Chapter 125. Malignant Fibrous, Fibrohistiocytic, and Histiocytic Tumors of the Dermis

Malignant fibrohistiocytic tumors are a heterogeneous group of mesenchymal neoplasms. These neoplasms occur in the dermis and subcutaneous tissue and may cause diagnostic difficulties. This is at least in part due to the fact that these tumors are relatively rare while at the same time there is a perplexing variety of morphological types and subtypes; thus, the individual physician usually has limited experience in these tumors. By light-microscopic examination cells constituting fibrohistiocytic tumors are characterized by morphologic similarities to fibroblasts and histiocytes. Notably, the term “fibrohistiocytic” only denotes this morphologic appearance, it does not necessarily account for the histogenesis of the respective neoplasm.

The initial descriptions of these tumors were based entirely on hematoxylin and eosin (H&E) morphology and the term “fibrohistiocytic” was chosen in an attempt to provide an organizing principle and nomenclature for this group of soft tissue tumors, composed of cells resembling fibroblasts and histiocytes.

Over the last decades all scientific attempts to demonstrate true histiocytic differentiation in these tumors failed. By means of electron microscopy, immunohistochemistry (IHC), and cytogenetics, it became increasingly obvious that the term “fibrohistiocytic” is a misnomer and falsely unite a heterogeneous group of tumors, many of them are probably unrelated. This notion has been also recently endorsed by the World Health Organization by the use of the terminology “So-called Fibrohistiocytic Tumors” indicating that this term is only used descriptively.1

The symptoms that call attention to a fibrohistiocytic tumor are usually those caused by its presence and growth at its site of origin. In most cases the patient may present with an asymptomatic mass. Thus, a biopsy (either open or large-gauge core needle) is needed to obtain adequate tissue for diagnosis. Care should be taken to ensure that the biopsy does not interfere with subsequent optimal definitive surgery. Moreover, it should be kept in mind that fibrohistiocytic tumors can be very heterogeneous: the smaller the biopsy sample, the more likely it is that only a temporary, working diagnosis becomes possible. This is of course particularly true for a purely cytological examination, since this can only evaluate individual cells. Nevertheless, in the hands of an experienced investigator, the cytological findings in most cases provide enough information to plan the subsequent therapeutic strategy.

The diagnosis of fibrohistiocytic tumors is done principally on the basis of the H&E-stained section. Despite the enormous increase in additional methods available, the H&E section remains the gold standard of morphological diagnosis. When necessary, IHC can be employed; this can reveal cell-line differentiation or antigen expression patterns typical for a particular tumor entity. Likewise, methods of genetic analysis allow the detection of chromosomal translocations, as well as gene deletions or amplifications. These methods are usually exercised when no tumor classification is possible on the basis of the H&E section even in combination with IHC. Chromosomal translocations can be detected in formalin-fixed paraffin-embedded (FFPE) tissue by fluorescence in situ hybridization (FISH) or by reverse transcription polymerase chain reaction (RT-PCR) for the product generated by gene fusion (hybrid RNA). The latter has the advantage of demonstrating not only the translocation, but also the sites of the breakpoints in the genes. Unfortunately, chromosomal translocations are not always diagnostically unambiguous.

Malignant fibrohistiocytic tumors of the dermis represent the malignant end of a spectrum that begins with fibroplasias and benign fibrous tumors. Fibrous lesions are often composed predominantly of stroma, and only in certain high-grade sarcomas the neoplastic nature of the lesion is immediately obvious. However, it should be noted that the identification of defined chromosomal abnormalities in some fibrohistiocytic lesions traditionally regarded as reactive suggests their neoplastic status. Thus, the classification of fibrohistiocytic tumors, like that for other tumor entities, is not static. New aspects or interpretations have to be taken into account and incorporated into clinical practice, i.e., it becomes necessary to update the tumor classification, modify it, or even alter major parts of it.1

A prominent example for such an evolution is malignant fibrous histiocytoma (MFH). MFH as a tumor entity has already been a subject of debate for sometime. Tumors were originally classified as MFH based on the assumption that the histiocytic tumor cells possess the ability to modulate into facultative fibroblasts. Indeed, MFH was regarded as the most common soft-tissue tumor of advanced adulthood, with pleomorphic MFH being the prevalent subtype. Subsequently, however, it was demonstrated that the phenotype of pleomorphic MFH can be adopted by various soft tissue malignancies by loss of differentiation; thus, in the majority of cases there is no independent tumor entity and the cells of pleomorphic MFH are basically dedifferentiated or undifferentiated cells of different origin. By means of more advanced techniques it was possible to demonstrate markers of residual differentiation for the majority of these tumors and thereby to remove such defined soft-tissue tumors from the group of pleomorphic MFH. According to the recommendations of the WHO, the remaining tumors that cannot be further subtyped, i.e., pleomorphic MFH in the narrower sense, should be described as undifferentiated pleomorphic sarcomas (UPS); notably, these very rare tumors are almost never cutaneous lesions. The tumor cells of the second prominent MFH subtype—the myxoid variant—are now understood as fibroblastic cells; thus, the preferred designation today is myxofibrosarcoma (MFS).

With regard to the treatment of “so-called malignant fibrohistiocytic tumors” surgery is the primary treatment of choice. In cases where surgery is not feasible, i.e., large primary tumors or inoperable metastatic disease, beneath chemotherapy and radiation the search for suitable molecularly targeted agents is strongly pursued.2 To achieve this goal, however, a pathogenetically essential molecular target is needed. This strategy up to now was successful in one tumor entity only, dermatofibrosarcoma protuberans (DFSP), which can be effectively treated with tyrosine kinase inhibitors (TKI) targeting the platelet-derived growth factor receptor (PDGFR), for example, imatinib. For all other entities of malignant fibrohistiocytic tumors, clinical studies investigating different targeted agents in an unselective manner did not show any promising results. Here, the key molecular pathways for pathogenesis and maintenance of the different tumor entities first have to be elucidated in more detail to subsequently serve as targets for a molecularly driven therapy.

Epidemiology

The incidence of DFSP ranges between 0.5 and 1:100,000, thus it is the most common cutaneous sarcoma. Although DFSP can present at birth or in children, most patients are middle-aged adults. There does not seem to be a gender or racial predilection for the tumor, however, the pigmented variant (Bednar's tumor) is more common in black patients.

Etiology and Pathogenesis

The histogenesis of DFSP is uncertain: fibrohistiocytic, purely fibroblastic, and neural-related differentiation have all been hypothesized. At the molecular level, DFSP is characterized cytogenetically by a reciprocal translocation t(17;22) (q22;q13), or more frequently, a supernumerary ring chromosome composed of hybrid material derived from t(17;22).2 The translocated chromosome and the supernumerary rings contain the same molecular genetic rearrangements. The t(17;22) translocation fuses the gene PDGFB on chromosome 22 with the strongly expressed collagen 1 alpha 1 (COL1A1) gene on chromosome 17. The PDFGB gene encodes the β chain of the PDGF, a ligand for the cell-surface receptor tyrosine kinase PDGFR (both PDGFRβ and PDFRα). PDGFβ is a growth factor that acts as a potent mitogen for a variety of connective tissue cells. The formation of the COL1A1-PFGFB fusion gene results in constitutive production of COL1A1-PDGFβ protein. After translation the COL1A1-PDGFβ fusion undergoes posttranslational processing to form functional PDGFβ. Thus, the production of PDGFβ can lead to autocrine stimulation of the tumor's own PDGFR, promoting tumor growth and survival. These observations suggest that deregulated expression of PDGFβ, with concomitant autocrine stimulation of PDGFR, is the critical molecular event in the pathogenesis of DFSP. Notably, both fibrosarcomatous transformation of DFSP and some cases of superficial fibrosarcoma (which actually may represent fibrosarcomatous transformed DFSP) have been shown to harbor these fusion transcripts, suggesting a close affinity between DFSP and fibrosarcoma.

In some patients, there is a history of previous trauma; in this regard it should be noted that DFSP has also been described as arising in scars, including surgical, burn, and vaccination sites.

Clinical Findings

DFSP is a slow-growing lesion that often presents on the trunk and proximal extremities, less frequently on the head and neck of patients. Due to its indolent onset, the patient may present rather late when the tumor is already several centimeters in size. The tumor is often misdiagnosed as a simple scar, keloid, or cyst (Box 125-1). Even when allowed to grow for many years, the tumor usually remains asymptomatic.

The clinical presentation of DFSP is variable. The most common presentation is a firm, indurated plaque, often skin-colored with red–brown exophytic nodules (Fig. 125-1A). Purely plaque-like DFSP never developing nodules or tumors consisting of only a single nodule are rare. Initially the tumor is freely moveable; subsequently, however, larger adherent tumors evolve. At this stage the overlying epidermis may be thinned and telangiectases appear. Bleeding and ulceration are uncommon. DFSP may less frequently present as a nonprotuberant, atrophic (Fig. 125-1B), violaceous lesion resembling morphea or a sclerosing basal cell carcinoma; this form is more common in childhood. The pigmented variant of DFSP is termed Bednar tumor.

Giant cell fibroblastoma is considered a variant of DSFP, i.e., the juvenile variant of DFSP. Giant cell fibroblastoma typically presents as a dermal or subcutaneous mass, which most frequently involves the trunk, thigh, or inguinal region. It presents much earlier in life than the typical DFSP, often within the first decade, although occurrences in adults have been reported.

Histopathology and Immunohistochemistry

DFSP is a dermal proliferation of monomorphous, slender, or slightly plump spindle cells with little pleomorphism arranged in a storiform pattern (Figs. 125-2A and 125-2B). The epidermis is usually uninvolved. The proliferation commonly infiltrates the subcutaneous fat along the fibrous septa, isolating adipocytes to form lucencies (“honeycomb” pattern). The periphery of the tumor is poorly defined, rendering histological control of the surgical margins difficult. In contrast to dermatofibroma, the tumor is much more cellular and usually does not have mature collagen interspersed between fascicles of spindle cells. Mitoses are present; a high mitotic rate may correlate with an impaired prognosis.

Variable histologic patterns described include myxoid, neuroid, fibrosarcomatous, and granular cell types. The tumor may be relatively monomorphous or may show combinations of various patterns within the original tumor or in the recurrences. The Bednar tumor is rich in melanocytes. Giant cell fibroblastoma is characterized by giant cells, irregular vascular-like space partially ligned by giant cells as well as myxoid to collagenous areas with elongated to stellated cells. Some lesions show overlap between giant cell fibroblastoma and DFSP. The fibrosarcomatous dedifferentiation appears histologically as cellular tumor zones with a fascicular growth pattern, cellular atypia, and numerous mitoses. These atypical cells are arranged in long fascicles in a herringbone (fibrosarcoma-like) pattern; this transformation appears to be related to mutations in the p53 pathway.

A very sensitive, although nonspecific, marker for DFSP is CD34.3 DFSP cells label diffusely and strongly with antibodies to CD34 (Figs. 125-2C and 125-2D) and vimentin; however, CD34 positivity may be lost in nodular regions; particularly the fibrosarcomatous dedifferentiated cellular zones can be negative for CD34. The low-affinity nerve growth factor receptor p75 has been reported positive in DFSP cells. Scattered Factor XIIIa positive cells may be present. Tenascin is negative at the dermoepidermal zone in DFSP. DFSP cells are negative for S100 protein, smooth muscle actin (SMA), desmin, keratins, and epithelial membrane antigen (EMA). In contrast to dermatofibroma, stromelysin 3 is not expressed in DFSP.

Clinical Course, Prognosis and Treatment

DFSP is a low-grade malignant tumor, often infiltrating diffusely through the dermis and into the subcutaneous fat but seldom metastasizing. Increased age, high mitotic index, and increased cellularity are predictors of poor clinical outcome. Approximately 30%–50% of DFSPs recur locally after simple excision. Local recurrences even after wide excision with 1–3-cm margins to the fascia or periosteum are common. Best results can be achieved by means of micrographic controlled surgery (Mohs micrographic surgery) for tumor extirpation. However, it should be kept in mind that by use of frozen sections the histomorphology is not as good as by use of formalin-fixed paraffin embedded sections—in some cases impede correct diagnosis. Metastases of DFSP are extremely rare, usually occurring in the setting of multiply recurrent tumors and tumor progression to fibrosarcoma. Metastases to the lung are most common, with nodal disease the next most common site of spread. Metastatic disease portends a poor prognosis. It has been suggested that tumors with fibrosarcomatous change may have a higher risk of recurrence or metastases. It is estimated that there is a 5% transformation rate from DFSP to conventional fibrosarcoma. The true impact of fibrosarcomatous changes seen within a DFSP remains uncertain.

Standard management of localized disease is complete local surgical resection. With standard excision, margins of 1–3 cm may be necessary to achieve clear margins. However, local recurrence rates are high (13%–52%), especially in fibrosarcomatous DFSP. Risk of local recurrence decreases with increasing surgical margins. Pathologic examination of margins during surgery is helpful in delineating the extent of the tumor. Multiple case series have shown Mohs micrographic surgery to be an extremely effective method of resection of DFSP, with an extremely low rate of local recurrence. As a result, Mohs micrographic surgery represents the preferred surgical approach of many practitioners.

The role of radiotherapy remains unclear. Radiotherapy in the adjuvant setting following surgery is a treatment option particularly when margins are positive or close after maximal resection, if there is concern about the adequacy of negative margins, or if the achievement of wide margins would result in a functional or cosmetic defect.

Targeting the PDGF receptor signaling by receptor TKI, such imatinib or nilotinib, has demonstrated remarkable clinical success in the setting of advanced, unresectable primary tumors or metastatic disease.4 These TKI are competitive antagonists of the adenosine triphosphate (ATP)-binding site, blocking the transfer of phosphate groups from ATP to tyrosine kinase residues of the substrates. This causes interruption of the downstream signaling process that leads to cell proliferation. The clinical activity of imatinib in patients with metastatic or locally advanced, unresectable DFSP was initially documented in case reports. The first published larger series of DFSP patients treated with imatinib confirmed the clinical activity with eight of eight patients with locally advanced disease obtained a clinical response. Four of these had a complete response; the other four patients were rendered free of disease after surgery following a partial response. Since 2007, imatinib has been approved in the United States and in the European Union for use in adult patients who have unresectable, recurrent, and/or metastatic DFSP and are no primary candidates for surgery. However, these observations raise the possibility of using PDGFR-specific TKI in the neoadjuvant setting in cases where surgery is associated with significant morbidity.2 Clinical trials are needed to determine whether neoadjuvant use of such TKI to reduce tumor burden and facilitate resection, as well as adjuvant use following complete surgery, particularly in fibrosarcomatous DFSP, can improve patient outcome. Several studies in the United States and in Europe are ongoing in these clinical settings.

Epidemiology

Desmoid tumors, or aggressive fibromatosis, are rare, with an estimated incidence rate of two to four cases per million per year. Desmoid tumors occur in a wide age range, between 16 and 79 years with a median age of 35, the majority being diagnosed before the age of 40.5 Desmoids are slightly more common in women than men, but there are no apparent differences by race.

Desmoid tumors usually occur sporadically, but can be associated with familial adenomatous polyposis (FAP). Indeed, their incidence is 1,000-fold more frequently in patients with FAP; approximately 2% of desmoid cases occur in the setting of FAP. FAP, characterized by a mutation in the adenomatous polyposis coli (APC) tumor suppressor gene, has a clinical manifestation of hundreds, if not thousands, of adenomatous polyps in the colon and rectum. Although the association of desmoid tumor with FAP has been noted earlier, Gardner described a familial syndrome characterized by intestinal polyposis, fibromas, and sebaceous and epidermal cysts. Gardner syndrome is viewed as a variant of FAP. Notably, intra-abdominal and extremity desmoids tumors represent common extracolonic manifestations of disease in Gardner's syndrome.

Etiology and Pathogenesis

The genetic predisposition to desmoid tumors in FAP patients prompted mutation analyses of the APC gene to elucidate the pathogenesis of fibromatosis. However, current evidence demonstrates that there are likely undefined genetic or clinical factors independent of APC that are responsible for the pathogenesis of fibromatosis.5

Because APC and CTNNB1 are both part of the Wnt signaling pathway, mutations in either gene result in β-catenin protein stabilization and subsequent downstream activation of the T-cell factor/lymphoid enhancer factor (TCF/Lef) family of transcription factors. In a transgenic mouse model, induction of stabilized β-catenin leads to the development of desmoid tumors and hyperplastic cutaneous wounds, suggesting that β-catenin plays a role in these fibroproliferative disorders. Indeed, in a study of sporadic desmoid tumors, 3 of 12 cases had a mutation in β-catenin. In another study, 16 of 19 cases of desmoid tumors had a mutation of the Wnt pathway (APC or CTNNB1). The resulting activation of this pathway may be a potential target for future studies and the development of tailored therapies.

Recently the differential expression of estrogen receptors in desmoid tumors has been reported. There appears to be an increased estrogen receptor-β expression in 80% of desmoid specimens. Increased expression of PDGF receptors and their ligands in desmoid tumors have been reported.

Clinical Findings

Desmoids are slowly growing tumors that may arise from the muscular aponeuroses at any site of the body, but are most commonly found on the trunk and extremities. In these locations, these solitary tumors tend to be located deep in the muscles or along fascial planes, such as at a point of muscular insertion. They may become quite large, displacing normal structures and hampering function. Patients will usually present with a greater than 5 cm, localized, firm mass with an indolent pattern of growth, which can be painless or minimally painful. The tumors of the abdominal wall occur along the anterior abdominal wall, most commonly in young women during or immediately after pregnancy. Desmoid tumors have been associated with a history of trauma or an operation. Thus, women undergoing cesarean sections are at higher risk.5

Histopathology and Immunohistochemistry

Desmoid tumors are characterized by a monoclonal fibroblastic proliferation typically arising from muscular or aponeurotic structures. They may resemble low-grade fibrosarcoma, but their histologic appearance lacks nuclear and cytoplasmic features of malignancy. Desmoid tumors consist of spindle-shaped cells, separated by collagen fibers. The tumor cells have regular nuclei and show few mitoses. The tumor cells are arranged in long fascicles. Variable prominent elongated and compressed vessely can be seen. An infiltration of tumor cells into surrounding tissue frequently observed. By IHC, these spindle cells usually stain for vimentin and SMA, but are generally negative for desmin, cytokeratins, and S100. 70% of these tumors show a nuclear staining with antibodies against β-catenin.

Clinical Course, Prognosis, and Treatment

Desmoid tumors are notoriously infiltrative and persistent. Moreover, trauma, including surgery, can stimulate desmoid tumor growth. Thus, recurrence after surgery is common. Albeit to date no agreement has been reached on the optimal treatment of desmoid tumors, complete resection is generally considered the best choice of initial treatment and is potentially curative. Ability to accomplish complete resection at the first attempt defines likelihood of recurrence. Preoperative diagnosis with core needle biopsy may be helpful in planning a radical resection. Due to the locally aggressive nature of desmoid tumors and the therefore needed safety margins the localization of the tumor is important for treatment planning. Thus, clinical evaluation should include radiologic studies by MRI to determine proximity to adjacent structures.

There are no strong data to support the use of radiation therapy in the adjuvant setting following complete surgical resection. Thus, its use may be deferred until recurrence is seen and not amenable to repeat resection. Because palliative resection in most cases neither improves symptoms nor lengthens survival, there should be a consideration of radiation therapy in truncal or extremity desmoid tumors when a complete resection is not feasible.

Systemic therapy is indicated for patients with unresectable lesions. A number of treatment regimens have been reported in single case studies. Given the slow natural course of the disease, a low-toxicity regimen of chemotherapy is preferred; the combination of methotrexate and vinblastine is one of the most studied regimens. Chemotherapy, however, is met with scepticism since oncologic dogma dictates that cytotoxic treatments are not particularly effective in indolent tumors without metastatic potential.

Noncytotoxic agents that have been used for systemic treatment of desmoid tumors include antihormonal, nonsteroidal anti-inflammatory, and molecularly targeted agents. Because of clinical and experimental evidence linking hormonal surges to desmoid growth, antiestrogen agents (tamoxifen, toremifene, and raloxifene) have been commonly used over the years. Control of disease (either tumor shrinkage or stabilization) has been observed in up to 50% of patients; notably, responses are sometimes seen after the medication is discontinued. Recently, preliminary reports on the clinical activity of imatinib in desmoid tumors have generated some enthusiasm, though the mechanism of its action remains unclear. Nevertheless, several case reports have described meaningful responses to imatinib and in a series of 19 patients with desmoid tumors control of disease was achieved in almost 40% of the patients. The notion that the Wnt/β-catenin signaling pathway is involved in the pathogenesis of desmoid tumors, opens new avenues for novel molecularly targeted agents.

Epidemiology

AFX is a rare, rapidly growing neoplasm of intermediate malignant potential. It occurs mainly on sun-exposed skin (face, neck, and hands) of elderly individuals, mostly in the eighth decade of life, and shows male predominance.6 However, in xeroderma pigmentosum (XP) patients, a rare, usually autosomal recessive disorder related to DNA repair defects, AFX does not only have a higher incidence but also occurs earlier in life, even in children.7 Moreover, several lines of evidence indicate that the incidence of AFX is dramatically higher in transplant patients receiving immune suppression.

Etiology and Pathogenesis

The nosologic nature of AFX has been the subject of much debate. Given its histologic appearance as well as its immunoperoxidase staining profile, AFX has traditionally been considered mesenchymal in origin. Because its histological appearance is similar to pleomorphic MFH, AFX is often regarded as a superficial version of this tumor. However, since the phenotype of “pleomorphic MFH” can be adopted by various soft-tissue tumors by loss of differentiation, AFX may also represent a tumor of dedifferentiated or undifferentiated cells of different origin. Thus, recently, some authors argue that AFX is an undifferentiated form of a spindle cell squamous cell carcinoma (SCC) or spindle cell melanoma. Indeed, one study has shown that depth-matched SCC and AFX behave similarly (Box 125-1).

Solar radiation probably represents a predisposing factor in the pathogenesis of AFX. This is supported by the common occurrence of the tumor on actinically damaged skin and its frequent association with other actinic-related lesions. The presence of cyclobutane pyrimidine dimers further supports a pathogenic role for ultraviolet radiation in the development of AFX.

Moreover, the majority of AFX cases are characterized by p53 immunoreactivity independent of acute stimuli for it expression; indeed, molecular analysis of the p53 gene in a case series revealed that there were abnormal single strand conformational polymorphism patterns in all p53-immune reactive cases.6 The increased incidence of AFX in XP patients also strongly suggests that UV-induced damage in the pathogenesis of the tumor.

Clinical Findings

The patient may report a lesion on sun-damaged skin of relatively rapid onset. The predominant locations are ears, cheeks, nose, and scalp. The background skin is often sun damaged. The lesion usually presents as an asymptomatic, solitary, often dome-shaped nodule, which may be eroded or ulcerated (Fig. 125-3A). The size of presentation is usually less than 2 cm in diameter. AFX may resemble an SCC, basal cell carcinoma, or even a necrotic pyogenic granuloma.

Histopathology and Immunohistochemistry

AFX is a poorly circumscribed hypercellular tumor that may extend deeply into the reticular dermis. It consists of an admixture of highly pleomorphic spindle, epithelioid (histiocyte-like), and multinucleated giant cells in the dermis (Figs. 125-3B and 125-3C). The proportion of individual cell types within individual lesions may vary, from predominantly spindle to predominantly epithelioid lesions. The neoplastic cells display pronounced atypia, with bizarre, large, round, or ovoid hyperchromatic nuclei with numerous mitotic figures (some of them atypical); large, prominent eosinophilic nucleoli; and abundant, occasionally vacuolated cytoplasm. An epidermal collarette at the periphery of the lesion is frequently observed and may extend along the base of the lesion. Skin adnexa are generally surrounded but not destroyed by the tumor. The deep margin is generally pushing rather than infiltrative. Surface ulceration precludes adequate evaluation of epidermal changes, for example, the presence of epidermal dysplasia or melanocytic proliferation.

At present, no single reliable immunohistochemical marker has been detected to confirm the diagnosis of AFX, which still remains a diagnosis of exclusion.6 A panel of antibodies is therefore mandatory to exclude its potential mimics. Immunohistochemically, AFX has variable profiles, but cells usually express vimentin and histiocytic markers such as α1-antitrypsin, α1-antichymotrypsin, and CD68. Focal smooth muscle positivity can be detected in as many as 45% of AFXs. Although diffuse and strong CD10 and CD99 positivity has been described in AFXs, these markers are nonspecific and noncontributory in the diagnosis of AFX. MIB-1 and Ki-67 are useful markers in this highly proliferative tumor (Fig. 125-3D). CD74 expression has been suggested to represent a marker of more aggressive behavior in this tumor. By definition, AFXs are consistently negative for various low- and high-molecular-weight cytokeratins, S100 and desmin. Reactive S100+ dendritic cells are frequently seen dispersed among the lesional cells.

Prognosis, Clinical Course, and Treatment

The growth pattern of AFX has a propensity of local invasion beyond the obviously involved skin, there by inflicting the risk of local recurrence after surgical excision. In the literature, the recurrence rate of AFX is estimated to be 5%. Large case series from the 1960s and 1970s showed recurrence rates ranging from 2% to 21%, whereas more recently reported recurrence rates, particular if micrographic controlled surgery (Mohs micrographic surgery) is used, are much lower. Thus, recurrent tumors may be better regarded as residual tumors.

AFX is a neoplasm with extremely low metastatic potential. In the largest case series reported to date by Ang et al, 3 out of 89 patients developed loco-regional or systemic metastases.6 In 2005, Cooper et al described five cases of what they termed “metastasizing atypical fibroxanthoma”8; in their comprehensive review of the literature they identified additional 16 published cases of metastasized AFX since 1961. Thus, with respect to the management of patients, it is important to recognize that any tumor diagnosed as AFX has the potential for regional or even distant spread, whether it is an aggressive form of AFX or histologically misinterpreted as AFX instead of SCC. AFX is often found in the setting of diffuse actinic damage and other nonmelanoma skin cancer, so close follow-up after complete tumor exstirpation is prudent.

Treatment of AFX is surgical. Studies have suggested that Mohs micrographic surgery provides a lower rate of recurrence than wide local excision. Mohs micrographic surgery was found to be tissue sparing. Notably, even for larger tumors, the margins needed in Mohs micrographic surgery to clear the tumor effectively were smaller than that needed in wide local excision. In the series of 91 patients reported by Ang et al analysis of the Mohs micrographic surgery margins showed that in cases in which Mohs micrographic surgery cannot be employed a 2-cm margin is needed to ensure clearance of 96.6% of tumors by wide local excision. Excision should be to the level of the deep subcutaneous tissue.

In addition, follow-up examinations including inspection and palpation of the surgical site and the regional lymph nodes, should be performed for at least 2 years, because this is the time during which nearly all of recurrences reported in the literature occurred.

Epidemiology

MFS represents a spectrum of malignant myxoid tumors of fibroblastic origin that exhibit a range of clinical and histopathologic features. For many years, this entity was generally known as myxoid MFH. However, several studies showed that MFS has reproducible cytoarchitectural features and consistent clinicopathologic characteristics and, therefore, these tumors appear to constitute a defined entity and are better referred to as MFS.1

MFS is the most common malignant mesenchymal neoplasm of the extremities/limb girdles of older adults.9 It shows marked predilection for subcutaneous tissue of the limbs and limb girdles; approximately more than two thirds of cases develop within the dermis or subcutis. MFS has no significant gender predilection and tend to affect patients in their sixth to eighth decades. However, the overall age range is wide, and cases in teenagers have been reported.

Etiology and Pathogenesis

Cytogenetics demonstrated variable complex chromosomal abnormalities with translocations, for example, t(2;15)(p23;q21.2) or t(13;17)(q10;q10), or ring chromosomes as a consistent feature. To date, the constituents of these chromosomes remain unknown. Thus, there seems to be a number of different chromosomal alterations that contribute to the histogenesis of MFS.

Clinical Findings

MFS is most frequently encountered on the extremities and limb girdles, but may also arise within the head and neck region, the trunk, hands, and feet. A gradually enlarging painless dermal or subcutaneous mass is the most frequent clinical presentation. The tumors are usually attached to a tendon or muscle but may also be superficially localized, presenting as multiple adherent cutaneous nodules, often with satellites. The most common clinical differential diagnosis is a benign dermal neoplasm such as lipoma, neurofibroma, or follicular cysts.

Histopathology and Immunohistochemistry

MFS typically presents as a multinodular tumor characterized by variable amounts of hyaluronic acid-rich myxoid stroma, delicate blood vessels, and spindle-shaped or stellate fibroblasts. MFS exhibits a remarkably broad spectrum of histopathologic features ranging from banal to high grade. MFS grading is somewhat controversial and can be performed using a 3- or 4-tier grading system, which will grade these tumors in high, intermediate, and low-grade, or grades I to IV, respectively.10 Both systems are based on the extent of the cellular components, nuclear pleomorphism, mitotic rate, and presence or absence of necrosis.

Low-grade MFS are hypocellular tumors comprised of relatively uniformly appearing spindle or stellate cells dispersed within a myxoid matrix; while nuclear pleomorphism and hyperchromasia may be present, mitotic figures and other overtly malignant features are absent. With increasing histological grade, MFS displays increasing cellularity, nuclear atypia, and mitotic activity. High-grade MFS is characterized by hypercellularity, marked nuclear atypia, hemorrhage and necrosis, and a high mitotic rate. It should be noted, however, that superficial portions of MFS tend to be morphologically low grade, regardless of the grade seen within the remainder of the tumor. Moreover, irrespective of the grade of MFS, the periphery is usually poorly defined, with finger-like extensions that account for satellites and a high recurrence rate.

At present, no single reliable IHC marker has been detected to confirm the diagnosis of MFS. The characteristic tumor cells in myxoid areas stain positively for vimentin, but are generally negative for CD68 or Factor XIIIa.

Prognosis, Clinical Course, and Treatment

The primary therapy for MFS is complete local surgical resection. Wide and deep local excision is required. The first excision offers the best chance for cure. Three-centimeter margins are usually suggested, but the deep extensions are hard to identify, even when one excises to the fascia; particularly as MFS is deceptively infiltrative, making clinical assessment of margins difficult. Thus, MFS has a high rate of local recurrence of almost 50%. The potential of MFS to recur and to spread seems to be related to the anatomic depth of the primary tumor and histologic grade; however, even histological bland lesions carry a significant risk of recurrence. Importantly, recurrent low-grade lesions may undergo progression to more malignant histopathology and this transition may be accompanied by increasing metastatic potential. Metastasis occurs in a significant number of high-grade tumors with an overall risk of approximately 20%–25%.10 Lung and bone are the most common metastatic sites, but spread to regional lymph nodes may also occur. The overall 5-year survival rate is 60%–70%.

Epidemiology

In the past, MFH has been considered to be the most common malignant soft-tissue tumor, with pleomorphic MFH being the prevalent subtype. However, the availability of more advanced techniques revealed markers of residual differentiation for the majority of these tumors; thus, MFH is not a distinct entity but rather a common histopathologic endpoint for several high-grade undifferentiated sarcomas and only such tumors that cannot be further subtyped, i.e., the pleomorphic MFH in the narrower sense, should be described as UPS1; notably, these very rare tumors are almost never cutaneous lesions.

Etiology and Pathogenesis

The pathogenesis of soft-tissue sarcomas in general and UPS, in particular, has not been well defined. Depending on the cells of origin, various genetic, physical, chemical, and viral etiologies have been suggested.

UPS may arise as a result of arrested maturation of tissue stem cells along the recently proposed differentiation spectrum from the fibroblastic mesenchymal stem-like cell to the fibroblast-myofibroblast-pericyte. It is possible that residual tumor stem cells that persist after treatment could have a role in progression or relapse, with implications for new therapeutic strategies.

Clinical Findings

UPS is almost never a cutaneous tumor. The skin may be involved as a result of direct extension or metastasis. About 15% of UPS cases are found in the subcutaneous tissue, the remaining majority of cases arise from the deeper soft tissues.

Histopathology and Immunohistochemistry

The most common appearance of tumor cells in UPS is that of spindle cells in a storiform pattern. The stroma may be finely fibrillary, myxoid, or densely collagenous. Bizarre epithelioid and giant cells may be present and may contain small amounts of lipid. Many mitotic figures, bizarre giant cells, and necroses are common. Ultrastructurally, the neoplastic cells have features consistent with fibroblastic, myofibroblastic, and histiocytic differentiation.

IHC using a broad antibody panel is required to rule out metastatic carcinoma, lymphoma, pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma, high-grade leiomyosarcoma, defifferentiated liposarcoma, melanoma, and similar lesions. UPS is characterized by negative immunostains for EMA, cytokeratins, CD34, SMA, desmin, and HMB45. Among stem cell markers, CD117 and occasionally nestin may be expressed.

Prognosis, Clinical Course, and Treatment

Up to 50% of patients presenting with an UPS may have distant metastases (lung most likely). UPS should be treated in analogy to other poorly differentiated sarcomas. When the disease appears localized, treatment is based on the prognosis. In general, small low-grade tumors with wide pathologically negative margins can be treated with surgery alone. Large or high-grade lesions may benefit from radiotherapy with a reduction in the incidence of local recurrence but with no benefit in overall survival (OS). Chemotherapy may be used before surgery to try to shrink the lesion, and after surgery to try to prevent its recurrence.

Although with rare exceptions metastatic UPS is incurable, substantial benefit can be derived from the appropriate use of chemotherapy or local control measures including surgery, radiotherapy, and other interventional techniques.

Epidemiology

ES is a relatively rare soft-tissue sarcoma of unknown histogenesis accounting for <1% of all soft-tissue sarcomas. ES is a slow-growing tumor with a seemingly benign pathomorphologic appearance due to which it is often misdiagnosed. The tumor may develop at any age with a peak in young adults and more frequently in males. A higher than usual proportion (i.e., one-fourth) of cases has been associated with prior trauma, including origin in scar tissue.

Etiology and Pathogenesis

The etiology and histogenesis of ES is obscure; in the current World Health Organization classification, ES is categorized as a tumor of uncertain differentiation and described as being of unknown lineage. The reported histomorphology and immunophenotype, however, suggest a mesenchymal neoplasm with multidirectional differentiation, including epithelial, histiocytic, fibroblastic, myofibroblastic, endothelial, and perineural differentiation.

There are no consistent or specific cytogenetic findings in ES. Some tumors are diploid and others polyploid. Abnormalities involving 18q11 and 22q11 (including 22q deletions) have been observed. Furthermore, chromosomal rearrangements t(8;22)(q22;q11) in classic ES and t(10;22) in two cases of proximal ES have been described. Additionally, inactivation of a tumor-suppressor gene Smarcb1, located at band 22q11, has been found in a subgroup of ES, i.e., the proximal type. Inactivating mutations in the Smarcb1 gene are a hallmark of rhabdoid tumors, i.e., especially lethal cancers that predominantly strike young children. SMARCB1 was the first member of an ATPase chromatin-remodeling complex to be implicated in the genesis of cancer. SMARCB1 loss causes cell-cycle progression in part via downregulation of p16INK4a and upregulation of E2F and Cyclin D. Heterozygous Smarcb1 knockout mice are born at the expected frequency and appear normal, but are predisposed to cancer with approximately 20% developing sarcomas at a median age of 12 months.

Clinical Findings

Clinically, ES usually presents as a painless, slow-growing, firm tumor. While most tumors are situated in the subcutaneous fat and fascia, some may arise in the dermis.11 When the skin is involved, one or more slowly growing nodules are seen, often accompanied by superficial ulceration, hemorrhage, necrosis, and plaques. Ulcerating ES lesions have raised margins and are nonhealing (Fig. 125-4). Deeper ES lesions can extend along tendon sheaths or aponeuroses. In any case the tumor may grow to a large size, up to 20 cm in diameter. The usual presentation is with symptoms of an infiltrative mass. Often, there is a delay in diagnosis due to the rare nature of this tumor and the resemblance to more common inflammatory skin lesions, such as granuloma anulare (Box 125-1).

ES can be differentiated by histology into two subtypes: classical and proximal ES (see below for details). Classic ES usually involves the extremities of young adults most often localized on the hands and fingers; whereas the proximal subtype occurs mainly in axial or proximal regions, including limb girdles, pelvis, perineum, or genitalia, mediastinum, and trunk. However, the classic and proximal types can each occur in either proximal or distal locations.

Histopathology and Immunohistochemistry

The histopathological diagnosis of ES can be quite difficult, as a superficial biopsy may only show necrobiosis or granulomatous inflammation, thereby mimicking infectious processes or granuloma anulare.

The tumor forms nodules composed of relatively uniform polygonal cells, often with loss of cohesion, which merge in the periphery into spindle cells without demarcation. The cells have relatively abundant deeply eosinophilic cytoplasm; mitotic figures are rare and only minimal pleomorphism is evident. Stromal changes include desmoplasia with cords of bland spindle cells sometimes with storiform pattern. The nodules frequently have central necrosis; hemorrhage is frequently observed.11

The proximal variant is characterized by marked cytologic atypia, frequent mitosis, vascular invasion, and absence of a granulomatous appearance. The tumor cells are large epithelioid and may mimic a carcinoma, furthermore, cells with a rhabdoid morphology can be seen. Rarely, tumors have features of both the classic and proximal variants. Notably, both variants can each occur in either proximal or distal locations.

Although there are several reported immunohistochemical studies on ES, a specific tumor marker for the diagnosis of this tumor has not yet been established. Most cases coexpress cytokeratins (particularly CK8, 14, and 19), EMA, and vimentin, but a few cases are vimentin-negative. CD34 staining is positive in more than half of ES; other endothelial markers such as CD31, however, are usually negative. SMA and neurofilament are often positive, especially in the spindle cells. Most cases are negative for S100. Recently, loss of INI-1 expression has been proposed to be of diagnostic benefit.12

Prognosis, Clinical Course, and Treatment

Because the classic location of ES on distal extremities often discourages early deep biopsy, and because ES may closely mimic various nonneoplastic lesions histologically such as granuloma anulare, it often evades diagnosis at an early, localized stage.

ES is an aggressive neoplasm, and the rate of local recurrence is very high, often with successive lesions appearing more proximally; distant metastases of ES are frequent. In the large series of Chase and Enzinger assessing 202 cases with follow-up, 77% recurred, and 45% metastasized, predominantly to the lungs (51%), local lymph nodes (34%), skin, bone, brain, liver, and pleura. Metastases developed in 36% of patients without local recurrence.11 The median OS of about 7 years for patients with localized disease, but only just months for patients with distant metastases. Adverse prognostic factors include proximal subtype, amount of necrosis and vascular invasion, and inadequate excision. Favorable factors are young age at first diagnosis, female sex, and small size of tumor.

Radical excision traditionally with clear margins has been the treatment of choice, but recurrences occur even with amputation. Conservative (limb-sparing) surgery combined with preoperative or postoperative radiation therapy has been tried, with results comparable with those reported for radical amputation.

For metastatic disease systemic chemotherapy is indicated. Of the chemotherapeutic agents that have been used to treat ES, the two currently most often used are doxorubicin and ifosfamide; the use of gemcitabine is also increasing. These drugs alone or in combinations were shown to elicit limited but distinct response rates ranging from <10% to >30%.