Mesothelial Hyperplasia
This lesion is a common response to chronic ascites, inflammation (such as pelvic inflammatory disease), operations, endometriosis, ovarian tumors, and metastatic tumors. Mesothelial hyperplasia confined to a hernia sac may reflect trauma or incarceration. Solitary or multiple small nodules may be visible at operation, but more commonly the process is an incidental microscopic finding.

The hyperplastic mesothelial cells are usually confined to the peritoneal surface in the form of nodules, plaques, or papillae. In occasional cases, however, small nests, trabeculae, tubules, papillae, or even single cells can become entrapped in reactive fibrous tissue or extend superficially into underlying tissues, including the walls of ovarian tumors, endometriotic cysts, and peritoneal inclusion cysts ("mural mesothelial proliferation"). This finding can have a worrisome infiltrative appearance that can sometimes be mistaken for invasive tumor. A clue to the correct diagnosis in such cases is that the hyperplastic mesothelial cells are often focally disposed within the tissue in linear, sometimes parallel, arrangements; also the cells are in continuity with the serosa rather than, in the instance of an ovarian tumor, the obviously neoplastic cells of the ovarian tumor. We have also seen cases of mesothelial hyperplasia on the surface of an ovarian tumor that have been misdiagnosed as serosal involvement by tumor, an error that would result in assignment of a stage of Ic rather than Ia. The hyperplastic mesothelial cells resemble normal mesothelial cells, being usually cuboidal with eosinophilic cytoplasm; the latter may contain vacuoles that stain for acid mucin (predominantly hyaluronic acid) but not for neutral (PASD+) mucin. There is usually only mild or occasionally moderate nuclear pleomorphism; multinucleated cells and occasional mitotic figures may be seen. Uncommon findings include psammoma bodies and eosinophilic strap-shaped cells resembling rhabdomyoblasts. In some cases, histiocytes may be admixed with the mesothelial cells, and may predominate in some cases.

Rarely, hyperplastic mesothelial cells can be found as an incidental finding in abdominopelvic lymph nodes where they may be misinterpreted as metastatic tumor. There is usually comcomitant mesothelial hyperplasia of the pelvic and/or abdominal peritoneum. The cells may form nests or papillary clusters within the sinusoids of the lymph node; in some cases the appearance is similar to that of sinus histiocytosis. The appearance of the cells on routine stains suggests the correct diagnosis, although distinction of the process from a metastatic serous borderline tumor can be difficult. If necessary, metastatic borderline tumor or carcinoma can be excluded with mucin and immunohistochemical stains (see page 9). If misdiagnosis of the process occurs in a woman with a known primary pelvic cancer, it could result in inappropriate staging and treatment, or in a different setting, could precipitate a fruitless search for an occult primary tumor.

Differential Diagnosis

1. Peritoneal malignant mesothelioma (PMM). Features that favor or indicate PMM include grossly visible nodules, deep infiltration, necrosis, a diffuse uniform tubulopapillary pattern, large "empty" cytoplasmic vacuoles, marked nuclear atypia, and atypical mitotic figures. Some of these features, however, such as marked nuclear atypia, may be absent or present only focally within a PMM. Although immunroeactivity for p53 and/or EMA favors PMM and desmin positivity favors hyperplasia, immunofindings cannot be relied upon to assist in this differential diagnosis in an individual case.
2. Serous borderline tumors (BSTs) of primary peritoneal or ovarian origin. Grossly visible ovarian or peritoneal tumor, columnar cells with or without cilia, neutral mucin, numerous psammoma bodies, and immunohistochemical markers for epithelial differentiation (page 9) all favor or indicate a BST.

References

1. Chan JKC, Loo KT, Yau BKC, Lam SY. Nodular histiocytic/mesothelial hyperplasia: A lesion potentially mistaken for a neoplasm in transbronchial biopsy. Am J Surg Pathol 21:658-63, 1997
2. Churg AC et al. The separation of benign and malignant mesothelial proliferations. Am J Surg Pathol 24:1183-200, 2000
3. Clement PB, Young RH. Florid mesothelial hyperplasia associated with ovarian tumors: A possible source of error in tumor diagnosis and staging. Int J Gynecol Pathol 12:51-58, 1993
4. Clement PB, Young RH, Oliva E, Sumner HW, Scully RE. Hyperplastic mesothelial cells within abdominal lymph nodes: A mimic of metastatic ovarian carcinoma and serous borderline tumor. Mod Pathol 9:879-86, 1996
5. Gupta A, Bhan AK, Bell DA. Can the implants of serous borderline tumors of the ovary be distinguished from mesothelial proliferations by the use of immunohistochemistry? Abstract. Mod Pathol 16:10A, 2003
6. Davidson B, Nielsen S, Christensen J et al. The role of desmin and N-cadherin in effusion cytology. Am J Surg Pathol 25:1405-12, 2001
7. Henderson DW, Shilkin KB, Whitaker D. Reactive mesothelial hyperplasia vs mesothelioma, including mesothelioma in situ. Am J Clin Pathol 110:397-404, 1998
8. Kerner H, Gaton E, Czernobilsky B. Unusual ovarian, tubal and pelvic mesothelial inclusions in patients with endometriosis. Histopathology 5:277-282, 1981
9. McCaughey WTE, Al-Jabi M. Differentiation of serosal hyperplasia and neoplasia in biopsies. Pathol Annu 21(1):271-292, 1986
10. Rosai J, Dehner LP. Nodular mesothelial hyperplasia in hernia sacs. A benign reactive condition stimulating a neoplastic process. Cancer 35:165-175, 1975

Peritoneal Inclusion Cysts
Peritoneal inclusion cysts (PICs) typically occur in women of reproductive age; rarely the lesions occur in males and in the pleural cavity. They may be unilocular or multilocular. Unilocular PICs Unilocular PICs are usually an incidental intraoperative finding. Single or multiple, small, thin-walled, translucent, unilocular cysts are attached or free-floating. The cysts have a smooth lining, yellow and watery to gelatinous contents, and a lining composed of a single layer of flattened, benign mesothelial cells. Most unilocular PICs are probably reactive, whereas some of those in the mesocolon, mesentery of the small intestine, retroperitoneum, and splenic capsule may be developmental. Multilocular PICs (MPICs) We prefer the designation "multiolocular peritoneal inclusion cyst" (MPIC) for this lesion, but it is also commonly referred to as "benign cystic mesothelioma, and in the older ltierature, "inflammatory peritoneal cyst" and "postoperative peritoneal cyst" were also used. In contrast to unilocular PICs, MPICs, which may reach 20 cm in maximal dimension, are usually associated with clinical manifestations, most commonly lower abdominal pain, a palpable mass, or both. MPICs are usually adherent to pelvic organs. MPICs may mimic a cystic ovarian tumor on clinical examination, at laparotomy, or even on pathological examination, especially if adherent to an ovary. The upper abdominal cavity, the retroperitoneum, or a hernia sac may also be involved.

Unlike unilocular PICs, the septa and walls of MPICs may contain considerable amounts of fibrous tissue. Their contents may resemble those of the unilocular cysts or be serosanguineous or bloody. MPICs 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. Unusual findings include squamous metaplasia, intracystic papillae or sheets of mesothelial cells, 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. The septa typically consist of fibrovascular connective tissue, but occasionally contain a striking acute and chronic cell infiltrate, abundant fibrin, granulation tissue, and evidence of recent and remote hemorrhage. One MPIC had a prominent xanthogranulomatous inflammatory reaction in its walls. Occasional MPICs are immunoreactive for estrogen receptors, progesterone receptors, or both. A history of a prior abdominal operation, pelvic inflammatory disease, or endometriosis can be found in as many as 84% of patients, suggesting a role for inflammation in the pathogenesis of the cysts. In cases that we consider MPICs, follow-up has not disclosed malignant behavior. In as many as one-half of the cases, however, the MPICs have recurred from months to many years postoperatively, but at least some of these "recurrences" are likely the result of new postoperative adhesions. GnRH-agonists and/or tamoxifen, both of which induce a hypoestrogenic state, have successfully reduced the size of unresectable recurrent MPICs.

Differential Diagnosis of MPICs

1. Multilocular cystic lymphangiomas. In contrast to MPICs, these lesions typically occur in children (especially boys), are usually extrapelvic (mesentery of the small intestine, omentum, mesocolon or retroperitoneum), contain chylous fluid, have mural lymphoid aggregates and smooth muscle, and lining cells that are immunoreactive for endothelial markers
2. Multicystic adenomatoid tumor. In contrast to MPICs, these tumors typically involve the myometrium, contain foci of typical adenomatoid tumor, and lack prominent numbers of inflammatory cells.

References

1. Brustmann H. Multilocular peritoneal inclusion cyst with extensive xanthogranulomatous stromal changes: A differential diagnosis of cystic pelvic tumors in women. Ann Diagn Pathol 2000;4:308-10
2. Carpenter HA, Lancaster JR, Lee RA. Multilocular cysts of the peritoneum. Mayo Clin Proc 57:634-638, 1982
3. Letterie GS, Yon JL. The antiestrogen tamoxifen in the treatment of recurrent benign cystic mesothelioma. Gynecol Oncol 70:131-3, 1998
4. McFadden DE, Clement PB. Peritoneal inclusion cysts with mural mesothelial proliferation. A clinicopathological analysis of six cases. Am J Surg Pathol 10:844-854, 1986
5. Ross MJ, Welch WR, Scully RE. Multilocular peritoneal inclusion cysts (so-called cystic mesotheliomas). Cancer 64:1336-1346, 1989
6. Sawh RN, Malpica A, Deavers MT, et al. Benign cystic mesothelioma of the peritoneum: A clinicopathologic study of 17 cases and immunohistochemical analysis of estrogen and progesterone receptor status. Hum Pathol 34:369-74, 2003
7. Weiss SW, Tavassoli FA. Multicystic mesothelioma: An analysis of pathologic findings and biologic behavior in 37 cases. Am J Surg Pathol 12:737-746, 1988

Well-differentiated Papillary Mesothelioma
These peritoneal lesions (WDPMs) are uncommon. Eighty percent of them have occurred in females, who are usually of reproductive age but occasionally postmenopausal. WDPMs are usually an incidental finding at laparotomy but rare tumors have been associated with abdominal pain or ascites. Occasional patients have had asbestos exposure (Butnor).

WDPMs are solitary or more often multiple, and are usually grey to white, firm, papillary or nodular lesions <2 cm in maximal size. The omental and pelvic (including ovarian) peritoneum is typically involved, or rarely, the gastric, intestinal, or mesenteric peritoneum. In contrast to malignant mesotheliomas, orderly fibrous papillae are lined by a single layer of flattened to cuboidal mesothelial cells with occasional basal vacuoles and benign nuclear features. Mitotic figures are rare or absent. Uncommon patterns include tubulopapillary, adenomatoid-like areas, branching cords, and solid sheets. The stroma may be extensively fibrotic. Multinucleated stromal giant cells and/or psammoma bodies are encountered in occasional cases.

Follow-up studies indicate that solitary WDPMs are usually clinically benign; occasional tumors have persisted for decades. One solitary apparently typical WDPM of the peritoneum in a 34-year-old male progressed and was fatal at 3 years (Butnor). When multiple tumors are present, they should each be removed for microscopic examination because Goldblum & Hart have shown that lesions with the appearance of a WDPM may be associated with other lesions that have the appearance of a malignant mesothelioma and progressive disease on follow-up. The behavior of multiple WDPMs has been indolent in some cases, but caes of this type have not been studied in sufficient numbers with prolonged follow-up to be certain of their behavior.

References

1. Butnor KJ, Sporn TA, Hammar SP, Roggli VL. Well-differentiated papillary mesothelioma. Am J Surg Pathol 25:1304-9, 2001
2. Daya D, McCaughey WTE. Well-differentiated papillary mesothelioma of the peritoneum. A clinicopathologic study of 22 cases. Cancer 65:292-296, 1990
3. Goldblum, J, Hart WR. Localized and diffuse mesotheliomas of the genital tract and peritoneum in women. A clinicopathological study of nineteen true mesothelial neoplasms, other than adenomatoid tumors, multicystic mesotheliomas and localized fibrous tumors. Am J Surg Pathol 19:1124-1137, 1995
4. Sant'Ambrogio S, Malpica A, Deavers MT, Ordonez NG, Silva EG. Well differentiated papillary and malignant mesothelioma of the peritoneum in women. Abstract. Mod Pathol 13:131A, 2000.

Malignant Mesothelioma

Clinical Features
Malignant mesotheliomas of the peritoneal cavity (PMMs) account for only 10% to 20% of all mesotheliomas, and in women are much less common than peritoneal papillary serous carcinomas. Two-thirds of patients with PMMs are male, although because of the rarity of pleural mesotheliomas in women, the ratio of peritoneal to pleural mesotheliomas is higher in women (1:2) than in men (1:5). The affected patients are usually middle-aged or elderly, but occasionally PMMs occur in young adults and children. The age range in the largest series of PMMs in women was 18 to 92 (mean, 49) years (Baker). The presenting manifestations are usually nonspecific, including abdominal discomfort and distension, digestive disturbances, and weight loss. Ascites is present in the majority of cases, and cytologic examination of the ascitic fluid may be diagnostic. Occasionally the tumor is more localized, such as within a hernia or hydrocele sac, or takes the form of a retroperitoneal, umbilical, intestinal, or pelvic tumor, or as cervical or inguinal lymphadenopathy. Prominent ovarian involvement in rare cases may result in an intraoperative appearance that mimics a primary ovarian tumor with peritoneal spread. Rare otherwise typical PMMs have been confined to the ovary, likely representing a primary ovarian malignant mesothelioma. Rarely, PMMs may present as a localized acute inflammatory lesion without an obvious mass, intraoperatively mimicking acute appendicitis or cholecystitis. Some PMMs may be an unexpected microscopic finding. For example, we recently encountered a case in whch a woman underwent laparotomy for intractable ascites. No obvious lesions were identified intraoperatively, but a PMM was found on microscopic examination of the omentectomy specimen.

Over 80% of the patients with PMM in one series (Kannerstein & Churg) had a history of asbestos exposure, but most of these patients were men who were identified because of an occupational exposure to asbestos. In contrast, three recent series of PMMs in women found no definite association with a history of asbestos exposure (Goldblum, Kerrigan, Baker). Although asbestos fibers have been identified with special techniques in some of these women, it appears that a high occupational exposure to asbestos, specifically amphiboles (amosite and crocidolite), is required to induce a malignant mesothelioma. In cases lacking such a history, other etiologic factors such as radiation, chronic inflammation, organic chemicals, and nonasbestos mineral fibers may play a role.

Most males with PMMs that have been reported in the literature survived <2 years after diagnosis, although there are occasional long-term survivors. Kerrigan et al, however, found in a recent study that approximately 40% of women with PMMs have a relatively indolent course, with survival for ≥4 years, and in some cases, for >10 years. None of the patients who survived ≥4 years had died of disease at the time of their last follow-up. No significant differences in the histology of the tumors with short survival compared to those with long survival were found.

Pathological Findings
The visceral and parietal peritoneum is usually diffusely thickened by nodules and plaques. The viscera are often encased by tumor, but visceral invasion and lymphatic and hematogenous spread are less common than in carcinomas with comparable degrees of peritoneal involvement. Some tumors incite a striking desmoplastic reaction. As noted above, rare PMMs form localized solitary masses or present as an inflammatory lesion without an obvious tumor mass.

Most PMMs are of epithelial type; biphasic and sarcomatoid tumors are much less common than in the pleura. For example, in the largest study of PMMs in women (Baker), 94% were of epithelial type, with only 6% being biphasic or sarcomatoid. In contrast, the frequency of biphasic and sarcomatoid pleural tumors in one study was 45% (Legha & Muggia). In epithelial PMMs, the tumor cells are arranged in tubular, papillary, and solid patterns, usually admixed; areas of necrosis may be present. There is usually evidence of invasion of subperitoneal tissues, such as the omentum. As noted above, intra- and extra-abdominal lymph nodes may be involved. The tumor cells usually retain some resemblance to mesothelial cells, with a cuboidal shape and eosinophilic cytoplasm. Usually there is mild to moderate nuclear atypicality and variably prominent nucleoli; sever atypia can occur but is uncommon. Mitotic figures are usually present, but are rarely numerous.

Uncommon patterns and cell types in mesotheliomas can complicate the differential diagnosis. In at least some of these cases, however, the focal presence of the characteristic tubulopapillary pattern and tumor cells resembling mesothelial cells will facilitate the differential diagnosis. Rare tumors have an exclusively solid pattern of polygonal cells with abundant eosinophilic glassy cytoplasm and prominent nucleoli ("deciduoid" PMMs). This pattern, based on a small number of cases, appears to be more common in the peritoneum of adolescent females or young adult women, although similar tumors in males and in the pleura have been recently reported. The prominent nucleoli, often brisk mitotic activity, and immunoreactivity of the tumors cells for cytokeratin exclude an ectopic decidual reaction. A deciduoid mesothelioma with prominent ovarian involvement could bring into the differential diagnosis a broad group of ovarian tumors with oxyphilic cells, as covered in detail elsewhere (Young & Scully). Similarly, rare peritoneal mesotheliomas focally have insular, trabecular, tubular, and retiform patterns, and even cells with nulcear gorooves, potentially mimicking a sex cord-stromal tumor.

As already noted, biphasic and purely sarcomatous mesotheliomas are rare in the peitoneum, but several biphasic mesotheliomas have had prominent ovarian involvement, tumors that may be potentially confused with an ovarian malignant mixed mesodermal tumor. The epithelial components of biphasic mesotheliomas usually resemble pure epithelial mesotheliomas, contrasting with the high-grade mullerian-type carcinomatous component of the typical MMMT. Heterologous sarcomatous elements can occur in both biphasic mesotheliomas and MMMTs, and thus their presence is not diagnostically helpful. Rare peritoneal mesotheliomas, one of which involved the ovaries (Kitazawa), have abundant foamy cytoplasm due to lipid within the tumor cells. Solid patterns in such tumors with ovarian involvement could lead to possible confusion with lipid-rich ovarian tumors such as steroid cell tumors. Minor foci of cells with clear cytoplasm are common in peritoneal mesotheliomas, and rarely they can be prominent. The presence of clear cells, especially if accompanied by hobnail cells and hyalinized papillae (a frequent finding), could raise a differential diagnosis with a clear cell carcinoma. In such cases, the absence of the typical tubulocystic pattern of clear cell carcinoma, relative blandness of nuclear features in mesotheliomas compared to clear cell carcinomas, and the different immunohistochemical features of the two tumors will resolve the diagnostic problem.

Occasional PMMs have a stiking myxoid stroma or a striking desmoplastic stroma, although the latter is more rare in our experience. Other tumors contain a prominent inflammatory infiltrate, which may include a dense lymphocytic infiltrate with lymphoid follicles, granulomas, or numerous foamy lipid-rich histiocytes ("lymphohistiocytoid mesotheliomas"). The histochemical and immunohistochemical features of PMMs are indicated below.

Differential Diagnosis
Some differential diagnostic considerations raised by uncommon patterns in PMMs have been alaready discussed. The differential diagnosis of typical PMMs uncludes:

1. Atypical mesothelial hyperplasia
2. Well differentiated papillary mesothelioma
3. Adenocarcinoma with diffuse peritoneal involvement, including metastatic adenocarcinomas and adenocarcinomas of primary peritoneal origin. Features favoring a diagnosis of PMM include a prominent tubulopapillary pattern, polygonal cells with moderate amounts of eosinophilic cytoplasm, only mild to moderate nuclear atypia, a paucity of mitotic figures, and the presence of acid mucin (alcianophilic material) rather than neutral (PAS+) mucin. PMMs usually lack immunoreactivity for a variety of "epithelial" antigens, including B72.3, Leu-M1 (CD15), Ber-EP4, CEA, CA19-9, S-100 protein, and placental alkaline phosphatase. Of these, Ber-EP4, B72.3, Leu-M1 (CD15), MOC-31, and CA19-9 are the most useful in the differential with primary peritoneal serous carcinoma. Antigens that are usually present in epithelial PMMs but not primary peritoneal serous carcinomas are cytokeratin 5/6, thrombomodulin, and calretinin. 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 the H&E and mucin stains.
4. Malignant vascular tumors of the peritoneum. Lin et al reported peritoneal epithelioid hemangioendotheliomas or epithelioid angiosarcomas that mimicked PMM. Features that suggested the diagnosis of PMM in some cases included epithelioid cells in a tubulopapillary pattern and the presence of reactive or neoplastic spindle cells resulting in a focal biphasic pattern. Variable degrees of vascular differentiation and immunoreactivity of the neoplastic cells for endothelial antigens (and negative or weak cytokeratin staining) excluded the diagnosis of PMM.
5. Reactive fibrosis (vs desmoplastic PMM). Features favoring or indicating PMM include nuclear atypia, necrosis, organized patterns of collagen deposition (fascicular, storiform), frankly sarcomatoid areas, and infiltration of adjacent tissues.

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