Peritoneal malignant mesothelioma (PMM) (see corresponding heading).

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  Features that favor or indicate PMM include grossly visible nodules, definite invasion, diffuse marked nuclear atypia, and necrosis. However, some of these features are often absent or present only focally within a PMM.

  
  
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  Reactive mesothelial cells, unlike PMMs, are typically positive for desmin and BAP1 (BRCA1-associated protein) but negative for EMA, IMP3, p53, GLUT-1, XIAP, and EZH2. EMA and IMP3 together are better than either marker alone (Chang et al.). GLUT-1 and IMP3 positivity strongly favors PMM, but negative expression does not exclude it; both markers are occasionally found in benign mesothelial proliferations.

  
  
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  Pillappa et al. found that loss of BAP1 expression in atypical mesothelial proliferations helps predict malignant mesothelioma.

  
  
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  Reactive mesothelial hyperplasias lack homozygous deletions of the 9p21 locus (that encodes deletions of p16/CDKN2A) by FISH that are present in PMMs (see latter heading).

Serous tumors of peritoneal or genital tract origin. Grossly visible ovarian or peritoneal tumor, columnar cells with or without cilia, neutral mucin, numerous psammoma bodies, and immunohistochemical markers for epithelial differentiation favor or establish the diagnosis of a serous tumor.

These are usually an incidental intraoperative finding. Single or multiple, small, thin-walled, translucent, unilocular cysts are attached to the peritoneum or an abdominal organ or are free-floating.

They have a smooth lining composed of a single layer of flattened, benign mesothelial cells, and yellow watery to gelatinous contents.

Most unilocular PICs are probably reactive (as with multilocular PICs; see below), whereas some in the mesocolon, small bowel mesentery, retroperitoneum, and splenic capsule may be developmental.

These lesions (MPICs), also referred to (inappropriately in our opinion) as ‘benign multicystic mesothelioma’, are usually associated with clinical manifestations, most commonly lower abdominal pain, a palpable mass, or both.

A history of a prior abdominal operation, pelvic inflammatory disease, or endometriosis has been found in up to 85% of patients in some studies, suggesting that most MPICs are reactive and a result of adhesions. Indeed, in some cases it may be arbitrary whether a process is best categorized as florid adhesions or an MPIC.

MPICs usually adhere to pelvic organs and may even simulate a cystic ovarian tumor on clinical examination, at laparotomy, or gross pathologic examination; the upper abdominal cavity, the retroperitoneum, or hernia sacs may also be involved. One MPIC with lymph node involvement has been reported.

The lesions may be large (up to 20 cm or rarely larger) with walls and septa often containing considerable amounts of fibrous tissue. Their contents may resemble those of the unilocular cysts or be serosanguineous or bloody.

The cysts are typically lined by a single layer of flat to cuboidal, occasionally hobnail-shaped, mesothelial cells with nuclear features that vary from bland to mildly atypical. Squamous metaplasia is occasionally seen.

Unusual findings include intracystic papillae or cribriform patterns, and mural proliferations of typical or atypical mesothelial cells arranged singly, as gland-like structures or nests, or in patterns resembling those in adenomatoid tumors. Occasional vacuolated mesothelial cells in the stroma may simulate signet-ring cells. Rare MPICs have contained foci of endometriosis.

The septa typically consist of fibrovascular connective tissue, but occasionally contain a marked acute and chronic inflammatory cell infiltrate, abundant fibrin, granulation tissue, and evidence of recent and remote hemorrhage.

The mesothelial cells are typically immunoreactive for calretinin, and in occasional cases, ER, PR, or both.

Follow-up has not disclosed malignant behavior. ‘Recurrences’ develop in as many as half the cases months to many years postoperatively, although these are often likely due to newly formed adhesions. Some MPICs have responded to treatment with GnRH agonists, oral contraceptive, or tamoxifen.

The differential diagnosis of MPICs includes:

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  Florid adhesions (see above). MPICs should be grossly evident as one or more cystic masses.

  
  
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  Multilocular cystic lymphangiomas. Differential features include typical occurrence in children (especially boys), usual extrapelvic location (small intestine mesentery, omentum, mesocolon, retroperitoneum), chylous fluid contents, mural lymphoid cells and smooth muscle, and endothelial lining cells.

  
  
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  Multicystic adenomatoid tumor. In contrast to MPICs, these tumors typically involve the myometrium, have a prominent component of smooth muscle, contain foci of typical adenomatoid tumor, and lack prominent inflammation. Serosal-based examples may be particularly challenging.

  
  
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  True multicystic mesothelioma (see Malignant Mesothelioma ).

PMMs account for only 10–20% of mesotheliomas, and in women are much less common than peritoneal involvement by serous carcinomas ( Chapter 19 ).

In most studies, males have predominated but one large study (Liu et al.) found an equal male:female ratio and an average age of 52 years (range 15–80). Occasional tumors occur in young adults and children.

The usually nonspecific presenting manifestations include abdominal discomfort and distension, digestive disturbances, and weight loss. Ascites is present in most cases; cytologic examination of the ascitic fluid may be diagnostic.

Rare presentations include localization to a hernia or hydrocele sac; as a retroperitoneal, umbilical, intestinal, pelvic, or splenic tumor; or as cervical, supraclavicular, or inguinal lymphadenopathy. The intraoperative appearance of rare cases with prominent ovarian involvement can mimic a primary ovarian tumor ( Chapter 17 ).

Two series of PMMs in women found no association with asbestos exposure, although asbestos fibers can be identified with special techniques in some cases. Radiation, chronic inflammation, organic chemicals, and nonasbestos mineral fibers are also potential etiologic agents.

Butnor et al. have noted rare cases of PMMs associated with Crohn’s disease but not ulcerative colitis. Lu et al. reported a PMM associated with Lynch syndrome (HNPCC) in a woman who had a previous endometrial endometrioid adenocarcinoma.

The visceral and parietal peritoneum is usually diffusely thickened by countless nodules and plaques that may coalesce and encase the viscera, but visceral invasion and lymphatic and hematogenous spread are less common than in carcinomas with similar degrees of peritoneal involvement. Some tumors, particularly if desmoplastic, may be associated with dense adhesions. Rare tumors are localized solitary masses.

Most PMMs are of epithelioid type. The typical patterns, in order of frequency, are tubular, papillary, and solid. These patterns often coexist (especially tubular and papillary), but occasionally one of them is the predominant or exclusive pattern. Small nests and cords of tumor cells may also be seen.

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  In contrast to serous tumors, the papillary pattern is usually nonhierarchical and without conspicuous cellular budding from the surfaces of the papillae. Additionally, the cores of the papillae are often hyalinized and/or contain foamy histiocytes (see below).

  
  
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  The tubules are usually small and round, but are occasionally cystic or slit-like; the latter may be branched or even retiform.

The tumor cells typically retain a resemblance to mesothelial cells, with a polygonal, cuboidal, or low-columnar shape and usually moderate amounts of eosinophilic cytoplasm. Small foci of spindled tumor cells are present in occasional otherwise purely epithelial tumors.

Tumor cells with variably sized cytoplasmic vacuoles are sometimes present and focally may suggest an adenomatoid tumor, or in other cases, a signet-ring cell adenocarcinoma. Rarely large numbers of these cells are present (see below).

Nuclear atypia is usually only mild to moderate, although severe atypia occurs in occasional tumors. Mitotic figures are seen but only rarely conspicuous.

Invasion of subperitoneal tissues is usually present; subtle invasion can be highlighted by cytokeratin staining. Tumor commonly dissects into the omental fat. As noted above, intra-abdominal lymph nodes may be involved.

The stroma varies from scanty to prominent, and from hyalinized to more cellular and desmoplastic. Rare tumors have a prominent myxoid stroma that widely separates the tumor cells.

Occasional tumors exhibit prominent inflammation, most commonly lymphocytes (sometimes with lymphoid nodules), plasma cells, or foamy histiocytes. Discrete granulomas are occasionally present.

Psammoma bodies are present in about a third of tumors, but are rarely as conspicuous as in serous tumors. Baker et al. found necrosis in about one-third of their tumors but it was prominent in only one-third of those.

Biphasic and sarcomatoid patterns.

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  These accounted for 6.6% of PMMs in females in one study (Baker et al.).

  
  
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  found that 2% of sarcomatoid MMs were peritoneal; Pavlisko and Roggli found that sarcomatoid MMs accounted for 4% of PMMs. In the latter study, patients with sarcomatoid PMMs were aged 48–85 years (median 66), with a male:female ratio of 3.25 : 1.

  
  
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  The epithelioid component of the biphasic tumors resembles that of the purely epithelioid tumors. The sarcomatoid component of the biphasic and purely sarcomatous tumors exhibits solid, fascicular, and/or storiform patterns, and usually consists of spindle cells with high-grade nuclei. However, in some spindle cell tumors, cytologic features can be deceptively bland focally.

Deciduoid pattern.

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  This pattern was initially thought to be more common in the peritoneum of young women, but found that only 6 of 21 patients were female and only 4 of 21 cases were peritoneal.

  
  
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  The cardinal histologic feature is the presence of large polygonal cells with well-defined cell borders, arranged in solid sheets, voluminous and dense eosinophilic cytoplasm, and single or multiple nuclei. Abundant cytoplasmic intermediate filaments likely account for the distinctive cytologic features.

  
  
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  In the cited series, the tumors were classified as low grade or high grade. Tumors in the latter exhibited a wide range of cell size and shape, frequent loss of cellular cohesion, marked nuclear atypia, a high mitotic rate (>5 mf/10hpf), and a mean survival of 7 months in contrast to 23 months for the low-grade group.

  
  
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  The previously reported aggressive behavior of deciduoid MMs appears to be largely related to their typical high-grade features.

Pleomorphic variant. These rare PMMs are characterized by large, often dyscohesive cells with a highly variable size and shape, copious eosinophilic cytoplasm, and single to multiple pleomorphic nuclei often with macronucleoli.

Signet-ring cell mesothelioma. These tumors are characterized by large numbers of signet-ring-like cells. In the two examples in the study, the signet-ring cells accounted for 15–25% of the tumors that were otherwise of epithelioid type with tubulopapillary and solid patterns. The vacuoles in the signet-ring cells were typically clear but occasionally contained a bluish granular material; mucicarmine staining was negative.

Multicystic pattern. These tumors have not been well characterized, but at least some exhibit invasion, cellular atypia, and/or other features inconsistent with an MPIC (Sethna et al.).

Unusual cell types that can be present in striking numbers include tumor cells with abundant clear (glycogen-rich) or foamy (lipid-rich) cytoplasm, hobnail-type cells, or cells resembling those of extrarenal rhabdoid tumors.

Heterologous elements. Tumors with these elements, which may include rhabdomyosarcoma, osteosarcoma, chondrosarcoma, are usually sarcomatoid or biphasic ( ).

In situ malignant mesothelioma. reported a putative case of in situ PMM in a male with ascites and minimal omental thickening on imaging, but no laparoscopically visible tumor. Omental biopsy showed a single layer of minimally atypical mesothelial cells with rare foci of superficial invasion. The lesional cells had loss of nuclear BAP1 staining and CDKN2A deletion (see next heading).

PMMs typically stain for calretinin, CK 5/6, WT1, podoplanin, thrombomodulin, mesothelin, CA125, EMA, EGFR, IMP3, D2-40, GLUT1, and EZH2. Claudin-4, MOC31, B72.3, CK20, CD15, CEA, ER, PR, PAX8, and p63 are typically (but not invariably) negative (Tandon et al.). Notable exceptions include PAX8 positivity in up to 15% of PMMs (Chapel et al.) and occasional calretinin− deciduoid PMMs (Dominiak et al.).

BAP1.

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  and Cigognetti et al. found that immunohistochemical loss of BAP1 (BRCA-associated protein 1) is 100% specific for MM whereas BAP1 is expressed in benign mesothelial cells and benign mesothelial tumors. Sheffield et al. found immunohistochemical loss of BAP1 in 27% of MMs but in 0% of benign mesothelial proliferations.

  
  
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  Andrici et al. found loss of BAP1 in 67% of PMMs. Combined BAP1 loss and p16 FISH deletions were 58% sensitive and specific for diagnosing MMs, particularly when invasion cannot be identified.

  
  
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  Shinozaki-Ushiku et al. found BAP1 loss and high EZH2 expression in 53% and 66% of MMs respectively, whereas no benign mesothelial lesion showed BAP1 loss or high EZH2 expression. Using both markers improved diagnostic accuracy.

  
  
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  Joseph et al. found biallelic inactivation of BAP1 in 9/13 PMMs and monoallelic BAP1 loss in 2/13; all 11 of these cases had loss of BAP1 nuclear staining. All other peritoneal lesions tested (PMMs without BAP1 alteration, MPICs, WDPMs, ATs, LGSCs) had intact BAP1 staining. Additionally, mutated genes included NF2 (3/13), SETD2 (2/13), and DDX3X (2/13).

p16 deletions.

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  Using p16 FISH, p16 deletions (or 9p21 deletions, the locus harboring the p16 gene) have been found in 52–88% of MMs (Hwang et al., Monaco et al., Sheffield et al., ) vs 0% of benign mesothelial lesions. found that homozygous deletion of p16 by FISH is 100% specific for MM.

  
  
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  Ito et al. found that 47.4% and 15.8% of PMMs showed, respectively, homozygous or heterozygous deletion of p16/CDKN2a ; all mesothelial hyperplasias and epithelial ovarian cancers were negative for p16 deletion.

  
  
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  Hwang et al. found that p16 FISH deletions in surface epithelial-type mesothelial proliferations predicted underlying invasive mesothelioma.

  
  
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  found homozygous deletion of p16/CDKN2A (with co-deletion of MTAP) and loss of p16 protein expression in 35% of PMMs. Patients with the deletion were all males, older (mean, 63 years), and had worse OS and DFS. Similarly, Borczuk et al. found that negative p16 staining (defined as absent or weak staining in <5% of cells) was associated with poor survival.

  
  
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  Hida et al., studying pleural MMs, found that p16 FISH results combined with BAP1 IHC provided higher confidence in diagnosis than either test alone.

  
  
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  found that FISH analysis of p16/CDKN2A and BAP1 IHC helped confirm the neoplastic (vs reactive) nature of the spindle cell component in biphasic mesotheliomas.

EWSR1/FUS–ATF1 fusions.

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  Desmeules et al. found recurrent EWSR1/FUS–ATF1 fusions in 16% of peritoneal and pleural MMs. Tumors with fusions occurred in young individuals without a history of asbestos exposure, and exhibited typical epithelioid morphology. BAP1 expression was retained in the fusion-positive tumors and in 80% of fusion-negative MMs.

Other findings.

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  Singhi et al. found that combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for PFS and OS in PMMs.

  
  
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  Takeda et al. found that 36% of PMMs exhibited 9p21 deletion by FISH vs 85% in their pleural counterparts.

  
  
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  Chirac et al., using comparative genomic hybridization, found chromosomal instability in PMMs and a genomic pattern similar to that of pleural MMs, including loss of chromosome regions 3p21, 9p21, and 22q12.

  
  
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  Joseph et al., using genomic profiling of PMMs, found recurrent alterations in epigenetic regulatory genes BAP1 , SETD2 , and DDX3X , suggesting opportunities for targeted therapies.

  
  
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  Enomoto et al. found that the common membranous staining for epidermal growth factor receptor in MMs is not related to gene copy number gain.

  
  
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  . found that rare PMMs show unique ALK rearrangements that may represent a novel pathogenetic mechanism with promise for targeted therapy. Such tumors lacked asbestos fibers as well as cytogenetic and molecular alterations typically found in PMMs.

Florid mesothelial hyperplasia (see corresponding heading).

Well-differentiated papillary mesothelioma. This diagnosis is favored when the lesion is solitary, small, comprised of exclusively bland mesothelial cells, and noninvasive.

Reactive fibrosis (vs sarcomatoid or desmoplastic PMM) (see Peritoneal Fibrosis).

Serous adenocarcinoma with diffuse peritoneal involvement.

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  Features favoring a diagnosis of PMM include a prominent tubulopapillary pattern, lack of psammoma bodies, polygonal cells with moderate amounts of eosinophilic cytoplasm, only mild to moderate nuclear atypia, a paucity of mitotic figures, acid mucin (alcianophilic material) rather than neutral (PAS+) mucin, and the immunoprofile noted above.

  
  
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  Serous carcinomas, unlike most PMMs, immunoreact for B72.3, MOC-31, Ber-EP4, PAX8, ER, and claudin-4. Kawai et al. found that serous carcinomas were Ber-EP4+/claudin-4+/PAX8+/calretinin− whereas PMMs had the reverse profile.

  
  
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  Comin et al. found that an h-caldesmon+/calretinin+/ER − /Ber-EP−profile strongly favors PMM over serous carcinoma. Yuan et al. have found that tenascin-X is a reliable marker for mesotheliomas, but is absent in ovarian (including serous) carcinomas.

  
  
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  Andrici et al. found loss of BAP1 expression in only 0.3% of serous carcinomas vs 67% of PMMs.

  
  
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  No single immunohistochemical stain is diagnostic in the separation of PMM from adenocarcinoma, and the results of a panel of antibodies should be interpreted in conjunction with stains.

  
  
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  As noted above, homozygous deletion of p16 by FISH would indicate PMM in this differential.

Ectopic decidua (vs deciduoid PMM). Prominent nucleoli, often brisk mitotic activity, and cytokeratin positivity exclude an ectopic decidual reaction with the caveat that some deciduoid mesotheliomas show only focal positivity for CK5/6 and calretinin.

Epithelioid hemangioendothelioma/angiosarcoma (see Sarcomas ).

Intra-abdominal ‘PEComatosis’. Salviato et al. described a tumor with diffuse peritoneal involvement that was composed of epithelioid and spindle cells with clear cytoplasm mimicking mesothelioma. The immunoprofile (HMB45+, melan-A+, smooth muscle actin+), however, suggested a myomelanocytic tumor or PEComa ( Chapter 9 ).

Krasinskas et al. (2015) found an overall median survival of 36 months. With cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, Yan et al. found a median survival of 53 months and 3- and 5-year survivals of 60% and 47%, respectively.

Kerrigan et al. found that a greater proportion of women with PMMs had a longer survival, some surviving for many years.

Tubulopapillary PMMs have the best prognosis, solid epithelioid/typical deciduoid PMMs have an intermediate prognosis, and pleomorphic/sarcomatoid tumors have the worst prognosis (Liu et al., ). Pavlisko and Roggli found a mean survival of 5 months (range 0–12) for sarcomatoid PMMs.

Other adverse prognostic factors have included a solid growth pattern, increasing nuclear/nucleolar size, a high mitotic index (>5 mf/50 hpf), CDNKN2A/p16 deletions ( ), loss of p16 staining (Borczuk et al.), and low WT1 expression.

Favorable prognostic factors include an age <60 years, localized tumor, no deep invasion, low nuclear grade, low mitotic count, prominent lymphocytic host response, complete/near complete tumor resection, and hyperthermic intraoperative peritoneal chemotherapy with cisplatin (Alexander et al.).

Valente et al. developed a two-tier grading system for epithelioid PMMs. The nuclear atypia score (graded 1, 2, or 3) was added to the mitotic score (1: 0–1 mf/10hpf; 2: 2–4 mf/10hpf; 3: ≥5 mf/10hpf) for an overall score. Low-grade tumors (overall score of ≤3) had a higher OS (median 11.9 years, 57% at 5 years) than high-grade tumors (overall score 4–6) (median 3.3 years, 21% at 5 years).

The International Collaboration on Cancer Reporting (ICCR) has recommended a data set for reporting malignant mesotheliomas ( ).

These tumors (DSRCTs) are of uncertain histogenesis, but may be a primitive tumor of mesothelial origin. Although most are intra-abdominal, similar tumors also occur in the pleura and rarely at a distance from mesothelial surfaces (parotid gland, central nervous system).

DSRCTs have a strong male predilection (M:F ratio 4 : 1) and are most common in adolescents and young adults (range 5–76 years) who usually have abdominal distension, pain, and a palpable abdominal, pelvic, or scrotal mass, sometimes in association with ascites. Occasionally the serum level of CA125 or neuron-specific enolase is elevated.

DSRCTs exhibit a unique reciprocal translocation [t(11;22) (p13;q12)] resulting in fusion of the EWS1 gene on chromosome 22 and the Wilms’ tumor suppressor gene ( WT1 ) on chromosome 11. This fusion results in the expression of the EWS/WT1 chimeric transcript detectable by FISH.

The EWS/ERG fusion gene characteristic of Ewing’s sarcoma/peripheral neuroectodermal tumors (PNETs) has been found in rare DSRCTs, suggesting some overlap between the two groups of tumors.

Laparotomy typically discloses a usually large, intra-abdominal mass or more often masses of varying size; tumor may be confined to the pelvis. Prominent ovarian involvement can mimic a primary ovarian tumor. The retroperitoneum is involved in some cases.

Treatment (debulking and postoperative chemotherapy, irradiation, or both) may result in an initial response, but >90% of patients die from tumor progression. The tumor tends to remain within the peritoneal cavity, but extra-abdominal metastases occur in some patients.

On gross examination, the tumors, which may reach 40 cm in maximal dimension, have smooth or bosselated outer surfaces and firm to hard, gray-white, focally myxoid and necrotic sectioned surfaces. Direct invasion of abdominal or pelvic viscera may occur.

Usual microscopic features:

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  Sharply circumscribed aggregates of small epithelioid cells are delineated by a cellular desmoplastic stroma. The aggregates vary from tiny clusters (or even single cells) to rounded or irregularly shaped islands.

  
  
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  Other common features include rounded rosette-like or gland-like spaces, peripheral palisading of basaloid cells in some nests, and central necrosis with or without calcification.

  
  
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  The typically uniform tumor cells have scanty cytoplasm and indistinct cell borders. Tumor cells with eosinophilic cytoplasmic inclusions and an eccentric nucleus, resulting in a rhabdoid appearance, are also frequently present.

  
  
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  Small to medium-sized, round, oval, or spindle-shaped hyperchromatic nuclei have clumped chromatin. Mitotic figures and single necrotic cells are numerous.

Unusual microscopic features:

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  Architectural features that may predominate and lead to diagnostic problems include a solid pattern, tubules, follicle-like spaces, glands (sometimes with luminal mucin), cysts, papillae, anastomosing trabeculae, cords mimicking lobular breast carcinoma, adenoid cystic-like foci, and a sparse desmoplastic stroma.

  
  
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  Cytologic features that can predominate include spindle cells, cells with abundant eosinophilic or clear cytoplasm, signet-ring-like cells, and cells with marked nuclear pleomorphism, including bizarre forms.

Invasion of vascular spaces, especially lymphatics, is common. Lymph nodes are occasionally involved by tumor.