Chapter 146. Inflammatory Diseases that Simulate Lymphomas: Cutaneous Pseudolymphomas

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 Some of these represent outdated synonyms, some refer to variants of the same entity, and some are misnomers for diseases now recognized to be true lymphomas.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

Some researchers classify CLH into follicular and diffuse variants based on the identification of lymphoid follicles in routinely stained sections. This distinction is probably not relevant biologically, because most of the apparently diffuse cases also exhibit B-cell follicles when examined immunohistologically. T cells are also present in all cases of CLH. They are found in small numbers within lymphoid follicles, for example, T follicular helper cells, but are concentrated mainly between follicles, constituting an interfollicular T-cell domain. This imparts an overall compartmentalization of B and T cells in CLH lesions. The CD4+ T-cell subset predominates over the CD8+ subset. There is a normal pattern of T-cell antigen expression except that CD7 may be moderately deficient at times, being expressed by only 20% to 40% of T cells. Germinal center B cells, mantle zone B cells, interfollicular B cells, and plasma cells also express the same complement of cell surface differentiation antigens expressed by their counterparts in reactive lymphoid tissues.

Unlike in most nodal follicular B-cell lymphomas (Chapter 145), the t(14;18) translocation, which results in inappropriate expression of the bcl-2 oncoprotein, is absent in CLH.5,25–27 Molecular biologic studies show that 5% to 33% of CLH cases defined by clinicopathologic and immunohistologic criteria contain occult dominant immunoglobulin gene rearrangements, which indicate the presence of a dominant B-cell clone.5,28–32 These cases, known as clonal CLH, have progressed in some cases to overt B-cell lymphoma exhibiting the same dominant B-cell clone. These findings support the view that CLH, clonal CLH, and primary CBCL exist as points along a continuum of cutaneous B-cell lymphoproliferative disorders. Progression across this spectrum of disease clearly occurs in some cases, most likely as the result of serial mutations within the dominant B-cell clone. This implies that patients with persistent CLH require regular monitoring for the development of lymphoma.22 Clonal T-cell receptor gene rearrangements have also been detected in up to one-third of CLH cases.28,33 This may represent an expanded reactive T-cell clone within the CLH infiltrate. Evidence for this has been observed in CLH related to human immunodeficiency virus infection.34 Other possibilities include a low-grade T-cell lymphoma such as the CD4+ small/medium pleomorphic type17,35 or an evolving B-cell lymphoma bearing T-cell receptor gene rearrangements.

Differential Diagnosis

The differential diagnosis of CLH includes all of the conditions listed in Box 146-1. Many of these entities, such as granuloma faciale, Merkel cell tumor, histiocytomas, granulomas, and metastatic carcinoma, are readily distinguished from CLH by their histopathologic features.

A principal challenge in the differential diagnosis of CLH is its distinction from CBCL of either the diffuse or follicular types (see Chapter 145).4–6,27,36 The most common variant of CBCL is diffuse large cell lymphoma, which is readily distinguished from follicular CLH on the basis of its diffuse architecture and monomorphous large cell composition. Differentiating follicular CLH from follicular CBCL can be difficult. Follicular CBCL tends to be more bottom heavy with adnexal infiltration and lymphoid follicles lacking the cellular heterogeneity, zonation, and macrophages typical of reactive follicles. Immunophenotyping shows that neoplastic B-cell follicles are either monotypic or immunoglobulin negative.18–20 Cases involving cutaneous lymphoid infiltrates that are hard to classify or that contain a dominant lymphoid clone often benefit from a staging workup as described in Section “Approach to the Patient.” In those instances representing lymphoma, workup will sometimes reveal extracutaneous involvement, and biopsy specimens from these lesions may be easier to diagnose as lymphoma. Staging also provides useful prognostic data and is essential for appropriate management of patients with overt lymphoma.

CLH must also be distinguished from other disorders with prominent lymphocytic infiltrates such as chronic lymphocytic leukemia, deep figurate erythemas, polymorphous light eruption, discoid lupus erythematosus, and Jessner's lymphocytic infiltration of the skin. All of these disorders tend to produce perivascular, and sometimes periadnexal, infiltrates whose density is far lower than that of the nodular or diffuse infiltrates typical of CLH. With the exception of chronic lymphocytic leukemia, these are all T-cell disorders. Chronic lymphocytic leukemia is a B-cell disorder that exhibits monotypic immunoglobulin and CD5 expression and involves the blood and bone marrow. CLH lesions rich in plasma cells must be distinguished from the lesions of secondary syphilis, plasmacytoma, myeloma, and immunocytoma. The infiltrate in secondary syphilis is generally richer in plasma cells or histiocytes than in small lymphocytes and is associated with epidermal hyperplasia, an interface inflammatory component, and positive results on serologic tests. The plasma cells in plasmacytoma and myeloma are monotypic and tend to exhibit mitotic figures, atypia, immaturity, and multinucleated forms. Monotypic immunoglobulin is also present in the tumor cells of primary cutaneous immunocytoma. This B-cell neoplasm is also known as marginal zone lymphoma, mucosa-associated lymphoid tissue (MALT)-type lymphoma, and low-grade skin-associated lymphoid tissue (SALT) B-cell lymphoma.5,27,37 It is composed of varying proportions of small lymphocytes, plasmacytoid lymphocytes, plasma cells, and marginal zone-like B cells. The latter have monocytoid features with a halo of cytoplasm visible around their nuclei. These cells often surround clusters of small lymphocytes, imparting a “reverse reactive follicle” appearance with smaller cells centrally and the larger monocytoid cells peripherally.

Other disorders that can contain dense cutaneous infiltrates of both T cells and B cells include (1) lymphomatoid keratosis,38 (2) pseudolymphomatous folliculitis,39 (3) systemic immunoglobulin IgG4-related plasmacytic syndrome (SIPS),40,41 and (4) CD4+ small/medium pleomorphic T-cell lymphoma.17,35 The first three are readily distinguished from classic CLH on clinicopathological grounds. Although it can mimic CLH clinically and contain abundant B cells and plasma cells, CD4+ small/medium pleomorphic T-cell lymphoma is recognized by its predominance of CD4+ atypical lymphoid cells, frequent dominant T-cell clonality, paucity of reactive lymphoid follicles, and T-follicular helper cell phenotype.

It should be noted that typical reactive lymphoid follicles with germinal centers are not specific for CLH. They can be seen in some lymphomas (e.g., marginal zone lymphoma), Kimura disease, angiolymphoid hyperplasia with eosinophilia, Castleman disease, inflammatory pseudotumor of the skin, and morphea and as part of the host response to tumors such as basal cell carcinoma. The broad histopathologic differential diagnosis of CLH also includes histiocytoses, especially Rosai–Dorfman disease (sinus histiocytosis with massive lymphadenopathy; see Chapter 148), as well as so-called small round cell tumors such as Merkel cell carcinoma (see Chapter 120), oat cell carcinoma, neuroblastoma, and Ewing sarcoma.

Differentiation between T-cell CLH and T-cell lymphomas relies on the fact that most cases of mycosis fungoides exhibit marked epidermotropism, and most nonmycosis fungoides cutaneous T-cell lymphomas are diffuse large cell types, although a pleomorphic small/medium cell type occurs rarely as discussed above. Many T-cell lymphomas show loss of one or more T-cell antigens, and most have monoclonal T-cell receptor gene rearrangements. Progression to T-cell lymphoma has been reported in occasional patients with T-cell CLH.19,20

Complications

One of the most challenging issues concerning cutaneous pseudolymphomas has been the nature of their relationship to true lymphomas. Many patients with CBCL have a history of prior diagnosis of biopsy specimens as CLH or atypical CLH. Patients with disorders such as lymphomatoid papulosis, lymphomatoid granulomatosis, and angioimmunoblastic lymphadenopathy with dysproteinemia have an increased risk of developing various forms of overt lymphoma.5,6,27,37 The advent of molecular biologic methods for determining B-cell or T-cell clonality by analyzing immunoglobulin or T-cell receptor gene rearrangements, respectively, has provided important insights into the relationship between pseudolymphomas and lymphomas.5,6,27 It appears that many forms of cutaneous pseudolymphoma represent the benign end of a lymphoproliferative continuum eventuating in true lymphoma at its malignant extreme. In between lies a spectrum of intermediate disorders that are often difficult to classify unless one conceptualizes the disorders along such a continuum. In some cases, such as the CLH–CBCL spectrum, lesions range from polyclonal CLH at the benign extreme, through an intermediate form known as clonal CLH, to overt CBCL at the malignant extreme. In other instances, such as the lymphomatoid papulosis–CD30+ lymphoma spectrum, dominant clonality is already present in most cases at the clinically benign end of the spectrum. The most compelling evidence for the validity of this concept of a continuum is that case studies verify that the same dominant lymphoid clone is involved in the clonal pseudolymphomatous precursor and the subsequent overt lymphoma when they arise in the same individual. This relationship between overt neoplasia and clonal precursor lesions is not unique to cutaneous pseudolymphomas. It is also seen in the connection between other forms of extranodal lymphoid hyperplasia and overt lymphoma and in the relationship between monoclonal gammopathy of uncertain significance (formerly termed benign monoclonal gammopathy) and subsequent B-cell malignancies.

The concept of a spectrum for cutaneous pseudolymphomas and associated lymphomas has several important implications for the diagnosis, management, and pathogenesis of these disorders. First, because some cases will exhibit lesions at an intermediate point along the lymphoproliferative continuum, they may be difficult to classify neatly into a specific disease entity. It is probably more important to recognize that they belong to a particular disease spectrum, because it is the spectrum that is often the most relevant factor for determining optimal therapy as well as the magnitude and nature of the subsequent lymphoma risk. Second, because many patients with cutaneous pseudolymphomas are at increased risk for a clonally related lymphoma, they should have regular clinical follow-up, and all reasonable attempts should be made to eradicate or suppress their disease. Third, patients with pseudolymphomas probably have underlying abnormalities in the regulation of lymphoid proliferation and/or clearance (e.g., via apoptosis). Clonal evolution and concomitant clinical disease progression are likely to occur through a sequence of somatic mutations that act through these mechanisms to confer progressively increasing autonomy to the dominant lymphoid clone. Elucidating these pathogenetic mechanisms will be important not only for developing novel therapies for cutaneous pseudolymphomas but also for improving the treatment of analogous lymphoproliferative disorders occurring in other organ systems.

Prognosis and Clinical Course

CLH lesions may resolve spontaneously or persist indefinitely. Nodular scabies (see Figs. 146-3 and 146-6) is a well-recognized form of persistent CLH. Solitary lesions sometimes regress after biopsy or may be eradicated by excision. Those lesions that are secondary to drug use usually regress when the offending agent is withdrawn.

Treatment

CLH related to infection with Borrelia burgdorferi (lymphocytoma cutis; see Chapter 187) responds to antibiotic therapy with cephalosporins, as do some cases of idiopathic CLH. Glucocorticoids (topical, intralesional, systemic), cryotherapy, antimalarials, minocycline, and radiation therapy have all been used with variable success (Box 146-2). The latter is particularly effective but is usually regarded as a treatment of last resort. Laser therapy and photodynamic therapy have also been beneficial in some cases.43,44 Local or distant recurrence can arise after any of these treatments. Cases of atypical CLH that cannot be distinguished from lymphoma are usually treated as localized lymphoma after staging rules out extracutaneous disease. Treatment typically involves local radiation therapy, which may be preceded by excision of the lesion.

Prevention

The principal preventive strategy is to avoid contact with, or ingestion of, agents known to induce CLH in those patients with a relevant clinical history. Examples include anticonvulsant medications, arthropods, gold jewelry, and hair dyes.45–49

Epidemiology

The skin lesions of Kimura disease and angiolymphoid hyperplasia with eosinophilia (AHLE) most commonly affect young to middle-aged adults. Kimura disease is more common in Asian men, whereas AHLE is more common in women.50–53

Etiology and Pathogenesis

It is possible that Kimura disease represents a florid, subcutaneously deep-seated form of the same basic pathogenetic process that gives rise to classic dermal CLH. Most favor the concept that Kimura disease and AHLE are distinct clinicopathologic entities despite some clinicopathologic overlap.54–56 The terms epithelioid hemangioma and pseudopyogenic granuloma have been used as synonyms for AHLE. Some regard AHLE essentially as a malformation of blood vessels caused by an underlying arteriovenous shunt. They consider the CLH-like aspects of the lesional infiltrate to be a secondary feature. There is also evidence of lymphatic vessel proliferation in AHLE.52 Compared with the lesions of Kimura disease, AHLE lesions tend to be smaller (Fig. 146-11) and more superficial (centered in the dermis rather than the subcutis) and exhibit a more prominent vascular hyperplasia, characterized by small blood vessels lined by plump endothelial cells with abundant cytoplasm and sometimes atypical nuclei (see Fig. 146-11). In addition, there is often evidence of arteriovenous anastomoses, the lymphoid infiltrate is less extensive, secondary lymphoid follicles are present in only a minority of cases, and lymphadenopathy is usually absent. Patients with both AHLE and Kimura disease have been shown to harbor dominant clonal T-cell populations in some cases.

Clinical Findings

Kimura disease presents as solitary or multiple nodules up to 10 cm in diameter centered in the subcutis, most commonly involving the head and neck.54–56 Peripheral eosinophilia and regional lymphadenopathy are characteristic. AHLE tends to present with multiple smaller, more superficial intradermal papulonodules that are typically unilateral. Salivary glands, lymph nodes, and other cutaneous sites can also be affected in either disorder, although such locations are more typical of Kimura disease.

Histopathologically, the dermis and/or subcutis exhibit hyperplasia of small blood vessels lined by plump endothelial cells similar to those present in the high endothelial venules of lymphoid tissues. These venules are a major point of lymphocyte trafficking between the blood and the paracortical T-cell domain of lymph nodes. Surrounding these hyperplastic vessels is a dense infiltrate composed of small lymphocytes, plasma cells, histiocytes, and eosinophils. The latter are typically prominent but may be absent in some cases. There are usually multiple secondary lymphoid follicles with prominent germinal centers, particularly in the subcutaneous lesions. In general, lesions are more superficial and the vascular features are more prominent in AHLE, whereas lesions are deeper and the lymphoid features are more prominent in Kimura disease.50,51,57

Differential Diagnosis

Kimura disease, which generally forms deeper, larger lesions, needs to be distinguished from CBCL, sinus histiocytosis with massive lymphadenopathy, soft tissue tumors, and subcutaneous deposits of metastatic carcinoma (Box 146-3). AHLE, which has smaller, more superficial lesions, should be differentiated from CLH, CBCL, hemangioma, angiosarcoma, pyogenic granuloma, nodular Kaposi sarcoma, bacillary angiomatosis, and bartonellosis. Many of these entities have distinctive histopathologic features. The distinguishing features of CLH and CBCL have been discussed earlier (see Section “Differential Diagnosis” under “Cutaneous Lymphoid Hyperplasia”).

Complications

Kimura disease has been associated with lichen amyloidosis and renal disorders such as nephrotic syndrome.58

Prognosis and Clinical Course

Some cases, such as those associated with dominant T-cell clonality, have exhibited a chronic clinical course marked by multiple recurrences and resistance to treatment.

Treatment

The treatment of Kimura disease and AHLE is not well established because of the rarity of the disorders. Many approaches have been tried in only a limited number of cases. The most common and distinctive therapies are listed in Box 146-4. Topical treatments are used mainly for AHLE. Local radiation therapy has been reported to be superior to surgery and corticosteroids for treatment of Kimura disease.51,58–60

Epidemiology

Castleman disease is also known as angiofollicular lymphoid hyperplasia or giant lymph node hyperplasia.61–64 Four subtypes are recognized: (1) hyaline-vascular, (2) plasma cell, (3) HHV-8-associated, and (4) multicentric, not otherwise specified.65 The hyaline vascular variant is more common in younger patients, the HHV-8 variant occurs among the immunosuppressed and the other variants tend to occur in older individuals.

Etiology and Pathogenesis

Castleman disease is a polyclonal lymphoproliferative disorder of undetermined etiology. The hyaline-vascular type might involve abnormalities of follicular dendritic cells or vascular endothelial growth factor (VEGF). Epstein–Barr virus (EBV) has been detected in 20/20 cases in Taiwan.66 Studies of multicentric Castleman disease demonstrate increased levels of lesional and circulating interleukins 1β and 6, which suggests that cytokine abnormalities may be pathogenic and mediate the systemic manifestations of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes).67,68 Castleman disease occurring in the setting of human immunodeficiency virus infection or other immunosuppression is associated with human herpesvirus type 8,69,70 which has also been detected in Kaposi sarcoma (see Chapter 128) and primary effusion lymphomas.

Clinical Findings

Cutaneous Lesions

Castleman disease most often presents as an isolated mediastinal mass, although a multicentric form of the disease also exists. Lesions can be nodal and/or extranodal. Rarely, it may present as solitary or multiple, subcutaneous or cutaneous tumors in various locations.

Related Physical Findings

The plasma cell variant can be associated with polyneuropathy, organomegaly, endocrinopathy, the presence of M protein, hyperpigmentation, and hypertrichosis (POEMS syndrome).68,71

Laboratory Tests

Three histopathologic variants of Castleman disease exist. The more common hyaline vascular variant exhibits small, concentrically whorled, lymphoid follicles surrounded by small lymphocytes arranged in a concentric, onionskin pattern. An extensive proliferation of capillaries is present between follicles. The rarer plasma cell variant exhibits large, hyperplastic secondary lymphoid follicles associated with a highly vascular interfollicular zone rich in plasma cells. An intermediate form has also been reported.

Differential Diagnosis

The differential diagnosis of cutaneous and subcutaneous Castleman disease includes eosinophil-poor AHLE, Kimura disease, plasmacytoma, myeloma, sinus histiocytosis with massive lymphadenopathy, CLH, angioimmunoblastic T-cell lymphoma, and follicular types of CBCL (Box 146-5). All of these diseases lack the characteristic features of the lymphoid follicles seen in the two histopathologic variants of Castleman disease. These disorders also lack prominent vascular hyperplasia except for AHLE and Kimura disease, whose characteristic endothelial cells aid in their recognition, and angioimmunoblastic T-cell lymphoma, which contains large clonal atypical T cells. Plasmacytoma and myeloma contain dense sheets of atypical plasma cells and differ in their associated clinical findings. CLH is usually centered in the dermis rather than the subcutis. Most cutaneous lymphomas have a diffuse, monomorphous appearance. The rare follicular types of CBCL have distinctive features, as summarized earlier in Section “Differential Diagnosis” under “Cutaneous Lymphoid Hyperplasia.” Sinus histiocytosis with massive lymphadenopathy is rich in S100+ histiocytes that exhibit emperipolesis (intact lymphocytes within their cytoplasm).

Complications

Castleman disease has been associated with paraneoplastic pemphigus, plane xanthomas, vasculitis, and peliosis hepatis.72,73 Lymphomas and follicular dendritic cell sarcomas can develop in the setting of Castleman disease.

Prognosis and Clinical Course

The clinical course is usually favorable for patients with localized and extranodal lesions.

Treatment

Surgical excision is effective therapy for localized Castleman disease. Radiation therapy, chemotherapy, and immunotherapy have been used to treat multicentric variants (Box 146-6).74,75

Epidemiology

Eruptions mimicking mycosis fungoides occur typically in adults. Both genders can be affected.

Etiology and Pathogenesis

Pseudo-T-cell lymphomas with a band-like or mycosis fungoides-like histopathologic pattern may arise spontaneously or may occur as a T-cell infiltrate coexisting with B-cell chronic lymphocytic leukemia, as a rare variant of the eruption of lymphocyte recovery (which occurs in the setting of leukocyte reconstitution after iatrogenic marrow aplasia), or in association with ingestion of various drugs, including hydantoins, carbamazepine, propyl valerate, imatinib mesylate, and dexchlorpheniramine maleate and other antihistamines.4–6,10,12,56,76

Clinical Findings

History

There may be a history of an associated disease or medication. Lesions may be pruritic or asymptomatic.

Cutaneous Lesions

The lesions present clinically as one or a few plaques on the trunk or extremities. Occasionally, several plaques or a Sézary-like syndrome develops.

Laboratory Tests

Histopathologically, there is a papillary dermal, band-like infiltrate containing mostly small and medium-sized atypical lymphocytes with clefted and cerebriform nuclei. Moderate numbers of histiocytes are admixed, but eosinophils and plasma cells are rare. The dermal–epidermal junction is obscured, and there is no grenz zone. The overlying epidermis may be hyperplastic and/or may contain a sparse to moderate atypical lymphoid infiltrate; however, compared with mycosis fungoides, epidermotropism is typically far less prominent and Pautrier's microabscess-like cell aggregates are rare. Most cases contain polyclonal T cells, although occasional cases exhibit dominant T-cell clonality.10,77

Differential Diagnosis

The differentiation of these pseudolymphomas from mycosis fungoides is aided by their tendency toward minimal epidermotropism in many cases, the small number of lesions, their tendency to be polyclonal, and their resolution after discontinuation of an inducing drug and/or local therapy.

Lichenoid drug eruptions caused by agents such as gold, thiazides, and antimalarials may also bear a histopathologic resemblance to atrophic forms of large plaque parapsoriasis and overt mycosis fungoides when they result in a band-like dermal lymphoid infiltrate that involves an atrophic epidermis. As in mycosis fungoides, eosinophils and plasma cells may also be present. However, these lesions lack lymphoid atypia, exhibit the clinical features of typical lichenoid drug rashes, and regress eventually after discontinuation of the causative agent. Poikilodermatous skin lesions of collagen vascular diseases and genodermatoses are distinguished from mycosis fungoides by their associated clinical and laboratory findings; by sparser infiltrates lacking atypia; and, for collagen vascular diseases, by dermal mucin, thickened epidermal basement membranes, and characteristic epidermal alterations. Lymphomatoid keratosis is a solitary keratotic lesion that contains a mixture of T cells and B cells, both of which can be epidermotropic. Chronic radiodermatitis may resemble poikilodermatous mycosis fungoides clinically but is distinguished by clinical history, sparse infiltrate, keratinocyte atypia, dermal fibrosis, and loss of adnexa. Some cases of secondary syphilis may also mimic mycosis fungoides, showing a dense, band-like, upper dermal infiltrate that obscures the dermal–epidermal junction and invades a nonspongiotic epidermis. However, the infiltrate contains more plasma cells and fewer lymphocytes than expected in mycosis fungoides; there is no lymphoid atypia; there may be neutrophils in the epidermis; and there is a deep perivascular extension of the infiltrate that is unusual in mycosis fungoides except in the tumor phase. Furthermore, the patient's history, the clinical appearance of the lesions, serologic testing, and response to antibiotic therapy will facilitate the correct diagnosis (Box 146-7).

Three other disorders that may mimic mycosis fungoides/Sézary syndrome clinically and/or pathologically are (1) follicular mucinosis, (2) lymphomatoid contact dermatitis, and (3) actinic reticuloid. Because of their distinctive features, each is discussed separately in this text.

Complications

Severe pseudomycosis fungoides eruptions such as erythrodermas may be associated with serious complications common to other forms of generalized exfoliative dermatitis, including local skin infection, sepsis, disrupted barrier function, and cardiovascular imbalance.

Prognosis and Clinical Course

Prognosis depends heavily on the clinical context and the ability to remedy the underlying cause of the pseudomycosis fungoides lesions. If this can be accomplished, then the lesions generally regress, although lichenoid infiltrates may require many months to resolve.

Treatment

When the disorder is drug induced, identification and withdrawal of the offending agent is the principal therapy (Box 146-8). Corticosteroids (topical or systemic) and various forms of phototherapy may also be beneficial in hastening the resolution of skin lesions. Excision can be effective for isolated or sparse lesions. When pseudomycosis fungoides is associated with a specific disease, treatment should be directed at that underlying disorder.

Prevention

Strategies for prevention are similar to those described for treatment.

Epidemiology

Lymphomatoid contact dermatitis has been observed in adults of both genders.

Etiology and Pathogenesis

Lymphomatoid contact dermatitis was described originally in four patients with persistent allergic contact dermatitis proven by patch testing.78 Responsible allergens include phosphorus sesquisulfide, para-tertiary butyl phenol formaldehyde resin, ethylenediamine dihydrochloride, N-isopropyl-N′-phenyl-p-phenylenediamine (IPPD), benzydamine hydrochloride, teak wood, cobalt naphthenate, gold, nickel, and para-phenylenediamine.79–86 The clinical and histopathologic changes in the lesions are said to resemble those of mycosis fungoides.

Clinical Findings

History

Skin lesions are generally pruritic. Patients may be aware of the offending contact allergen.

Cutaneous Lesions

Clinically, lymphomatoid contact dermatitis is characterized by generalized red, scaly papules and plaques that may become confluent (Fig. 146-12) with resultant exfoliative erythroderma.

Laboratory Tests

Results of patch tests for a variety of common allergens, such as ethylenediamine dihydrochloride, may be positive.

Histopathologically, lymphomatoid contact dermatitis exhibits a superficial lymphocytic dermatitis that contains foci of spongiosis simulating the appearance of cutaneous T-cell lymphomas. It must be differentiated from mycosis fungoides (Fig. 146-13), usually on the basis of changes within the epidermis; specifically, in mycosis fungoides more atypical lymphocytes have a tendency to form Pautrier's microabscesses. Frequently, there is edema in the papillary dermis in lymphomatoid contact dermatitis, a finding that is usually absent in mycosis fungoides. Immunohistopathologic investigations indicate that lymphomatoid contact dermatitis represents a T-cell pseudolymphoma. Examination of the cells in the infiltrate by electron microscopy reveals many atypical lymphocytes with cerebriform nuclei like those in mycosis fungoides.

Differential Diagnosis

Concern for mycosis fungoides is based mainly on the histopathologic features of the lesions. Recognition of the contact allergen is central to the correct diagnosis, aided by the microscopic distinctions noted in the preceding section. Other causes of spongiotic dermatitis and, in severe cases, erythroderma should also be considered (Box 146-9).

Complications

Although in rare cases lymphomatoid contact dermatitis has been reported to evolve into lymphoma, it is possible that those patients had lymphoma from the outset.

Prognosis and Clinical Course

Avoidance of the responsible allergens leads to eventual resolution of the condition in most cases.

Treatment

A thorough search for the offending antigen by way of patch testing is necessary if the process of lymphomatoid contact dermatitis is to be interrupted. Topical application of glucocorticoids is beneficial (Box 146-10).

Prevention

The only relevant preventive measure for lymphomatoid contact dermatitis is avoidance of known causes.78–80,86–91

Epidemiology

The vast majority of cases of lymphocytic infiltration of the skin (LIS) occur in middle-aged adults, with a roughly equal gender ratio. Children have been affected rarely. There is also a rare familial variant.92

Etiology and Pathogenesis

The etiology of LIS is unknown. Some regard it as a distinct disease, whereas retrospective studies have allowed some authors to reclassify many cases as dermal variants of lupus erythematosus or, less commonly, CLH, polymorphous light eruption or other dermatoses.93,94 Some of the CLH-like cases have been associated with B. burgdorferi in Europe. One case appeared due to hydroquinone, suggesting that dermal delayed-type hypersensitivity reactions can be an etiology.95 Photoexacerbation occurs in a minority of patients according to some observers. Immunologic investigations have shown decreased natural killer cell function as well as elevation in circulating immune complexes, the levels of which were reported to parallel disease activity.96 Skin lesions known as arcuate dermal erythema may arise in female carriers of chronic granulomatous disease. These lesions resemble LIS clinically and microscopically.

Clinical Findings

History

Skin lesions are typically asymptomatic.

Cutaneous Lesions

LIS, which was first described by Jessner and Kanof,97 presents as one or more erythematous plaques or nodules, generally localized to only one or a few sites on the face, neck, upper trunk, or arms.98,99 Pustules, pruritus, and epidermal alterations are absent. In contrast to discoid lupus lesions, LIS lesions show no epidermal atrophy or follicular plugging.

Laboratory Tests

Histopathologic examination reveals a superficial and deep, perivascular and variably periadnexal infiltrate of small mature lymphocytes, often with a minor admixture of histiocytes, plasmacytoid monocytes, and plasma cells. Lymphoid follicles and eosinophils are absent. The epidermis is unremarkable. Results of direct immunofluorescence studies are negative or nonspecific. Immunohistologic studies have demonstrated a predominantly HLA-DR− Leu-8+ T-cell infiltrate with some B cells and histiocytes admixed. In contrast, most of the T cells in discoid lupus are HLA-DR+ Leu-8−.100–102 Immunopathologic studies have shown a predominance of CD8+ T cells within lesional infiltrates. Initial studies indicate that the infiltrate lacks dominant clonality.5,103,104

Differential Diagnosis

The differential diagnosis of LIS includes chronic cutaneous lupus erythematosus, polymorphous light eruption, CLH, lymphocytic lymphoma and leukemia, deep figurate erythemas such as erythema chronicum migrans, granuloma faciale, and reticular erythematous mucinosis (Box 146-11). In considering differential diagnostic features, keep in mind that some authors regard both LIS and reticular erythematous mucinosis to be misdiagnosed lupus erythematosus, CLH, or other miscellaneous disorders.93,94 Discoid lupus generally exhibits epidermal changes, an interface inflammatory component, and a lupus band on direct immunofluorescence. The tumid variant of discoid lupus is typified by abundant dermal mucin and subtle alterations at the dermal–epidermal interface. These changes are not seen in LIS. Antinuclear antibody (ANA) panel results and erythrocyte sedimentation rate are also normal in most cases; however, positive ANAs have been reported in some patients leading to reclassification of their disease as lupus. Polymorphous light eruption exhibits papillary dermal edema, which is absent in LIS. CLH contains nodular or diffuse, dermal lymphoid infiltrates that are much denser than the predominantly perivascular infiltrate of LIS. Furthermore, LIS lacks reactive B-cell follicles. Well-differentiated or small lymphocytic lymphoma/leukemia is usually a monoclonal B-cell process, and there is a peripheral lymphocytosis in the leukemic form of the disease. These findings are absent in LIS. In erythema chronicum migrans and some cases of CLH, there is serologic evidence of active infection with B. burgdorferi, whereas this is rarely seen in LIS except when there has been suspicion of misdiagnosis of CLH as LIS.94 Granuloma faciale is rich in neutrophils and eosinophils that are not features of LIS. Reticular erythematous mucinosis has a reticulated clinical appearance, favors the trunk rather than the head and neck, and shows bipolar fibroblasts. These are not features of LIS.

Complications

Postinflammatory pigmentary alterations and corticosteroid-associated skin atrophy may complicate the clinical course of LIS, especially in cosmetically sensitive locations.

Prognosis and Clinical Course

LIS has a chronic course and may show periods of spontaneous remission and eventual resolution. Lesions may recur at their original sites or elsewhere. Some patients have subsequently developed features typical of lupus erythematosus.93,94

Treatment

LIS may respond favorably to topical or intralesional glucocorticoids, calcineurin inhibitors, antimalarials, pulsed-dye laser or thalidomide; however, a persistent, indurated variant has been described that may require systemic glucocorticoid therapy to achieve remission105 (Box 146-12).

Prevention

Photoprotection may be helpful in those cases with a history of photoexacerbation.