Pleomorphic Sarcomas

Clinical Features

AFX presents as a skin-colored nodular lesion in the head and neck area of older patients. The nodule is usually less than 2 cm in diameter, and frequently there is a history of rapid growth. Ulceration may be present, but is, in our experience, relatively uncommon.

Pathologic Features

Histologically, all cases of AFX are centered in the dermis, generally abutting the epidermis, although occasionally a grenz zone may be present. The lesion is usually well circumscribed, often polypoid, and the overlying epidermis may form a collarette around the tumor ( Fig. 7.1A and B ). AFX is a cellular neoplasm composed of a haphazard and/or fascicular arrangement of highly pleomorphic and spindle-shaped cells. Multinucleated giant cells with monomorphic or pleomorphic nuclei are frequently present. The cytoplasm is as a rule easily discernible, eosinophilic, or amphophilic, and may occasionally contain lipid droplets; variable amounts of clear cell change and granular cell change may rarely be present. Mitotic activity, including both typical and atypical mitotic figures, is generally marked (see Fig. 7.1C ). A spindle-cell (nonpleomorphic) variant of AFX characterized by a fascicular proliferation of spindle-shaped cells with pale eosinophilic cytoplasm and without an overtly pleomorphic component is recognized (see Fig. 7.1D ). AFX has an expansile growth pattern, frequently with a “pushing” border, and may be surrounded by a mononuclear inflammatory infiltrate. The overlying epidermis is normal, but when ulceration is present, the lesion often cannot be evaluated for the presence of epidermal dysplasia or junctional activity, important in excluding the differential diagnostic options of sarcomatoid (spindle-cell) carcinoma and melanoma. Invasion into subcutaneous fat (even minimal, or deeper) or the presence of necrosis, lymphovascular, or perineural invasion are not features of AFX and exclude AFX as a diagnostic consideration.

Immunohistochemistry

In addition to nonspecific staining for vimentin, the lesions are frequently positive for CD10 and characteristically show strong, diffuse staining for p53 (see Fig. 7.1E ), although, in our experience, a very small number of otherwise typical examples of AFX (<5%) do not stain for p53. Weak positivity for smooth muscle actin may focally be present. Most importantly, S-100 protein and keratins are negative.

Molecular Genetics

Ultraviolet light–induced TP53 mutations, and, more recently, ultraviolet light–induced TERT promoter mutations, all supporting a sun exposure–induced etiology, have been identified in AFX.

Differential Diagnosis

The differential diagnosis includes primarily spindle-cell (sarcomatoid) carcinoma, melanoma, atypical intradermal smooth muscle tumor, and cutaneous involvement by (metastatic) leiomyosarcoma, which may all exhibit a pleomorphic and spindle-cell appearance. Diligent clinical correlation (to exclude metastatic disease from a known or unknown primary lesion elsewhere), together with an appropriate immunohistochemical panel, including several keratins, melanoma markers, smooth muscle actin, and desmin, is generally sufficient to reach the correct diagnosis. Lesions otherwise typical of AFX but characterized by infiltration into subcutaneous fat, necrosis, lymphovascular, or perineural invasion, all predictive of aggressive behavior including (distant) metastases, are best classified as pleomorphic dermal sarcoma, not otherwise specified. Therefore the diagnosis of AFX cannot be rendered based on superficial (shave) biopsies, where the base of the lesion cannot be visualized. In such samples, the interim designation atypical intradermal spindle-cell/pleomorphic neoplasm , with a comment recommending complete excision prior to definite diagnosis, is appropriate.

Prognosis and Treatment

Surgical excision with free margins is curative. Although there is some debate as to whether AFX is benign, if the previously mentioned criteria are strictly applied, AFX behaves in a benign manner with a risk of local recurrence if incompletely excised. There are rare reports of AFX with metastases, but such cases are often incompletely illustrated for optimal evaluation of the minimal diagnostic criteria for AFX (discussed earlier), or stem from the pre- and early immunohistochemistry era (without or with inadequate immunohistochemical workup). Consequently, these lesions may not represent typical AFX and possibly include malignant nonmesenchymal tumors such as poorly differentiated and sarcomatoid carcinoma and amelanotic melanoma. A very recent and more convincing study of putative AFX with (distant) metastases has been published; nevertheless, the conclusions need to be interpreted with caution, and further studies are required to support the validity of these findings.

Clinical Features

Undifferentiated sarcomas as a whole probably account for 5% to 10% of sarcomas in adults older than 40 years of age. These tumors generally arise in the deep (subfascial) soft tissues of older patients (in the sixth decade and older). They have a predilection for the extremities (lower limbs), followed by the trunk, and a small proportion (no more than 10%) arise in the subcutaneous tissues and retroperitoneum.

Pathologic Features

Grossly, the tumors vary in size from 5 to 15 cm, are usually firm with a grayish color, are usually well circumscribed (with or without a pseudocapsule derived from adjacent compressed tissue) but may show infiltrative margins, and frequently contain visible areas of necrosis and/or hemorrhage ( Fig. 7.3 ). Histologically, tumors are composed of a haphazard, storiform, fascicular, or nested arrangement of predominantly or variably highly pleomorphic, spindle-shaped, epithelioid or round cells, with a variable amount of eosinophilic or amphophilic cytoplasm and numerous typical and atypical mitoses. Stroma is usually collagenous with or without an inflammatory infiltrate and occasionally (osteoclastic) giant cells may be prominent ( Fig. 7.4 ). Ancillary ultrastructural studies are, by definition, not helpful in identifying a particular line of differentiation.

Immunohistochemistry

Usually only the nonspecific marker vimentin is convincingly positive. The degree of immunohistochemical positivity required to define a particular line of differentiation remains a controversial issue in soft tissue pathology, although generally one requires more than just rare positive cells for an immunohistochemical marker to support specific differentiation ( Table 7.3 ).

Molecular Genetics

Cytogenetically, karyotypes are usually highly complex and nonspecific ( Table 7.4 ).

Differential Diagnosis

The differential diagnosis includes (metastatic) sarcomatoid carcinoma, (metastatic) melanoma, anaplastic large-cell lymphoma, and other high-grade pleomorphic sarcomas (high-grade myxofibrosarcoma, pleomorphic leiomyosarcoma, pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma, DDLPS, and malignant peripheral nerve sheath tumor [MPNST] without or with heterologous rhabdomyoblastic differentiation [malignant triton tumor]). The clinical context and an appropriate immunohistochemical panel usually resolve any diagnostic dilemmas in the distinction from carcinoma, melanoma, and lymphoma (see Table 7.1 ). Generous sampling and the judicious use of immunohistochemistry (see Table 7.3 ) should facilitate the identification of foci with myogenic or neurogenic features (leiomyosarcoma/rhabdomyosarcoma or MPNST), lipoblasts (pleomorphic liposarcoma), contiguous foci of atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDLPS), or areas with myxoid stroma and curvilinear vessels (myxofibrosarcoma). Because undifferentiated (high-grade) sarcoma remains a diagnosis of exclusion (as detailed previously), extensive sampling is mandatory in order to maximize the chance of identifying a (histologically, immunohistochemically, or ultrastructurally) recognizable line of differentiation, facilitating accurate and clinically useful classification.

Prognosis and Treatment

Wide surgical excision with free margins and adjuvant radiotherapy is the primary therapeutic modality of choice. Prognostically, tumors are usually high grade, have distant metastases at presentation in 5% to 10% of cases, and have a 5-year survival of 50% to 60%. Tumor size, tumor depth, grade, the presence of necrosis, and local recurrence appear to correlate with metastatic rate and survival, although these do not per se appear to be independent variables for the prediction of outcomes.

The importance of maximizing efforts in accurate classification becomes apparent when one realizes that DDLPS has a 5-year metastatic rate of only 15% to 20%, compared with a 5-year metastatic rate of 30% to 35% for high-grade myxofibrosarcoma, and a far higher 5-year metastatic rate (>60%), together with a significantly inferior relapse-free survival rate, for pleomorphic leiomyosarcoma and rhabdomyosarcoma.

Clinical Features

PHAT is a rare tumor occurring in adults (age range 10 to 80 years; median age 50 years) with an equal gender distribution. It arises primarily in the subcutaneous tissues of the lower limbs and less frequently at other sites. Patients usually present with a slowly enlarging painless swelling, which not infrequently has been present for a long period of time before medical attention is sought.

Pathologic Features

Grossly, tumors are usually poorly circumscribed with infiltrative margins and vary in size from less than 1 cm to more than 10 cm in diameter, with an average size of 3 to 4 cm. On sectioning, tumors are grayish-brown to tan in color, depending on the extent of intralesional vascularity and hemosiderin deposition. Histologically, clusters of thin-walled ectatic vessels, which may be either hyalinized or show extensive fibrinoid change involving the full thickness of the vessel wall, frequently with intraluminal thrombosis, are prominent ( Fig. 7.5A and B ). The stromal cells vary from being spindle-shaped to highly pleomorphic with bizarre, hyperchromatic nuclei often containing intranuclear pseudoinclusions (derived from the cytoplasm; see Fig. 7.5C and D ). Mitoses are scarce, usually less than 1 per 50 high-power fields, and any increase in mitotic activity is generally regarded as not being compatible with a diagnosis of PHAT. A variable inflammatory infiltrate composed of eosinophils, lymphocytes, and plasma cells is usually present, and deposits of hemosiderin may occasionally be prominent. Importantly, in a number of cases of putative PHAT, primarily in peripheral regions of the tumor, variably cellular areas composed of hemosiderin-laden spindle-shaped cells with wavy nuclei and a fascicular orientation morphologically similar to HFLT are present, infiltrating adjacent fat, while cases of putative PHAT with morphologic overlap with MIFS have also been reported, supporting grounds for a morphologic continuum within these three entities.

Ancillary ultrastructural studies to date have not been of help in identifying a line of differentiation.

Immunohistochemistry

The neoplastic cells do not demonstrate a specific immunohistochemical profile. Lesional cells are positive for CD34 in roughly half of cases, but they are negative for S-100 protein, important in the distinction from “ancient” schwannoma.

Molecular Genetics

At a cytogenetic level, a variety of molecular alterations have been identified in PHAT, some of which (primarily a t[1;10]) appear to be shared (to a limited extent) with MIFS and HFLT, and consequently additional data are required to define the exact nature of the relationship between these three entities.

Differential Diagnosis

The differential diagnosis primarily includes ancient schwannoma and a hemangioma with degenerative changes (symplastic hemangioma). The immunohistochemical negativity for S-100 protein excludes schwannoma, whereas the presence of a vascular component intimately associated with obviously atypical stromal cells argues against a vascular lesion.

As a result of the increasing recognition and awareness of overlapping morphologic and cytogenetic features between PHAT, HFLT, and MIFS, although still preliminary, experts are beginning to believe that PHAT, HFLT, and MIFS may fall within one morphologic spectrum.

Prognosis and Treatment

Wide surgical excision with free margins is the primary therapeutic modality of choice. Typical cases of PHAT are characterized primarily by nondestructive local recurrences, although longer-term follow-up data are needed to determine more accurately the exact biologic behavior of this entity; if indeed there is a biologic continuum with MIFS (which may show high-grade progression, as discussed later) and HFLT, this will have implications for treatment and follow-up guidelines.