Soft Tissues PDF

41 Soft Tissues Figure 41.64 A monotonous population of mononuclear cells in a giant Figure 41.65 Sheets of mononuclear cells and xanthoma cells in a diffuse- cell tumor of tendon sheath. No giant cells are seen in this case. type giant cell tumor....

41 Soft Tissues Figure 41.64 A monotonous population of mononuclear cells in a giant Figure 41.65 Sheets of mononuclear cells and xanthoma cells in a diffuse- cell tumor of tendon sheath. No giant cells are seen in this case. type giant cell tumor. The lesion is benign but locally recurs in 10%–20% of cases.341,350,351 These recurrences are nondestructive and can be reexcised without much difficulty. Very rarely, malignancy seems to arise in the setting of a giant cell tumor (malignant giant cell tumor of tendon sheath). This designation should be reserved for tumors with unequivocal malignant areas that arise either next to or subsequent to classical giant cell tumor.352,353 The malignant areas are usually composed of sheets or discrete nodules of large ovoid cells with prominent nucleoli, although some resemble fibrosarcoma or UPS.353 Up to 50% of these tumors metastasize, usually to regional lymph nodes. Wide local excision or even amputation is the recommended mode of therapy. Giant Cell Tumor of Tendon Sheath, Diffuse-Type/ Pigmented Villonodular Synovitis The diffuse giant cell tumor of tendon sheath can be regarded as Figure 41.66 Traumatic neuroma with a haphazard distribution of nerve the extra-articular counterpart of pigmented villonodular synovitis, trunks surrounded by fibrous tissue. which is an intra-articular process. In the majority of cases, soft tissue involvement is secondary to extensive growth from an intra- articular process, but some cases are exclusively in the soft Neuroma tissues.345,354,355 These lesions are far less common than the localized The large majority of neuromas follow trauma—hence their designa- type, and they tend to occur in younger patients, with a peak incidence tion as traumatic neuromas. When a peripheral nerve is severed or in the fifth decade of life.345 They most commonly occur near the crushed, the distal end undergoes wallerian degeneration, whereas knee, followed by the ankle and foot. Unlike the localized form, the proximal end regenerates. If it fails to meet the distal end, a they arise as a less circumscribed process with infiltration of sur- tangled mass of nerve fibers results. Microscopically, all the elements rounding tissues, accounting for the much higher rate of local of a nerve can be recognized: axons, Schwann cells, perineurial cells, recurrence. The cellular constituents and immunophenotype are and fibroblasts (Fig. 41.66). In addition, scar tissue is often present. identical to those seen in the localized form, although giant cells Not surprisingly, this lesion may be exquisitely painful. Immuno- tend to be less conspicuous (Fig. 41.65). CSF1 aberrations are also histochemically, the Schwann cells of traumatic neuroma show seen in these tumors, indicating a clear histogenetic connection to aberrant expression of the macrophage-associated antigens CD68 the localized form. Given the high rate of local recurrence, therapy and Ki-M1P, in keeping with the macrophagic properties that they should be directed at an attempt to remove the tumor as completely are known to acquire under these circumstances.356 Amputation as possible while minimizing morbidity. neuroma, a term made popular during the First World War, is a type of traumatic neuroma in which the original trauma involves Tumors and Tumorlike Conditions of the loss of part or all of an extremity. Morton neuroma (Morton metatarsalgia) can be regarded as a Peripheral Nerves subtype of traumatic neuroma caused by repeated mild trauma to Proliferative lesions of peripheral nerves are divided into non- the region.357 Its typical location is the interdigital plantar nerve neoplastic (such as traumatic neuroma), benign tumors (such as between the third and fourth toes. The lesion is more common in schwannomas, neurofibromas, and perineuriomas), and malignant female adults. Microscopically, the affected nerve is markedly distorted tumors, collectively designated as MPNSTs. Despite the fact that with extensive perineurial fibrosis, often arranged in a concentric these lesions may overlap and coexist with each other, it is important fashion. to make a distinction among them in view of their markedly different Palisaded encapsulated neuroma (solitary circumscribed natural history. neuroma) presents as a small, solitary, asymptomatic papule in the 1838  Tumors 41 Schwannoma Neurofibroma Malignant MPNST Figure 41.67 Schematic drawing emphasizing the main differences between the three major types of peripheral nerve tumors. Note diameter of nerve involved and behavior of neurites (thin black lines) in relation to the neoplasm. MPNST, malignant peripheral nerve sheath tumor. skin,358,359 usually arising on the face of middle-aged individuals. Microscopically, the lesion is centered in the dermis (in contrast to schwannoma, which is rarely seen in this location) and is characterized by a proliferation of Schwann cells and numerous axons located within a capsule derived from perineurium.360 Immunohistochemi- cally, the Schwann cells are reactive for S-100 protein, the axons for neurofilaments, and the capsule for EMA, the latter indicating the presence of perineurial cells.360,361 Schwannoma (Neurilemoma) Schwannoma (neurilemoma) is one of the few truly encapsulated neoplasms. Its most common locations are the flexor surfaces of the extremities, neck, mediastinum, retroperitoneum, posterior spinal A roots, and cerebellopontine angle. The nerve of origin often can be demonstrated in the periphery, flattened along the capsule but not penetrating the substance of the tumor (Fig. 41.67). Since this is a benign neoplasm that only rarely recurs locally, every attempt should be made to preserve the nerve, if this is of any clinical significance (e.g., facial nerve or vagus nerve). The great majority of cases occur sporadically, while a small percentage of cases are associated with type 2 neurofibromatosis (caused by a germline mutation in the NF2 gene located on 22q12, which encodes merlin, also known as schwannomin).362 Grossly, the larger schwannomas often contain cystic areas (Fig. 41.68). The microscopic appearance is distinctive with Antoni A and B zones (Figs. 41.69 to 41.72). The Antoni A zones, which in small tumors comprise almost their entirety, are quite cellular, composed of spindle cells often arranged in a palisading fashion or in an organoid arrangement (Verocay bodies). In Antoni B zones, the tumor cells are separated by abundant edematous fluid that may form cystic spaces. Occasionally, isolated cells with bizarre hyper- chromatic nuclei are observed (so-called ancient schwannoma) and are of no particular significance.363 Mitoses are usually absent or rare. Thick-walled hyalinized blood vessels are a characteristic finding, sometimes with thrombosis. Some cases show prominent nuclear palisading, but this is not unique to schwannoma, as this feature B may also be seen in smooth muscle tumors, among others. The traditional wisdom is that (in contrast to neurofibromas, see later) Figure 41.68 Gross Appearances of Schwannoma. The tumor shown axons are not present in schwannoma, except in the portion of the in B has undergone marked secondary cystic changes. 1839 41 Soft Tissues Figure 41.69 Low-power view of schwannoma with capsule and Antoni A and B areas. A B Figure 41.70 Junction of Antoni A and B zones in a schwannoma. Figure 41.72 Schwannoma. A, Large hyperchromatic nuclei are seen. This does not necessarily indicate malignant change. B, Thick-walled hyalinized blood vessels are a prominent feature. Figure 41.71 Verocay bodies in a schwannoma. Figure 41.73 Epithelioid schwannoma with epithelioid Schwann cells capsule where the nerve is attached; however, recent studies employing deposited in a myxoid matrix. an antibody against neurofilament have challenged that assumption.336 Collections of foamy macrophages are sometimes seen, especially in larger neoplasms. More unusual is the presence of clusters of predominate, the tumor has been referred to as benign epithelioid granular cells similar to those seen in granular cell tumors.364 The schwannoma (Fig. 41.73). Recently, it has been found that almost rare occurrence of plexiform areas in schwannoma may cause them 50% of these lesions showed loss of INI1 expression.367a Some of to be mistaken for neurofibroma. Most of these plexiform schwannomas these lesions can show striking cytologic atypia and in rare cases are found superficially in the dermis or subcutaneous tissue, but can transform into epithelioid MPNST. A few cases of schwannoma they can also be deep-seated.365,366 containing a glandular component have been described (benign Epithelioid areas can also be present, although much less com- glandular schwannomas).368,369 These should be distinguished from monly than in neurofibroma and MPNST.367 When these areas the pseudoglandular formations lined by low columnar or cuboidal 1840  Tumors 41 Schwann cells having an epithelial-like appearance,370,371 as well as Cellular schwannoma is the term used for highly cellular schwan- from entrapped sweat glands. nomas that are exclusively composed of Antoni A areas but lack Rare schwannomas are found to contain melanin pigment. When Verocay bodies (Fig. 41.75).384–386 These changes can be accompanied this feature is prominent and accompanied by psammoma body by nuclear atypia, mitotic activity, and focal necrosis. Most reported formation, the possibility of the tumor representing a psammomatous cases have been in the retroperitoneum, pelvis, and mediastinum. melanotic schwannoma should be considered372 (see subsequent The differential diagnosis with a low-grade MPNST is a difficult sections). Rarely, schwannomas (and neurofibromas) can exhibit a distinction, but strong and diffuse S-100 protein staining is in keeping lipoblastic component, accompanied by cells with signet ring–like with a cellular schwannoma. features.373 Other schwannomas have a predominant microcystic/ Psammomatous melanotic schwannoma is a distinctive type reticular appearance; these manifest a predilection for visceral loca- of peripheral nerve sheath tumor that occurs as a component of the tions, particularly the gastrointestinal tract.374 Carney complex.372 Most arise from the spinal nerve roots. As the Exceptionally, otherwise typical schwannomas or those with name indicates, the tumor is characterized microscopically by the epithelioid features have been found to contain foci of small, round presence of melanin pigmentation and the deposition of psammoma hyperchromatic Schwann cells with scanty cytoplasm, sometimes bodies (Fig. 41.76). In contrast to all other types of schwannoma forming rosettes and simulating neuroblastoma.375,376 described in this section, the psammomatous melanotic variety is By electron microscopy, the tumor cells show features of schwann- regarded as a low-grade malignancy because of its tendency for local ian differentiation with a continuous and often reduplicated basal recurrence and ability to metastasize. In fact, Torres-Mora et al. argue lamina; numerous, extremely thin cytoplasmic processes; aggregates that the term “malignant melanotic schwannian tumor” is more of intracytoplasmic microfibrils; peculiar intracytoplasmic lamellar appropriate given that 44% of patients in their series developed bodies; and extracellular long-spacing collagen.377 Immunohistochemi- metastatic disease.387 cally, the tumor cells show immunoreactivity for S-100 protein (Fig. 41.74), calretinin (in contrast to neurofibromas) and basal lamina components (such as laminin and type IV collagen).335 Curiously, keratin is often expressed in retroperitoneal schwannomas but virtually never in peripheral schwannomas.378 Genetically, schwannoma, whether sporadic or associated with type 2 neurofibromatosis, is characterized by somatic mutation (sporadic form) or germline mutation (type 2 neurofibromatosis) of the NF2 gene in one allele, and loss of NF2 in the remaining allele through deletion or mono- somy 22.379,380 Malignant transformation of schwannoma is—in contrast to neurofibroma—an exceptionally rare event, but undoubtedly occurs.381,382 Interestingly, in most of these cases the malignant component has exhibited an epithelioid morphology.383 Figure 41.75 Cellular schwannoma with a compact proliferation of spindle cells arranged in short fascicles. Verocay bodies are not seen. Figure 41.76 Psammomatous melanotic schwannoma in a patient with Figure 41.74 S-100 protein immunoreactivity in a schwannoma. Carney syndrome. 1841 41 Soft Tissues Histochemically, the cytoplasmic granules contain large amounts Granular Cell Tumor of hydrolytic enzymes (such as acid phosphatase), and they are The classic location of granular cell tumor is the tongue, but it has consistently positive for Luxol fast blue.396 Ultrastructurally, they been reported in innumerable other locations, such as skin, vulva, have the appearance of lysosomes. Other interesting electron breast, larynx, bronchus, throughout the gastrointestinal tract, and microscopic findings are the presence of a second cell population soft tissue, among others.388,389 Some patients have multiple lesions, with “angulated bodies” resulting in a Gaucher cell-like appear- particularly in the GI tract.390 There are reports of congenital lesions, ance389,397 and of replicated basal lamina material around the granular most of which arise in the gingiva, but such lesions are S-100-negative cells, the latter suggesting repeated cycles of cellular injury and repair. and probably represent a distinct entity (congenital epulis).391,392 Immunohistochemically, virtually all cases stain strongly for S-100 These tumors are usually small, although we have seen cases protein, as one would expect for a schwannian neoplasm; most also measuring up to 5 cm in diameter. They have a hard consistency express Sox10.398 Other stains often expressed include CD68, cal- and ill-defined margins. This, together with the ulceration sometimes retinin, and inhibin.399,400 complicating the larger cutaneous tumors, explains why they are The large majority of granular cell tumors pursue a benign clinical sometimes confused clinically and on gross inspection with a course. Most cases reported in the old literature as malignant granular malignant neoplasm. The individual cells are large and their cytoplasm cell myoblastomas are in reality examples of alveolar soft part sarcoma. is filled with small, regular granules (Figs. 41.77 to 41.80). They However, there have been several well-documented cases of tumors alternate with larger round droplets having a homogeneous eosino- with a light and electron microscopic appearance entirely consistent philic appearance and strong PAS positivity. The pattern of growth with that of granular cell tumor that have resulted in distant metas- is ill-defined and pseudoinvasive; some can be found in the wall or tases.401 Features favoring malignancy include necrosis, high mitotic lumen of blood vessels, not to be taken as a sign of malignancy.393 activity, spindling of tumor cells, vesicular nuclei with large nucleoli, If the tumor grows near an epithelial surface (e.g., skin, vulva, or and high MIB-1 values.401 larynx), pseudoepitheliomatous hyperplasia occurs that may be Although it is clear that most lesions diagnosed as true granular incorrectly diagnosed as squamous cell carcinoma.394 Elastosis is cell tumors show evidence of schwannian differentiation, a subset often present in the stroma.395 of tumors with granular cells likely are unrelated, particularly those Figure 41.79 Pseudoepitheliomatous hyperplasia in squamous epithelium Figure 41.77 Granular Cell Tumor of Skin. There is an ill-defined overlying a granular cell tumor. permeation of the dermis by whitish tissue. Figure 41.78 Granular Cell Tumor. The cells contain innumerable fine Figure 41.80 Granular cell tumor growing concentrically within and around cytoplasmic granules as well as scattered larger eosinophilic globules. a nerve cut transversely. 1842  Tumors 41 Figure 41.81 Well-circumscribed neurofibroma of soft tissue. The tumor has a gelatinous appearance. that are S-100 protein negative402–405; many of these are cutaneous, polypoid lesions which stain for CD68 and NKI/C3.403 The precise Figure 41.82 Typical gross appearance of a plexiform neurofibroma. line of differentiation of these rare tumors remains obscure. Granular This tumor is indicative of neurofibromatosis type 1. cell change may also be found in a number of other unrelated tumors including vascular and smooth muscle tumors.406,407 We favor making the diagnosis of granular cell tumor only when the entire lesion is granular and S-100 protein positive and to designate the other cases according to their basic component, noting that focal granular changes are present. Neurofibroma The gross, microscopic, and ultrastructural features of neurofibroma, as well as its natural history, are distinct from those of schwannoma. The fact that in some instances the differential diagnosis may be difficult or that in isolated cases features of both lesions may coexist does not justify lumping them together. The gross appearance of neurofibroma varies a great deal from lesion to lesion. As a rule, the tumors are not encapsulated and have a softer consistency than schwannoma (Fig. 41.81). The more superficial tumors appear as small, soft, pedunculated nodules Figure 41.83 Neurofibroma with spindle cells deposited in a collagen protruding from the skin (“molluscum pendulum”). Deeper tumors matrix with a “shredded carrot” appearance. grow larger. Tumors resulting in diffuse tortuous enlargement of peripheral nerves are designated as plexiform neurofibromas (Fig. 41.82) and are usually seen in the context of type 1 neurofibromatosis (von are immunoreactive for S-100 protein and surrounded by basement Recklinghausen disease, caused by a germline mutation in the NF1 membrane components.411 A population of factor XIIIa-positive and gene located on 17q11.2, which encodes neurofibromin).408,409 The CD34-positive cells is also present; the nature of these cells and diffuse involvement of the nerves may make a complete resection their histogenetic relationship with normal nerve constituents is not impossible. This particular form of neurofibroma is more commonly clear.412,413 EMA-positive perineurial cells are common in plexiform seen in the orbit, neck, back, and inguinal region. but not in ordinary neurofibromas.414 The stroma contains a rich Microscopically, neurofibromas are formed by a combined prolif- network of collagen fibers, among which almost all major types eration of all the elements of a peripheral nerve: axons, Schwann cells, are represented (I, III, IV, V, and VI).411 Mucinous changes in the fibroblasts, and (in the plexiform type) perineurial cells. Schwann stroma may be prominent and result in a mistaken diagnosis of cells usually represent the predominant cellular element. Most have myxoma or even myxoid liposarcoma.415 As with schwannomas, markedly elongated nuclei, with a wavy, serpentine configuration neurofibromas may exhibit scattered large hyperchromatic nuclei; and pointed ends (Fig. 41.83). Ultrastructurally, they are seen to these neurofibromas with atypia may also have increased cellularity but enclose axons in plasmalemmal invaginations (mesaxons).410 They mitotic activity is absent (Fig. 41.84).416 The stroma of neurofibromas 1843 41 Soft Tissues Figure 41.84 Neurofibroma with large bizarre hyperchromatic nuclei. Figure 41.85 Marked deformation of distal upper extremity by diffuse neurofibromatosis. This patient developed a malignant peripheral nerve sheath tumor. often contains numerous mast cells. Distorted organoid structures resembling Wagner–Meissner bodies or Pacinian corpuscles are sometimes seen. Patients with this disease may also have GISTs, which are often In contrast to schwannomas, Verocay bodies, palisading of nuclei, present as multiple nodules in the small bowel,424 and lack mutations and hyaline thickening of vessel walls are almost always absent in in KIT and PDGFRA.425,426 neurofibromas. Sometimes, otherwise typical neurofibromas contain Type 2 neurofibromatosis is genetically distinct from type 1, melanin, a feature not unexpected in view of the embryologic relation- resulting from an alteration of the NF2 gene located on chromosome ship between Schwann cells and melanocytes.415 These pigmented 22q12 encoding merlin.427 It is characterized by the presence of a neurofibromas should be differentiated from blue nevi and malignant variety of neoplasms in the CNS, the most distinctive of which are melanomas. Occasionally, an otherwise typical neurofibroma will bilateral acoustic schwannomas. Meningiomas, astrocytomas, and show foci of skeletal muscle differentiation (neuromuscular hamartoma; tumors of other types also occur.428 benign triton tumor).417 Some neurofibromas (as well as other types A small proportion (between 5% and 20%) of patients with type of benign and malignant peripheral nerve tumors) may be partially 1 neurofibromatosis develop MPNST,429 usually in large nerve trunks composed of granular cells, similar in all respects to those of granular of the neck or extremities. For practical purposes, peripheral superficial cell tumor.418 Rare examples have prominent epithelioid features, neurofibromas never become malignant, and the only reasons for similar to those seen in schwannoma and MPNST.367 surgical removal are size and unsightliness. Neurofibromas that occur in the setting of type 1 neurofibromatosis typically show a germline mutation of NF1 in one allele and loss or mutation of NF1 on the other allele, conforming to the “two-hit Perineurioma hypothesis” in tumorigenesis.419 The genetic alterations are less clear Benign tumors of the peripheral nerve composed predominantly or in sporadic neurofibromas, but NF1 alterations are present in at exclusively of perineurial cells are increasingly recognized. Microscopi- least some cases.420 cally, they are composed of extremely elongated cells arranged in Malignant transformation of neurofibroma should be suspected parallel bundles, the appearance being not too dissimilar from that in the presence of mitotic activity in conjunction with increased of neurofibroma or pacinian neurofibroma.430 Some cases have a cellularity, cytologic atypia, and the formation of fascicles. storiform pattern of growth and may correspond to the former Neurofibromatosis. Multiple neurofibromas represent the most storiform perineurial fibromas.431 The diagnosis of perineurioma should important component of the genetically determined disorder known be suspected in myxoid lesions of soft tissue in which a storiform as type 1 neurofibromatosis or von Recklinghausen disease. This is or fascicular pattern of growth is evident (Fig. 41.86). There is an one of the most common autosomal dominant diseases in humans, intraneural variant of perineurioma, associated with nonrandom affecting one in about 3500 individuals.421 The responsible gene chromosomal abnormalities and therefore presumably neoplastic.432 (NF1) is located on chromosome 17q11.2 and encodes a ubiquitous It seems likely that at least some of the cases reported in the past protein known as neurofibromin, which is necessary for the correct as localized hypertrophic neuropathy belong in the same category.433 negative regulation of RAS proteins.422 In this setting, neurofibromas Other recently recognized variants of this tumor include sclerosing may occur in every conceivable site: axilla, thigh, buttock, deep soft perineurioma, which has a predilection for the fingers and palms of tissue, orbit, mediastinum, retroperitoneum, tongue, gastrointestinal young adults434; reticular (retiform) perineurioma, with a predominant tract, and many others. Plexiform neurofibromas may result in massive lace-like or reticular growth pattern composed of anastomosing cords enlargement of a limb or some other part of the body (“elephantiasis of spindle cells; plexiform perineurioma; and the exceptionally rare neuromatosa”) (Fig. 41.85). In addition to neurofibromas, patients granular cell perineurioma.435 Hybrid forms of schwannoma and often have café au lait spots. This consists microscopically of an perineurioma have also been described,436 as well as malignant forms increase in the amount of melanin in the epidermal basal layer and of perineurioma, the latter representing a subtype of MPNST is sometimes seen overlying a neurofibroma. It can be distinguished (see later). from the pigmented spots associated with McCune-Albright syndrome Ultrastructurally, perineurioma is characterized by nonbranching, by virtue of its distribution and smooth, delicate margins.423 Solitary thin cytoplasmic processes coated by an external lamina and joined café au lait spots are common in normal individuals, but when five at their ends by a tight junction, few organelles, actin and vimentin or more are detected, type 1 neurofibromatosis should be suspected. filaments, and numerous pinocytotic vesicles (Fig. 41.87).437 1844  Tumors 41 A Figure 41.88 Epithelial membrane antigen immunoreactivity in perineurioma. Dermal Nerve Sheath Myxoma This is a benign, superficial myxoid neoplasm that most commonly arises on the distal extremities, particularly the fingers. Although originally categorized as a neurothekeoma, this lesion seems unrelated to cellular neurothekeoma, and there is compelling evidence to suggest true nerve sheath differentiation.441,442 It has a gross and microscopic appearance reminiscent of myxoma, except for the B prominent multinodularity with a fibrous border and the presence of plumper, epithelial-like cells and a distinct fascicular or plexiform Figure 41.86 A and B, Two morphologic appearances of perineurioma. arrangement (Fig. 41.89). Immunohistochemically, the cells stain The tumor shown in A simulates a myxofibrosarcoma. for S-100 protein, unlike cellular neurothekeoma. Up to 50% locally recur. Malignant Peripheral Nerve Sheath Tumor MPNST is the currently preferred term for the neoplasm also known over the years as malignant schwannoma, neurogenic sarcoma, and neurofibrosarcoma. Approximately half of these tumors arise de novo, and the other half from neurofibromas as part of type 1 neuro- fibromatosis. Some arise in areas of previous irradiation typically after a latent period of at least 10 years,443 and a few have originated from the Schwann cell-like (satellite cell) component of a ganglioneuroma.444 The large majority of MPNSTs arise in adults, but they have also been recorded in children.445 The most common locations are the neck, forearm, lower leg, and buttock. They can also arise from cranial nerves or their branches. Grossly, the finding of a large mass producing fusiform enlargement of a major nerve, such as the sciatic nerve, is characteristic. Most MPNSTs are deep-seated, but they can Figure 41.87 Electron Microscopic Appearance of Perineurioma. occur in the subcutis or even in the skin.446 Thin perineurial cell cytoplasmic processes with prominent pinocytotic Because of its difficult microscopic recognition, errors are often vesicles. The processes are coated by a continuous basal lamina. (×42000; made, more often than not by diagnosing MPNST as some other Courtesy of Dr. Robert A. Erlandson, Memorial Sloan-Kettering Cancer type of soft tissue sarcoma. There are two circumstances in which Center.) the diagnosis of MPNST should be the primary consideration in the presence of a malignant tumor of soft tissues composed of spindle cells: (1) when the tumor develops in a patient with type Immunohistochemically, the tumor cells are positive for EMA (Fig. 1 neurofibromatosis; or (2) when the tumor is obviously arising 41.88), GLUT-1, CD34, and claudin-1, but they are negative for S-100 within the anatomic compartment of a major nerve or in continuity protein.438 At the cytogenetic level, many cases show deletion of part with a neurofibroma. In the absence of these circumstances, the or all of chromosome 22.439 In addition, mutations of the NF2 gene light microscopic diagnosis of MPNST is often only presumptive and loss of chromosome 13 have also been documented.440 and dependent on a combination of features, none of which is 1845 41 Soft Tissues Figure 41.90 Malignant Peripheral Nerve Sheath Tumor. The marked hypercellularity and high mitotic activity in the absence of significant pleomorphism are commonly seen in this tumor type. A B C Figure 41.89 Dermal Nerve Sheath Myxoma. A, Low power. B, Medium Figure 41.91 Malignant peripheral nerve sheath tumor with plump, almost power. C, High power. The lesion has a distinct lobulated appearance. epithelioid cells surrounding a blood vessel, a common feature of this tumor. diagnostic by itself. They include: serpentine shape of the tumor cell neoplasm with easily identified mitotic figures. Although most cells; arrangement in palisades or whorls; marked contrast between tumors are quite monomorphic (a feature they share with mono- the deeply hyperchromatic nuclei and the pale cytoplasm (“punched- phasic synovial sarcoma), some can be extremely bizarre. At the out nuclei”); perivascular concentration of tumor cells, with a light microscopic level, the latter can simulate the appearance of plumper shape; epithelioid appearance of the endothelial cells of an UPS. Metaplastic tissues (heterologous elements) are present in these vessels; presence of large gaping vascular spaces resulting in approximately 15% of the cases, including chondrosarcomatous, a hemangiopericytoma-like appearance; and geographic areas of osteosarcomatous, rhabdomyosarcomatous, or angiosarcomatous necrosis, with tumor palisading at the edges (Figs. 41.90 to 41.92). differentiation (Figs. 41.93 and 41.94).447,448 The most well-known In most areas the appearance is that of an extremely cellular spindle variant is characterized by the presence of rhabdomyosarcomatous 1846  Tumors 41 Figure 41.93 Malignant peripheral nerve sheath tumor with divergent angiosarcomatous differentiation as well as rare mucin-producing glands. Figure 41.92 Malignant peripheral nerve sheath tumor with an area of necrosis. A B Figure 41.94 Malignant peripheral nerve sheath tumor with rhabdomyosarcomatous differentiation (so-called Triton tumor, A) with positive immunoreactivity for myoglobin (B). 1847 41 Soft Tissues Figure 41.95 Epithelioid malignant peripheral nerve sheath tumor. Figure 41.96 Strong S-100 protein immunoreactivity in epithelioid malignant peripheral nerve sheath tumor. differentiation, often referred to as malignant triton tumor.449 Areas of recognizable MPNST should be present to make such a diagnosis in these metaplastic tumors; otherwise a diagnosis corresponding to the morphologic appearance of the tumor is appropriate, even if the patient has type 1 neurofibromatosis. Although rare MPNSTs show foci of glandular differentiation (Fig. 41.93), this feature is found only in patients with type 1 neurofibromatosis.450 In some MPNSTs, part or most of the tumor is composed of plump cells with polygonal acidophilic cytoplasm and an epithelioid- like appearance; these are designated as epithelioid MPNST (Fig. 41.95).451,452 These account for approximately 5% of all MPNSTs. Interestingly, most of the MPNSTs that have arisen from malignant transformation of benign schwannomas have been of the epithelioid type. Histologically, most cases show a vaguely nodular appearance with epithelioid cells arranged in sheets or cords. The cells have melanoma-like nuclei with prominent nucleoli. Some examples show rhabdoid morphology with paranuclear inclusions. Most stain strongly Figure 41.97 Patchy S-100 protein immunoreactivity in a spindle cell for S-100 protein, a pattern that contrasts with spindled MPNST type of malignant peripheral nerve sheath tumor. (Figs. 41.96 and 41.97).452 They lack melanoma-associated antigens (HMB-45 and Melan-A) and typically do not stain for cytokeratins. of staining in a higher percentage of cases as tumor grade increases.456a Almost 50% show loss of staining for SMARCB1 (also known as Although this marker is not particularly sensitive, it does seem to INI1) which is typically retained in melanoma.453 be highly specific for MPNST. Other markers reported in MPNST Conventional MPNST does not have a characteristic immuno- include nestin,457 HMGA2,458 and CD57.459 phenotype. Between 50% and 90% of these tumors stain for S-100 The clinical evolution is generally that of a highly malignant protein, typically in a patchy fashion.454 Although often taken as neoplasm, with frequent local recurrences and distant metastases.460–462 evidence of nerve sheath differentiation, this marker lacks specificity Prognostic factors vary among studies; however, tumor size and given that other lesions in the differential diagnosis (e.g., synovial metastatic disease at initial presentation are consistently identified sarcoma) also stain for this antigen. More recently, Sox10, a neural as important variables. Most metastases occur in the lungs. crest transcription factor, has been found to be expressed in the MPNSTs usually show a complex karyotype with numerical and majority of MPNSTs, including those which are S-100 protein nega- structural abnormalities.380,463 Whether occurring sporadically or in tive.398,455,456 CD34 and EMA may also be expressed in MPNSTs, the setting of type 1 neurofibromatosis, both alleles of the NF1 gene likely reflecting focal perineurial differentiation. More recently, loss are often inactivated.464 In addition, there are commonly mutations of histone H3K27 trimethylation by immunohistochemistry has in the TP53 gene, deletion of CDKN2A (9p21), and gain or amplifica- been noted in approximately 50% of MPNSTs, with complete loss tion of 17q25, probably involving BIRC5/SURVIVIN.465–468 More 1848  Tumors 41 A Figure 41.98 Gross Appearance of Lipoma. Except for the circumscrip- tion, the appearance is indistinguishable from that of normal fat. recently, loss of function mutations of the Polycomb repressive complex 2 (PRC2) components (EED or SUZ12) was identified in the vast majority of MPNSTs, including both NF1-associated and radiotherapy-associated MPNSTs.468a Tumors of Adipose Tissue Lipoma B Benign fatty tumors can arise in any location in which fat is normally present. The majority occur in the upper half of the body, Figure 41.99 Chondroid Lipoma. A, Low-power and B, High-power particularly the trunk and neck, but they can develop in any other views. site, including hands and feet. Most lipomas are subcutaneous, an important point in the differential diagnosis with liposarcomas, which are almost always deep-seated. However, lipomas can also occur in the deep soft tissues; these are subclassified into intramus- biochemical extraction and the activity of lipoprotein lipase is cular (most common in the trunk) and intermuscular (most common different.474 in the anterior abdominal wall).469 Most patients are in the fifth Morphologic variations that lipomas may exhibit include the or sixth decade of life. Only rarely are children affected. Lipomas following: may be single or multiple. Multiple lipomas are more common in 1. Fibrolipoma. This is characterized by the presence of prominent women; many are seen in a familial setting, and some occur in bundles of mature collagenous or myxocollagenous stroma patients with neurofibromatosis or multiple endocrine neoplasia. intermixed with mature adipocytes, usually involving the distal In diffuse lipomatosis, massive enlargement of a limb may be extremities.475,476 seen as a result of diffuse proliferation of mature adipose tissue. 2. Myxolipoma. This tumor shows extensive stromal myxoid change In the familial variant of this process, lipomatosis has a symmetric and should not be overdiagnosed as myxoid liposarcoma.477 distribution.470 3. Chondroid lipoma. This variant is usually deep-seated and is Lipomas can grow to a large size; they are usually encapsulated characterized by a component of eosinophilic and vacuolated when located in the superficial soft tissues but tend to be poorly cells containing glycogen and lipid that resembles brown fat cells, circumscribed when arising in deeper structures. Grossly, lipomas lipoblasts, and chondroblasts (Fig. 41.99).478,479 This tumor can consist of bright yellow fat separated by fine fibrous trabeculae (Fig. be mistaken for either chondrosarcoma or myxoid liposarcoma. 41.98). Microscopically, they are composed of mature adipose tissue 4. Myolipoma. This tumor is characterized by an admixture in with no cellular atypia. They are cytologically and immunohistochemi- variable proportions of mature adipose tissue and bundles of cally indistinguishable from normal fat, including positivity for S-100 well-differentiated smooth muscle.480 protein and calretinin.471 5. Spindle cell lipoma. This is a benign fatty tumor characteristically Areas of fat necrosis, infarct, and calcification may be present. It located in the regions of the shoulder, upper back, and posterior is important not to confuse the histiocytes associated with fat necrosis neck of middle-aged adults but also found in many other locations, with lipoblasts. The fact that they are often seen arranged in a cir- including the limbs, face, oral cavity, and trunk. It is composed cumferential fashion around a large lipid droplet (as is also the case of an admixture of mature lipocytes and uniform spindle cells in fat necrosis at other sites) is a helpful diagnostic sign. Rarely, set in a mucinous and fibrous background (Fig. 41.100).481 Features lipomas harbor foci of mature metaplastic cartilage or bone.472 that assist in distinguishing it from myxoid liposarcoma include Ultrastructurally, only univacuolar mature adipocytes are present the absence of lipoblasts and of a prominent plexiform vascular in typical lipomas.473 Although the light microscopic and electron pattern, the presence of thick (“ropey”) collagen bundles, and microscopic appearance of a lipoma does not differ significantly the great uniformity of the proliferating small spindle cells. In from that of normal adult fat, its lipid content as determined by some instances the presence of irregular branching spaces with 1849