Tumor-like Lesions and Tumors of the Peritoneum (Non-müllerian)

Tumor-Like Lesions

Inflammatory and Reparative Lesions

Granulomatous Peritonitis ( Figs. 20.1–20.2 )

  • Granulomatous peritonitis, which can be caused by a variety of infectious and noninfectious agents, can result in peritoneal nodules, potentially mimicking disseminated cancer. Most of the following show a histiocytic response that may be to varying degrees granulomatous.

  • Peritoneal tuberculosis, which is not uncommon in developing countries, can mimic advanced ovarian cancer both clinically (pelvic masses, ascites, elevated CA125) and intraoperatively.

  • Other less common infectious causes include fungal infections (histoplasmosis, coccidioidomycosis, cryptococcosis) and parasitic infestations (schistosomiasis, oxyuriasis, echinococcosis, ascariasis, strongyloidiasis).

  • Noninfectious causes include:

    • Foreign material such as starch granules from surgical gloves, douche fluid, and lubricants; talc (from surgical gloves or in drug abusers); cellulose and cotton fibers from surgical pads and drapes; microcrystalline collagen hemostat (Avitene); oily materials (hysterosalpingographic contrast medium, mineral oil, paraffin); Oxyplex gel (an adhesion inhibitor); escaped bowel contents; and bile.

    • Sebaceous material and keratin from ruptured dermoid cysts.

  • Peritoneal granulomas may also form in response to implants of keratin, usually derived from endometrial or ovarian endometrioid carcinomas with squamous differentiation, or less commonly, squamous cell carcinomas of the cervix or atypical polypoid adenomyomas ( Chapter 9 ).

    • Laminated deposits of keratin, sometimes with ghost squamous cells, are surrounded by foreign-body giant cells and fibrous tissue.

    • If identified on intraoperative frozen-section examination, all visible lesions should be excised and examined microscopically to exclude viable tumor.

    • Follow-up data suggest that the granulomas have no prognostic significance, although the number of cases with long follow-up is limited.

  • Peritoneal granulomas may occur after diathermy ablation of endometriosis. The granulomas typically have necrotic centers surrounded by histiocytes, including foreign-body-type giant cells, sometimes with black (carbon) and hematoidin pigment.

  • Granulomatous peritonitis has also been described secondary to Crohn’s disease, sarcoidosis, silicosis, and Whipple’s disease.

Fig. 20.1

Keratin granuloma involving ovarian serosa in a patient with an endometrial endometrioid adenocarcinoma with squamous differentiation. Left: Gross appearance. Center: Keratin granuloma (right) on ovarian surface (left). Right: Higher-power view showing ghost outlines of necrotic squamous cells.

Fig. 20.2

Postcautery necrotic granuloma of peritoneum.

Nongranulomatous Histiocytic Lesions ( Figs. 20.3–20.8 )

  • Nodular, plaque-like, or more extensive collections of histiocytes are occasionally encountered as a nonspecific peritoneal inflammatory response. They may be more commonly associated with ovarian rather than other intra-abdominal tumors. The lesions may be visible intraoperatively but are more commonly a microscopic finding.

    • Microscopically there is typically a monotonous population of histiocytes with moderate amounts of pale eosinophilic cytoplasm. Some nuclei may be reniform and/or contain a groove (resembling Langerhans’-type histiocytes) or have ‘raisinoid’ nuclear contours (Michal et al.).

    • Admixed mesothelial cells (‘nodular histiocytic/mesothelial hyperplasia’) and lymphocytes (predominantly T cells) may also be present. Staining for cytokeratin can highlight the mesothelial cells whereas the histiocytes show strong diffuse staining for CD68, CD163, CD4, and CD64 (Michal et al.).

    • Awareness of this finding, and if necessary, immunostains, facilitate the diagnosis. We have seen a case in which peritoneal histiocytes were initially misinterpreted as metastatic granulosa cell tumor.

  • Peritoneal collections of foamy and/or ceroid-rich histiocytes (usually a microscopic finding) can be a response to endometriosis or a peritoneal decidual reaction.

  • Peritoneal ‘melanosis’ is a rare finding, usually associated with an ovarian dermoid cyst, some with preoperative rupture. Rare cases have also been associated with a serous or mucinous cystadenoma or metastatic malignant melanoma to the peritoneum.

    • Tan to black peritoneal staining or pigmented tumor-like nodules involving the pelvic peritoneum and omentum may mimic metastatic tumor at laparotomy. The dermoid cysts also may have pigmentation of their contents and lining that may be associated with foci of ulcerated gastric mucosa.

    • The peritoneal lesions consist of pigment-laden histiocytes. Jaworski et al. found that the pigment lacked the histochemical features of both melanin and hemosiderin, but was rich in iron. In our experience, the pigment frequently is proven to be melanin with special stains, but occasional cases are of uncertain nature.

    • Awareness of this lesion and the histiocytic nature of the pigmented cells facilitate distinction from metastatic malignant melanoma.

  • Peritoneal pigmentation may also occur following enteroscopic tattooing with India ink. In one case, a subsequent laparoscopy revealed multifocal black speckling of the peritoneum, the appearance mimicking endometriosis. Biopsy revealed black pigment within multinucleated histiocytes.

  • Mucicarminophilic histiocytosis is characterized by histiocytes that contain polyvinylpyrrolidone (PVP), a substance used as a blood substitute.

    • The histiocytes are found within and outside the female genital tract, including pelvic lymph nodes and the omentum.

    • The vacuolated basophilic to lavender cytoplasm and an eccentric nucleus may suggest signet-ring cell adenocarcinoma. The histiocytes are mucicarminophilic but unlike neoplastic signet-ring cells, are PAS-negative. Additionally, cytokeratin stains are negative.

  • A peritoneal reaction similar to mucicarminophilic histiocytosis has been described secondary to oxidized regenerated cellulose, a topical hemostatic agent. The histiocytes have abundant, granular, basophilic, and mucicarminophilic cytoplasm.

Fig. 20.3

Peritoneal histiocytic infiltrate.

Fig. 20.4

Peritoneal histiocytic nodule. A circumscribed focus of histiocytes is seen on the peritoneal surface.

Fig. 20.5

Peritoneal histiocytic nodule. Left: H&E. Right: CD68 stain.

Fig. 20.6

Peritoneal melanosis associated with a dermoid cyst of the ovary. There is brown pigmentation of the lining of the dermoid cyst (left panel) and the omentum (right panel, lower left corner).

Fig. 20.7

Peritoneal melanosis. Histiocytes are filled with brown pigment.

Fig. 20.8

Peritoneal pigmentation. The material in this case appeared brown–black at operation. The material failed to stain for melanin or iron. The exact nature of the material is unclear. The patient had Peutz–Jeghers syndrome.

Fibrotic Lesions (Including Sclerosing Peritonitis and Mesenteritis) ( Figs. 20.9 20.10 )

  • Reactive peritoneal fibrosis is a common nonspecific response, most commonly to peritonitis, a surgical procedure, or endometriosis. Fibrous adhesions are a common complication. Occasionally the fibrosis can take the form of well-circumscribed fibrous nodules.

  • Localized hyaline plaques are a common incidental finding on the splenic capsule, and peritoneal fibrous thickening can occur in patients with hepatic cirrhosis and ascites.

  • Sclerosing peritonitis, which is a reactive proliferation of the submesothelial mesenchymal cells to a variety of stimuli, often encases the small bowel (‘abdominal cocoon’) causing bowel obstruction. The fibrosis may involve the muscularis layers in rare cases (‘mural fibrosis’) (Hauglustaine et al.)

    • The causes or associations include practolol therapy, chronic ambulatory peritoneal dialysis, peritoneovenous shunts, bacterial or mycobacterial infection, sarcoidosis, carcinoid syndrome, familial Mediterranean fever, foreign materials, lupus erythematosus, and luteinized thecomas (thecomatosis) ( Chapter 16 ). Some cases are idiopathic.

    • Several patients with sclerosing peritonitis have been successfully treated by antiestrogens and/or GnRH agonists.

  • Sclerosing mesenteritis (mesenteric panniculitis, mesenteric lipodystrophy) typically presents as a localized mass, usually in the small bowel mesentery. Varying degrees of fibrosis, inflammation, and fat necrosis are present.

    • Some cases have been IgG4-related (Abe et al., ). IgG4-related disease is a systemic disease with elevated levels of serum IgG4 and multiorgan involvement (including the retroperitoneum and mesentery) by a dense lymphoplasmacytic infiltrate, storiform-type fibrosis, and obliterative phlebitis.

    • However, Avincsal et al. concluded that conclusive IgG4-related cases with all the characteristic features (high serum IgG4 levels, tissue IgG4 elevation, multi-organ involvement, response to glucocorticoid therapy) have not yet been reported.

    • IgG4-related cases should be distinguished from idiopathic sclerosing mesenteritis and idiopathic retroperitoneal fibrosis.

  • Reactive nodular fibrous pseudotumor.

    • Yantiss et al. applied this term to lesions that involved the gastrointestinal tract or mesentery in adults. They were single or multiple and up to 6 cm in size. Some infiltrated the bowel wall, but all had a benign course.

    • Microscopic examination revealed a hypocellular proliferation of fibroblasts, collagen, and sparse mononuclear inflammatory cells. The cells were variably positive for vimentin, CD117, actins (MSA, SMA), and desmin, but not CD34 or ALK-1.

  • The differential diagnosis of reactive fibrous proliferations includes desmoplastic mesothelioma.

    • Features favoring or indicating the latter include nuclear atypia, necrosis, organized patterns of collagen deposition (fascicular, storiform), frankly sarcomatoid areas, and invasion.

    • Immunoreactivity for cytokeratins, calretinin, and D2-40 also favor mesothelioma as does immunohistochemical loss of BAP1 (see below). Some reactive fibrous proliferations, however, may contain submesothelial spindle cells with a mesothelial immunophenotype.

Fig. 20.9

Reactive subperitoneal fibrosis that forms a circumscribed nodule.

Fig. 20.10

Sclerosing peritonitis involving the omentum in a woman with a luteinized thecoma of the ovary.

Vernix Caseosa Peritonitis ( Fig. 20.11 )

  • Amniotic fluid spilled at cesarean section containing vernix caseosa (keratin, squames, sebum, lanugo hair) can result in peritonitis that rarely mimics an acute abdomen. The histologic findings include a mixed inflammatory infiltrate (neutrophils, histiocytes including giant cells) and anucleate fetal squamous cells.

Fig. 20.11

Vernix caseosa peritonitis. There is a granulomatous response to flakes of keratin (bottom center of field).

Meconium Peritonitis ( Fig. 20.12 )

  • Intestinal perforation with release of meconium (containing bile, pancreatic, and intestinal secretions) can result in a peritoneal inflammatory response. Intravascular spread of meconium may also occur.

  • Calcified foci (amorphous, granular, or psammomatous) are surrounded by histiocytes including foreign-body giant cells and loose myxoid adhesions (Forouhar). Occasionally, the only residue is a sharply demarcated calcified nodule that may have a fibrous pseudocapsule (Olnick and Hatcher).

Fig. 20.12

Meconium peritonitis. Note striking calcification and small foci of bile pigment.

Pulse Granulomas

  • Pulse granulomas (PGs) can form a tumor-like peritoneal mass (usually on the bowel serosa) and represent a reaction to food particles reaching the serosa as a result of mucosal trauma (Nowacki et al.).

  • Histologic examination reveals hyaline ribbons and rings (somewhat reminiscent of a corpus albicans), inflammation, foreign-body giant cells, calcification, stellate fibrosis, and food particles.

  • Hyaline-predominant PGs can mimic amyloid, cellular-predominant PGs can mimic spindle cell neoplasms, and fibrotic PGs can mimic sclerosing mesenteritis.

Mesothelial Lesions

Mesothelial Hyperplasia ( Figs. 20.13–20.22 )

  • This process is a common response to chronic effusions, inflammation (such as pelvic inflammatory disease), endometriosis, and ovarian tumors. Occasionally it is confined to a hernia sac as a result of trauma or incarceration.

  • Most commonly the process is an incidental microscopic finding but occasionally may be associated with adhesions, granularity, or small nodules.

  • Microscopic examination reveals sheets, nests, cords, tubules, and papillae that are usually on the surface. Endophytic growth can result in linear, often parallel or irregular arrays of reactive mesothelial cells, often forming tubules, within reactive fibrous tissue or the walls of ovarian tumors, endometriotic cysts, and peritoneal inclusion cysts (see below).

  • The papillae vary from tall and broad-based to delicate and filiform to small and serous-like. These findings, particularly if associated with foci of microcalcification, may raise concern for a low-grade serous neoplasm.

  • Aggregates of mesothelial cells may lie within spaces that in some cases appear to be artifactual but in other cases are intravascular.

  • The cells usually have appreciable eosinophilic cytoplasm, mild to moderate nuclear atypia, multinucleation, and occasional mitotic figures. The mesothelial cells may contain cytoplasmic vacuoles that stain for acid mucin (predominantly hyaluronic acid), and when prominent may result in signet-ring-like appearance.

  • Uncommon findings include a deciduoid morphology (potentially mimicking deciduoid mesothelioma; see Malignant Mesothelioma ), eosinophilic strap-shaped cells resembling rhabdomyoblasts, and psammoma bodies.

  • Mesothelial cells in abdominal lymph nodes may be misinterpreted as metastatic tumor, especially in women with a known primary pelvic cancer. There may be concomitant mesothelial hyperplasia of the pelvic and abdominal peritoneum. The appearance of the cells on routine stains suggests the correct diagnosis, and can be confirmed by histochemical and immunohistochemical staining.

Fig. 20.13

Mesothelial hyperplasia. Two main patterns of this process are seen – a sheet-like growth (left of center) and papillae.

Fig. 20.14

Mesothelial hyperplasia. Circumscribed aggregates of mesothelial cells involve the surface of the omentum.

Fig. 20.15

Mesothelial hyperplasia. A slightly complex papillary proliferation is seen adjacent to endometriosis, the latter a major clue to the papillary process being reactive.

Fig. 20.16

Mesothelial hyperplasia. Papillary to polypoid projections are seen and are associated with bland mesothelial tubules.

Fig. 20.17

Mesothelial hyperplasia. Papillae covered by bland mesothelial cells are seen. Note the stromal giant cells, which are occasionally seen in such reactive processes.

Fig. 20.18

Mesothelial hyperplasia within entrapment of mesothelial cells within reactive fibrous tissue. Note linear arrangement of entrapped cells that parallel the surface.

Fig. 20.19

Mesothelial hyperplasia within wall of endometriotic cyst. Small mesothelial tubules are irregularly distributed within reactive fibrous tissue.

Fig. 20.20

Hyperplastic mesothelial cells with prominent cytoplasmic vacuoles, resulting in a signet-ring-like appearance.

(Courtesy of Dr. J. Irving.)

Fig. 20.21

Mesothelial hyperplasia with small papillae and foci of calcification. In some cases, the papillae may raise concern for a serous neoplasia (borderline or low-grade carcinoma).

Fig. 20.22

Hyperplastic mesothelial cells occupy a subcapsular sinusoid within a pelvic lymph node.

Differential diagnosis

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

    • 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.

    • 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.

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

    • 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.

Peritoneal Inclusion Cysts ( Figs. 20.23–20.29 )

Unilocular PICs

  • 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.

Fig. 20.23

Peritoneal inclusion cyst. This unilocular cyst has a translucent paper-thin wall.

Fig. 20.24

Multilocular peritoneal inclusion cyst.

Fig. 20.25

Multilocular peritoneal inclusion cyst. The typical convoluted pattern is seen. The mesothelial lining varies from a single layer to multilayered and focally squamous in character.

Fig. 20.26

Multilocular peritoneal inclusion cyst. Multilocular peritoneal inclusion cyst. Multiple variably sized cystic spaces are separated by a reactive fibrous stroma.

Fig. 20.27

Multilocular peritoneal inclusion cyst.

Fig. 20.28

Multilocular peritoneal inclusion cyst. Spaces are lined by flattened to cuboidal mesothelial cells with mild nuclear atypia.

Fig. 20.29

Multilocular peritoneal inclusion cyst. An area resembling an adenomatoid tumor is depicted.

Multilocular PICs

  • 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:

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

    • 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.

    • 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.

    • True multicystic mesothelioma (see Malignant Mesothelioma ).

Miscellaneous Lesions

Splenosis ( Fig. 20.30 )

  • Splenosis, which results from implantation of splenic tissue, is typically an incidental finding at laparotomy or autopsy months to years after splenectomy for traumatic splenic rupture. In rare cases, pelvic pain and/or a mass are present.

  • A few to innumerable, red–blue, peritoneal nodules, up to 7 cm in diameter, are scattered throughout the abdominal, and less commonly, the pelvic cavity.

  • The intraoperative appearance may mimic endometriosis, benign or malignant vascular tumors, or metastatic cancer.

  • The differential includes splenic–gonadal fusion (see Chapter 12 ).

Fig. 20.30

Splenosis. Omentectomy specimen contains several reddish-purple nodules that on histologic examination were composed of splenic tissue.

Trophoblastic Implants ( Fig. 20.31 )

  • Implants of trophoblast on the pelvic or omental peritoneum can occur after a ruptured tubal pregnancy, and are more common with a distal tubal implantation.

  • The implants may also be a complication of the operative treatment of tubal pregnancies and are more common in cases managed by salpingotomy than salpingectomy.

  • An initial postoperative decline in the serum hCG level is followed by a rising level, abdominal pain, and in some cases, intra-abdominal hemorrhage.

  • Microscopic examination of the implants reveals viable trophoblastic tissue (that may include chorionic villi) and rarely, fetal parts. Occasionally, the lesions resemble a placental site nodule or plaque ( Chapter 10 ).

  • The differential diagnosis is with rare cases of peritoneal trophoblastic gestational disease (see Rare Primary Tumors ).

Fig. 20.31

Peritoneal placental site plaque.

Infarcted Appendix Epiploica ( Fig. 20.32 )

  • Torsion, infarction, and subsequent calcification of an appendix epiploica can result in a firm to hard mass or occasionally a cystic lesion attached or loose in the peritoneal cavity.

  • In the late stages, layers of hyalinized connective tissue surround a central necrotic and calcified zone in which infarcted adipose tissue in usually recognizable.

Fig. 20.32

Infarcted appendix epiploica.

Other Tumor-Like Lesions

  • Rare cases of microscopic extraovarian sex cord proliferations have been described in subperitoneal tissues (appendiceal serosa, pelvic side wall, para-ovarian connective tissue, periovarian adhesions) similar to those described in the fallopian tube (see Chapter 11 , Rare Ectopic Tissues).

  • Cartilaginous metaplasia of the peritoneum has been reported rarely, usually as one or more incidentally discovered nodules in patients who have had previous abdominal surgery. The nodules are usually <2 cm and consist of mature hyaline cartilage.

  • Spillage with peritoneal/ovarian implantation of gallstones is a complication of laparoscopic treatment of cholelithiasis that may result in abdominal pain and/or a nidus for granulomatous inflammation or infection.

  • Ardakani et al. reported five cases of extramedullary hematopoiesis within organizing peritoneal hematomas in women with gynecologic disorders. The hematopoietic elements included erythroid precursors (5 cases), granulocytic precursors (2 cases), and megakaryocytes (3 cases). None of the patients had a hematologic disorder at presentation or on follow-up.

  • Dill et al. reported a case of tophaceous gout in the pelvis of a 36-year-old woman who presented with abdominal pain but no history or physical evidence of gout. Laparoscopy revealed multiple firm, white, pelvic nodules of eosinophilic, partially calcified material containing refractile needle-shaped crystals consistent with urate crystals.


Mesothelial Neoplasms

Adenomatoid Tumor

  • This benign tumor of mesothelial origin rarely arises from extragenital peritoneum, such as the omentum or mesentery, but is much more commonly encountered in the myometrium and fallopian tube.

  • Its pathologic features are discussed in Chapter 10 .

Well-Differentiated Papillary Mesothelioma ( Figs. 20.33 20.34 )

  • Evaluating the literature on tumors reported as well-differentiated papillary mesothelioma (WDPM) is difficult because morphologically identical foci can be seen in unequivocal malignant mesotheliomas. Overlap between the two tumors is further indicated by the presence of invasion in some tumors reported as WDPMs. We use the designation WDPM sparingly, especially if a mesothelioma is multifocal and/or bulky, findings that are prognostically adverse.

  • Given the variable morphology of mesotheliomas, thorough sampling is crucial, and when multiple lesions are present, they should each ideally be removed for microscopic examination. These caveats being noted, the features of WDPM below are based on the published literature.

  • WDPMs are uncommon; 80% of them have occurred in females, who are in the reproductive and postmenopausal age groups. They are usually an incidental finding at laparotomy, but rare tumors are associated with abdominal pain or ascites. There is no apparent association with asbestos exposure.

  • Solitary or multiple, grey to white, firm, usually papillary, nodular, or rarely cystic lesions up to 2 cm in size involve the abdominal and/or pelvic peritoneum. The most commonly involved sites are the omentum, cul-de-sac, colonic serosa, small bowel mesentery, and uterine serosa.

  • Fibrous papillae are lined by a single layer of flattened to cuboidal mesothelial cells with occasional basal vacuoles. The nuclear features are benign and mitotic figures are rare or absent. Solitary lesions with these features have been clinically benign.

  • Other patterns are tubulopapillary, adenomatoid tumor-like areas, branching cords, sheets, nests, or individual cells. The stroma may be extensively fibrotic. Multinucleated stromal giant cells and/or psammoma bodies are rarely present.

  • reported the presence of invasion in WDPMs, most of which were in females, multiple, and peritoneal. The invasive foci varied from simple glands invading the stalks of papillae to solid foci with higher cytologic grade. The tumors were negative for p16 deletion by FISH, but two-thirds had abnormal karyotypes. Invasion, however, should always raise concern for a conventional mesothelioma particularly when the lesions are multiple.

  • A potential pitfall in diagnosis of WDPM is their aberrant strong diffuse nuclear staining with PAX8 in >50% of tumors (Banet et al., Xing et al.). Banet et al. found stronger staining with polyclonal (vs monoclonal) antibodies, and that smaller WDPMs (1–3 mm) with fibrotic cores and bland mesothelial cells were PAX8 negative.

  • . have recently found that WDPMs are genetically defined by mutually exclusive mutations in TRAF7 and CDC42 .

  • On follow-up, typical WDPMs are clinically indolent, although rare tumors recur or persist. In contrast, recurrences (multiple in 50%) developed in 40% of WDPMs with invasive foci, but were rarely fatal. Follow-up of patients with WDPMs is prudent because of occult multifocal lesions, possible recurrences, or initial misdiagnosis of an undersampled malignant mesothelioma.

  • The main tumor in the differential diagnosis is malignant mesothelioma (see below).

Fig. 20.33

Well-differentiated papillary mesothelioma. Note the lack of penetration of mesothelial cells into the stromal compartment of the lesion, as is typically seen in malignant mesothelioma.

Fig. 20.34

Well-differentiated papillary mesothelioma. Note the innocuous appearance of the mesothelial cells covering the papillae.

Malignant Mesothelioma ( Figs. 20.35–20.47 )

Clinical features

  • 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.

Fig. 20.35

Malignant mesothelioma with extensive peritoneal involvement.

Fig. 20.36

Malignant mesothelioma. This low-power view shows the sometimes helpful feature of the mesothelial proliferation coating the peritoneal surface and irregular infiltrative tubules involving the subjacent stroma.

Fig. 20.37

Malignant mesothelioma. A complex papillary proliferation is evident and is common in peritoneal mesothelioma.

Fig. 20.38

Malignant mesothelioma. A higher-power view of the prior illustration shows the bland cytology of the mesothelial cells but the complex papillary pattern is indicative of a malignant process.

Fig. 20.39

Malignant mesothelioma, papillary pattern. The papillae have hyalinized cores.

Fig. 20.40

Malignant mesothelioma. Small tubules ramify within the stroma of large papillary to polypoid excrescences.

Fig. 20.41

Malignant mesothelioma, tubular pattern.

Fig. 20.42

Malignant mesothelioma. A rare tubulocystic pattern is striking.

Fig. 20.43

Malignant mesothelioma. Vacuoles resembling those of an adenomatoid tumor are conspicuous. Consideration of the gross features may be important when this pattern is encountered.

Fig. 20.44

Malignant mesothelioma. The neoplastic cells are predominantly cuboidal, with eosinophilic cytoplasm and moderate nuclear atypia.

Fig. 20.45

Malignant mesothelioma. A calretinin stain in this case with a prominent tubular pattern highlighted the infiltrative nature of the tubules into the subjacent fat.

Fig. 20.46

Malignant mesothelioma. The diagnosis of epithelioid malignant mesothelioma (left) was aided in this case by strong D2-40 expression (right).

Fig. 20.47

Malignant mesothelioma, deciduoid type.

Typical pathologic findings

  • 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.

    • 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).

    • 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.

Unusual histologic variants and findings

  • Biphasic and sarcomatoid patterns.

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

    • 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.

    • 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.

    • 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.

    • 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.

    • 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.

    • 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).

Immunohistochemical and molecular findings

  • 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.

    • 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.

    • 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.

    • 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.

    • 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.

    • 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.

    • 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.

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

    • 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.

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

    • 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.

    • 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.

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

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

    • 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.

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

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

    • . 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.

Differential diagnosis

  • 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.

    • 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.

    • 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.

    • 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.

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

    • 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.

    • 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 ).

Behavior and prognostic factors

  • 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 ( ).

Intra-Abdominal Desmoplastic Small Round Cell Tumor

Clinical features

  • 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.

Pathologic features ( Figs. 20.48–20.54 )

  • 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:

    • 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.

    • 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.

    • 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.

    • 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:

    • 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.

    • 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.

Feb 9, 2020 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Tumor-like Lesions and Tumors of the Peritoneum (Non-müllerian)
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