Soft tissue/Bone Flashcards
Aggressive angiomyxoma.
Aggressive angiomyxoma is a rare mesenchymal tumor arising primarily in the soft tissue of the pelvis and perineum of adults. The term aggressive refers to its infiltrative nature and propensity for local recurrence, but it is an indolent tumor with low metastatic potential. F:M = 6.6:1. It occurs predominantly in women of reproductive age with a peak incidence in the 4th decade and an age range of 11 to 77. In women, it arises in the vulvovaginal region, perineum, and pelvis. In men, it arises in the inguinoscrotal region and perineum. AAM is often clinically mistaken for entities such as Bartholin cyst, vaginal or labial cyst, abscess, leiomyoma, lipoma, fibroepithelial polyp, and inguinal or perineal hernia. Grossly, AAM is unencapsulated, is poorly circumscribed, and may blend imperceptively with surrounding soft tissue. The tumor is tan-pink to tan-gray, bulky, and has a rubbery consistency with a glistening, gelatinous cut surface. Microscopically, AAM is a sparsely cellular tumor composed of pale to eosinophilic stroma studded with numerous haphazardly arranged blood vessels ranging in size from thin-walled capillaries and venules to larger muscular arteries. The stroma is myxoid with intermixed wispy collagen fibrils, scattered smooth muscle bundles, and extravasated RBCs. The tumor cells are cytologically bland and have a spindled, ovoid, or stellate appearance with ill-defined cytoplasmic borders. There is minimal to no cellular atypia and mitoses are rare. IHC shows diffuse positivity for ER, PR, vimentin, and desmin. DDx for AAM includes angiomyofibroblastoma, superficial angiomyxoma, fibroepithelial stromal polyps, myxoid lipomatous tumors, and myxoid leiomyoma.
Epithelioid angiomyolipoma.
Originally believed to be a hamartomatous lesion, angiomyolipoma (AML) is currently defined as a benign mesenchymal tumor composed of a variable proportion of adipose tissue, spindle and epithelioid smooth muscle cells, and abnormal thick-walled blood vessels. AML is a member of the PEComa family. Although most AMLs arise in kidney, extrarenal AMLs are also described in various sites. The epithelioid variant of AML (EAML) is mainly characterized by a predominance of epithelioid cells. In contrast to their classical counterpart, EAMLs are now considered a potentially malignant neoplasm. EAMLs are more often associated with tuberous sclerosis complex than classical AMLs. EAMLs mimic morphologically a variety of neoplasms such as RCC, renal oncocytoma, adrenal cortical neoplasm, epithelioid smooth muscle tumor, epithelioid peripheral nerve sheath tumor, epithelioid GIST, epithelioid melanoma, hepatoblastoma, and HCC. Morphologic clues to diagnosis such as islands of mature fat and abnormal vessels should be diligently searched for in surgical specimens, and prudent use of IHC may be needed.
Epithelioid angiosarcoma.
Angiosarcomas are classified into cutaneous, visceral, and soft tissue subtypes. Most cases of epithelioid angiosarcoma are soft tissue angiosarcomas (usually intramuscular), with a minority falling into the visceral (thyroid gland, adrenal gland) and cutaneous categories. Epithelioid angiosarcoma has a male predilection and the highest incidence is in the 7th decade. Histologically, there are sheets (but islands or cords may be seen) of large, mildly to moderately pleomorphic, round to polygonal epithelioid cells, with central to eccentrically located nuclei containing prominent nucleoli. Within the nucleus, the chromatin is peripherally marginated, yielding a vesicular appearance. Most cells are filled with abundant eosinophilic cytoplasm, but occasional cells with intracytoplasmic lumina containing RBCs can usually be ID’d, aiding in diagnosis. On H&E, focal areas of irregularly anastomosing vessel formation are usually present; purely epithelioid lesions are uncommon, but a completely epithelioid focus may be encountered in scant specimens. Mitoses are numerous, and varying degrees of necrosis and hemorrhage are present. As with all types of angiosarcoma, the epithelioid variant is strongly vimentin positive. Factor VIII and CD31 are also positive. PanCK stains more than 35% of angiosarcomas, with positivity ranging from 78-100% in smaller studies specifically investigating the epithelioid variant.
Examples of pseudoneoplastic lesions in soft tissue and their related neoplastic mimes.
Neuromuscular choristoma (peripheral nerve sheath neoplasms). Fibrolipomatous hamartoma (lipomas). Nodular fasciitis (sarcomas). Proliferative myositis (sarcomas). Myositis ossificans (osteosarcoma). Tumefactive fibroinflammatory lesions (eg, idiopathic retroperitoneal fibrosis) (fibromatoses). Florid (tumefactive) lymphocytic myositis (lymphoma). Atypical decubital (ischemic) fibroplasia (sarcomas).
Examples of pseudoneoplastic lesions in the bones and joints and their related neoplastic mimes.
Bizarre osteochondromatous proliferations (Nora lesion) of digits [cartilaginous neoplasms]. Synovial chondrometaplasia/chondrocalcinosis [cartilaginous neoplasms]. Fibrous dysplasia and fibroosseous lesions [osteosarcoma and fibrosarcoma]. Proliferative-phase Paget disease of bone [osteosarcoma]. Aneurysmal bone cyst [telangiectatic osteosarcoma]. Giant-cell reparative granuloma [giant-cell tumor]. Avulsion fractures of ischial tuberosities [osteosarcoma]. Brown tumor of hyperparathyroidism (osteitis fibrosa cystica) [giant-cell tumor].
Histologic spectrum of angiosarcomas.
Ranges from well-differentiated tumors that mimic benign vascular lesions to poorly differentiated tumors that present as undifferentiated malignant neoplasms. Well-differentiated angiosarcoma consists of irregular interanastomosing channels that infiltrate surrounding tissue. Cytologic features can be deceptively bland in some cases. However, hyperchromasia, mild pleomorphism, prominent nucleoli, mitotic figures, or multilayering are usually present. Within dermis, well-differentiated angiosarcoma entraps and surrounds collagenous stroma to form intraluminal papillary structures. Atypical lymphatic and/or capillary proliferations are frequently present at the periphery of an angiosarcoma, at times making assessment of surgical margins difficult. Moderate and poorly differentiated angiosarcomas have very heterogenous cytoarchitectural features. The cytologic appearance can be epithelioid, spindled, or pleomorphic, while the architecture can be vasoformative, sievelike, kaposiform, or solid. Various combinations of patterns and degrees of differentiation can be present within a single tumor.
Inclusion body myositis?
Is seen mainly in older white males. Is characterized by slowly progressive weakness primarily involving the quadriceps and finger flexors, rapid development of muscle atrophy, and dysphagia. 5 year survival is 100%, but there is much functional disability. Immune processes include a predominant cytotoxic T lymphocyte mediated process involving perforin, with CD8 T cells accompanied by smaller numbers of macrophages surrounding and invading otherwise normal-appearing myocytes in endomysial areas. The MHC class I antigen is upregulated on the surface of the majority of muscle fibers, even those not affected by inflammation. These immune processes are the same as in polymyositis.
Osteoblastoma.
Osteoblastoma accounts for ~1% of all primary bone tumors. It most commonly affects adolescents and young adults, but can be seen in 6-75 yo. Spine and sacrum account for ~1/3 of cases, but any bone can be involved. Progressive pain is the most common symptom. Very rare examples of osteoblastoma progressing to osteosarcoma have been reported. Grossly, osteoblastoma is usually sharply demarcated from adjacent bone, often with a scalloped edge, and is often surrounded by a rim of sclerotic host bone. Some tumors have a central sclerotic nidus. Some are very hemorrhagic with cystic areas. Microscopically, osteoblastoma is composed of interanastomosing trabeculae of woven bone, set within loose edematous fibrovascular stroma. Most tumors show a spectrum of bony maturational changes ranging from cords and clusters of activated osteoblasts associated with minimal osteoid to lacelike wispy osteoid to broad anastomosing trabeculae of woven bone to sclerotic sheets of woven bone. As a rule, the osseous trabeculae are lined by a single layer of osteoblasts. Osteoclastic giant cells are usually abundant. Osteoblastoma does not permeate adjacent bone or invade soft tissue. The cytologic features of osteoblasts are variable. Large immature osteoblasts have abundant, eccentric, basophilic, finely granular cytoplasm; perinuclear hof consistent with Golgi apparatus; and large vesicular nucleus with a prominent nucleolus. Mature osteoblasts are smaller with less cytoplasm and smaller nuclei, while mature osteocytes are smaller yet and contained within the bony matrix. Mitotic activity is low. Osteoclasts vary from polygonal cells with only a few nuclei to large multinucleated giant cells with dozens of nuclei. DDx includes osteoid osteoma, aneurysmal bone cyst, giant cell tumor of bone, osteoma with osteoblastoma-like features, and osteoblastoma-like osteosarcoma.
Osteoblastomas associated with a tooth root are called ___.
Osteoblastomas associated with a tooth root are called cementoblastomas. Osteoblastoma occurs more often in the mandible than the maxilla. It is often associated with the root of a tooth, where it forms an ossified, well-demarcated tumor. Microscopically, the bony matrix tends to be abundant in these tumors and to radiate from the tooth root in parallel arrays.
Perivascular epithelioid cell tumor.
PEComa is a mesenchymal tumor with perivascular epithelioid clear cells that coexpresses melanocytic and muscle markers. Most of these rare tumors are seen in females. Histologically, these tumors are composed of epithelioid and spindle cells, with 1 or both cell types arranged in a fascicular or nested pattern. A prominent intrinsic vasculature can be present, with tumor cells often arranged in a radial fashion around blood vessels. Multinucleated tumor giant cells are a frequent finding. The cells have clear to granular eosinophilic cytoplasm, and small, central, round to oval nuclei with small nucleoli. PEComas vary significantly in nuclear grade, mitotic activity, tumor cell necrosis, and ALI. In addition to melanocytic and smooth muscle markers, PEComas are often positive for vimentin, and can be positive for CD1a, CD10, desmin, S100, and caldesmon. They are usually negative for CD68, pankeratin, LCA, CD117, CD34, and inhibin. This tumor family includes angiomyolipoma (renal and extrarenal), clear cell “sugar” tumor (lung and extrapulmonary), lymphangioleiomyomatosis, and related tumors of the falciform ligament/ligamentum teres, skin, uterus, and other viscera and soft tissue. There is no known normal counterpart to the perivascular epithelioid cell.
What are 4 predisposing factors to angiosarcoma?
Although most are sporadic, important predisposing conditions include radiation, chronic lymphedema, exposure to toxins such as vinyl chloride, and foreign bodies such as arteriovenous fistulas.
What is the most common tumor of the paranasal sinuses?
Osteoma. Osteomas are benign, generally slow-growing, bone-forming tumors limited almost exclusively to craniofacial and jaw bones. They can be subdivided into bone surface tumors (or exostoses) that primarily involve the cranial vault, mandible, and external auditory canal and the more common sino-orbital (or paranasal sinus) osteomas that arise from bones that define the paranasal sinuses, nasal cavity, and orbit. Frontal, ethmoid, maxillary, and sphenoid sinuses are most frequently affected in that order. Histologically, while surface exostoses are usually formed of compact bone, sino-orbital osteomas are composed of variable amounts of compact and cancellous bone. Some osteomas have been designated as “osteomas with osteoblastoma-like features” and are difficult to distinguish from osteoblastomas or osteoid osteomas. Osteoblastoma is most commonly located in the vertebrae and long bones, but mandible is also a relatively common location, where it is often associated with the root of a tooth and referred to as cementoblastoma. However, primary osteoblastoma of the paranasal sinuses is very rare. Osteoid osteomas are vary rare in the craniofacial and jaw bones. They are distinguished from osteoblastoma only by size with a nidus usually less than 1 cm, since the histologic features are essentially indistinguishable. Microscopically, although focally indistinguishable from osteoblastoma, osteoma with osteoblastoma-like features has much more mature bone in the form of solid/compact (ivory osteoma) and dense cancellous (mature osteoma) bone. In addition, the outer contour of an osteoma has a smooth rounded surface, often lined by respiratory mucosa, representing the outer surface of its polypoid growth within the sinus cavity. True osteoblastomas, in contrast, will from an expansible intramedullary or periosteal bone tumor.
Myogenin and MyoD1 stain (skeletal/smooth) muscle.
Myogenin and MyoD1 stain skeletal muscle.
Solitary fibrous tumors have a unique staining pattern, staining with (3 stains).
Solitary fibrous tumors have a unique staining pattern, staining with CD34, CD99, and bcl-2. They typically arise from serosal surfaces. On low power, they are described as having a “patternless pattern”, which means something like “nonstoriform-nonherringbone-nonfascicular”.
Papillary endothelial hyperplasia.
Papillary endothelial hyperplasia is a pattern of organizing thrombus that may occur within a vessel or hematoma. It may be seen incidentally in a surgical specimen or represent a symptomatic small mass by itself, in which case it is called a Masson’s tumor. It is composed of tiny papillae made of fibrin and red blood cells (but no true fibrovascular cores) covered by thin, bland endothelial cells.
What differentiates osteoid osteoma from osteoblastoma?
Size. Osteoid osteomas are 1.5 cm.
Sclerosing mesenteritis is an idiopathic inflammatory and fibrotic process which has been referred to by a variety of names, including…
Sclerosing mesenteritis is an idiopathic inflammatory and fibrotic process which has been referred to by a variety of names, including refractile mesenteritis, lipogranuloma of the mesentery, primary liposclerosis of the mesentery, multifocal subperitoneal sclerosis, mesenteric panniculitis, and mesenteric lipodystrophy.
What 2 bacterial organisms can cause an HLA-B27-linked post-infectious arthritis?
C. jejuni and Y. enterocolitica can cause the development of a reactive arthropathy (so-called enteropathic arthritis) in persons with HLA-B27.
In the bladder, how do you distinguish postoperative spindle cell nodule from inflammatory myofibroblastic tumor?
IMFTs tend to reach a larger size, have greater prominence of the myxoid stroma, lesser degree of cellularity, greater pleomorphism, and lesser tendency for keratin immmunoreactivity.
Epidemiology and radiographic and histologic appearance, and differential diagnosis of unicameral bone cyst.
UBCs are AKA simple gone cysts or solitary bone cysts. >80% are detected in the first 2 decades of life. M:F = ~3:1. The etiology of UBC is uncertain. It tends to affect the metaphysis of skeletally immature patients, and 75% of lesions are seen in the humerus and femur. UBCs may be asymptomatic or discovered incidentally, but many are discovered because of pain, local swelling, or occasionally, a pathologic fracture. Radiographically, UBCs are a central, intramedullary radiolucent lesion, which thins the cortex symmetrically and is marginated by a thin zone of sclerosis. In the young, UBCs are near the epiphyseal plate, migrating distally in time to abut or involve the diaphysis. In resected specimens, the cyst appears unilocular with prominent internal bony ridges that are filled with serous to blood-tinged fluid. Its wall is lined by a delicate, fibrous membrane containing amorphous material that can calcify with a cementum-like appearance. Cases that have undergone fracture may also contain hemosiderin pigment and osteoid and giant cells within the cyst wall. Most commonly, specimens consist of curetted bony fragments, whose only diagnostic clues are sparse fragments of thin, fibrous membranes adherent to bone. The differential diagnosis includes aneurysmal bone cysts, intraosseous ganglia, and fibrous dysplasia with cystic degeneration.
Differentiating unicameral bone cyst from aneurysmal bone cyst, intraosseous ganglia, and fibrous dysplasia with cystic degeneration.
ABCs are lytic, “blown-out,” intramedullary bony lesions exhibiting explosive growth with eccentric expansion. They are characterized by blood-filled spaces lined by a thick and more-cellular membrane, with a prominent multinucleated giant cell component. Conversely, the UBC membranes are delicate and composed of fibrous tissue often containing a cementum-like material, never seen in ABC. Intraosseous ganglia are usually smaller radiolucent lesions in the epiphysis and subchondral region; areas not involved by UBC. They are generally asymptomatic and discovered incidentally in young as well as mature skeletons. They contain mucoid material, not present in UBC, which contains thin, serous fluid. Intraosseous ganglia when associated with osteoarthrosis may be difficult to divorce from large subchondral cysts. Fibrous dysplasia sometimes undergoes cystic degeneration, but the presence, at the periphery of the cystic space, of cellular fibrous tissue with sparse osteoid spicules and no osteoblastic rimming is characteristic of fibrous dysplasia and is never seen in UBC.
Epidemiology, and radiographic and histologic appearance of aneurysmal bone cyst.
Most affected patients are in the first 2 decades of life with 80% younger than 20 years. The most common complaint is pain, often with swelling and loss of function of the adjacent joint. Pathologic fracture can occur. ABCs may occur in almost any portion of the skeleton. Long tubular bones are affected in >50% of cases, with the region about the knee most commonly involved. The spine is affected in 12-30% of cases, and the pelvis in ~50% of flat bone cases. Most reported cases are classified as primary, but ~20-30% is secondary to an identifiable preexisting lesion. Radiographically, ABC appears as an expanded, radiolucent, eccentric, “blown out” lesion, in a long bone metaphysis or in a vertebral body or its posterior arch. An ABCs margins are well defined by a most or less continuous shell of reactive periosteal bone. Grossly, ABC appears as a spongy mass composed of large, blood-filled cystic spaces separated by tan-pink, gritty, fibrous septa. In solid areas, careful sampling may reveal an underlying primary tumor. Histologically, “primary” ABC shows cellular fibrous septa containing uniform fibroblasts with scattered osteoclast-like giant cells. Giant cells seen in ABC are mainly related to vascular spaces or hemorrhagic foci in the septa. A delicate meshwork of osteoid spicules is usually present in the fibrous septa lining aneurysmal spaces. The osteoid is characteristically delicate and deposited parallel to the vascular space surface. In rare cases, chondroid foci may be present. Most “secondary” ABC are associated with benign neoplasms, which can be focal, requiring careful sampling of the most solid areas.
Fibrous dysplasia epidemiology, and radiographic and histologic appearances?
FD, AKA osteitis fibrosa or generalized fibrocystic disease of bone, is a benign fibro-osseous process that may be monostotic or polyostotic. FD affects both sexes equally. 75% of patients are diagnosed in their first three decades. Monostotic and polyostotic forms share the same radiographic appearance, histologic features, and anatomic sites of involvement, but the mandible is often more-commonly affected in monostotic forms, and long bone involvement prevails in polyostotic FD. Although FD may be quite variable radiologically, lesions characteristically show an intramedullary radiolucency that may be eccentric or involve the entire width of a bone. The presence of intralesional, delicate spicules of woven bone gives the affected segment a “ground-glass” appearance. Endosteal scalloping of an affected bone may be present with suggestive, coarse trabeculation within the lesion. Resected lesions show an expanded bone that encases a firm, gritty, white to tan lesion. Cystic degeneration may be present, with the cyst containing serous fluid. Focally, islands of cartilage may be present (fibrocartilaginous dysplasia). Histologically, the lesion characteristically appears well circumscribed and sharply delineated by the host lamellar bone. It is composed of uniformly cellular fibrous tissue containing a proliferation of bland and uniform spindle cells with sparse mitotic activity. Scattered across the fibrous matrix are lamellae or rounded nests of woven bone without significant osteoblastic rimming. Lesions of FD do not characteristically form lamellar bone. There is some morphologic variability in the woven bone spicules. The classic, most commonly seen pattern is that of curvilinear, “Chinese alphabet” spicules of woven bone separated by abundant fibrous stroma.
Fibrous cortical defect/Nonossifying fibroma.
FCS and NOF describe the same histologically benign entity. Radiographically, both FCD and NOF affect the metaphysis of long bones. Classically, the term FCD is applied to smaller lesions situated solely in the cortex on imaging. Nonossifying fibroma describes a larger lesion, which, although cortically based, involves the intramedullary cavity and parallels the long axis of the bone on imaging. Gross and histologic aspects of FCDs and NOFs are identical. They appear soft and tan and are composed of uniform, plump fibroblasts arranged in a whorled to storiform pattern. The nuclei are ovoid with fine chromatin and small nucleoli. The cytoplasm is eosinophilic with indistinct cell boundaries. Mitoses may be observed but are generally sparse and typical. Scattered lymphocytes and hemorrhagic foci with hemosiderin pigment are usually present, as well as multinucleated osteoclast-like giant cells, evenly distributed in the lesion. Regressing lesions tend to have more foamy histiocytes with fibrosis of the matrix and peripheral reactive ossification, and can resemble fibrous histiocytoma or giant cell reparative granuloma. Additional changes may be observed in cases undergoing fracture, including focal osteoid production, increased mitotic activity, and focal necrosis or complete infarction.
Bone island/enostosis.
The terms bone island and enostosis may be used interchangeably to describe the same lesion, namely, a localized area of compact bone within the medullary cavity of a bone. The area may be encompassed by the medullary cavity or show focal attachment to the inner cortex of the host bone. Bone islands are characteristically asymptomatic and discovered incidentally. They are most common in the pelvis, proximal femora, and ribs. Over time, some may decrease in size and disappear, while others may grow. Rare cases may exceed 2 cm (giant bone island). Rarely, multiple bone islands are noted, a condition known as osteopoikilosis. In the rare case of a biopsied bone island, the histology shows compact lamellar bone with prominent Haversian canals. Thickened trabeculae of lamellar bone, when radiating from the periphery of the lesion, usually blend with the bone trabeculae of the host bone.
Osteochondroma.
Osteochondromas are the most-common bone lesions (30-50% of benign resected lesions). 85% are solitary and sporadic. The 15% of osteochondromas with multiple lesions is indicative of a condition transmitted with a dominant pattern of inheritance known as hereditary osteochondromatosis. Both solitary and multiple forms have no sex predilection. Osteochondromas may occur in any bone formed by enchondral ossification. The most common sites, in decreasing order of frequency, are the metaphyses of the distal femur, the upper humerus, the upper tibia, and the fibula. Grossly, osteochondromas are sessile or pedunculated bony projections covered by a smooth, rounded to bosselated, cartilagenous cap of uniform thickness, usually a few millimeters thick. The base is continuous with the neighboring bone marrow. The cartilage cap is invested by perichondrium and composed of hyaline-type cartilage with clustered chondrocytes embedded in an abundant matrix. Its deepest portion is identical to growth plate cartilage and is arranged in columns that undergo enchondral ossification.
Chondrosarcoma arising from osteochondroma.
Chondrosarcoma may arise in osteochondroma, more commonly in patients with multiple osteochondromas. Malignant transformation is frequently associated with clinical symptoms, such as pain, neurologic symptoms, and growth of a previously stable lesion. The mean age of patients with malignant transformation of an osteochondroma is 35 years (1 to 2 decades younger than patients with primary chondrosarcoma). Radiographically, sarcomatous transformation is suspected if there is an increase in size after growth plate closure, or surface irregularities with inhomogeneous mineralization. The most common sites for malignant transformation are the pelvic bones and proximal and distal femur for solitary lesions. In patients with multiple osteochondromas, the pelvic bones, scapula, and thoracic spine are the most common sites, particularly if they have been directly or indirectly included in radiation ports, especially during active skeletal growth. Malignancy is usually associated with soft tissue infiltration, most often by nodules separated from the main tumor mass, by bone stalk permeation, by host lamellar bone entrapment, by markedly increased cellularity with atypia, and by mitotic activity, myxoid stromal changes, and tumor necrosis. The prognosis of chondrosarcoma ex-osteochondroma is generally excellent, provided complete resection is possible.
Chest wall hamartoma/mesenchymal hamartoma of the chest wall.
Chest wall hamartoma is a nonneoplastic, congenital lesion that affects the chest wall of infants. In ~40% of cases, it is present at birth or diagnosed in utero. Although generally intrathoracic, a hamartoma may protrude into the chest wall soft tissue. Hamartomas originate from the posterior or lateral aspect of a rib, and multiple ribs may be involved. The most commom symptom is respiratory distress. On radiographs, a chest wall hamartoma appears as a mineralized mass that, if expansive, may partially destroy neighboring ribs. Gross specimens usually appear as circumscribed lesions composed of tan-white soft tissue, surrounding large, cystic, blood-filled spaces. Microscopically, the solid areas consist of fibrous tissue containing mature hyaline cartilage with variable enchondral ossification and areas resembling aneurysmal bone cyst. Symptomatic lesions may require resection. Others may be followed and tend to regress.
What genetic abnormality do mesoblastic nephroma, infantile fibrosarcoma, and secretory carcinoma of the breast share?
t(12;15).
What are the 3 main types of multinucleated giant cells?
Foreign body giant cells, Langhans giant cells, and Touton giant cells. All three types are transformed macrophages; mononuclear phagocytes fused under the influence of cytokines. Foreign body giant cells have nuclei that are randomly distributed but often aggregate as centrally located, overlapping nuclei. Langhans giant cells have a peripheral ring-like arrangement of nuclei in an arcuate configuration but no rim of clear cytoplasm. Touton giant cells have a ring of nuclei separating a peripheral clear or foamy rim of cytoplasm from central, more eosinophilic cytoplasm. The peripheral cytoplasm appears clear due to high lipid content. Touton giant cells are seen in lesions with high lipid content, such as xanthomas, xanthogranulomas, and fat necrosis. Touton giant cells can also be seen in dermatofibroma. Other types of multinucleated giant cells include epithelium-derived MGCs, which can be prominent in certain viral infections such as measles (Warthin-Finkeldey cells), RSV, HSV/VZV, and parainfluenza. Also, MCGs derived from neoplastic cells may be formed in a variety of neoplasms.
How can fibromatosis be distinguished from nodular fasciitis?
Fibromatosis: Painless, slow-growing, non-circumscribed. 60% have lymphoid aggregates at the periphery. Spindle cells forming interlacing fascicles with variable collagen deposition and cellularity. No/rare mitotic figures.
Nodular fasciitis: Painful, fast-growing, circumscribed. Ropy keloid-type collagen, micro-hemorrhages/RBC extravasation. Zonation effect with hypocellular central region and hypercellular periphery. Often frequent mitotic figures (but no atypical forms).
Hyalinizing spindle cell tumor with giant rosettes is now regarded as a variant of (type of sarcoma).
Hyalinizing spindle cell tumor with giant rosettes is now regarded as a variant of low grade fibromyxoid sarcoma.
Hyalinizing spindle cell tumor with giant rosettes is also called low grade fibromyxoid sarcoma with giant collagen rosettes.
96% of low grade fibromyxoid sarcomas show a characteristic balanced translocation involving the __ gene on chromosome __ and the __ gene on chromosome __.
96% of low grade fibromyxoid sarcomas show a characteristic balanced translocation involving the FUS gene on chromosome 7 and the CREB3L2 gene on chromosome 16.
How can myxofibrosarcomas and low grade fibromyxoid sarcomas be distinguished from each other?
Unlike LGFMS which occurs in the deep soft tissues of young adults, myxofibrosarcoma typically occurs in the subcutaneous tissues of elderly patients. Histologically, myxofibrosarcoma is uniformly myxoid and lacks the alternating fibrous areas seen in LGFMS. Furthermore, myxofibrosarcoma invariably shows a greater degree of cytologic atypia and nuclear pleomorphism.
What staining patterns for PAS, PAS-D, TFE3, muscle markers, cytokeratin, EMA, GFAP, synaptophysin, and S100 are seen in alveolar soft part sarcoma?
PAS stain shows intracytoplasmic glycogen and PAS positive diastase resistant rhomboid crystals, a characteristic feature of ASPS. Nuclear expression of TFE3 is usually present. Muscle markers are expressed in less than half of cases. Cytokeratin, EMA, GFAP, and synaptophysin are negative. S100 is occasionally positive.
Tenosynovial giant cell tumors.
Tenosynovial giant cell tumors (TSGCT) are a group of generally benign intra-articular and soft tissue tumors with common histologic features. They can be roughly divided into localized and diffuse types. Localized types include giant cell tumors of tendon sheath (localized TSGCT) and localized pigmented villonodular synovitis (intra-articular, localized TSGCT), whereas diffuse types encompass conventional pigmented villonodular synovitis (intra-articular, diffuse-type giant cell tumor) and diffuse type giant cell tumor (extra-articular, diffuse TSGCT). Malignant TSGCT/malignant PVNS is rare. Localized tumors are generally indolent, whereas diffuse tumors are locally aggressive. Recent developments indicate that tenosynovial giant cell tumors are clonal neoplastic tumors driven by overexpression of CSF1 (macrophage Colony Stimulating Factor 1). Most giant cell tumors of tendon sheath (localized TSGCT) occur in the digits, especially the fingers, and usually on volar surfaces. Localized pigmented villonodular synovitis (intra-articular, localized TSGCT) is morphologically identical to GCTTS. The knee is the most common location. The most common location for conventional pigmented villonodular synovitis (intra-articular, diffuse-type giant cell tumor) is the knee. Diffuse type giant cell tumor (extra-articular, diffuse TSGCT) is defined by invasive, extra-articular disease, regardless of whether the GCT arose from a joint or soft tissue.
Histologic appearance of tenosynovial giant cell tumors.
Tenosynovial giant cell tumors (TSGCT) are a group of generally benign intra-articular and soft tissue tumors with common histologic features. They can be roughly divided into localized and diffuse types. Localized types include giant cell tumors of tendon sheath (localized TSGCT) and localized pigmented villonodular synovitis (intra-articular, localized TSGCT), whereas diffuse types encompass conventional pigmented villonodular synovitis (intra-articular, diffuse-type giant cell tumor) and diffuse type giant cell tumor (extra-articular, diffuse TSGCT).TSGCTs have a polymorphous cell population comprising large histiocytoid cells with abundant eosinophilic cytoplasm and eccentric vesicular nuclei, smaller mononuclear stromal cells with oval or reniform nuclei, osteoclast-like giant cells, and xanthoma cells. Mitotic figures can sometimes be very abundant. Large hemosiderin deposits, zones of fibrosis including areas resembling osteoid, sheets of xanthoma cells, and dyshesive cellular areas forming a pseudoalveolar pattern are common findings. Conventional pigmented villonodular synovitis (intra-articular, diffuse-type giant cell tumor) will have additional features: unencapsulated, pronounced villonodular architecture, often contains elongated synovial-line spaces, erosion into underlying cortex and articular cartilage. Diffuse type giant cell tumor (extra-articular, diffuse TSGCT) is defined by invasive, extra-articular disease, regardless of whether the GCT arose from a joint or soft tissue. It widely infiltrates and entraps adjacent soft tissue and frequently erodes bone. Pseudoalveolar spaces and cellular areas devoid of giant cells are often present.
What are the two most common causes of angulated, atrophic fibers (AAFs) in muscle?
Denervation and type-2 fiber atrophy. Group atrophy of AAF is an important feature that distinguishes denervation atrophy from type-2 fiber atrophy.
What are adenosine triphosphate stains used on muscle for?
Adenosine triphosphate stains are used for distinguishing type-1 (slow, oxidative) and type-2 (fast, glycolytic) fibers. These are stains for enzyme activity, which require frozen sections, and can be technically difficult to perform. With the stain for myosin ATPase at pH ~10.5, type 2 myofibers are stained brown, and type 1 fibers are stained pink with an eosin counterstain to make them visible. The same stain, performed at a pH of ~4.3, would demonstrate staining of the type 1 myofibers, such that the section would show exactly the reverse pattern. Staining of normal muscle shows a random, almost checkerboard distribution of the 2 types of myofibers. However, IHC stains for slow myosin found in type-1 fibers and fast myosin found in type-2 fibers is available. Also, the IHC stains are permanent, but the myosin ATPase stain fades after a few months.
Tracheopathia osteoplastica.
This is usually an incidental asymptomatic tracheal and bronchial multinodular growth arising from the cartilaginous components of the airway. Its distribution along the cartilaginous surfaces of the airway is radiographically and bronchoscopically distinct, sparing the membranous surface of the trachea. Cases that involve the bronchus can cause obstruction necessitating resection. The nodules are composed of cartilage and ossification, with or without adipose tissue. Bone marrow elements can also be seen.
What is a Triton tumor?
A benign Triton tumor is a neuromuscular hamartoma/choristoma. It is a rare developmental lesion of mature skeletal muscle and nerve. Microscopically, is made up of multiple nodules, each 3-5 mm, separated by narrow bands of connective tissue. Nodules are composed of fasicles of striated muscle of varying size with nerve fibers (myelinated or not) within same perimysial fibrous sheath. Stroma may be more cellular with bland spindle cells and resemble fibromatosis. A malignant Triton tumor is made up of both malignant schwannoma cells and malignant rhabdomyoblasts, and is classified as a MPNST with rhabdomyosarcomatous differentiation. The name “triton” was first used in reference to observation of supernumerary limbs containing bone and muscle growing the backs of tritons (a name given to some species of sea snails) after the implantation of the sciatic nerve into the soft tissues of the back.
What are the 2 forms of fibrous dysplasia?
Fibrous dysplasia is a benign fibro-osseous lesions, which may present in either monostotic or polyostotic forms. The monostotic form occurs most frequently and represents ~75% of FD cases. This form occurs, in decreasing order of frequency, in the craniofacial bones, ribs, femurs, tibias, and humeri. The monostotic form of FD may present with pain or a pathologic fracture, usually in patients aged 10 to 30 years. The degree of bone deformity is relatively less severe compared with that of the polyostotic type.
A small subset of cases of the polyostotic form of fibrous dysplasia (~3%) occurs along with endocrine abnormalities and coast of Maine cafe-au-lait spots, a triad called ___ syndrome.
A small subset of cases of the polyostotic form of fibrous dysplasia (~3%) occurs along with endocrine abnormalities and coast of Maine cafe-au-lait spots, a triad called McCune-Albright syndrome.
What gene mutation is associated with fibrous dysplasia and McCune Albright syndrome?
Molecular findings in FD, and especially those for MAS, suggest it is caused by a somatic mutation early in embryonic life that causes a gene mosaicism. The earlier the mutation occurs, the more widespread the effects will be. The gene is located on 20q13, an area that codes for the alpha subunit on G-protein receptors. This mutation is also present in various endocrine tumors as well as FD. The G-proteins begin a cascade that ultimately leads to activation of the enzyme adenylyl cyclase that produces cAMP. In MAS, there is a missense mutation that causes the substitution of arginine in position 201 of the Gs-alpha gene. Normally, there is an almost immediate deactivation of adenylyl cyclase and a breakdown of the cAMP. In MAS, that does not occur. Overproduction of cAMP leads to increased amounts of activity that affect each tissue differently based on its designated function.
What is the histologic appearance of fibrous dysplasia?
FD has a classic histology of low to moderately cellular fibrous stroma surrounding irregular, curvilinear trabeculae of woven bone, which is arranged in a pattern commonly referred to as “Chinese letters.” The stroma may be variably collagenized, and the ratio of fibrous tissue to bone can range from being totally fibrous to being densely packed with dysplastic trabeculae. The trabeculae may even contain transverse lines mimicking Paget disease. A key feature is the conspicuous absence of osteoblastic rimming. Secondary changes, such as a metaplstic chondroid component or aneurysmal bone cyst-like changes, can include cystic degeneration with xanthomatous histiocytes and/or giant cells and myxoid change. IHC serves no purpose in the diagnosis of FD other than to rule out the possibility of a malignant lesion with a pertinent history.
What is the histologic differential diagnosis of fibrous dysplasia?
The histologic differential diagnosis is similar to the radiographic differential diagnosis, including osteofibrous dysplasia, fracture callus, nonossifying fibroma, and low-grade osteosarcoma. Low-grade chondrosarcoma may be part of the differential diagnosis if there is a prominent chondroid component. Osteofibrous dysplasia and fracture callus can be difficult to differentiate, but the history and location should help, and they typically have prominent osteoblastic rimming around the bone trabeculae. Fracture callus should have a history of trauma, and osteofibrous dysplasia occurs almost exclusively in the tibia and fibula. Nonossifying fibroma resembles benign fibrous histiocytoma with a storiform arrangement of the spindle cells and occasional multinucleated giant cells. However, bone-matrix formation is absent. Particularly when the mandible is involved, ossifying fibroma must be considered in the differential diagnosis.
__% of cases of fibrous dysplasia undergo malignant transformation.
1% of cases of fibrous dysplasia undergo malignant transformation. The frequency of malignant change is increased with the polyostotic form of FD, especially in patients with McCune-Albright syndrome, Mazabraud syndrome, or prior radiation exposure. Osteosarcoma (~70%), fibrosarcoma (~20%), chondrosarcoma (~10%), malignant fibrous histiocytoma (~4%). Once FD is diagnosed, routine follow-up should be done on a yearly basis with x-ray examination.
Kaposi sarcoma overview.
Kaposi sarcoma (KS) is a low-grade vascular tumor associated with Kaposi sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8) infection. Kaposi sarcoma lesions predominantly present at mucocutaneous sites, but may involve all organs and anatomic locations. Recognized epidemiologic-clinical forms of KS include classic, African (endemic), AIDS-associated (epidemic), and iatrogenic KS. New clinical manifestations have been described, such as antiretroviral therapy–related KS regression or flares. Kaposi sarcoma lesions evolve from early (patch stage) macules into plaques (plaque stage) that grow into larger nodules (tumor stage). Newer histologic variants include anaplastic, hyperkeratotic, lymphangioma-like, bullous, telangiectatic, ecchymotic, keloidal, pyogenic granuloma–like, micronodular, intravascular, glomeruloid and pigmented KS, as well as KS with sarcoidlike granulomas and KS with myoid nodules. Latency-associated nuclear antigen (HHV8) is the most specific immunohistochemical marker available to help distinguish KS from its mimics. KS remains one of the most common AIDS-defining malignancies.
Kaposi sarcoma pathogenesis.
With the advent of genomic technologies, proliferating KS spindle tumor cells are now known to be of endothelial origin, confirming former studies that used histochemistry and ultrastructural findings. Circulating blood mononuclear and endothelial “progenitor cells” are believed to be the source of early KS lesions. Infection with HHV8 reprograms the host’s blood endothelial cells so that they resemble lymphatic endothelium, upregulating several lymphatic-associated genes such as lymphatic vessel endothelial receptor 1 (LYVE1), podoplanin, and vascular endothelial growth factor receptor 3 (VEGFR3). However, HHV8 infection alone appears to be insufficient for the development of KS. Kaposi sarcoma progression relies also on some degree of host immune dysfunction and the local inflammatory milieu. Kaposi sarcoma growth involves the upregulation of many key HHV8 gene products, such as the latency-associated nuclear antigen (LANA-1 or LNA-1). Like other herpesviruses, HHV8 remains latent within cells and has developed a variety of mechanisms to evade the host immune system.
For the 4 types of Kaposi sarcoma, list the epidemiology, clinical distribution, and behavior.
Classical type: Mainly males aged 40-70 years, of Mediterranean or Jewish Ashkenazi origin. Skin of the lower extremities, but mucosal and visceral lesions may develop. Indolent. African type: Middle-aged black adults and children from equatorial Africa. Multiple localized skin tumors, involving lower extremities and/or lymph nodes. Progressive; lymphadenopathic form is aggressive. AIDS-associated type: Mainly homosexual males and IVDUs aged 20-50 years; now equally affects women and children in Africa. Disseminated mucocutaneous and visceral involvement. Aggressive; lesions may regress or flare with initiation of antiretroviral therapy. Iatrogenic type: Immunosuppressed persons of any age from autoimmune disease, drugs, or transplantation. Localized mucocutaneous or disseminated KS, with possible visceral lesions. Variable; may regress after immunosuppression is discontinued.
Histologic appearance of Kaposi sarcoma.
Early patch-stage KS is characterized by abnormal vessels lined by thin endothelial cells dissecting the dermis. Ramifying proliferating vessels often surround larger ectatic vessels and skin adnexa, producing the so-called promontory sign. This sign is not pathognomonic for KS, as it has also been described in other vascular lesions including benign vascular tumors and angiosarcoma. Sparse chronic inflammatory cells, extravasated red blood cells, and hemosiderin-laden macrophages are frequently present in patch KS lesions. These early histologic changes may be inconspicuous, and for that reason can be easily missed on biopsy. Plaque-stage KS lesions are characterized by a proliferation of both spindle cells and vessels, which in the skin involve most of the dermis, and sometimes even the subcutis. Well-developed KS tumors consist of several fascicles of these spindle-shaped tumor cells, often admixed with a variable chronic inflammatory infiltrate composed of lymphocytes, plasma cells, and dendritic cells. Kaposi sarcoma lesions also contain several hemosiderin-laden macrophages. Iron staining may help distinguish KS from similar-appearing interstitial granuloma annulare lesions that lack iron. In cross section, KS nodules display a sievelike appearance caused by the transection of spindle cells with intervening slitlike spaces. Eosinophilic and PAS–positive hyaline globules are a common finding in advanced KS lesions. These globules may be located within lesional cells or extracellularly. Typical KS lesions are devoid of marked cellular pleomorphism, necrosis, or a significant number of mitotic figures. In rare instances, AIDS-KS lesions may harbor concomitant pathologic findings, usually an opportunistic pathogen (eg, cryptococcosis, mycobacterial granulomas, or molluscum contagiosum).
What are pre-Kaposi sarcoma lesions and anaplastic Kaposi sarcoma?
These are at the two opposite ends of the spectrum of Kaposi sarcoma. Pre-KS lesions are also referred to as an “in situ” form of KS. These pre-KS lesions are characterized by groups of abnormal capillary-like vessels admixed with an inflammatory infiltrate, similar to patch-stage KS lesions. They are associated with lymphangiogenesis arising in the setting of chronic lymphedema. On the other end of the spectrum is anaplastic KS, sometimes referred to as pleomorphic KS. Anaplastic KS is an infiltrative, solid proliferation of spindle cells without vascular spaces, seen mainly in AIDS involving acral sites. This aggressive variant displays a greater degree of cellular and nuclear atypia, high mitotic index (eg, 5 to 20 mitoses per 10 high-power fields), and occasional necrosis.
IHC for Kaposi sarcoma.
Kaposi sarcoma lesional cells stain positively with the endothelial markers factor VIII–related antigen, CD31 (PECAM-1), and CD34. CD34 tends to show stronger expression than CD31 in advanced-stage lesions of KS. KS spindle cells also express several lymphatic specific markers such as D2-40 (which binds to the podoplanin antigen), LYVE-1 (a homologue of the CD44 glycoprotein receptor for hyaluronan), VEGFR-3 (the receptor for vascular endothelial growth factor C), and Prox-1. Bcl-2 also shows positivity in KS, related to the tumor’s mechanisms of resisting apoptosis. The identification and localization of HHV8 within KS lesional cells by using LNA-1 (also called LANA-1) is the most diagnostically helpful immunostaining technique available to differentiate KS from its mimics. LNA-1 immunoreactivity in KS cells appears as stippled nuclear staining. However, HHV8 is not entirely limited to KS and has been detected in some angiosarcomas, hemangiomas, and dermatofibromas. LNA-1 IHC is favored over PCR detection of HHV8 in the evaluation of problematic vascular proliferations because contaminating mononuclear inflammatory cells may also harbor this herpesvirus, especially in HIV-positive patients.
Histologic differential diagnosis for the patch, plaque, and nodular stages of Kaposi sarcoma.
Clinical history, such as HIV infection or status post transplant, may strongly support the diagnosis of KS. The differential diagnosis of patch-stage KS includes targetoid hemosiderotic hemangioma, fibrous histiocytoma, and interstitial granuloma annulare. The differential diagnosis of plaque-stage KS includes tufted angioma, targetoid hemosiderotic hemangioma, microvenular hemangioma, and acroangiodermatitis (“pseudo-Kaposi sarcoma”). The differential diagnosis of nodular KS includes bacillary angiomatosis, other vascular tumors (eg, spindle cell hemangioma and Kaposiform hemangioendothelioma), fibrohistiocytic tumors (eg, cellular, angiomatoid, and atypical variants of fibrous histiocytoma, and dermatofibrosarcoma protuberans), resolving dermal fasciitis, spindle cell melanoma, and several other spindle cell mesenchymal neoplasms (eg, cutaneous leiomyosarcoma).
Nerve sheath myxoma. Clinical presentation, histologic appearance, and differential diagnosis.
Nerve sheath myxomas are rare, distinct tumors of the peripheral nerve sheath, with a peak incidence in the 30’s. Patients present with solitary, superficial, multinodular, painless masses up to 2.5 cm, usually in the extremities. Tumors are typically slow growing, and often were present for years before being resected. They typically involve the dermis or subcutis, forming multinodular, avascular masses with abundant myxoid matrix and a peripheral fibrous border. Epithelioid Schwann cells are present in corded, nested, or syncytial-like aggregates. Stellate Schwann cells with cytoplasmic-nuclear invaginations are also present. The Schwann cells are strongly immunoreactive for S100 protein, GFAP, NSE and CD57. Occasional EMA+ perineurial cells are usually present, primarily in fibrous tissue. There are few/no mitotic figures. The differential diagnosis includes low grade fibromyxoid sarcoma of soft tissue, which typically has MFH-like areas, curvilinear vessels (thick walled with a broad arc) with condensation of cells around the vessels, and often non-specific cytogenetic aberrations. Neurothekeomas may have a myxoid stroma, but are distinct lesions by differential gene expression profiles and immunohistochemistry, and thought to be a variant of fibrous histiocytoma.
What are the 4 subtypes of hemangioendothelioma?
Epithelioid, spindle cell, retiform, kaposiform.
Synovial sarcoma is a spindle cell tumor arising in soft tissue which displays variable epithelial differentiation including glandular formation. It also has a specific genetic alteration, a chromosomal translocation ___, that results in a fusion between ___ and ___.
Synovial sarcoma is a spindle cell tumor arising in soft tissue which displays variable epithelial differentiation including glandular formation. It also has a specific genetic alteration, a chromosomal translocation t(X;18), that results in a fusion between the SS18 (SYT) gene on chromosome 18 and one of the SSX genes on the X chromosome, creating SS18-SSX1, SS18-SSX2, or SS18-SSX4 chimeric genes.
Monophasic synovial sarcoma histologic appearance.
In the WHO classification there are two major categories of synovial sarcoma: the monophasic and the biphasic subtypes. The biphasic variant usually carries the SS18-SSX1 translocation, while the monophasic variant can have either fusion (SS18-SSX1 or SS18-SSX2). Monophasic SS typically demonstrates densely cellular sheets or vague fascicles of uniform, relatively small, ovoid neoplastic cells, with occasional nuclear palisading. Many tumors show s prominent hemangiopericytic growth pattern with staghorn-like vasculature arrangements, at least focally. Sometimes an extensive sampling can reveal a glandular epithelial component. Stromal collagen is generally scant. Myxoid change is usually focal with alternating areas of hypercellularity and hypocellular areas with microcyst formation. Mast cells may be abundant in this component.
The histologic appearance of monophasic synovial sarcoma can simulate that of several other soft tissue neoplasms including ___.
The histologic appearance of monophasic synovial sarcoma can simulate that of several other soft tissue neoplasms including fibrosarcoma, leiomyosarcoma, MPNST, and SFT.
Synovial sarcoma and TLE-1.
TLE1 is one of four transducin-like enhancer of split (TLE) genes that encode human transcriptional repressors. It is an important protein in the Wnt/Beta-catenin pathway, a signaling pathway that is strongly associated with SS. Strong nuclear TLE1 expression is a robust IHC biomarker for SS, particularly in those cases that do not exhibit biphasic histology, and helps distinguish this tumor from other spindle cell tumors. In an appropriate clinical background and morphology, strong nuclear TLE1 expression in a CD34-negative spindle cell tumor containing scattered CK-positive cells can be regarded as diagnostic of SS.
How can enchondroma be differentiated from chondrosarcoma?
Enchondroma can have a similar microscopic appearance to well-differentiated chondrosarcoma, demonstrating a lobular architecture, cells with hyperchromatic nuclei, and multinucleation. In the hands and feet, an enchondroma can be hypercellular and have cellular atypia, features considered malignant when present at other sites. One useful morphologic distinction is the separation of cartilaginous lobules by hematopoietic marrow in enchondroma, different from the fibrous septa that separate the lobules in chondrosarcoma. Also, enchondromas do not permeate trabecular bone. Lastly, chondrosarcomas often have >10% myxoid degenerative changes and mitotic figures while enchondromas have neither. In cases lacking clear characteristic features, distinguishing enchondroma from well-differentiated chondrosarcoma may not always be possible. It should be kept in mind that acral enchondromas are far more common than chondrosarcomas.
The natural progression of bone healing following fracture has been described as being composed of three major phases. Describe.
During the initial reactive phase, occuring during the first few days, hemorrhage and a proliferation of small spindle cells are generated within the fracture. After about one week, proliferation is so intense that spindle cells can form a malignant-appearing, sarcoma-like, mitotically active mass intermixed with capillaries; atypical mitoses are absent. Typically, over the next two to four weeks, periosteal cells proximal to the fracture gap transform first into chondroblasts and then hyaline cartilage, while cells distal to the gap become bone forming osteoblasts, the former producing specialized collagen matrix and the latter osteoid. The two populations fuse forming a temporary fracture callus which is eventually replaced by first woven and then, by way of endochondral ossification, lamellar bone. The entire process in healthy individuals takes upwards of 6-8 weeks. Although early fracture callus formation can histologically resemble a malignant process, the radiographic features of a fracture callus do not. Thus, close clinical/radiologic/pathologic correlation is critical.
Malignant peripheral nerve sheath tumor overview.
MPNSTs arise from peripheral nerves or show differentiation along the lines of nerve sheath elements (Schwann cells, perineural cells, fibroblasts). MPNSTs account for 5-10% of all soft tissue sarcomas, and one-fourth to one-half of them occur in patients with NF-1. Most lesions present as enlarging masses with or without associated pain and arise in association with major nerve trunks including the brachial plexus, sacral plexus and the sciatic nerve.
IHC for MPNST.
IHC stains for S100, CD57, myelin basic protein, and p53 are usually positive. Staining for S100 should be focally positive, but if strong, diffuse staining is present, a diagnosis of cellular schwannoma should be considered. MPNSTs are commonly negative for EMA, CK7, and CK19, which can differentiate this tumor from synovial sarcoma.
How are cellular schwannomas defined?
Cellular schwannomas can be mistakenly diagnosed as malignant due to their high cellularity, mitotic activity and occasional bone destruction. This entity is defined as a schwannoma that is composed predominantly of Antoni A areas (usually less than 10% Antoni B areas) with absence of Verocay bodies. These lesions occur in the deep soft tissues of the extremities in ~1/4 of cases. Histologically, cellular schwannomas show short, intersecting fascicles and whorls of Schwann cells that can be arranged in a herringbone pattern. Mitotic activity can be seen, but is usually low. Cellular schwannomas lack the hyperchromatic and anaplastic cells seen in MPNSTs and display strong positivity for S100 protein.
Clear cell sarcoma overview.
Clear cell sarcoma of soft tissue is a rare tumor that affects the extremities in young adults and shows melanocytic differentiation. This tumor is usually associated with tendons or aponeuroses and presents as a slow growing mass. Microscopically, the tumor grows in a uniform, nested to fascicular pattern with thin fibrous septa. Tumor cells are polygonal to spindle-shaped with abundant clear or eosinophilic cytoplasm and prominent nucleoli. Multinucleated giant cells are present in half of cases, and intracellular melanin can occasionally be seen. Clear cell sarcoma is positive for S100 protein, HMB45, and other melanocytic markers and shows a reciprocal translocation, t(12;22)(q13;q12), that results in EWS/ATF1 gene fusion.
How can angiolymphoid hyperplasia with eosinophilia be distinguished from Kimura lymphadenopathy?
ALHE can have a striking histologic similarity to KL. ALHE is present mostly in Caucasians and can be confused with early stage KL. ALHE more often affects females and is seen in soft tissues and superficial dermis forming clusters of eosinophilic cells. ALHE typically presents as cutaneous papules rather than a mass lesion, and histology reveals non-nodal collections of eosinophils with hypertrophic endothelial cells that protrude and occlude vascular lumina in a tombstone pattern. Lymphadenopathy, which is an essential feature in KL, is not frequently seen in ALHE.
Overview of myxoid liposarcoma with a round cell component (myxoid/round cell liposarcoma).
Myxoid liposarcoma and round cell liposarcoma were historically considered separate subtypes of liposarcoma. The frequent transition areas between myxoid liposarcoma and round cell areas in the same tumor, along with the shared t(12;16)(q13;p11) chromosomal translocation, support a single classification as myxoid/round cell liposarcoma. The translocation results in fusion of the FUS (TLS) and CHOP genes on chromosomes 12 and 16, respectively. Myxoid/round cell liposarcoma accounts for approximately 30–35% of liposarcomas. These tumors occur almost exclusively in adults, usually in the third to eighth decade with a male preponderance (male: female ratio of 3:1). Myxoid/round cell liposarcoma is somewhat unusual among soft tissue tumors in that it often metastasizes to unusual sites such as the soft tissue of the trunk or axilla before metastasizing to the lung.
What are the three most common sarcomas in the retroperitoneum?
The three most common sarcomas in the retroperitoneum are liposarcoma, leiomyosarcoma, and pleomorphic sarcoma (malignant fibrous histiocytoma).
Ancillary studies for myxoid/round cell liposarcoma.
In small biopsy specimens or cases with few, if any, lipoblasts, the detection of the t(12;16) translocation may be extremely helpful in the differential diagnosis. Fresh tissue placed in RPMI may be used for complete karyotyping. Fluorescence in situ hybridization (FISH) for chromosome 12 (CHOP, 12q13) and reverse transcriptase polymerase chain reaction (RT-PCR) for the FUS-CHOP fusion transcripts may be performed on formalin-fixed paraffin-embedded tissue. Immunohistochemistry is of limited utility.
What is a gangliorhabdomyosarcoma?
Embryonal rhabdomyosarcoma is a primitive soft tissue sarcoma with small blue cells resembling embryonic skeletal muscle. It is the most common rhabdomyosarcoma (RMS) subtype (65% of RMS cases), and usually occurs in children ages 3-10 years in the head and neck (nasal and oral cavities, orbit, ear), prostate or paratesticular regions. Gangliorhabdomyosarcoma is a rare variant of embryonal rhabdomyosarcoma which also has cells exhibiting neuronal differentiation. A related entity is malignant ectomesenchymoma, composed of a malignant mesenchymal component (often but not exclusively rhabdomyosarcoma) and a neuroectodermal component (often ganglion cells or neuroblasts). The differential diagnosis includes Triton tumor (rhabdomyosarcoma plus MPNST), Wilms tumor, and teratoma. Optimal treatment is not well defined for this rare tumor, but most authors recommend a combination of surgery, radiotherapy, and a chemotherapeutic protocol based on the RMS component.
Hibernoma is an uncommon benign tumor of brown adipose tissue, representing approximately __% of all adipocytic tumors and occuring predominantly in adults, with a peak incidence in the __ to __ decade.
Hibernoma is an uncommon benign tumor of brown adipose tissue, representing approximately 1.1% of all adipocytic tumors and occuring predominantly in adults, with a peak incidence in the 3rd to 4th decade.
Microscopically, hibernomas display a lobulated architecture composed of what 3 cell types?
Granular, eosinophilic cells; multivacuolated cells; and univacuolated white fat cells. Intermediate forms of the brown fat cells are also present, ranging in appearance from cells with abundant granular, eosinophilic cytoplasm and few vacuoles to paler cells with multiple intracytoplasmic vacuoles containing oil red O-positive lipid droplets.
What are the four histologic variants of hibernoma?
- The “typical” hibernoma, which includes pale cell (pale hibernoma cells and pale white fat cells), mixed cell (an even mixture of pale and eosinophilic hibernoma cells), and eosinophilic cell (a predominance of eosinophilic hibernoma cells) subtypes. 2. The “lipoma-like” variant, with only scattered hibernoma cells among abundant white adipose tissue. 3. The “myxoid” variant, with tumor cells separated by acellular myxoid stroma. 4. The “spindle cell” variant, which has combined features of hibernoma and spindle cell lipoma (interspersed spindled cells and thick collagen bundles).
Cytogenetic and IHC characteristics of hibernoma?
Cytogenetically, hibernomas are often associated with rearrangements of chromosomal bands 11q13-21; however, other benign lipomatous tumors may also display such abnormalities. By IHC, hibernomas are variably positive for S100 protein and spindle cell components are positive for CD34.
Histopathological diagnosis of myelolipoma involves demonstration of…
Histopathological diagnosis of myelolipoma involves demonstration of (a) lipomatous compartment, which is composed of mature adipocytes and (b) hematopoietic compartment, which includes any of the three lineages (myeloid, erythroid, and megakaryocytic). An exclusively lymphocytic, monocytic or histiocytic cell infiltration will not constitute the myeloid (marrow) compartment’s equivalence. In addition, caution should be exercised in tumors that show only mature myeloid cells (granulocytes, or eosinophils); granulocytic cells can be part of the inflammatory infiltrate within a lipoma, and do not constitute a true myeloid compartment. Similarly, immature myeloid cells, such as blasts, can be present in soft tissue involvement by leukemia (myeloid sarcoma), and hence should be interpreted with caution. Unequivocal proof of myeloid (marrow) compartment of myelolipoma is provided by the presence of erythroid colonies and/or megakaryocytic cells.
Hepatic angiosarcoma has been associated with exposure to what agents?
Thorotrast (radiologic contrast material), arsenic (such as from insecticide exposure), and vinyl chloride (typically from polyvinyl chloride polymerization plants). However, since the use of these carcinogens has dramatically decreased, most current cases of hepatic angiosarcomas are sporadic in nature or are associated with anabolic steroid use.
What hematologic abnormalities may patients with hepatic angiosarcoma present?
Thrombocytopenia (secondary to entrapment of platelets in the tumor/Kasabach-Meritt syndrome). Microangiopathic hemolytic anemia (due to red cell fragmentation in the tumor). Disseminated intravascular coagulation.
What is the FNCLCC grading system for soft tissue sarcomas?
The 2 most widely used grading systems are the FNCLCC (Federation Nationale des Centre de Lutte Contre la Cancer) and NIH systems. The CAP recommends the French system over the NIH system for reasons of ease of use/reproducibility and perhaps slightly superior performance. The FNCLCC grade is determined by 3 parameters: differentiation (histology specific), mitotic activity, and extent of necrosis. Each parameter is scored: differentiation 1-3, mitotic activity 1-3, and necrosis 0-2. The scores are summed to designate grade: score of 2 or 3 = grade 1, score of 4 or 5 = grade 2, and score of 6-8 = grade 3. The tumor differentiation score is histology specific and is generally scored as follows: Score 1 is for sarcomas closely resembling normal, mature mesenchymal tissue. Score 2 is for sarcomas of definite histologic type. Score 3 is for synovial sarcomas, embryonal sarcomas, undifferentiated sarcomas, and sarcomas of unknown/doubtful tumor type.
Amplification of MDM2 region in 12q15 and DDIT3-CHOP region in 12q13 is associated with what sarcoma?
Liposarcoma. Mouse Double Minute 2 homolog (MDM2) is a protein that is a negative regulator of p53 encoded by the MDM2 gene. DNA Damage Inducible Transcript 3, AKA C/EBP homologous protein (CHOP), is a transcription factor encoded by the DDIT3 gene.
Signet ring cells in the stomach. The differential diagnosis includes ___.
Lymphoma with artifactual signet ring cells due to cytoplasmic shrinkage (CD45 is usually positive in lymphoma). Metastases from breast or lung (clinical history, plus the use of appropriate immunostains such as TTF1 or GCDFP-15 is helpful). Reactive epithelial atypia associated with radiation treatment or chemotherapy. Xanthoma.
Elastofibroma overview.
Elastofibroma usually presents as a painless, slow growing mass which is discovered incidentally. Most cases of elastofibroma are localized to the lower subscapular region, are nonadherent to the overlying skin and surrounding musculature, but have irregular margins and are often adherent to the posterior chest wall. The scapula may overlie the lesion thereby masking it. This lesion is most often diagnosed in the elderly population, with greater than 90% female predominance. Elastofibroma is thought to be a degenerative, non-neoplastic pseudotumor arising as a result of excessive collagen deposition and abnormal elastogenesis secondary to mechanical irritation of the tissue plane between the inferior edge of the scapula and the chest wall. Some patients provided a history of significant manual labor involving the shoulder girdle possibly accounting for the right-sided predominance of this lesion. A genetic predisposition to this condition has been suggested. Its complete resection is considered curative with no tendency to recur.
Histologic appearance of elastofibroma.
Histologically the mass is hypocellular, patternless and contains a mixture of haphazardly arranged collagen bundles, myxoid matrix and elastic fibers. Adipose tissue can be seen within the lesion. The elastic fibers have a characteristic beaded and fragmented appearance. This pattern as well as the enormous number of elastic fibers can be highlighted by an elastic stain. Elastofibroma is immunohistochemically positive for vimentin, and negative for S-100, actin and desmin.
Differential diagnosis for elastofibroma.
Spindle cell lipoma also occurs in the shoulder/back region, but it is more common in men. It shows thick, rope-like collagen bundles and characteristic spindled cells, often admixed with mast cells. Low grade myxofibrosarcoma is rarely seen in the trunk region. It characteristically shows a distinct multinodular growth pattern, prominent myxoid matrix, curvilinear blood vessels and cytologic atypia. Nuchal-type fibroma is more common in men and shows thick, haphazardly arranged collagen fibers and elastic-poor fibrous tissue. Many cases are associated with diabetes mellitus. Desmoid-type fibromatosis shares the infiltrative pattern and poor margination with elastofibroma. However, it is usually hypercellular and associated with skeletal muscle. Elastofibroma in contrast is not muscle invasive. A myxoid variant of neurofibroma certainly enters the differential diagnosis but immunohistochemical staining for S-100 and the typical wavy nuclei help to distinguish it from elastofibroma.
What entities are in the differential diagnosis of Wilms tumor?
The differential diagnosis of Wilms tumor includes other primary renal tumors of childhood, including malignant rhabdoid tumor, congenital mesoblastic nephroma (classic and cellular variants), clear cell sarcoma of the kidney, and renal cell carcinoma. Other diagnostic considerations include other small cell tumors of the kidney (synovial sarcoma, primitive neuroectodermal tumor of the kidney, desmoplastic small round cell tumor, neuroblastoma, lymphoma) and a variety of benign tumors (cystic nephroma, infantile ossifying tumor of the kidney, oncocytoma, and others).
What translocation is seen in myxoid/round cell liposarcoma?
A t(12;16)(q13;p11) chromosomal translocation, resulting in fusion of the FUS (TLS) and CHOP genes on chromosomes 12 and 16, respectively.
Myxoid/round cell liposarcoma overview.
Myxoid liposarcoma and round cell liposarcoma were historically considered separate subtypes of liposarcoma. The frequent transition areas between myxoid liposarcoma and round cell areas in the same tumor, along with the shared t(12;16)(q13;p11) chromosomal translocation, support a single classification as myxoid/round cell liposarcoma. The translocation results in fusion of the FUS (TLS) and CHOP genes on chromosomes 12 and 16, respectively. Myxoid/round cell liposarcoma is the most common subtype of liposarcoma, accounting for approximately 30–35% of liposarcomas. These tumors occur almost exclusively in adults, usually in the third to eighth decade with a male preponderance (male: female ratio of 3:1). Myxoid/round cell liposarcoma is somewhat unusual among soft tissue tumors in that it often metastasizes to unusual sites such as the soft tissue of the trunk or axilla before metastasizing to the lung. Lymph node metastases are also more common in myxoid liposarcoma than many other soft tissue malignancies.
Peripheral ossifying fibroma.
AKA peripheral fibroma with calcification. Is a reactive proliferation of fibrous tissue with mineralization exclusive to gingiva. May be associated with chronic irritation. Origin is cells from periosteum and/or periodontal ligament. Micro: Cellular fibroblastic stroma with a mineralized component (trabecular bone, woven bone, dystrophic calcification, cementum, or a combination of the above). Surface may be ulcerated.
Mucosal neuroma.
Proliferation of nerves, often in a plexiform pattern. Seen on tongue and lips most commonly. Most cases of multiple lesions are seen in patients with MEN2B. Micro: Nonencapsulated, with a haphazard distribution. Hyperplasia of nerve bundles. Prominent thickening of perineurium. DDx: Neurofibroma (may blend with surrounding tissue, has spindle cells with variable collagen). Traumatic neuroma (lacks the prominent perineurium seen in mucosal neuroma). Palisaded encapsulated neuroma (encapsulated at least partially, has spindle cells). Schwannoma (neurilemoma) (characteristic Antoni A and B areas, Verocay bodies, and hyalinized vessels).
What entities are in the differential diagnosis of osteomyelitis in the head and neck region?
Osteomyelitis AKA osteitis is inflammation or infection of bone and bone marrow. Top differential diagnoses include inflammatory reaction (inflammation part of fracture repair; present at tumor borders; lack of acute inflammation and dead bone), lymphoma (atypical lymphoid infiltrate with bone remodeling and dense fibrosis), sarcoid (noncaseating, tight, well-formed granulomas), bisphosphonate therapy (bone necrosis with death, followed by active remoderling; more often a chronic process), and radiation osteitis (bone necrosis and death with chronic inflammation).
What is cherubism?
Cherubism is an inherited disease characterized by progressive, painless, symmetrical expansion of the jaws, resulting in a cherubic facial appearance. M:F = 2:1, with 100% penetrance in males and 50-70% penetrance in females. Mutations in the SH3BP2 gene have been identified in about 80 percent of people with cherubism. In most of the remaining cases, the genetic cause of the condition is unknown. There are germline point mutations in the SH3BP2 gene on chromosome 4p16.3.
What is the genetic mutation in fibrous dysplasia?
Postzygotic, somatic, activating missense mutations in GNAS1 gene coding for alpha subunit of stimulatory G protein are a consistent finding (~3/4 of cases). The GNAS1 gene is on chromosome 20q13.2-13.3. The abnormal G1 protein stimulates cAMP, and the osteoblastic cells expressing this mutation have a higher rate of DNA synthesis than normal cells. This abnormal growth leads to the formation of a disorganized fibrotic bone matrix with primitive bone formation, and lack of maturation to lamellar bone. Mineralization is also abnormal. There is a failure of the bone to align in response to mechanical stress. The extent of disease is related to the stage at which the postzygotic mutation in Gsα has occurred, whether during embryonic development or postnatally.
Postzygotic, somatic, activating missense mutations in GNAS1 gene coding for alpha subunit of stimulatory G protein are a consistent finding (~3/4 of cases) in what condition?
Fibrous dysplasia.
