(1)
Department of Pathology, University of Manitoba Max Rady College of Medicine, Winnipeg, MB, Canada
Keywords
Alveolar soft part sarcomaDesmoplastic small round cell tumorEpithelioid sarcomaEwing SarcomaExtrarenal rhabdoid tumorExtraskeletal myxoid chondrosarcomaHemosiderotic fibrolipomatous tumorIntramuscular myxomaMyoepitheliomaPerivascular epithelioid cell neoplasm (PEComa)Undifferentiated high-grade pleomorphic sarcomaAlthough numerous soft tissue neoplasms resemble various connective tissues in the body, some have no identifiable histologic counterpart. Like other diagnostic groups, the behavior of tumors of uncertain differentiation varies from benign to highly malignant. Repetitive genetic aberrations are frequent among these neoplasms and can be used for diagnostic purposes.
12.1 Intramuscular Myxoma
Intramuscular myxoma is a benign neoplasm that most frequently occurs as a well-delineated and deeply situated mass in the thigh. It arises in adults in the fifth to seventh decade of life, and some patients note symptoms of pain or tenderness [1, 2]. Patients with Mazabraud syndrome have a combination of multiple intramuscular myxomas and fibrous dysplasia of the bone [3].
Pathology
Microscopically, these tumors show abundant background myxoid substance that contains scattered stellate cells with small, bland nuclei (Figs. 12.1 and 12.2). Macrophages containing mucinous material can sometimes be seen [4].
Fig. 12.1
Skeletal muscle fibers surrounded and dissected by intramuscular myxoma
Fig. 12.2
Intramuscular myxoma with occasional cells with small and stellate nuclei
Ancillary Studies
The diagnosis is primarily based on histologic features.
The majority of intramuscular myxomas contain mutations in the GNAS1 gene [5].
Differential Diagnosis
Myxoid liposarcoma
Myxofibrosarcoma
Low-grade fibromyxoid sarcoma
Comment
- 1.
Intramuscular myxomas can have similar features with other myxoid tumors, such as myxofibrosarcoma, myxoid liposarcoma, and low-grade fibromyxoid sarcoma.
- 2.
Myxoid liposarcoma has a more conspicuous interconnecting “chicken wire” capillary network with scattered lipoblasts.
- 3.
Myxofibrosarcoma contains more atypical mesenchymal cells with nuclear hyperchromasia that are associated with curvilinear vessels.
- 4.
Low-grade fibromyxoid sarcoma shows a more organized pattern of alternating fibrous and myxoid stroma and is positive for a MUC4 immunohistochemical stain.
- 5.
Given limited material, the diagnosis of intramuscular myxoma on a needle core biopsy can be difficult. A descriptive interpretation of “low-grade myxoid neoplasm” is sometimes made.
- 6.
Intramuscular myxoma is a benign neoplasm. Surgical excision is generally curative [4].
12.2 Superficial Angiomyxoma
Superficial angiomyxomas present as polypoid or nodular lesions in the dermis of the head and neck, trunk, or lower limbs in children and adults [6]. The majority of these lesions measure from 1 to 5 cm in greatest dimension [7]. They are morphologically identical to the myxomas in Carney syndrome , a condition associated with endocrine overactivity, spotty pigmentation, and multiple myxomas [8].
Pathology
Superficial angiomyxomas often have a multinodular architecture and contain a myxoid background with bland-appearing stromal cells (Fig. 12.3). Small to medium delicate blood vessels course through the lesion, and scattered associated neutrophils and lymphocytes can be seen (Fig. 12.4). Some angiomyxomas are associated with an epidermoid cyst [7].
Fig. 12.3
Superficial angiomyxoma with conspicuous blood vessels in the background of myxoid material
Fig. 12.4
(a) Superficial angiomyxoma with small blood vessels (arrow) (b) Higher power examination of these vessels reveals associated scattered neutrophils (arrow)
Differential Diagnosis
Superficial acral fibromxyoma
Myxofibrosarcoma
Myxoid liposarcoma
Comment
- 1.
Superficial angiomyxoma should be distinguished from other myxomatous neoplasms that occur in the extremities, such as myxoid liposarcoma, superficial acral fibromyxoma, and myxofibrosarcoma.
- 2.
Superficial acral fibromyxomas are confined to the distal extremities and lack the associated inflammatory infiltrate of superficial angiomyxoma.
- 3.
Myxofibrosarcoma contains mesenchymal cells with more nuclear atypia.
- 4.
Myxoid liposarcoma arises in the deep soft tissue of the extremities, has scattered lipoblasts, and manifests highly specific translocations involving the DDIT3 gene.
- 5.
12.3 Hemosiderotic Fibrolipomatous Tumor
Hemosiderotic fibrolipomatous tumor (HFLT) is a lesion that often arises in the subcutaneous tissue around the ankles of adult women, most commonly in the fifth decade of life. Prior to pathologic examination, these can be mistaken for lipomas or ganglion cysts [10–12].
Pathology
Under the microscope, HFLT shows background adipocytic tissue that is traversed by fibrous septa containing bland-appearing spindle cells (Fig. 12.5). Associated lymphocytes, mast cells, and hemosiderin deposition are typically seen (Fig. 12.6). Small to medium sized blood vessels with thickened walls typically course through the fat as well.
Fig. 12.5
Hemosiderotic fibrolipomatous tumor with adipose tissue that is traversed by bands of fibrous tissue
Fig. 12.6
High-power examination of this hemosiderotic fibrolipomatous tumor shows deposition of golden–brown hemosiderin pigment
Ancillary Studies
The spindle cells are positive for a CD34 immunohistochemical stain.
Differential Diagnosis
Dermatofibrosarcoma protuberans
Fibrous histiocytoma
Pleomorphic hyalinizing angiectatic tumor
Comment
- 1.
Hemosiderotic fibrolipomatous tumor can resemble fibrous and fibrohistiocytic tumors such as dermatofibrosarcoma protuberans, fibrous histiocytoma, and pleomorphic hyalinizing angiectatic tumor.
- 2.
The spindle cells in dermatofibrosarcoma exhibit a whorling pattern and entrap the surrounding adipose tissue in a “honeycomb” pattern.
- 3.
Fibrous histiocytoma does not demonstrate the septated pattern of hemosiderotic fibrolipomatous tumor.
- 4.
Hemosiderotic fibrolipomatous tumors share morphologic and cytogenetic features with pleomorphic hyalinizing angiectatic tumor and are suspected to be related lesions [14].
- 5.
12.4 Myoepithelioma of Soft Tissue
Myoepitheliomas of the soft tissue occur in children and adults over a broad age range. They often arise in the extremities or the head and neck area. These can be infiltrative or well circumscribed and measure up to 20 cm in size [16, 17].
Pathology
Myoepitheliomas display a wide variety of morphologic appearances. The myoepithelial cells can appear as epithelioid, ovoid, or spindle cells that are arranged in sheets, clusters, cords, or interconnected strands (Fig. 12.7a, b). Benign myoepitheliomas contain bland appearing nuclei while malignant ones contain either hyperchromatic or vesicular nuclei and prominent nucleoli (Fig. 12.8).
Fig. 12.7
(a) Myoepithelioma of soft tissue with epithelioid cells. (b) Myoepithelioma with an interconnected network of more spindled cells
Fig. 12.8
Malignant myoepithelioma of soft tissue with vesicular nuclei and prominent nucleoli
Ancillary Studies
Differential Diagnosis
Ossifying fibromyxoid tumor
Extraskeletal chordoma
Extraskeletal myxoid chondrosarcoma
Comments
- 1.
Given their highly variable appearance, myoepitheliomas can mimic many types of neoplasms. Common considerations include extraskeletal myxoid chondrosarcoma, extraskeletal chordoma, and ossifying fibromyxoid tumor.
- 2.
Ossifying fibromyxoid tumor has ovoid cells but usually has at least a partial peripheral shell of bone surrounding the lesion.
- 3.
Cells in a chordoma can have a similar appearance to some myoepithelial tumors. Unlike soft tissue myoepithelioma, chordomas rarely arise in the peripheral soft tissue and are positive for a brachyury immunohistochemical stain.
- 4.
Extraskeletal myxoid chondrosarcoma also demonstrates rearrangements involving the EWSR1 gene; however, these tumors have different partner genes (e.g. NR4A3) than myoepithelioma.
- 5.
The behavior of soft tissue myoepithelioma is difficult to predict.
- 6.
Of myoepithelial tumors that appeared histologically benign, 18% recurred locally and none metastasized [17].
- 7.
Of myoepithelial tumors that had histologically malignant features, 42% recurred locally and 32% metastasized [17].
- 8.
Complete surgical excision is the primary treatment for these tumors [12].
12.5 Ossifying Fibromyxoid Tumor
Ossifying fibromyxoid tumors arise in the subcutaneous tissue or muscle in the upper and lower extremities and head and neck region. These occur in adults with a median age of presentation of 50 years. They are typically painless and develop slowly [20].
Pathology
Ossifying fibromyxoid tumors are composed of round to oval cells with vesicular nuclei that are arranged in a linear or reticular pattern (Fig. 12.9a). On closer examination, the tumor cells contain bland nuclei and are in the background of a fine collagenous or myxoid stroma (Fig. 12.9b). A partial shell of mature bone often surrounds the lesion (Fig. 12.10).
Fig. 12.9
(a) Ossifying fibromyxoid tumor with a cord-like and reticular arrangement of ovoid cells. (b) Neoplastic cells of ossifying fibromyxoid tumor with bland nuclei and fine collagen background
Fig. 12.10
Peripheral bone of an ossifying fibromyxoid tumor
Ancillary Studies
Differential Diagnosis
Myoepithelioma of soft tissue
Chondroid syringoma
Extraskeletal myxoid chondrosarcoma
Comment
- 1.
The cord-like arrangement of cells in ossifying fibromyxoid tumor can resemble patterns seen in extraskeletal myxoid chondrosarcoma, chondroid syringoma, or myoepithelioma of soft tissue.
- 2.
Unlike chondroid syringoma and myoepithelioma of soft tissue, ossifying fibromyxoid tumor only rarely expresses cytokeratins and usually has at least focal peripheral osteoid deposition.
- 3.
Extraskeletal myxoid chondrosarcoma typically has translocations involving the EWSR1 gene.
- 4.
Typical ossifying fibromyxoid tumor has a recurrence rate of 17% and a metastatic rate of 5% [23].
- 5.
Histologically malignant ossifying fibromyxoid tumors demonstrate high cellularity, increased mitoses (over 2 per 10 high power fields), and high nuclear grade [23].
- 6.
Malignant ossifying fibromyxoid tumors have a metastatic rate of 22% [21].
12.6 Alveolar Soft Part Sarcoma
Alveolar soft part sarcomais a malignant tumor that primarily arises in adolescents and young adults (median age of 22 years). The most common sites of occurrence include the buttock, leg, and trunk [24]. In younger patients, these can arise in the head and neck [25]. A subset of patients have metastasis at the time of diagnosis.
Pathology
Microscopically, these tumors are composed of nests of neoplastic cells with eosinophilic and granular cytoplasm. The central cells in these nests drop out, giving the tumor an alveolar appearance similar to lung tissue (Fig. 12.11). The nuclei of the tumor cells are enlarged and prominent nucleoli can be seen (Fig. 12.12).
Fig. 12.11
Nests of eosinophilic cells forming an alveolar architecture in this alveolar soft part sarcoma
Fig. 12.12
Neoplastic cells of an alveolar soft part sarcoma with enlarged nuclei and prominent nucleoli
Ancillary Studies
Differential Diagnosis
Granular cell tumor
Renal cell carcinoma
Comments
- 1.
Alveolar soft part sarcoma can be confused for other tumors with eosinophilic cytoplasm, such as granular cell tumor and renal cell carcinoma.
- 2.
Alveolar soft part sarcoma lacks the S100 staining seen in granular cell tumor and cytokeratin or PAX-8 staining seen in renal cell carcinoma.
- 3.
These tumors are aggressive from a long-term perspective. While the 5-year overall survival is 87%, the 20-year survival is 15%.
- 4.
- 5.
Treatment consists of radical surgical excision and possible radiotherapy and chemotherapy [9].
12.7 Clear Cell Sarcoma of Soft Tissue
Clear cell sarcoma is a malignant soft tissue tumor that arises in young adults at a median age of 30 years. These typically occur as slow-growing nodules in the foot, ankle, or hands and are intimately associated with a tendon [28, 29].
Pathology
Microscopically, these tumors are composed of bundles of spindle cells with eosinophilic to clear cytoplasm in the background of fibrotic stroma (Fig. 12.13). The cells contain enlarged vesicular nuclei and prominent nucleoli (Fig. 12.14). Scattered associated giant cells and melanin pigment can occasionally be seen.
Fig. 12.13
Clear cell sarcoma of soft tissue with vaguely spindle cells containing clear and eosinophilic cytoplasm
Fig. 12.14
The cells in this clear cell sarcoma contain large nuclei and prominent nucleoli
Ancillary Studies
Differential Diagnosis
Spindle cell or desmoplastic melanoma
Malignant peripheral nerve sheath tumor
Leiomyosarcoma
Comments
- 1.
Clear cell sarcoma of the soft tissue can be confused for other spindle cell neoplasms such as desmoplastic melanoma, leiomyosarcoma, or malignant peripheral nerve sheath tumor.
- 2.
The absence of an overlying skin lesion helps differentiate this lesion from a melanoma. Melanoma typically lacks mutations involving the EWSR1 gene.
- 3.
Malignant peripheral nerve sheath tumor demonstrates only focal (if any) S100 staining.
- 4.
Leiomyosarcoma lacks S100 staining and is positive for desmin and smooth muscle actin.
- 5.
Clear cell sarcoma is an aggressive tumor. Approximately 14% recur and 63% metastasize [29].
- 6.
The 5-year survival rate is approximately 66%. Complete surgical excision is the primary treatment, and radiation therapy has been used if the surgical margins are positive [28].
12.8 Extraskeletal Ewing Sarcoma
Ewing sarcoma is a malignancy that is usually associated with the bone; however, approximately 20% of these tumors will arise in extraskeletal locations such as the pelvis, thigh, paraspinal area, or foot [33, 34]. Most patients with Ewing sarcoma are between 5 and 20 years old, and the median occurrence is at 14 years of age [35].
Pathology
This tumor is a classic example of a “small round cell sarcoma.” Compared to other aggressive mesenchymal tumors, the cells are smaller in size and have a high nuclear to cytoplasmic ratio (Fig. 12.15). Sometimes this limited cytoplasm can have a clear appearance due to increased glycogen (Fig. 12.16). The cells are usually arranged in sheets but sometimes can be seen in a circular arrangement, termed a Homer-Wright rosettes [36].
Fig. 12.15
The high nuclear to cytoplasmic ratio of the tumor cells of this Ewing sarcoma can be confused for other malignancies, such as lymphoma
Fig. 12.16
The tumor cells of this Ewing sarcoma contain scattered clear cytoplasmic vacuolizations consistent with increased glycogen content (arrow)
Ancillary Studies
Differential Diagnosis
Rhabdomyosarcoma
Desmoplastic round cell tumor
Poorly differentiated synovial sarcoma
Comment
- 1.
Ewing sarcoma must be differentiated from other tumors that are composed of similar undifferentiated “small round cells,” such as rhabdomyosarcoma, desmoplastic synovial sarcoma, and poorly differentiated synovial sarcoma.
- 2.
Rhabdomyosarcoma typically expresses MyoD1 and myogenin, which is usually not seen in Ewing sarcoma.
- 3.
Desmoplastic round cell tumor contains a similar “small round cell” population, but these are usually positive for desmin.
- 4.
Unlike Ewing sarcoma, synovial sarcoma frequently expresses TLE-1 and has distinct translocations involving the SYT gene.
- 5.
Modern treatment consists of surgical resection and either radiotherapy or chemotherapy. Survival for localized tumors is approximately 75%. However, approximately 25% of patients have clinically identifiable metastasis at diagnosis [12, 39].
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