Part 2 book “Biopsy interpretation series biopsy interpretation of soft tissue tumors” has contents: Soft tissue lesions with clear or granular cells, small round cell tumors, deep vascular tumors, superficial vascular lesions and mimics, myxoid tumors of deep soft tissue, plexiform soft tissue tumors,… and other contents.
12 SOFT TISSUE LESIONS WITH CLEAR OR GRANULAR CELLS INTRODUCTION Clear cell change can be seen in some examples of myoepithelioma (Chapter 6), smooth muscle tumors (Chapter 7), atypical fibroxanthoma (Chapter 13), Ewing sarcoma (Chapter 14), rhabdomyosarcoma (Chapter 14), and gastrointestinal stromal tumor (Chapter 5) Tumors in which clear cell change can be predominant include glomus tumor (Chapter 7), alveolar soft part sarcoma, clear cell sarcoma, PEComa, and paraganglioma, as well as metastases from other organs including carcinomas Lesions with lipoblastic and pseudolipoblastic differentiation can also enter the differential diagnosis and are discussed in Chapter 15 Granular cell or oncocytic change is seen in granular cell tumor, and in some examples of hibernoma (Chapter 15), myoepithelioma (Chapter 7), smooth muscle tumors (Chapter 6), nerve sheath tumors (Chapter 9), dermatofibroma (Chapter 4), dermatofibrosarcoma protuberans (Chapter 4), atypical fibroxanthoma (Chapter 13), and benign and malignant PEComas Finally, reactive and neoplastic histiocytic proliferations can present in soft tissue as clear or granular cell tumors The differential diagnoses are summarized in Tables 12.1 and 12.2 CLEAR CELL SARCOMA OF SOFT TISSUE Clinical Features This is a tumor of young adults (more often in females) that arises predominantly in the extremities, especially the foot and rarely in trunk or head and neck sites as a slowly growing firm mass The usual location is deep subcutaneous or subfascial tissue, often with involvement of tendon sheath or aponeurosis This is an aggressive neoplasm that metastasizes to lymph node, lung and bone, with survival rates of 67%, 33%, and 10% after 5, 10, and 15 years, respectively.1,2 A genetically distinct subset of clear cell sarcoma arises in the gastrointestinal tract, where it presents with obstruction, bleeding, or mass effect Neither subtype is related to clear cell sarcoma of kidney 256 Epidermal hyperplasia, areas of typical dermatofibroma, peripheral collagen bundles Raised firm nodule on extremities, young adults Sun-exposed areas, elderly patients Subcutaneous welldemarcated nodule, any age Extremities especially lower limb, young adults In subcutis or deeper tissue, it involves tendons Subset in GI tract Subcutaneous in adults, especially in head and neck sites Also in various organs Clear cell cutaneous fibrous histiocytoma Clear cell atypical fibroxanthoma Ossifying fibromyxoid tumor Clear cell sarcoma (soft tissue) Granular cell tumor (Continued) S100 protein+, HMB45+ and melan-A+ (except in GI tract), other markers negative t(12;22) (q13;q12), EWSR1-ATF1 or t (2;22)(q33;q12), EWSR1-CREB1 (mostly GI cases) S100 protein+, CD68+, CEA+ Nested pattern, round nuclei with central nucleolus, clear or granular cytoplasm, sometimes spindling, multinucleated cells, melanin pigment No junctional activity Infiltrative sheets and cords of large polygonal cells, coarsely granular cytoplasm Clear cell areas often present also S100 protein+, GFAP+, desmin/SMA+ in some, rarely CK+ CD10+ in some cases, S100 protein–, HMB45–, melan-A–, desmin–, AE1/3– CK–, SMA–, desmin–, S100 protein– Ancillary Investigations Partial shell of bone in many, thick fibrous capsule, cords of rounded glomus-like or occasionally spindled cells, fibromyxoid stroma Atypical variant can have increased cellularity, mitoses, intralesional osteoid Sheets of clear cells with pleomorphic nuclei, and prominent cell membranes Microscopic Features Typical Clinical Features TABLE 12.1 Differential Diagnosis of Clear Cell and Granular Cell Tumors SOFT TISSUE LESIONS WITH CLEAR OR GRANULAR CELLS 257 Childhood or adult Single mass or multicentric Mesenteric, retroperitoneal, other sites Alveolar soft part sarcoma TFE3+, desmin+ t(X;11) (p11;q25) TFE3-ASPL Adult females, extremities, dermal nodule Paraganglioma-like dermal melanocytic tumor Nests of large polygonal cells with uniform vesicular nuclei and clear or finely granular cytoplasm A solid pattern of closely packed nests is sometimes seen especially in childhood cases CD56+, NF+, SYN+, CG+ S100 protein+ in sustentacular cells Nests of ovoid cells with clear or granular cytoplasm and variable nuclear pleomorphism Prominent or sinusoidal thin-walled blood vessels, sometimes fibrosis In locations of paraganglia—carotid body, base of skull, mediastinum, retroperitoneum Some are functional— hypertension, vagal symptoms Paraganglioma S100 protein+, HMB45+, melan-A± SMA+, desmin+, h-caldesmon+, S100 protein– Granular cell areas within epithelioid or spindle cell smooth muscle tumor Rare focal change in smooth muscle tumors of soft tissue or gynecologic origin Granular cell leiomyoma Circumscribed or infiltrative, can extend into subcutis Nests of cells within slender fibrous septa, uniform rounded nuclei, small nucleoli, abundant clear or amphophilic cytoplasm CD34+, S100 protein– Sheets of granular cells involving dermis and superficial subcutis Areas of typical dermatofibrosarcoma usually present, with transitional forms Like typical dermatofibrosarcoma Granular cell dermatofibrosarcoma Ancillary Investigations Microscopic Features Typical Clinical Features TABLE 12.1 Differential Diagnosis of Clear Cell and Granular Cell Tumors (Continued) 258 BIOPSY INTERPRETATION OF SOFT TISSUE TUMORS Adult or fetal (median: y) type in head and neck, or (mostly female) genital tract locations Also cardiac rhabdomyoma (adult type) Intra-abdominal, soft tissue or gynecologic locations Mainly in sacrum/coccyx, or skull base, rarely other vertebrae Can extend into adjacent tissues as tumor mass F > M Gynecologic sites Retroperitoneum, bowel wall or wall of vessel including IVC, renal vein Related to wall of any part of alimentary tract (most commonly stomach, small intestine), Also, in retroperitoneum, omentum Rhabdomyoma PEComa (other than organ-specific subtypes) Chordoma Epithelioid leiomyosarcoma Epithelioid gastrointestinal stromal tumor S100 protein+, CK+, EMA+, brachyury+ SMA+, desmin+, h-caldesmon+, CD117– Some HMB45+ CD117+, DOG1+, CD34+, h-caldesmon+ SMA variable, desmin+ rarely, S100 protein+ rarely CK sometimes+ after therapy KIT or PDGFRA mutations Cords and nests of polygonal cells with eosinophilic cytoplasm, resembling adenocarcinoma Larger vacuolated (physaliferous) cells Can have areas of dedifferentiation Sheets of polygonal cells with clear or finely granular cytoplasm Not usually pleomorphic Typical spindle cell areas can coexist Sheets of clear or epithelioid cells often with a focal spindle component Organoid pattern, plasmacytoid or rhabdoid change can be seen (Continued) SMA+, HMB45+, melan-A+, desmin+ in some, CD117+ in some, S100 protein+ rarely, TFE3+ in some, Cathepsin-K in some Desmin+, myogenin+ (in nuclei), MyoD1+ (in nuclei) Nests of ovoid or spindled cells with clear or granular cytoplasm, delicate fibrous septa Malignant variants often epithelioid with large polygonal cells, pleomorphism, mitoses, necrosis Sheets of large polygonal cells with abundant eosinophilic cytoplasm Fetal rhabdomyoma has long spindle cells in myxoid stroma (immature type) or spindled and round cells with variable skeletal muscle differentiation (intermediate type) SOFT TISSUE LESIONS WITH CLEAR OR GRANULAR CELLS 259 Origin in kidney, can present as metastasis Origin in adrenal gland Can be functioning or nonfunctioning Renal cell carcinoma Adrenal cortical carcinoma Sheets of clear or granular cells with small nuclei and occasional pleomorphism Lacks sinusoidal vascular pattern Inhibin+, melan-A+, CD56+, CK usually negative CK+, EMA+, RCCpositive, CD117 (oncocytoma), vimentin (chromophobe carcinoma) S100 protein+, AE1/3+, melan-A+, SMA+ Sheets of clear or granular cells, pleomorphic lipoblasts Usually focal, more typical pleomorphic liposarcoma elsewhere Deep soft tissue, extremities, rarely retroperitoneum, rarely subcutis Epithelioid pleomorphic liposarcoma Clear or granular cells in sheets, or adenopapillary formations Variable nuclear grade Can have sarcomatoid change with divergent differentiation Ancillary Investigations Microscopic Features Typical Clinical Features TABLE 12.1 Differential Diagnosis of Clear Cell and Granular Cell Tumors (Continued) 260 BIOPSY INTERPRETATION OF SOFT TISSUE TUMORS Skin or subcutis, rarely associated with tendon sheath or joint synovium Hyperlipidemia or normolipidemia Dermal nodule, extremities or trunk, young adults Children or young adults Lymph node or soft tissue mass Epithelioid benign cutaneous fibrous histiocytoma Rosai-Dorfman disease Reticulohistiocytoma Solitary cutaneous or multicentric reticulohistiocytosis affecting skin and synovium of joints Xanthoma lymphocytes, mild or moderate focal nuclear enlargement and hyperchromasia Admixed plasma cells, lymphocytes Large cells with abundant clear cytoplasm, phagocytosis of Overlying epidermal hyperplasia, bland plump cells, sometimes spindle component, peripheral collagen bundles, lymphocytic infiltrate (Continued) S100 protein+, CD68+, CD1a– SMA+, CD34–, S100 protein–, desmin− Multinucleated giant cells predominate, with PAS+ (diastase resistant) plump histiocytes and mixed inflammatory CD68+, CD163+, cells MiTF+ (nuclear) in some Circumscribed or diffuse, sheets of foamy lipid-laden macrophages, variable admixture of siderophages, cholesterol clefts with giant cells, fibrosis Infants or young children, trunk, Monotonous sheets of macrophages, intramuscular occasional foamy or multinucleated cells Juvenile xanthogranuloma, deep CD68+, S100 protein–, CD1a– Infiltrative dermal lesion Sheets of CD68+, CD163+, S100 histiocytes Older lesions have more foamy protein–, CD1a– cells and more Touton giant cells Infants, head and neck, trunk, proximal limbs Yellow-brown plaque or nodule Juvenile xanthogranuloma, cutaneous Ancillary Investigations Microscopic Features Typical Clinical Features TABLE 12.2 Differential Diagnosis of Histiocytic Tumors in Soft Tissue SOFT TISSUE LESIONS WITH CLEAR OR GRANULAR CELLS 261 History of injection or implant, with recent change Lumpy swelling History of urinary tract infection Can form perinephric mass Related to surgery, often hip joint replacement Silicone granuloma Malakoplakia Granular histiocytic reaction S100 protein+, CD1a+, langerin+ CD68+ in some Birbeck granules on EM Sheets of ovoid cells with folded or grooved nuclei, no nucleoli Admixed eosinophils Nodules and sheets of histiocytes with granular, eosinophilic cytoplasm infiltrate fat Sometimes adjacent amorphous foreign material Sheets of discohesive polygonal cells with eosinophilic cytoplasm and dot-like inclusions (Michaelis-Gutmann) HIV-positive patients, in lymph Sheets of spindle cells with storiform pattern Ziehl-Neelsen stain and plump epithelioid macrophages, for acid-fast bacilli is nodes, skin, spleen, lung, bone foamy and multinucleated cells positive marrow, brain Mycobacteria often atypical species Mycobacterial spindle cell pseudotumor CD68+, S100 protein− Associated with B cell lymphoma or myeloma, rarely other causes Crystal-storing histiocytosis Cells expanded by cytoplasmic rod-like crystals Mucicarmine+, CD68+, CK−, EMA−, S100 protein− CD68+, S100 protein−, epithelial markers negative Von Kossa stain+, CD68+ Foamy lipoblast-like cells, foreign body giant CK−, S100 protein− cells, birefringent material, fibrosis Ancillary Investigations Microscopic Features Polyvinylpyrrolidone Following IV plasma expander, Sheets of macrophages containing bubbly storage disease exposure to some cosmetics or mucin-like material drugs containing PVP Bone, lung, lymph node, spleen, pituitary, or other affected Occasionally seen in a biopsy for suspected soft tissue tumor Langerhans cell histiocytosis Typical Clinical Features TABLE 12.2 Differential Diagnosis of Histiocytic Tumors in Soft Tissue (Continued) 262 BIOPSY INTERPRETATION OF SOFT TISSUE TUMORS SOFT TISSUE LESIONS WITH CLEAR OR GRANULAR CELLS 263 Pathologic Features This is a firm white tumor that can appear lobulated or multinodular (e-Fig 12.1) and can be focally necrotic Melanin pigmentation is rarely seen on gross examination Histologically, the tumor is typically composed of uniform nests, separated by delicate connective tissue septa, of round cells with clear or finely granular eosinophilic cytoplasm and centrally located rounded nuclei each with a single basophilic nucleolus (Figs 12.1 and 12.2, e-Figs 12.2–12.9) Cells can be spindled with a fascicular architecture in some cases (e-Fig 12.5), but pleomorphism is rare and mitotic activity often low Multinucleated giant cells are seen in some examples (e-Fig 12.4), and rarely there is myxoid change (e-Fig 12.6) The intestinal subtype can have osteoclast-like giant cells Melanin pigment is seen in tumor cells in about half of the soft tissue cases Ancillary Investigations Reticulin staining shows a pattern of small nests (e-Fig 12.10) Histochemical stains for melanin pigment (e.g., Fontana Masson) can sometime reveal it when unapparent on H and E, and melanosomes can be found with electron microscopy in many cases Immunohistochemistry is diffusely positive for S100 protein (e-Fig 12.11) and usually for HMB45 (e-Fig 12.12) and melan-A The latter two, however, are negative in the intestinal subtype Neural markers and rarely cytokeratin have been reported in occasional cases CD117 is usually negative in contrast to some cases of melanoma, but because many of the latter are also negative this is of limited value for diagnosis Genetically, clear cell sarcoma of soft parts is characterized by t(12;22) (q13;q12) with fusion of EWS and ATF1 genes, as well as additional FIGURE 12.1 Clear Cell Sarcoma Uniform tumor cells form variably sized nests separated by fibrous septa of varying thickness 264 BIOPSY INTERPRETATION OF SOFT TISSUE TUMORS FIGURE 12.2 Clear Cell Sarcoma The cells have round nuclei, distinct nucleoli, and moderate amounts of amphophilic cytoplasm The multinucleated cell shown here is a frequent feature of these tumors in soft tissue aberrations.3 The intestinal variant, though morphologically similar, has a different translocation, t(2;22)(q33;q12), which results in the EWS-CREB1 gene fusion The subtypes are not wholly distinct since both fusion genes have been identified in examples of both.4 These two translocations are identical to the genetic rearrangements in some examples of angiomatoid fibrous histiocytoma, a morphologically and immunophenotypically different entity (see Chapter 17).5,6 PARAGANGLIOMA Clinical Features Tumors of paraganglia arise in a variety of locations, of which the principal ones are carotid, mediastinal, retroperitoneal (from aorticosympathetic paraganglia or organ of Zuckerkandl), jugulotympanic, and vagal Rarer sites are larynx, orbit, nasopharynx, heart, and cauda equina Although the chromaffin reaction has fallen into disuse, the terminology extra-adrenal paraganglia is sometimes used for chromaffin-positive tumors, which are presumed to be similar to pheochromocytoma of adrenal medulla, and can cause raised amounts of urinary catecholamines, whereas those of chemoreceptor (branchiomeric) type are chromaffin-negative and usually nonfunctional Paragangliomas usually present with symptoms due to a mass, and are sometimes multifocal, especially in familial examples Some, such as glomus jugulare tumors, can have functional effects, including on blood pressure, and vagal paragangliomas can affect cranial nerves at the base of the SOFT TISSUE LESIONS WITH CLEAR OR GRANULAR CELLS 265 FIGURE 12.3 Paraganglioma Cells in nested pattern The cells are arranged in discrete nests, separated by delicate fibrovascular septa The cells have rounded nuclei with small nucleoli The variation in nuclear size and staining is typical and does not indicate malignant potential skull Mediastinal tumors, arising from aortic arch or pulmonary artery paraganglia (anterior mediastinum) or sympathetic paraganglia (posterior mediastinum), can be part of Carney triad Most paragangliomas are benign, but those in retroperitoneum or mediastinum tend to be more aggressive Malignant examples can metastasize to lymph nodes and lung or bone.7 Pathologic Features These tumors are usually encapsulated and are composed of round or polygonal cells with central nucleoli and finely granular, clear or sometimes vacuolated cytoplasm, arranged in nests or cords within a vascular stroma (Fig 12.3, e-Figs 12.13–12.16) The cells are larger than normal and nuclei can show pleomorphism The nests are surrounded to a variable extent by sustentacular cells with elongated cytoplasmic processes A more syncytial pattern can be found in retroperitoneal paragangliomas Nuclear variation and hyperchromasia are not uncommon (e-Fig 12.15), and the cells can display clear cytoplasm (e-Fig 12.16) The stroma can be focally hyalinized8 (e-Fig 12.17), and the vessels can be hemangiopericytomatous (e-Fig 12.18), with both features coexisting in some examples Features suggestive of malignancy include marked nuclear pleomorphism, mitotic activity, necrosis, vascular invasion However, none is reliably predictive of behavior, and tumors without these features have metastasized Ancillary Investigations The lesional cells are immunoreactive for chromogranin, synaptophysin, and neurofilament proteins and CD56 (e-Fig 12.19), and the sustentacular ... sarcoma (soft tissue) Granular cell tumor (Continued) S100 protein+, HMB45+ and melan-A+ (except in GI tract), other markers negative t( 12; 22) (q13;q 12) , EWSR1-ATF1 or t (2; 22) (q33;q 12) , EWSR1-CREB1... a biopsy for suspected soft tissue tumor Langerhans cell histiocytosis Typical Clinical Features TABLE 12. 2 Differential Diagnosis of Histiocytic Tumors in Soft Tissue (Continued) 26 2 BIOPSY INTERPRETATION. .. granules are secondary lysosomes of various types (e-Figs 12. 32 and 12. 33) 26 8 BIOPSY INTERPRETATION OF SOFT TISSUE TUMORS FIGURE 12. 5 Granular Cell Tumor Sheets of tumor cells with rounded small