination of systemic disease or relapse of existing leukemia. Reported incidence varies from less than 5%–40%, depending on the type of leukemia, both acute and chronic, including the leukemic phase of non-Hodgkin lymphoma and hairy cell leukemias. It most commonly occurs with acute monocytic leukemia (AML-M5) and acute myelomonocytic leukemia (AML-M4).

Pattern of presentation of skin lesions in LC is variable and may have features that overlap with other (inflammatory) eruptions. Most common lesions are small (2–5 mm) papules (Figs. 144-9 and 144-10), nodules (Fig. 144-11), or plaques. LC lesions are usually somewhat more pink, violaceous, or darker than normal skin, always palpable, indurated, firm, or guttate psoriasiform or lymphomatoid papulosis-like lesions, but usually not tender. They are localized or disseminated; usually on trunk (Fig. 144-9), extremities, and face (Fig. 144-10), but may occur at any site. They may be hemorrhagic when associated with thrombocytopenia or may ulcerate. Erythroderma may (rarely) occur. Leukemic gingival infiltration (hypertrophy) occurs with acute monocytic leukemia. Similar lesion morphologies occur with different types of leukemia or specific types of leukemia may present with a variety of morphologies.

Inflammatory disorders occurring in patients with leukemia are modified by the participation of leukemic cells in the infiltrate, resulting in unusual presentations of such disorders (e.g., psoriasis with hemorrhage or erosions/ulcerations). Also, there are a number of cutaneous inflammatory diseases that may be associated with leukemia: Sweet syndrome (see Chapter 32), bullous pyoderma gangrenosum (see Chapter 33), urticaria (see Chapter 38), and necrotizing vasculitis (see Chapter 163).

Systemic symptoms are those associated with hematologic malignancy. Not infrequently, cutaneous manifestation may be the initial presenting symptom and may contribute importantly to the diagnosis.

The diagnosis is made by suspicion and verified by skin biopsy, immunophenotyping, and B- or T-cell receptor rearrangement studies. Hematologic studies with complete analysis of bone marrow aspirate and peripheral blood smear are then needed to make the diagnosis. If cutaneous findings precede any systemic disease, careful assessment of peripheral blood smears and bone marrow biopsies must be made.

The prognosis of LC is directly related to the prognosis for systemic disease. Therapy is usually directed at the leukemia itself.

Cutaneous lymphomas (CLs) represent clonal proliferations of neoplastic T or B lymphocytes and rarely of natural killer (NK) cells or—for historical reasons— plasmacytoid dendritic cells. CLs have been recognized as a heterogeneous group with distinct variability in clinical presentation, histopathology, immunophenotyping, and prognosis.

Primary CLs often show a completely different clinical behavior and prognosis than do histologically similar systemic lymphomas, which may involve the skin secondarily. Therefore, primary CLs require different approaches to treatment. For this reason, a consensus classification has been created based on both the European Organisation for Research and Treatment of Cancer (EORTC) classification for primary CLs and the World Health Organization (WHO) classification for tumors of hematopoietic and lymphoid tissues. This first common classification (WHO-EORTC)1 categorizes the entities according to lineage and then according to a combination of morphology, immunophenotype, genetic features, and clinical syndromes (Box 145-1) and constituted the basis for the classification of CLs in the new WHO classification 2008.2 This chapter discusses the most frequent cutaneous T-cell lymphomas (CTCLs)—mycosis fungoides (MF), Sézary syndrome (SS), primary cutaneous anaplastic large-cell lymphoma (cALCL), and lymphomatoid papulosis (LyP)—and the most frequent cutaneous B-cell lymphomas (CBCLs)—primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma (PCLBCL), leg type. These seven types of cutaneous lymphoma represent nearly 90% of all CLs.3 Rare entities occurring primarily in the skin are also described.

CLs represent the second most common group of extranodal lymphomas after the primary gastrointestinal lymphomas.4 The annual incidence is estimated to be 1 per 100,000.5

CTCLs are non-Hodgkin lymphomas characterized by a dominant skin-homing T-cell clone. They represent approximately 80% of all CLs. The most common forms (approximately 65% of CTCL) are MF and SS, with an annual incidence of five new cases per million people. After MF and SS, the primary cutaneous CD30+ lymphoproliferative disorders comprising LyP and cALCL represent the second most common group of CTCLs (approximately 27%).

For many years, CTCLs were thought of as a disease of long-term antigen stimulation in which an initial inflammatory response in the epidermis leads to T-cell proliferation and, finally, to the emergence of a malignant clone.6 Despite much effort to identify such an antigen, the etiology remains unknown.

Endogenous Factors

Due to the above-mentioned hypothesis of antigen stimulation several studies have analyzed the HLA background of affected individuals. Two independent studies showed an association of distinct HLA class II molecules and MF or SS, i.e., the alleles HLA-DRB1*11 and DQB1*03 are significantly overrepresented in these patients.7,8

Exogenous Factors

A viral etiology for CTCLs was an attractive hypothesis given the cutaneous similarities to adult T-cell lymphoma/leukemia, which is associated with human T-cell lymphotrophic virus type 1 (HTLV-1) infection (see Chapter 197). The results of studies to determine an association between CTCL and HTLV-1 are contradictory. Although few studies reported detection of HTLV-1 or -2 sequences by polymerase chain reaction (PCR) analysis in peripheral blood mononuclear cells (PBMCs) or skin biopsies of CTCL patients,9,10 most reports of American and European populations repeatedly failed to demonstrate an association of MF with HTLV-1 infection by PCR, Southern blot, and reverse transcriptase assays.11–13 These data suggest that HTLV-1 does not play an important role in the etiology of CTCLs, and that the only reason to screen patients for antibodies is suspicion that the diagnosis is adult T-cell lymphoma/leukemia rather than MF. Epstein-Barr virus (EBV) has also been proposed as a causative pathogen.14 Given its association with other lymphoproliferative disorders and lymphomas, such as Burkitt lymphoma, this seemed logical. Several studies have shown that EBV is detectable only in a minor percentage of CTCL lesions. In these studies, EBV detection was related to a poor prognosis and its presence is more likely related to immunosuppression caused by either the disease or the therapy, than to etiology of CTCL.15 However, a strong association of EBV and a rare cutaneous lymphoproliferative disease with a hydroa vacciniforme-like appearance, which occurs mostly in people of Asian origin has been observed.16

Bacterial infections have also been implicated in the etiology of CTCLs.17 Of special interest has been the hypothesis that superantigens from Staphylococcus aureus may be responsible for chronic antigenic stimulation.18 In several studies, S. aureus has been detected in a high percentage on the skin of CTCL patients with a high tumor burden, while patients in early stage disease did not show significant differences to control groups.19,20 Though these studies conclusively demonstrated the involvement of S. aureus in disease exacerbation and clinical improvement following antibiotic treatment, the missing difference in S. aureus colonization of early stages of CTCL and control groups questions the involvement of S. aureus or superantigens produced by these bacteria in initiation of CTCLs.

Besides infectious pathogens, it has also been suggested that environmental and occupational risk factors play a causative role in CTCL, because an indolent dermatitis often precedes the diagnosis. Exposure to carcinogens in the work environment could provide the suspected long-term antigenic stimulation for the initiation of the clonal expansion. In epidemiologic studies,21,22 several occupations like glass formers, potters, or paper and wood industry workers have been associated with a higher risk for development of MF. However, neither are the results of the different studies consistent nor could a common denominator like exposure to known carcinogens be identified. With regard to chronic antigenic stimulation by occupational contact allergens it has to be taken into account that MF arises typically on body areas like the lateral trunk, which are protected by clothing during working time. Also other environmental risk factors, like consumption of alcohol, smoking, or exposure to ultraviolet (UV) radiation, were not consistently observed in association with an increased risk for CTCLs.

The clinical entities encompassed by the term cutaneous T-cell lymphomas share several components: the epidermal and/or dermal microenvironment, a clonal T-cell population, and a modulated antitumor response.23,24 It has to be kept in mind that due to the rare occurrence of CTCLs in general and of the less prevalent subtypes in particular, nearly all of the knowledge on pathogenetic events has arisen from studies on specimens from MF and SS patients.

The basis for CTCLs as a malignancy confined to the skin, at least in the initial stages of the disease, is the expression of skin-specific homing receptors on the malignant T-cell clone. Skin-homing T cells can be distinguished from other T cells by a unique cell surface receptor called cutaneous lymphocyte-associated antigen (CLA). CLA is an inducible posttranslational carbohydrate modification of the ubiquitously expressed T-cell surface protein, P-selectin glycoprotein ligand 1 by α(1,3)-fucosyltransferase and is expressed on 30% of memory T cells in the peripheral blood.25 It has been shown that induction of CLA expression on T cells occurs during the transition from naive to memory T cells and is mediated by dendritic cells isolated from peripheral skin draining lymph nodes.26 CLA-positive cells have the ability to home to the skin by binding to E-selectin, which is expressed on endothelial cells of dermal postcapillary venules and is superinduced during cutaneous inflammation. As T cells in CTCLs express CLA and CD45RO, a memory T-cell marker, it is though that CTCLs arise from skin homing memory T cells. However, as CLA expression is strongly detectable in skin biopsies from both MF and inflammatory dermatoses, it cannot be used for the distinction of malignant and reactive T cells or malignant from inflammatory skin conditions.27 In addition to CLA, expression of the chemokine receptors CCR4 and CXCR3 has been implicated in homing of the malignant cells to the epidermis and dermis. Furthermore, the respective ligands, i.e., the chemokines CCL17 and CCL22 have been found in skin lesions of CTCLs.28 Interestingly, diminished expression of these skin homing receptors seems to be associated with more aggressive disease, i.e., large cell transformation, tumor formation. and dissemination of tumor cells into the blood or lymph nodes.29,30

Besides chemokines that attract the T cells into the skin, cytokines play an important role in the pathogenesis of CTCLs. Because of the memory phenotype of the tumor cells the cytokines interleukin 7 (IL-7) and IL-15, which are necessary for long-term survival and basal homeostatic proliferation of CD4 memory T cells, are of special interest.31 In vitro studies and immunohistochemical analyses on skin biopsy specimens from lesions of MF demonstrate the presence of IL-15 and IL-7 and their capacity to prolong survival of a cell line derived from a SS patient in vitro, probably by an upregulation of the antiapoptotic protein bcl-2. As source of these cytokines both keratinocytes and the tumor cells themselves have been discussed.32,33

Direct genetic analysis of the clonal T cells and the identification of pathogenetically relevant genes in CTCLs have been hampered by the difficult differentiation of malignant and reactive lymphocytes in skin specimens on the one hand and by a large variety of reported genetic alterations on the other. The basis for the latter phenomenon is a chromosomal instability in tumor cells of patients with CTCLs, which has been described repeatedly.34 In the last years, the application of large-scale genome analysis by comparative genomic hybridization and array technologies has elucidated the genetic basis for established pathogenetic factors and disclosed several new pathways, which are of central importance in the pathogenesis of CTCLs. These studies were conducted on samples with high tumor load from MF (skin biopsy specimens from tumors) and SS (PBMCs) patients, and also demonstrated considerable differences of these two entities in regard to genetic abnormalities.35 The most consistent results were obtained for chromosomal and transcriptional gains affecting the proto oncogene MYC and loss of the tumor suppressor gene TP53, a combination for which it is shown to induce genetic instability by disrupting cell cycle control and apoptosis.36 Furthermore, gains of genes important for the generation of survival signals, for example, the cytokine IL-7, the IL-2 receptor or transcription factors like STAT3/5, as well as alterations in members of the NFκB pathway, have been described.37 In addition to gains, losses of well-known tumor suppressor genes, for example, CDKN2A (p16), were detected.38

Loss of Fas expression on tumor cells is of special importance as the Fas receptor/Fas ligand (FasL) pathway is involved in activation induced cell death of physiologically activated T cells. Loss of Fas has been linked to escape from the antitumoral immune response in diverse cancer entities.39 Fas receptor and FasL are transmembrane proteins of the tumor necrosis factor family and are expressed on cells of lymphoid and myeloid lineage. On binding of the Fas ligand to Fas, a cascade of events is initiated that finally leads to apoptosis.

Aberrations of the Fas/FasL pathway have been studied in CTCLs. Immunohistochemical studies of Fas expression in skin biopsy specimens from MF lesions demonstrated loss of Fas expression the in tumor stage, while expression was clearly detectable in early patch and plaques stage.40 In addition to the loss of Fas expression on the cell surface, upregulation of intracellular proteins like cFLIP, which inhibit Fas-initiated apoptosis has been shown in CTCL cells.41 Thus, downregulation or loss of Fas expression as well as disturbance of intracellular pathways activated by death receptors may counteract proapoptotic signals given to the tumor cells by antitumoral immune cells, finally resulting in immune escape of the tumor cells in CTCLs.

In conclusion, specific mechanisms for all features that have been proposed to be necessary for the evolution of tumor cells,42 like evasion of apoptosis, generation of growth or survival signals and insensitivity to antigrowth signals, mechanism of tissue homing and metastasis have nowadays been demonstrated in CTCL cells.

Finally CTCLs exhibit a modulated antitumor response. It is well established that patients with CTCLs have variable production and response to T helper 1 and 2 (Th1, Th2) cytokines. Early studies that measured the messenger RNA (mRNA) levels of Th1 and Th2 cytokines showed that, at any stage of disease, mRNA of the Th2 cytokines interleukin 4 and 5 (IL-4, IL-5), could be found, with the persistence of Th2 cytokine mRNA in skin more frequent in the tumor stage. Correlation of the amount of the Th2 cytokine IL-10, which has immunosuppressive functions, and disease stage in CTCLs has been described.43 The decline in interferon (IFN)-γ and predominance in Th2 cytokines, which is accompanied by a decreasing number of circulating dendritic cells in the blood, might be responsible for the loss of immunosurveillance, which allows CTCL to progress. Lesions of CTCLs often have a CD8+ T-cell component. Although they were once thought to be innocent bystanders in the epidermis, data have now defined the responsibility of CD8+ T cells in the antitumor response. The first insight into defects in the integrity of normal T-cell function in patients with advanced stages of CTCLs came from the observation of patients who had been treated with extracorporeal photochemotherapy (ECP).44 Responding patients had significantly lower CD4/CD8 T-cell ratios and higher absolute numbers of CD8+ T cells in their peripheral blood at the outset of treatment than did nonresponders. In general, skin biopsy specimens of MF lesions in early stages (T1 and T2) harbor a higher proportion of CD8+ cells than lesions in advanced stages. Improved long-term prognosis was correlated with the presence of these CD8+ tumor-infiltrating lymphocytes (TIL) in MF.45 It is now believed that these CD8+ cytotoxic T cells play an important part in the pathogenesis of CTCLs, mainly in mediating an antitumor response.

An interesting hypothesis pursued during the recent years, proposes that the malignant T cells themselves exhibit properties of regulatory T cells (T regs) and thereby are able to modulate the antitumoral immune response.46 However, the results of studies enumerating T regs in CTCL biopsy specimens were inconsistent. These conflicting results may be due to the fact that both a decrease of T regs as well as an increase of CD25-negative T regs, which then are phenotypically identical with the malignant clone, can be observed in SS.47

Mycosis Fungoides

Definition

MF is the most frequent disease among CTCLs, usually arising in mid-to-late adulthood (median age at diagnosis, 55–60 years) with a male predominance of 2:1.

Clinical Findings

Skin Signs

Clinically, MF is categorized as being in the patch, plaque, or tumor stage, but patients may simultaneously have more than one type of lesion. In early patch-stage MF (Figs. 145-1 and 145-2), there are single or multiple erythematous, scaly macules and patches that vary in size and are usually well defined. The color of the lesions may vary from orange to a dusky violet–red. The distribution classically favors nonsun-exposed sites, with the “bathing trunk” and intertriginous areas predominant early in the course of the disease. The eruption may be intensely pruritic or asymptomatic and occasionally may be transitory, disappearing spontaneously without scarring. Diagnosis at this stage may be difficult. Often a patient will recall a preceding “chronic dermatitis” for 10–20 years that may have been considered to be therapeutically resistant contact dermatitis, atopic dermatitis, psoriasis, or eczema. In any patient with a dermatosis that is refractory to the usual modalities of treatment, multiple biopsy specimens should be taken to pursue a diagnosis.

Patches may last for months or years before progressing to the plaque stage (Fig. 145-3), or plaques may arise de novo. Plaques appear as sharply demarcated, scaly, elevated lesions that are dusky red to violaceous and variably indurated (Figs. 145-3 and 145-4). Lesions in this stage may regress spontaneously or may coalesce to form large plaques with annular, arcuate, or serpiginous borders, and may clear centrally with disease activity remaining at the periphery of the lesion. There may be purpuric hyperpigmentation or hypopigmentation and poikiloderma.

Tumors may occur anywhere on the body, but have a predilection for the face (Figs. 145-5 and 145-6) and body folds: axillae, groin, antecubital fossae, and, in women, the inframammary area. These may occur in preexisting plaques or patches of MF, which coincides with an extension of these lesions in the vertical dimension (Fig. 145-3). At this point, the neoplastic cells behave in a biologically more aggressive manner, with pronounced tumor cell accumulation that leads to the clinical appearance of an expanding dermal nodule (see Fig. 145-6). De novo occurrence suggests metastatic spread by cells of a malignant T-cell clone. The nodules are reddish brown or purplish red and smooth surfaced, but they often ulcerate and may become secondarily infected. Growth rate is variable. Patients with tumors tend to have a more aggressive form of the disease than patients with patch and plaque disease.

Erythroderma (Fig. 145-7A) may start de novo or develop in MF. The nomenclature for erythrodermic phases of CTCL varies. It has been proposed that erythroderma be defined as the involvement of 80% of body surface area with lesions of ill-defined borders and that patients with a history of preexisting MF be defined as having a separate syndrome of “erythrodermic MF.”

The skin is diffusely bright red with readily apparent scaling, but there may be characteristic islands of uninvolved skin, termed nappes claires (Fig. 145-2). There may be sparing of the areas of skin that are frequently folded, such as the abdomen and antecubital and axillary areas. This sparing produces a finding often called the deck chair or folded luggage sign. Some patients with the erythrodermic form of CTCL develop tumors.

Other Symptoms

Patients may complain of fever, chills, weight loss, malaise, insomnia secondary to the overwhelming pruritus, and poor body temperature homeostasis. There may be hyperkeratosis, scaling and fissuring of the palms and soles, alopecia, ectropion, nail dystrophy, and ankle edema, with the integument being shiny and hidebound. These changes result in pain on walking and extreme difficulty with tasks requiring manual dexterity. Such patients experience severe restrictions by the extent and localization of their skin manifestations. Pruritus is often intense, which results in excoriation, exudation, and secondary infection that may dominate the clinical picture.

Differential Diagnosis

The differential diagnosis of MF is summarized in Box 145-2.

Histopathology

In the patch, plaque, and also in the erythrodermic stage, there is a band-like infiltrate in the upper dermis composed of reactive T cells and neoplastic T lymphocytes, which are characterized by hyperconvoluted cerebriform nuclei. The neoplastic T cells show an epidermotropism with formation of intraepidermal Pautrier's microabscesses (Figs. 145-8 and 145-9). In the tumor stage, a nodular infiltrate in the dermis is found, and the epidermal component is much less pronounced (Fig. 145-10). Immunohistologically, the malignant cells express a mature peripheral T-cell (CD4+) phenotype. Partial loss of pan-T-cell antigens such as CD7 and CD3 may be a feature of MF but is not pathognomonic of the disease. Analysis of T-cell receptor genes (TCR) typically shows a clonal rearrangement as demonstrated by PCR or Southern blot techniques.

Treatment and Prognosis

Treatment should be stage-adapted and alleviate symptoms (see Sections “Staging of Cutaneous T-Cell Lymphomas” and “Principles of Treatment of Cutaneous T-Cell Lymphoma”). The prognosis depends on the type and extent of skin involvement (plaques, tumors, or erythroderma), the presence of lymph node involvement, and the presence of visceral disease. Overall, patients with MF limited to the skin have a 5-year survival rate of 80%–100%. In contrast, patients with lymph node involvement show a 5-year survival rate of 40%.

Mycosis Fungoides Variants

Folliculotropic Mycosis Fungoides

Folliculotropic MF represents a distinct variant of MF characterized by preferential involvement of the head and neck by folliculotropic T-cell infiltrates, with or without mucinous degeneration of the hair follicles (Fig. 145-11B). Previously, this variant was called follicular mucinosis or alopecia mucinosa. Folliculotropic MF affects mostly adults and is rarely observed in children and adolescents. Patients may have grouped follicular papules (see Fig. 145-11A), acneiform lesions, indurated plaques, and sometimes tumors, which usually involve the head and neck region. The occurrence of hair loss within the lesions, most conspicuous on the eyebrows, an intense pruritus, and secondary bacterial infections is common.

Hypopigmented Mycosis Fungoides

Patients with dark skin develop hypopigmented MF, a variant of patch MF. In darker skinned individuals, this may be the most common presentation of the disease. Patients respond to therapy by repigmentation, and the reappearance of hypopigmented lesions often indicates a relapse.

Pagetoid Reticulosis

Pagetoid reticulosis (Woringer–Kolopp disease) is a distinct variant of MF that is characterized by the presence of localized patches or plaques with an intraepidermal proliferation of neoplastic cells. Patients present with a solitary psoriasiform or hyperkeratotic patch or plaque, which is usually localized on the extremities (Fig. 145-12) and is slowly progressive. Unlike in classic MF, extracutaneous dissemination has not been observed.

In the past, the term pagetoid reticulosis also included a disseminated form (called Ketron–Goodman type). As this type usually shows a more aggressive behavior, it is now classified as an aggressive primary cutaneous epidermotropic CD8+ T-cell lymphoma (see Section “Primary Cutaneous Aggressive Epidermotropic CD8+ T-Cell Lymphoma”).

Granulomatous Slack Skin

Granulomatous slack skin is a rare subtype of MF characterized by localized areas of bulky folding of the skin, with a predilection for the axillae and groins (Fig. 145-13). Light microscopy reveals a dense granulomatous infiltrate in the entire dermis. In addition to small atypical cells with cerebriform nuclei, macrophages and multinucleated giant cells occur and loss of elastic fibers is observed. The neoplastic cells express a CD3+ CD4+ CD8– phenotype.48

Sézary Syndrome

Definition

SS is characterized by the triad of diffuse erythroderma, generalized lymphadenopathy, and circulating malignant T cells with cerebriform nuclei, the so-called Sézary cells.

Clinical Findings

The erythroderma is often accompanied by severe scaling or fissuring of the palms and soles (see Fig. 145-7A–C), alopecia, and onychodystrophy and may be associated with marked exfoliation, edema, and lichenification and an intense pruritus.

Laboratory Findings

SS demonstrates histologic features similar to those of MF, but repeated biopsies may be necessary as specimens often show nondiagnostic findings. Therefore, several diagnostic criteria for the blood involvement proposed by the International Society for Cutaneous Lymphoma—including an absolute Sézary cell count in the peripheral blood of at least 1,000 cells/mm3 detected by light microscopic examination of a blood smear, or an increased CD4/CD8 ratio of more than 10 measured by fluorescence-activated cell-sorting analysis, or evidence of a circulating T-cell clone detected by cytogenetic methods—were included in the WHO–EORTC classification.1 Patients lacking the atypia on the peripheral blood smear or the corroborating evidence are considered to have erythrodermic CTCL.49

Treatment and Prognosis

Compared with patients with patch- or plaque-stage MF, patients with SS have a markedly decreased 5-year survival rate of 24%. By the time the SS appears, there is very little normal immunity left. Indeed, SS patients often die because of infectious complications.50

Primary Cutaneous CD30+ Lymphoproliferative Disorders

Primary cutaneous CD30+ lymphoproliferative disorders consist of LyP and cALCL. Both entities are now recognized to form the ends of a spectrum, which includes borderline cases that, on histomorphologic grounds alone, cannot be clearly assigned to LyP or cALCL.

Lymphomatoid Papulosis

Definition

LyP was first described by Macaulay in 1968. It is an uncommon chronic disorder (incidence of 1.2–1.9 cases in 1,000,000) characterized by recurrent self-healing crops of papules and papulonodules.

Clinical Findings

Disseminated recurrent self-healing papules and papulonodules occur that may become necrotic in the center (Fig. 145-14) and often erupt over a period of months or several years. The lesions typically involve the trunk and extremities, and lesions in various stages of evolution may be present concurrently.

Histopathology

LyP shows a highly variable histologic picture that closely mimics that of malignant lymphoma. Three major histologic types, designated as A, B, and C, have been recognized.51 Types A and C are characterized by the presence of large atypical blasts, including mononucleated and binucleated or multinucleated cells resembling Reed–Sternberg cells characteristic of Hodgkin lymphoma. The atypical blasts express one or more T-cell antigens as well as the lymphoid activation antigen CD30 (Fig. 145-15). Although in type A these cells are embedded in a dense inflammatory background consisting of histiocytes, small lymphocytes, neutrophils, and/or eosinophils, in type C they form large sheets closely simulating cALCL. LyP type B is composed of small-to-medium-sized CD30-negative T cells showing epidermotropism and thus closely resembles classic MF. Importantly, different histologic types of LyP can be present in one patient, because the histologic picture also correlates with the age of the individual lesion.

Treatment and Prognosis

Because a curative therapy is not available and none of the available treatment modalities affects the natural course of the disease, the short-term benefits of active treatment should be balanced carefully against the potential side effects. Low-dose methotrexate (5–20 mg/week) is the most effective therapy to suppress the development of new skin lesions. Treatment with psoralen plus ultraviolet A light (PUVA) has been reported to yield beneficial effects but duration of response is often short-lived after discontinuation of treatment. Therefore, in patients with few, nonscarring lesions, long-term follow-up without active treatment should be considered.52

In general, LyP shows a benign clinical course and a favorable 10-year survival rate of nearly 100%. However, in a proportion of patients, estimated at 10%–20% of cases, LyP can precede, coexist with, or follow malignant lymphoma, especially MF, Hodgkin lymphoma, or nodal anaplastic large cell lymphoma. In many of these cases, the same clonal TCR rearrangements have been found in the LyP as well as in the associated lymphoma. In the majority of LyP cases, despite the sometimes extremely long course of the disease, there is no evolution of a secondary lymphoma.

Cutaneous Anaplastic Large Cell Lymphoma

Definition

The cutaneous lymphoma cALCL is characterized by large tumor cells, of which the majority express the CD30 antigen, with no evidence or history of MF or another type of primary CTCL. Regardless of the morphology of the tumor cells (anaplastic, immunoblastic, or pleomorphic large cells), the clinical presentation and behavior are identical.

Clinical Findings

CD30+ cutaneous large-cell lymphomas occur in adults and rarely in children and adolescents, with a male–female ratio of 1.5:1. The clinical picture is characterized by the solitary or locoregional occurrence of reddish to brownish nodules and tumors, which frequently ulcerate (Fig. 145-16A). Although secondary involvement of the regional lymph nodes is observed in roughly 10% of the patients, it is not necessarily associated with an unfavorable prognosis.

Histopathology

A nodular or diffuse nonepidermotropic infiltrate of large cells is seen in the dermis (see Fig. 145-16B). In the majority of cases, the neoplastic cells show an anaplastic morphology with oval or irregularly shaped nuclei, prominent nucleoli, and an abundant cytoplasm. Less commonly, a pleomorphic or immunoblastic appearance is observed. Atypical mitotic figures are frequent. In the periphery of the lesions, inflammatory cells (lymphocytes, eosinophils, and neutrophils) are present, sometimes imitating the histologic picture seen in LyP.

By definition, at least 75% of the large cells are CD30+. In addition, they express a CD4+ phenotype with variable loss of pan-T-cell antigens such as CD2, CD3, and CD5. Cases with CD8+ neoplastic cells occur rarely. Unlike nodal CD30+ lymphomas, CD30+ large-cell lymphomas of the skin test negative for CD15 and epithelial membrane antigen, and expression of the anaplastic lymphoma kinase ALK is also absent in most cases of cALCL. Clonal TCR rearrangements are detected in most cases.53

For diagnosis clinicopathologic correlation is crucial. The histologic picture may suggest LyP, but lesions of CD30+ cutaneous large cell lymphoma are clinically larger and localized, and they usually do not tend to disappear spontaneously.

Treatment and Prognosis

In cases of solitary or localized skin lesions, excision or radiotherapy is the treatment of choice. Successful treatment with PUVA in combination with IFN-α has been reported. If skin lesions are generalized systemic therapy with methotrexate (20 mg/week) is preferred and in the case of extracutaneous dissemination multiagent chemotherapy should be considered. A chimeric monoclonal anti-CD30-antibody has shwon promising results in phase II study in CD30+ CTCL.54 In contrast to extracutaneous large-cell lymphomas, CD30+ cutaneous large-cell lymphomas of the skin have a favorable prognosis, with a disease-related 5-year survival rate of 90%.

Subcutaneous Panniculitis-Like T-Cell Lymphoma

Definition

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is defined as a cytotoxic T-cell lymphoma characterized by the presence of primarily subcutaneous infiltrates of small, medium-sized, or large pleomorphic αβ T cells and many macrophages, predominantly affecting the legs and occasionally complicated by a hemophagocytic syndrome. Subcutaneous lymphomas with a γ/δ phenotype of the TCR show a more aggressive course and are nowadays classified within the cutaneous γδ T-cell lymphomas.

Clinical Findings

SPTL is characterized by subcutaneous nodules and plaques, which usually involve the extremities and the trunk, less commonly the face. Patients may present with B symptoms, i.e., weight loss, fever, and fatigue.

Histopathology

Histologic examination shows subcutaneous infiltrates simulating a lobular panniculitis. Infiltrates contain a mixture of neoplastic pleomorphic cells of various sizes and macrophages. Rimming of individual fat cells by neoplastic T cells is a helpful diagnostic feature. Immunophenotyping shows that the neoplastic cells express CD3, CD8, CD45RO, T cell-restricted intracellular antigen 1 (TIA-1), perforin, granzyme B, and the TCR α/β. The neoplastic T cells show a clonal TCR gene rearrangement.

Treatment and Prognosis

The optimal therapy has not been defined so far and patients have been treated with immunosuppressive agents like prednisone or multiagent chemotherapy. However, the prognosis of the SPTL with a TCRα/β-phenotype seems to be favorable with a 5-year survival rate of 85% and therefore justifies an initial treatment approach with corticosteroids alone.55

Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type

Definition

Extranodal NK/T-cell lymphoma, nasal type, is a lymphoma that is nearly always EBV-positive. The tumor cells are small, medium, or large, and usually have an NK-cell or, more rarely, a cytotoxic T-cell phenotype. The skin is the second most common site of presentation after the nasal cavity.1

Clinical Findings

Extranodal NK/T-cell lymphoma either affects the naso-oropharynx, which leads to destruction of the nasal region (formerly described as lethal midline granuloma) or manifests in skin, subcutis, lungs, viscera, and testes. Skin lesions enclose subcutaneous tumors, erythematous plaques, ulcers, or an exanthematous eruption with macules and papules. The clinical course is often aggravated by a hemophagocytic syndrome with pancytopenia.

Histopathology

This type of lymphoma shows dense infiltrates involving the dermis and, often, the subcutis. Epidermotropism may be present. Prominent angiocentricity and angiodestruction are often accompanied by extensive necrosis. Immunophenotypically, the neoplastic cells express CD56, and cytotoxic proteins (TIA-1, granzyme B, perforin) and are characteristically positive for EBV. While they show positivity for CD3ϵ in the cytoplasm, they lack CD3 on the surface.

Treatment and Prognosis

Even with aggressive chemotherapy, the disease is often lethal within months.56 A study of the EORTC cutaneous lymphoma group suggested that bone marrow transplantation may be the treatment of choice.57

Provisional Entities of Cutaneous T-Cell Lymphoma

In addition to the diseases discussed in the preceding sections, a number of provisional entities are included in the WHO-EORTC classification system. These primary CTCLs display characteristic histologic features, but no distinct clinical presentation and/or outcome has been defined so far.

Pleomorphic Small- or Medium-Sized Cutaneous T-Cell Lymphoma

Definition

A neoplastic proliferation of pleomorphic, small- or medium-sized T cells in the skin without any clinical signs of classic MF defines the pleomorphic, small- or medium-sized CTCL.

Clinical Findings

Patients have one or several red-purplish papules or nodules with a predilection for the head and neck area.58 Because histologic differentiation from MF and MF-associated follicular mucinosis can raise problems, the absence of patches and plaques in pleomorphic small- or medium-sized CTCL is the decisive criterion.

Histopathology

Histologically, a dense, diffuse or nodular infiltrate containing small- to medium-sized pleomorphic cells is observed within the dermis and, sometimes, the subcutis. Epidermotropism may be present. The neoplastic cells express a T-helper cell phenotype with frequent loss of pan-T-cell markers. Demonstration of an aberrant phenotype and of T-cell clonality, as well as predominance of pleomorphic T cells in the infiltrate, serve as useful criteria for the exclusion of pseudolymphomas, which often show an identical histologic pattern. MF is excluded by the absence of a dominant cerebriform tumor cell population.59 In cases of CD8 expression these tumors show a more aggressive clinical course and are grouped within the primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma.

Therapy and Prognosis

Solitary lesions are often excised for diagnostic purposes. If excision is not possible or lesions are localized, radiotherapy is the preferred mode of treatment. PUVA therapy, possibly in combination with IFN-α, is useful in cases with disseminated lesions.

A 5-year survival rate of between 60% and 90% is reported for this type of lymphoma.

Primary Cutaneous Aggressive Epidermotropic CD8+ T-Cell Lymphoma

Definition

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma is a CTCL characterized by a proliferation of CD8+ cytotoxic T cells that exhibit a strong epidermotropism and an aggressive clinical behavior. Differentiation from other types of CTCL expressing a CD8+ cytotoxic T-cell phenotype, as observed in pagetoid reticulosis and rare cases of MF, LyP, and cALCL, is based on the clinical presentation and clinical behavior.

Clinical Findings

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma presents with hyperkeratotic patches and plaques, or by papules and tumors. A metastatic spread to unusual sites such as the lung, testis, central nervous system, and oral cavity, but not to the lymph nodes is often observed.

Histopathology

Histologically, band-like infiltrates consisting of pleomorphic lymphocytes or immunoblasts are observed, displaying a diffuse infiltration of the epidermis with variable degrees of spongiosis, intraepidermal blistering, and necrosis. The neoplastic cells express the Ki67 antigen at a high frequency and are positive for CD3, CD8, CD45RA, and TIA, whereas CD2 and CD5 are frequently lost. Expression of TIA identifies these lymphomas derived from a cytotoxic T-cell subset.

Treatment and Prognosis

Even with multiagent chemotherapy the disease shows an aggressive course, and median survival is 32 months.

Cutaneous G/δ T-Cell Lymphoma

Definition

Cutaneous γ/δ T-cell lymphoma encompasses the peripheral T-cell lymphomas with a clonal proliferation of mature, activated γ/δ T cells with a cytotoxic phenotype. This group includes cases previously termed subcutaneous panniculitis-like T-cell lymphoma with a g/d phenotype.1

Clinical Findings

Patients have disseminated ulceronecrotic nodules or tumors, particularly on the extremities, but other sites may be affected as well. Involvement of mucosal and other extranodal sites is frequent, but involvement of lymph nodes, spleen, or bone marrow is uncommon. A hemophagocytic syndrome may occur.

Histopathology

Histologically, three major patterns of involvement can be present in the skin: epidermotropic, dermal, and subcutaneous. The neoplastic cells are generally medium-to-large with coarsely clumped chromatin. Large blastic cells with vesicular nuclei and prominent nucleoli are infrequent. Apoptosis and necrosis are common, often with vessel invasion. Immunohistologically the tumor cells have a βF1–, CD3+, CD2+, CD5–, CD7+/–, CD56+ phenotype with strong expression of cytotoxic proteins. Most cases lack both CD4 and CD8, although CD8 may be expressed in some cases. In frozen sections, the cells are strongly positive for TCR δ (antibody testing is not available for paraffin sections). If only paraffin sections are available, the absence of βF1 may be used to conclude a γ/δ origin.

Treatment and Prognosis

Most patients have aggressive disease resistant to multiagent chemotherapy and/or radiation therapy. Median survival is 15 months.

Primary cutaneous peripheral T-cell lymphoma, unspecified

Definition

PTL, unspecified, is a diagnosis of exclusion of any of the above-characterized subtypes of CTCL.

Clinical Features

Usually adult patients, present with solitary, localized, or generalized nodules or tumors without predilection for specific locations.

Histopathology

The infiltrate is nodular or diffuse and shows varying numbers of medium-sized and at least 30% large-sized pleomorphic or immunoblast-like T cells. Epidermotropism is unusual. Immunohistologically, the cells are in general CD4-positive but otherwise demonstrate a variable loss of pan-T-cell antigens.

Treatment and Prognosis

The 5-year survival rate is less than 20% and therefore multiagent chemotherapy is the treatment of choice.

Staging of Cutaneous T-Cell Lymphomas

After the diagnosis of a cutaneous T-cell lymphoma has been established, appropriate staging investigations are obligatory to exclude secondary involvement of the skin by an extracutaneous lymphoma and to determine the extent of disease. The first classification and staging system of CTCLs has been published in 1979 by the MF cooperative group. In the meantime, it has been recognized that this staging system does not apply to all entities of CTCLs listed in the current WHO classification. Furthermore, the Ann Arbor system, commonly used for staging of nodal non-Hodgkin lymphomas, is not suitable for all entities of CTCLs. Because of these facts and new data on prognostic factors, both revisions of the staging and classification for MF and SS and a TNM classification system for CLs other than MF and SS have been proposed by the EORTC and the International Society for CLs in the recent years.60,61 It has to be mentioned that staging according to the TNM system has been proven to be useful to choose an appropriate therapy for patients with MF and SS, but data correlating results of the TNM staging and prognosis are missing for some entities of CTCLs. Staging examination for all entities of CTCLs include examination of the entire skin, chest radiography, and ultrasonography of abdominal organs and peripheral lymph nodes (cervical, axillary, and inguinal). Blood investigations should include complete blood cell count, clinical chemistry with liver enyzmes, kidney function tests and lactate dehydrogenase level, as well as T-cell clonality. Staging may be completed by computed tomographic scan and/or histologic and molecular (TCR rearrangement) investigations of suspicious lymph nodes and/or visceral organs. Staging examination should be repeated at relapse or progression of disease. A bone marrow examination is only recommended at a B2 blood rating (Table 145-1) or unexplained hematological abnormalities. However, this procedure is not of direct clinical relevance, as detection of atypical cells in the bone marrow has not been shown to be an independent prognostic factor.

The aforementioned investigations allow for classification according to the tumor, lymph node, metastases (TNM) system (Table 145-1 and Box 145-3). Although the prognostic value and applicability of TNM staging for different CTCLs is controversial, the TNM scheme directs the decision-making process toward an appropriate therapeutic regimen for most CTCLs.

Principles of Treatment of Cutaneous T-Cell Lymphoma

Every successful strategy in managing CTCL with generalized skin lesions begins with goals, tumor-burden assessments, questionnaires, and a timetable. The primary goals of therapy are to achieve a remission, improve the quality of life, to prolong life, and if possible to cure. The chronic disease course of the most prevalent CTCL subtypes MF and SS, makes surrogate markers necessary, and tumor burden is still the best surrogate marker for survival. Additionally, measures of symptoms like pruritus or quality of life assessments are commonly used. Currently, skin scores provide a measure of objective responses to therapy, and questionnaires guide the assessment of subjective responses to therapy. It has not been shown that reducing disease in a patient from T3 to T1 is accompanied by any benefit in survival, yet it is also recognized that cure is unattainable unless the patient is first in remission with a skin score of 0 by whatever skin scoring system is used. Thus, remission is the first step toward achieving a cure.

A few principles help guide therapy strategies.62 Excellent long-term results have been reported with the localized treatment of localized disease. More widespread disease requires total skin or systemic therapy. However, it is not known at what percentage of skin surface involvement it becomes imperative to treat the entire skin. Once remission is achieved, maintenance therapy has a role in preventing relapse. Because many patients will undergo treatments that span decades, it is also important to minimize exposure to therapies that have cumulative toxicities on keratinocytes (i.e., mutagens) or the bone marrow.

With these principles in mind, one can approach the treatment of a given patient based on the patient's individual presentation. The clinical presentation of the patient can be matched up with a successful therapy modality for both the remission-induction phase of therapy and the maintenance phase. For patients with several types of lesions, priority is given to those further down in Table 145-1. For example, a patient with both patches and tumors would be approached as a patient with tumors until those lesions are cleared.

The therapies used to treat a patient with CTCL can best be categorized into skin-directed therapies, biologic response modifiers (BRMs), cytotoxic therapies, and combination therapies. Within each category, the individual modalities have unique properties that are discussed in the following sections in the context of how these modalities are used.

Unilesional/Localized Cutaneous T- Cell Lymphomas: Skin-Directed Therapy

The modalities considered for inducing a remission of unilesional/localized disease depend on the type and localization of the lesion as well as on the specific entity.

Distinct demarcated nodules as they are commonly seen in small- or medium-sized CTCL and CD30+ lymphoproliferations are best treated by excision or spot X-ray therapy. Patches and plaques can be approached with spot X-ray therapy, but also with topical chemotherapy with carmustine (BCNU), and topical retinoid therapy with bexarotene due to their superficial flat appearance.

Spot radiotherapy is the most reliable and rapid method of inducing a remission of solitary or localized lesions. Radiotherapy is widely available, and most lesions, no matter where they occur on the body (e.g., eyelid, buttock crease, ear), can be treated with this modality. There are no compliance problems, with each treatment session conducted by a professional radiotherapist. The immediate toxicity is minimal, but the long-term toxic effects of radiation dermatitis and cutaneous malignancy encourage conservative use of this modality.

The limitations of topical BCNU therapy are the systemic toxicity from absorption of the chemotherapeutic agent and local irritation. As a result, topical BCNU is used primarily for a limited body surface area. The initial protocols for BCNU administration called for an alcohol-based solution kept in the refrigerator. However, ointment-based protocols are now more common. BCNU can be easily made up in 10-mg/100 g or 20-mg/100 g ointments with a petrolatum base. Patients typically apply BCNU ointment at night and wash it off in the morning. Locally, a dose-related irritation and/or hyperpigmentation may appear over the 8–20 weeks needed to clear lesions. Monitoring includes performing complete blood cell counts every 2 weeks to check for marrow suppression. The cumulative toxicity of BCNU is primarily structural damage with skin thinning and telangiectasias. The patient must be reliable and adherent to the regimen for this therapy to succeed.63

The limitations of topical bexarotene gel are also due primarily to dose-related irritant effects. Hence, bexarotene gel is typically used for lesions on less than 15% of body surface area, as was the case in most of the patients in the pivotal trial that led to its approval.64 The gel is commercially available in a 1-% formulation, so that dose intensity is varied by changing the frequency of application. Patients typically initiate therapy with nightly lesional applications of bexarotene gel. After a week, the frequency is increased to twice daily, and the patient has to be made aware of the possibility of an irritant dermatitis at the site of the lesions. Complete clearance of lesions will usually occur after 12–16 weeks of therapy. Irritant responses can be managed by decreasing the frequency of application.65 Successful topical bexarotene therapy also requires a patient who adheres to the treatment regimen and is willing to put up with the irritant properties of this synthetical retinoid.

Disseminated Skin-Limited Disease

Cutaneous T-cells recirculate through the vascular system and are capable of patrolling the entire skin. When CTCL lesions are scattered, the most successful treatment strategies are those that treat the entire skin so as to extend the antilymphoma effect to the entire range of the cutaneous T cell. Recirculating CTCL cells are detectable even in limited disease, and such recirculating cells are capable to induce disease recurrences. These cells provide some of the rationale for the use of maintenance therapy after a complete response has been achieved in the management of patients with disseminated patch/plaque disease. Due to the variation in biological behavior, the therapy of disseminated disease differs markedly in CTCLs. The total skin treatment modalities most commonly used as first-line therapy against disseminated patch/plaque disease of MF are phototherapies, topical chemotherapy, and total skin electron-beam radiotherapy. However, CD8+ epidermotropic CTCL or blastic plasmacytoid dendritic cell neoplasm (BPDCN), also presenting with plaque disease show a much more aggressive course and polychemotherapy is the treatment of choice. Furthermore widespread disease of CD30+ lymphoproliferations responds well to low-dose methotrexate therapy in most instances.

Phototherapies

PUVA (see Chapter 238) can produce a definite clinical response and complete remissions of long duration in patients with patch/plaque CTCL. PUVA therapy requires regular treatments, initially three to four times a week, for up to 3 months or until remission occurs. The follow-up of a patient receiving PUVA for CTCL includes an assessment to be sure there is some mild degree of phototoxicity. Otherwise, dosing of either the psoralen or the UVA light may be insufficient. Risks of the treatment include possible induction of cutaneous epithelial neoplasms and cataract formation. Therefore, all patients should be observed closely and checked regularly for the development of skin cancer. In addition, patients are advised to protect their eyes for 12 hours after PUVA therapy and to have annual ophthalmologic examinations. These precautions should be enforced early, because PUVA is a therapy that may continue for years as a maintenance treatment. Even after poor responses to conventional therapy, patients have experienced complete clearing of the skin with PUVA.66 However, maintenance therapy may be needed, as shown by the prolongation of clinical remission with continued PUVA.67 For this reason, a gradual taper of therapy from thrice weekly to one session every 2–4 weeks after the patient has achieved a stable remission is typical. Combination of PUVA with IFN-α reduces the total UV dose necessary to induce a remission and prolongs the duration of remission.

UVB and narrow-band UVB light are both effective in treating CTCL. These phototherapies are more convenient for patients, although their efficacy, especially for plaque disease, may not be as great as that of PUVA. Patch-stage MF can often be completely cleared with UVB or narrowband UVB light. A complete response can typically be induced with three to five treatment sessions per week for a duration of 2–3 months. After a complete response has occurred, phototherapy can be continued on a maintenance schedule, initially once a week. The immediate adverse effects are primarily phototoxicity; the long-term toxicity is an increased risk for cutaneous malignancy.

Total Skin Topical Chemotherapy

Total skin topical chemotherapy consists of nitrogen mustard (mechlorethamine hydrochloride) applied as either an ointment or a freshly prepared aqueous solution. As an initial dose, 10 mg of the drug is dissolved in approximately 50 mL of tap water. The entire amount is then applied to the whole body surface by the patient. The patient should wear protective plastic gloves while applying the solution. A delayed hypersensitivity reaction may complicate treatment, and it is possible to desensitize patients, although their confidence in the therapy may be compromised. Ointment-based mechlorethamine, typically 10 mg/100 g strength, may be less sensitizing and is shelf stable for a long period. Other side effects from mechlorethamine hydrochloride therapy, besides hypersensitivity reactions and primary irritant reactions, include the development of second cutaneous malignancies and hypo- as well as hyperpigmentation. This therapy is relatively easy for the patient to use at home, but daily whole-body application is required for maintenance therapy once remission is induced.

Total Skin Radiation Therapy

The radiosensitivity of CLs has been therapeutically exploited by the administration of total skin electron-beam radiation. Because electrons penetrate only to the upper dermis, electron-beam therapy may be used without systemic effect. The limited penetration of the electrons is advantageous because it spares the mucous membranes, bone marrow, gastrointestinal tract, and other vital internal organs. Only those portions of the skin that are directly exposed to the beam are irradiated. Therefore, the palms, soles, scalp, axillae, and perineum may need separate exposures to ensure total body treatment. The eyelids are routinely covered with lead eye shields to protect the cornea and lens from the effects of radiation. If the eyelids are involved, 5-mm-thick contact lenses are worn between the lid and cornea within the conjunctival sac. Nail shields may also be used to prevent anonychia.

Whole body electron-beam irradiation brings about complete remission in 80%–95% of patients. The relapse rate is highest in the later stages of CTCL, i.e., in those patients with tumors, lymphadenopathy, and visceral involvement. Patients with limited plaque disease were found to have the highest relapse-free rate (42% at 10 years). Most relapses occurred within the first year after completion of therapy, and relapses were very rare 3 years or more after completion of therapy. The median disease-free interval was longer than 3 years in the limited plaque group, approximately 1 year for patients with generalized plaque or erythrodermic disease, and less than 6 months for patients with cutaneous tumors. The total dose of radiation is important. A dose of 30 cGy (3,000 rad) or more gives higher complete remission rates and disease-free survival than do lower doses. The major disadvantages are that this type of therapy must be provided at a specialized center and up to 3 months are required for complete treatment.

Local side effects include alopecia, atrophy of sweat glands and skin generally, radiodermatitis, and edema. When the total dose is highly fractionated, these complications are minimized and often avoided. The question is, what is the maximum radiation tolerance of the skin? When the highly fractionated approach is used, patients can receive a second course of electron-beam therapy of 36 cGy (3,600 rad) to reinduce a remission. As the total radiation dose increases, so does the risk of squamous cell carcinoma and radiodermatitis. Small-field or spot orthovoltage radiotherapy using soft X-rays (60–100 kV with half-value layers of 1–1.5 mm Al) fractionated to doses of 0.75–5 cGy (75–500 rad) and total doses of 8–15 cGy (800–1,500 rad) will adequately eliminate most lesions.

In many patients, a second or even third complete course of total skin electron-beam radiation can be safely given. The strategy of administering electron-beam radiation for repeat courses requires the use of a highly fractionated dose of 1 Gy per dose.

Maintenance Therapy and Topical Steroid Therapy

The concept of treating normal skin evolved from the clinical experiences with skin-directed therapies. There are two components to this approach: the treatment of normal skin during remission-induction skin-directed therapy and the treatment of normal skin during the remission–maintenance phase. Topical chemotherapy, PUVA, and total skin electron-beam radiation all involve the exposure of normal skin as an integral component of their success in achieving remission. This success reflects the ability of the therapy to interrupt the critical skin-based phase of the life cycle of a recirculating CTCL cell. Once a remission has been achieved, normal skin can be maintained with lower doses and frequencies of the therapies used to clear it. Maintenance therapies have been described with PUVA, total skin application of nitrogen mustard, ECP, and IFN. The most commonly used maintenance therapy is PUVA (see Chapter 238) or UVB irradiation (see Chapter 237). As a maintenance therapy, PUVA is initially administered at once-weekly intervals until 1 year has passed. At this point, the schedule is changed to every other week for another year, to every third week for the following year, and finally to every fourth week for 2 years. At this point, the patient should have been in remission for 5 years. Consideration should be given to stopping therapy at this point. A cure is defined as freedom from disease for 8 years off all therapy. This definition arose from the experience with nitrogen mustard treatment and total skin electron-beam radiotherapy showing that after a patient achieves a remission-off therapy of 5–8 years, late relapse is extremely rare. This would imply that malignant cutaneous T cells recirculate without causing lesions for up to 5 years. With 5 years of intermittent PUVA, it is less likely that one of these cells will survive, but it is still possible. After therapy has been discontinued, patients should not be considered cured unless they remain clear of disease for 8 years.

The management of suspected relapse often includes the use of topical glucocorticoids and reflects the critical role this modality can play in the treatment of suspicious lesions. Early in the course of CTCL and in a recurrence of the disease in a patient in remission, the T-cell activation process can be blunted by the aggressive use of topical glucocorticoids. Indeed, most patients have a history of using these agents before a firm diagnosis is made. A regimen for treating early lesions of MF is twice-daily applications of a class I topical glucocorticoid for 8 weeks. This regimen is one of the first-line modalities for suspected relapse, and it can help identify which patients need to undergo a 4-week “wash-out” before repeat biopsies are performed.

Erythroderma

In erythrodermic CTCLs, immune dysfunctions and inflammatory processes initiated by the malignant cells result in total skin redness, scaling, and discomfort. It is not surprising that immune-based therapies take the forefront in the management of these disorders. The three major BRMs used in the treatment of erythrodermic CTCLs are (1) oral retinoids, (2) ECP via an intravenous route, and (3) subcutaneous injections of IFN-α. In the clinical trials of these agents, patients have undergone monotherapy for what has usually been heavily pretreated refractory disease. In practice, these treatments are often used as first-line monotherapy in erythroderma, and other agents are incorporated for combination therapies if the response is incomplete. With these agents, partial responses are more common than complete responses. Thus, if the goal is remission, combination therapy is used more commonly than monotherapy. If the goal is palliation, monotherapy with a BRM is often sufficient. The BRMs differ in terms of their administration, side effects, interactions with other therapy modalities, and availability.

Retinoid Therapy

The first-generation retinoids such as isotretinoin have an effect on CTCL. The synthetic retinoid bexarotene binds the retinoid X receptor with high selectivity, whereas the other available retinoids have less specific binding patterns. In the monotherapy trials, bexarotene was dosed at 300 mg/m2. Responses were seen in patients in all stages of the disease: plaques, erythroderma, and tumors. Responses paralleled the secondary end points: decreases in overall body surface area involved and in overall tumor aggregate area, and improvement in pruritus. Erythrodermic patients may experience increased desquamation during the first few weeks of oral bexarotene therapy. Improvement typically starts by week 12 of therapy.68

Although there appeared to be a dose-response relationship with respect to efficacy, the higher dosages were also associated with a higher rate of adverse events and dose-limiting toxicities, of these hyperlipidemia/hypercholesterolemia and neutropenia were most common. Elevations in lipid levels occurred rapidly, within 2–4 weeks, and were associated with serious, but reversible, pancreatitis. Monitoring of lipids and the use of lipid-lowering drugs were helpful in controlling the lipid levels.69 Dosage reduction of bexarotene capsules was also required in some patients. Drug interactions of oral bexarotene with gemfibrozil and warfarin have been observed.

Patients started on bexarotene therapy develop central hypothyroidism with low levels of thyroid-stimulating hormone and free thyroxine within weeks of starting the medication. Symptoms of hypothyroidism may be subtle and include feeling fatigued and feeling cold, which may wrongly be attributed to the disease itself. Supplementation with levothyroxine while patients are taking bexarotene alleviates the symptoms and improves tolerance of treatment. The condition is reversible within weeks of stopping therapy. There is no immunosuppression with bexarotene therapy. Patients taking bexarotene typically have monthly monitoring visits to follow lipid, liver, and thyroid parameters.

Extracorporeal Photochemotherapy

(See Chapter 238). ECP involves the treatment of a portion of a patient's lymphocyte compartment with 8-methoxypsoralen in the presence of UVA light, followed by reinfusion of these cells. The treatment is performed via an intravenous line that feeds into an UVA-radiation device, and the procedure typically requires the patient to remain recumbent for 3 hours. Treatments are conducted on two consecutive days every 4 weeks. Erythrodermic CTCLs can be managed with ECP monotherapy, but treatment of other disease stages with monotherapy has not been rigorously studied. In a multicenter study involving erythrodermic CTCL patients, approximately one-fourth had a complete response, one-fourth had no response, and the remainder had partial responses. However, it is clear that even a partial response can improve the quality of life of these patients. Improvement sometimes began as early as 6 weeks into therapy, but some patients did not show complete lesion clearance until 12 months after starting therapy. There were occasional temporary responses immediately after a 2-day cycle of therapy. On average, after 4–6 months there was typically a gradual and permanent decrease in erythema, scaling, and pruritus. Patients often notice more subtle changes, such as the return of body hair, loss of rigors, and a return of the ability to sweat. Partial responses may also decrease the morbidity these patients experience in terms of infectious complications. More heavily involved and inflamed skin is more readily colonized, providing both a reservoir and access point for microbes to invade the host. Thus, cutaneous improvement can also minimize complications of CTCLs.

The clinical experiences with ECP for erythrodermic MF and SS suggest that the therapeutic response may well be based in the immune system. One feature is that when less than 5% of the malignant lymphocyte pool is photoinactivated with 8-methoxypsoralen and UVA light, clinical responses can be seen, with more than 95% of the malignant lymphocytes disappearing over time. It also appears that most immunocompetent patients respond. Patients who were heavily pretreated, with longer disease durations, were less responsive. Also, patients with normal or only slightly decreased CD8+ lymphocyte levels were responsive to ECP. In one study, total skin electron-beam radiotherapy was combined with ECP in patients with T3 and T4 disease. Comparison of patients receiving skin-directed radiotherapy plus BRM with historic controls who underwent electron-beam radiotherapy at the same institution demonstrated the impact of ECP, because patients in the skin-directed therapy plus BRM group showed significantly longer survival.70

Interferon‐α Therapy

The most-studied IFN has been IFN-α, but clinical trials have also been done with IFN-β and IFN-γ in the treatment of CTCLs. The initial studies using IFN-α as monotherapy showed rates of complete responses that varied from 10%–27% with treatment durations of less than 6 months.71 Again, the heterogeneity of the disease and the pretreatments patients undergo affect outcomes and make comparisons with other modalities impossible. IFN-α is typically started at 3 million units (MU), three times a week, and can be increased to a maximally tolerated dose, typically in the range of 9 MU/day. As with the other BRMs, the response to IFN is gradual, and 3–6 months are needed to determine the maximal response. After patients achieve a maximal response, IFN dosage can be lowered to a maintenance level of 1 MU daily.72

All IFNs have similar toxicities. Initially IFN therapy is complicated by a flu-like illness that is characterized by fever, headache, myalgia, and fatigue. As this wears off, patients are often left with a slight feeling of chronic fatigue. The long-term toxicity that causes most concern is neurologic: depression, neuropathy, dementia, and myelopathy. Autoimmune phenomena, such as thyreoiditis, may occur. Furthermore, toxic effects of the liver and bone marrow may occur. Monitoring of IFN therapy includes blood counts and urinanalysis along with questionnaires assessing the impact on the patient's quality of life.

Other BRMs

DAB389IL-2 (Denileukin Difititox, Ontak®) is a recombinant cytotoxic fusion protein composed of the receptor binding domain of IL-2 and a mutated diphtheria toxin (DT) molecule. After binding to the IL-2-receptor, which is expressed on activated lymphocytes and monocytes as well as CTCL cells, and after internalization of DAB389IL-2, the DT fragment becomes active and inhibits the protein synthesis leading to cell death. DAB389IL-2 is administered intravenously and has shown efficacy in a phase III trial in CTCL patients with an overall clinical response rate of 30%. Side effects are generally mild, but few patients suffered from allergic reactions or a capillary-leak syndrome.73

Alemtuzumab is a humanized monoclonal IgG antibody binding to CD52, which is expressed on monocytes, granulocytes, and normal and malignant lymphocytes. In a phase II trial efficiency, including complete remissions, but also fatal infectious complications were seen in patients with therapy refractory advanced MF/SS.74 Efficiency has also been shown with lower doses and s.c. application resulting in less administration-related and infectious complications.75 Because of the side effects, alemtuzumab should be reserved for patients with advanced MF/SS disease who did not respond to previous systemic therapies.

Vorinostat: The first histone deacetylase inhibitor (HDACI) approved by the FDA was vorinostat for the treatment of therapy refractory CTCL. The increased histone acetylation by HDACI favors transcription of genes involved in cell differentiation, cell cycle arrest, and apoptosis. In a phase II trial, mostly partial remissions and a decrease in pruritus were seen in CTCL patients refractive to previous therapies. Common adverse events of HDACI were fatigue, nausea, and thrombocytopenia.76

Primary CBCLs are B lymphocyte-derived malignancies that develop in the skin without extracutaneous involvement at the time of diagnosis. CBCLs comprise approximately 20% of all CLs. The primary cutaneous marginal zone B-cell lymphoma (PCMZL) and the PCFCL are indolent subtypes, whereas the diffuse large B-cell lymphoma, leg type (PCLBCL, leg type) has an intermediate to aggressive clinical behavior. These three entities [i.e., (1) PCMZL, (2) PCFCL, and (3) PCLBCL] together comprise 97% of the CBCL.

As for CTCL an infectious trigger has been hypothesized to be involved in the etiology of CBCL. A strong association of gastric extranodal marginal zone lymphomas (MZL) and Helicobacter pylori infection is well known. In a minority of PCMZL from European patients but not in American or Asian patients Borrelia burgdorferi has been detected. It has recently been hypothesized that two different types of PCMZL exist: one that is phenotypically related to gastric MZL, triggered by B. burgdorferi infection, while the majority of PCMZL is not. A viral agent, in particular Hepatitis C virus, has also been suspected to be of relevance in the etiology of CBCL, but the results of the studies were contradictory.

Because of the rarity of the CBCL subtypes, studies investigating pathogenetic events in CBCL have been mainly conducted on small series of cases. However, in the recent years considerable progress has been made.

A phenomenon called aberrant somatic hypermutation (SHM) that has been previously reported in nodal B cell lymphomas has been detected in all three main types of CBCL.77,78 This term describes the activity of the enzyme activation induced deaminase, which contributes to the process of affinity maturation of immunoglobulins (Ig) by SHM, in regions of the genome that do not encode Ig genes. If this process occurs in oncogene-containing gene loci, in association with the loss of the physiologically high-fidelity DNA repair mechanisms, tumorigenic mutations may occur and contribute to lymphomagenesis.79

Furthermore, genetic investigations demonstrated distinct differences of CBCL subtypes. A genetic basis for differentiation of histological akin PCFCL with a diffuse growth pattern of large cells and PCLBCL, leg type, was shown. The gene expression profiles, of these entities were consistent either with germinal center B cells for PCFCL or with activated B cells for PCLBCL, leg type.80 Alike results were found in a study focusing on pro- and antiapoptotic genes. While PCLBCL, leg type with a poor prognosis had a genetic profile called activate apoptosis cascade, PCFCL and cases of PCLBCL, leg type with a favorable prognosis had a high expression level for genes that are associated with an antitumoral cytotoxic immune response.81 These findings also give an explanation the more favorable prognosis of PCFCL compared to PCLBCL, leg type.

Furthermore, PCMZL were found to arise in a different pathogenetic background than extranodal MZL. The main differences were the high percentage of CXCR3-negative PCMZL, which also, in contrast to other extranodal MZL, exhibited an Ig class switch and a Th2 cytokine milieu.82 How this relates to the presence of plasmacytoid DCs in PCMZL, which were also found in cutaneous pseudolymphomas, but not in DLBCL and only rarely in PCFCL, has to be investigated in the future.83

Primary Cutaneous Follicle-Center Lymphoma

Definition

PCFCL can be defined as a neoplasm of clonal centrocytes (small and large cleaved follicle center cells) and centroblasts (large follicle center cells with prominent nucleoli) with or without formation of follicles.

Clinical Findings

Patients with PCFCL present with nonscaling solitary or grouped papules, plaques or tumors. Patients with PCFCL have a median age of 58 years at diagnosis and men are nearly two times more often affected than women.84 Occasionally, an annular erythema can be observed in the surrounding area (Fig. 145-17A). A typical finding is the occurrence of lesions in a circumscribed area of the head and neck region or the trunk but rarely on the legs.

Histopathology

The typical histologic finding in PCFCL is a nodular or diffuse infiltrate with sparing of the epidermis. In the initial lesion a mixture of centrocytes, few centroblasts, and many reactive T cells is present that creates a follicular growth pattern or remnants of follicles with a network of CD21+ follicular dendritic cells (fDC). In parallel with progression of the tumor, the number and size of neoplastic B lymphocytes increases and the infiltrate is more diffuse with scattered fDC. In persisting lesions large follicle center cells (centrocytes and centroblasts) dominate (see Fig. 145-17B). The abnormal follicles show a reduced or even absent mantle zone, lack tingible body macrophages, and contain malignant bcl-6+ follicle center cells. The typical immunophenotype of the neoplastic cells is CD20+ CD79a+. Expression of CD10 is found only in infiltrates with a follicular pattern. Unlike in nodular follicular lymphomas, the t(14;18) translocation is not present. Bcl-2 protein may be detectable in few cases but only in a minority of tumor cells and in a weak-staining intensity. Therefore, detection of bcl-2 in the majority of tumor cells is indicative of a secondary cutaneous involvement of a systemic lymphoma. A clonal rearrangement of the variable part of the immunoglobulin heavy chain gene is detected in 60%–80% of cases.85

Treatment and Prognosis

Radiotherapy is the preferred mode of treatment; solitary lesions may also be excised. Immune therapies such as administration of IFN-α or monoclonal antibodies against CD20 may be beneficial in cases with disseminated lesions. Chemotherapy should be considered only in rare cases where more generalized skin lesions are present. With an estimated 5-year survival rate of 97%, the follicle center cell lymphoma is classified as an indolent type of primary CBCL. In untreated patients, the skin lesions increase in size over the years, but extracutaneous dissemination is uncommon.

Primary Cutaneous Marginal-Zone B-Cell Lymphoma

Definition

PCMZL is an indolent B cell lymphoma composed of small B-lymphocytes, marginal zone cells, lymphoplasmacytoid cells, and plasma cells, which are initially localized in the marginal zone of a follicular center. In the current WHO classification, it is classified within the extranodal marginal zone lymphoma of Mucosa-associated lymphatic tissue. In a subgroup of PCMZL, B. burgdorferi is thought to have an etiologic role.

Clinical Findings

PCMZLs are seen most commonly on the upper extremities or the trunk and occur at a median age of 55 years; they predominate in females. Patients have small red to violaceous papules, plaques, or nodules that, in contrast to the lesions of PCFCL, frequently occur in multiple locations. PCMZL accounts for 25% of primary CBCLs.

Histopathology

Histologic analysis of well-developed lesions shows dense nodular or diffuse infiltrates with sparing of the epidermis. The infiltrate is composed of marginal zone cells, small to medium-sized cells with indented nuclei, lymphoplasmacytoid cells and plasma cells. The marginal zone cells are found in the periphery of reactive germinal centers, the atypical plasma cells in the periphery of the infiltrate. Monotypic expression of immunoglobulin light chains can be observed in approximately 75%–85% of cases. Importantly, the number of neoplastic cells within the infiltrate is variable and may be very low and is often accompanied by a substantial number of reactive T cells.

The typical immunophenotype is CD20+ CD79a+ CD5– CD10– and bcl-2+, bcl-6–. An immunoglobulin light chain restriction can frequently be found. Monoclonal immunoglobulin gene rearrangement can be demonstrated by molecular genetic methods such as PCR or Southern blotting.

Treatment and Prognosis

In case of detection of B. burgdorferi, a systemic antibiotic treatment should be given first. Otherwise radiotherapy or excision is the treatment of choice for solitary tumors. However, in most cases PCMZL present with multifocal lesions and systemic therapy is mandatory. Chlorambucil and rituximab have been used with success and a good safety profile.86,87 For relapsing disease immune agents such as IFN-α may be administered subcutaneously or intralesionally. In the absence of symptoms a watch and wait strategy can be followed. The disease has an indolent course with an excellent prognosis, and the 5-year survival rate is nearly 100%. However, local recurrences are frequently observed. Extracutaneous involvement is extremely rare.

Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type

Definition

PCLBCL, leg type has been identified as a distinct clinical entity because of its perceived poor outcome compared with the indolent subtypes described above. This entity shows an intermediate and in some patients aggressive clinical course and is defined by tumors composed of large B cells that presents in the overwhelming majority of cases on the legs, but can also arise at other locations. It has been shown that the majority of patients with PCLBCL, leg type have aberrations on chromosome 9p21 and that loss of this region, which contains the CDKN2A gene is associated with a worse prognosis.88

Clinical Findings

PCLBCL, leg type affects elderly patients (over 65 years), with a predominance in females. Typically, patients have solitary or clustered bluish erythematous plaques and tumors located on one or, sometimes, both legs (Fig. 145-18A). Ulceration is common and sometimes leads to the misdiagnosis of an ulcer due to chronic venous insufficiency.

Histopathology

The diffuse infiltrate spares the epidermis and often extends into the subcutaneous tissue. Monotonous populations or confluent sheets of centroblasts and immunoblasts with a high mitotic rate are admixed with few reactive T cells (see Fig. 145-18B). The neoplastic B-lymphocytes express CD20, CD79a, multiple myeloma-1/IFN regulatory factor-4 (MUM-1/IRF4), and the bcl-2 molecule. Staining for bcl-6 gives positive results in most cases, whereas results for CD10 are negative. A clonal immunoglobulin rearrangement is detected in most cases.

Treatment and Prognosis

This tumor belongs to the intermediate aggressive group of CBCLs. Patients develop rapidly growing painless lesions, which initially disseminate along the lymph vessels. The tumor can involve the regional lymph nodes and progress to extracutaneous involvement. In cases of solitary or localized skin lesions, radiotherapy may be undertaken; in all other cases and when progression is observed, multiagent chemotherapy in combination with an immunotherapy agent {e.g., CHOP [cyclophosphamide, hydroxydaunomycin, Oncovin (vincristine), prednisone] plus anti-CD20 antibody treatment} should be administered. An unfavorable prognosis is reported, with a 5-year-survival rate of 55%.

Primary Cutaneous Diffuse Large B Cell Lymphoma, Other

This term covers diffuse large cell B cell lymphomas, which do not belong to PCLBCL, leg type, or PCFCL. These cases may represent a skin manifestation of systemic lymphomas. T cell/histocyte rich B-cell lymphomas with skin lesions only are also included; these cases show, in contrast to their nodal counterparts, an excellent prognosis.

Intravascular Cutaneous B-Cell Lymphoma

Intravascular cutaneous B-cell lymphoma is characterized by clusters of large neoplastic B cells within dermal and subcutaneous blood vessels. Occasionally, slight extravascular infiltrates of atypical cells are observed. Clinically, red to bluish, indurated plaques occur on the legs or trunk. Sometimes, a panniculitis-like pattern can be seen. Multiagent chemotherapy is the preferred mode of treatment.

Staging of Cutaneous B-Cell Lymphoma

Staging of cutaneous B-cell lymphoma includes examination of the entire integument, a complete blood cell count, blood chemistry including lactate dehydrogenase level, and if indicated a serum electrophoresis to exclude a monoclonal gammopathy and/or flow cytometry on peripheral blood. In endemic regions, Borrelia serologic testing and PCR of skin biopsy specimens should be performed. Imaging studies include a contrast-enhanced CT scan with or without positron emission tomography, for chest, abdomen, and pelvis, and if lesions arose on the head and neck area, of the neck. Staging is completed by a bone marrow biopsy.89 Although the necessity of a bone marrow biopsy has been questioned for MZL appearing in the skin, a definite diagnosis of PCMZL can not be made without a complete staging procedure.90 With the results of the staging examinations patients can be classified according to a proposal of the ISCL/EORTC. While the T stage is not of prognostic significance for PCMZL and PCFCL, for PCLBCL, leg type an increasing T stage seems to be prognostically relevant.91

Principles of Treatment of Cutaneous B-Cell Lymphoma

Treatment of primary CBCLs should be adapted to the favorable prognosis of these entities, in particular of PCFCL and PCMZL. Because no curative regimen has been defined so far, therapy depends on the entity and the dissemination of the cutaneous lesions. In the case of solitary lesions, complete excision of the tumor is the treatment of choice. Alternatively or in the case of few localized lesions local irradiation (single dose of 3–4 Gy; total dose of 30–40 Gy) by X-ray or electron beam is effective. When this regimen is used, long-lasting remissions can be achieved.

Systemic treatment is recommended for disseminated PCMZL or PCFCL with chlorambucil or anti-CD20 antibodies, respectively. For recurrence of indolent CBCLs with disseminated lesions a wait and see-strategy in conjunction with treatment of symptomatic lesions may be followed.

Systemic treatment regimens are recommended in cases of PCLBCL, leg type, and in PCFCL with localization on the legs, as these PCFCL have a worse prognosis or when secondary extracutaneous manifestations are present. Polychemotherapy (six cycles of CHOP, COP), in combination with an anti-CD20 antibody is recommended. In patients, that would not tolerate such an aggressive treatment local radiotherapy or rituximab monotherapy may be considered.

Blastic Plasmacytoid Dendritic Cell Neoplasm

Definition

In the WHO-EORTC classification CD4+/CD56+ hematodermic neoplasm was included for the first time as a clinically aggressive neoplasm with a high incidence of cutaneous involvement and risk of leukemic dissemination. The blastic cytologic appearance and CD56 expression initially suggested an NK precursor origin. More recent studies suggested derivation from a plasmacytoid dendritic cell precursor and therefore this entity is classified as BPDCN.

Clinical Findings

BPDCN commonly presents in the skin as solitary or multiple nodules or tumors (Fig. 145-19) with or without concurrent extracutaneous manifestations. Approximately 50% of patients have nodal or bone marrow involvement at presentation. Most patients who have only skin lesions when they first come for treatment rapidly develop involvement of bone marrow, peripheral blood, lymph nodes, and extranodal sites.

Histopathology

The typical findings are diffuse monomorphous infiltrates of medium-sized cells separated by a grenz zone from the epidermis. Perivascular patchy infiltrates and an Indian file pattern are observed occasionally. Angiotropism is uncommon. The neoplastic cells express CD4, CD43, and CD56, as well as TCL1. Tests for the lineage markers CD20, CD3, or other markers like CD30, TIA1, granzyme B give negative results. The cells further express CD123 and blood dendritic cell antigen 2, both of which support a relationship to plasmacytoid dendritic cells. TCR genes are in germline configuration. Tumor cells test negative for EBV.

Treatment and Prognosis

BPDCN is associated with a highly aggressive clinical course and thus a poor prognosis (median survival of 14 months). Although systemic chemotherapy is the first choice for treatment of this disease, the results are often disappointing. Studies suggest that patients can best be treated with regimens used to treat acute myeloid leukemias, including bone marrow transplantation.

Prevention

Not applicable.

Cutaneous pseudolymphoma is a term used to describe skin lesions that bear a clinical and/or histopathologic resemblance to lymphoma. Over the years, a wide variety of designations have been included in this category. Some of these represent outdated synonyms, some refer to variants of the same entity, and some are misnomers for diseases now recognized to be true lymphomas. The relevant entities that are discussed in this and other chapters can be organized into several distinct disorders based on their lymphoid subset composition, pattern of cutaneous infiltration, and associated clinical findings (Table 146-1).

Epidemiology

Cutaneous lymphoid hyperplasia (CLH) has a worldwide distribution and affects all races and ethnic groups. It occurs in both adults and children. Females are more commonly affected than males.

Etiology and Pathogenesis

CLH is characterized by a relatively dense lymphoid infiltrate, centered in the reticular dermis, which is usually B-cell rich and may resemble lymphoma clinically and/or histopathologically. Many terms are used to refer to this type of pseudolymphoma, including Spiegler–Fendt sarcoid, lymphocytoma cutis, lymphadenosis benigna cutis, and cutaneous lymphoplasia. Cutaneous lymphoid hyperplasia is the preferred term because it accurately describes the underlying pathophysiology of the lesion and is unlikely to be confused with terms used to describe various forms of cutaneous lymphoma.1–6

In most cases, CLH is idiopathic; however, some lesions are associated with exposure to foreign antigens from arthropods (bites, stings, infestations), infections (herpes zoster, Borrelia burgdorferi, Helicobacter pylori), tattoos, acupuncture, trauma, gold jewelry, vaccinations, hyposensitization injections, or medications (Figs. 146-1, 146-2, 146-3, and 146-4).1–9 Medications that may induce CLH include phenytoin, carbamazepine, phenobarbital, β blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, allopurinol, d-penicillamine, penicillin, mexiletine chloride, cyclosporine, and agents that inhibit binding of histamine to H1, H2, or H1c receptors. These drugs include conventional H1 and H2 antagonists, as well as tricyclic and nontricyclic antidepressants and phenothiazines.10 It has been proposed that, rather than being the target of an immune response themselves, these latter agents may alter lymphocyte reactivity in a way that promotes a CLH response to other antigens in some individuals.11,12

Clinical Findings

Approach to the Patient

Although the details of the workup for individual patients will vary with the specific type of pseudolymphoma being considered, certain data are generally important for establishing the correct diagnosis, identifying potential causative factors, and ruling out an underlying lymphoma. The clinical history taking should elicit information about the duration and symptomatology of lesions; the nature and pace of clinical progression; past treatment; local or systemic exposure to foreign antigens, including medications; and personal or family history of other lymphoproliferative disorders. It should also include a review of systems focusing on so-called lymphoma B symptoms, such as fever of unknown origin, unexplained weight loss, night sweats, fatigue, and malaise. A general physical examination is important, with special attention to the type and distribution of skin lesions and to the status of peripheral lymph nodes, liver, and spleen. A complete blood count with differential review, general chemistry panel, and a chest radiograph are screening tests that help to exclude extracutaneous involvement. Lesional skin biopsy is an essential part of the diagnostic evaluation. The use of topical and systemic glucocorticoids should be discontinued approximately 4 weeks before biopsy if possible, because these agents can attenuate lymphoid infiltrates and thereby confound their interpretation. Skin specimens should be large enough and deep enough to ensure representative sampling and to provide adequate tissue for routine histopathologic, immunohistologic, and molecular biologic studies. As with squamoproliferative skin lesions, the most diagnostic areas within cutaneous lymphoid infiltrates are often their deepest portions (Fig. 146-5). For cost-effectiveness, one can often perform these biopsy studies in a sequential fashion, proceeding to the next test only if a firm diagnosis cannot be made based on the results of preceding analyses. However, rigorous characterization of a pseudolymphomatous infiltrate requires the full complement of these assays. If there is only a solitary lesion, it is generally best to obtain all biopsy material at one time, because inflammatory changes induced by the initial biopsy may interfere with the interpretation of subsequent specimens from the same locale.

In the event that there is still uncertainty as to whether the lymphoid infiltrate represents a pseudolymphoma or a lymphoma, additional workup can be helpful. This includes computed tomographic scans of the chest, abdomen, and pelvis, as well as bone marrow aspiration and biopsy. Biopsy can be performed on abnormally enlarged lymph nodes identified by physical examination or radiography and the specimens evaluated as described in the preceding paragraph for skin lesions. It is possible for patients with atypical cutaneous B-cell infiltrates manifesting as only one or a few skin lesions to have an otherwise unremarkable workup until radiographic scans of deep lymph nodes or bone marrow sampling demonstrates advanced-stage B-cell lymphoma with minor skin involvement.

History

There may be a history of contact with an etiologically relevant foreign antigen; however, the majority of CLH cases are idiopathic. Lesions may be pruritic or asymptomatic. Occasionally, they may be slightly tender.13

Cutaneous Lesions

CLH presents most commonly as a solitary nodule, but it can also appear as a localized array of nodules, plaques, or papules. Generalized forms occur rarely. The head, neck, extremities, breasts, and genitalia are common sites (see Figs. 146-1, 146-2, 146-3, and 146-4). Lesions have a doughy to firm consistency and range from red–brown to violaceous in color. Lesions secondary to arthropod bites can be pruritic, ulcerated, or crusted. Occasionally, reactive lymphadenopathy may be present in the area of regional lymphatic drainage.13,14

Hydantoin-associated pseudolymphoma syndrome is caused by anticonvulsant drugs such as phenytoin. This syndrome is characterized by fever, lymphadenopathy, hepatosplenomegaly, arthralgia, eosinophilia, and generalized cutaneous macules and papules or, rarely, nodules.4,6 Nodules may contain aggregates of large lymphoid cells that raise concern for lymphoma; however, both B and T cells are polyclonal. Subcutaneous lymph nodes may exhibit reactive follicular hyperplasia or atypical features suggestive of lymphoma. The macular and papular lesions of this syndrome share histopathologic features with those of hypersensitivity reactions to other drugs.

Acral pseudolymphomatous angiokeratoma of children presents as a unilateral eruption of angiomatous papules on the extremities.15 There is a dense lymphoid infiltrate associated with histiocytes, plasma cells, and prominent, thickened capillaries.16 This disorder is probably a variant of CLH secondary to arthropod bites.

Large cell lymphocytoma, originally reported as a cutaneous pseudolymphoma, most likely represents a mixed cell or large cell form of primary cutaneous B-cell lymphoma (CBCL).5

Laboratory Tests

Histopathology

Histopathologic examination of CLH lesions reveals a dense, nodular or diffuse lymphoid infiltrate that is concentrated in the reticular dermis (see Figs. 146-5 and 146-6). It tends to be top heavy and to taper out in the lower dermis, although more widespread dermal infiltration with extension into the subcutis can sometimes be seen. In most cases, the epidermis is normal and separated from the underlying infiltrate by a narrow grenz zone of uninvolved papillary dermis. Occasionally, the epidermis may exhibit variable degrees of hyperkeratosis, parakeratosis, acanthosis, dyskeratosis, spongiosis, and basal vacuolar degeneration. Arthropod-induced reactions may show prominent epidermal hyperplasia or ulceration. Rarely, retained mouth parts may be seen associated with foreign-body granulomatous reactions. The dermal infiltrate is composed primarily of small mature lymphocytes, with a minor component of large lymphoid cells containing large, pale vesicular nuclei with small nucleoli (Fig. 146-7). Fewer than half of cases exhibit well-defined reactive lymphoid follicles discernible in routinely stained sections (see Figs. 146-5 and 146-8). These B-cell follicles may be either primary or secondary. The former are composed of homogeneous small lymphocytes, whereas the latter are compartmentalized into a peripheral mantle zone of small lymphocytes surrounding a germinal center composed of a heterogeneous mixture of small and large lymphoid cells with cleaved and noncleaved nuclei known as centrocytes and centroblasts. Germinal centers contain CD4+ T-follicular helper cells characterized by expression of PD-1, Bcl-6, and CXCL13.17 Also present in germinal centers are tingible-body macrophages, so named because they contain phagocytized debris from apoptotic lymphoid cells. Mitotic figures may be numerous within germinal centers but are usually uncommon elsewhere in the infiltrate. Various types of histiocytes, including macrophages, dermal dendritic cells, and Langerhans cells, are scattered throughout the infiltrate in variable proportions. Capillary hyperplasia and endothelial swelling are often present. Other cells are sometimes admixed, including plasma cells, eosinophils, mast cells, neutrophils, and histiocytic giant cells. The first two are particularly common in arthropod-induced reactions such as nodular scabies (see Fig. 146-6).13,14

In the less common T-cell CLH, there are only rare B cells.4–6,18–20 Lesions may be idiopathic or secondary to drugs or arthropod bites. Sparse to moderate epidermotropism by atypical lymphoid cells may be seen. The dermal infiltrate has a nodular or diffuse pattern and may contain cerebriform cells, immunoblasts, and histiocytes mixed with a preponderance of small mature lymphocytes. The histiocytes are sometimes numerous enough to impart a vaguely granulomatous appearance.18 The author has seen one such case presenting as multiple nodules on the trunk and extremities that was associated with rheumatoid arthritis and eventuated in T-cell lymphoma.

Special Tests

CLH is just one special case of extranodal lymphoid hyperplasia that may occur in a variety of organ systems. In their most well-developed form, these extranodal reactions recreate the immunoarchitectural features of reactive follicular lymphoid hyperplasia occurring in lymphoid tissues. CLH is generally a mixed B-cell/T-cell disorder. B cells may be organized into primary or secondary lymphoid follicles, simple clusters devoid of the follicular dendritic cell network seen in B-cell follicles, or may be randomly scattered throughout the infiltrate (Fig. 146-9). A defining immunophenotypic feature of CLH is that the small, nongerminal center B cells and plasma cells are polytypic; i.e., instead of restriction to only one type of immunoglobulin light chain, there is a mixture of κ-positive and λ-positive cells.21–23 The follicular dendritic cell networks in lymphoid follicles coexpress both immunoglobulin light chains because of the polytypic nature of the immunoglobulins bound to these networks (Fig. 146-10). The larger germinal center B cells are also polytypic but generally have very low levels of immunoglobulin expression, which is obscured by the more intense staining of the follicular dendritic cell networks in which they are enmeshed.24 Consistent with their role as a site of antigen selection and apoptosis, reactive germinal centers test negative for the bcl-2 oncoprotein.5