Normal Peritoneum

Knowledge of the peritoneum is important in understanding the pathology of the female genital tract. The uterine corpus, along with the fallopian tubes, the cervix, and the upper part of the vagina, develop from the müllerian ducts, which in turn derive from the mesenchyme of the urogenital ridge and the celomic lining epithelium (mesothelium) or primitive peritoneum. The mesothelium lining the peritoneal cavity is a single layer of flat or cuboidal cells with small round central nuclei and a single nucleolus. Cytoplasm is minimal with well-defined cell borders. On an ultrastructural basis, mesothelial cells show prominent and numerous long microvilli. This is in contrast to many müllerian epithelia, especially serous epithelia, where cilia are obvious by light microscopy and greatly overshadow the slender microvilli. The microvilli in typical müllerian adenocarcinomas tend to be shorter, stubbier, and are fewer in number than those of mesothelial cells.

Submesothelial mesenchyme anchors the mesothelium to the underlying tissue. Submesothelial stromal cells are important in the development of deciduosis, endosalpingiosis, endometriosis, and disseminated peritoneal leiomyomatosis. Microscopically, these peritoneal lesions are characterized by müllerian differentiation and are thought to derive from the so-called ‘secondary müllerian system,’ i.e., the pelvic and lower abdominal mesothelium and the underlying mesenchyme of females. In fact, the concept of the secondary müllerian system refers to a mechanism by which benign lesions and tumors of müllerian histology might arise from the peritoneum.

In females, the peritoneum is a nearly continuous membrane only interrupted in the pelvis by the fallopian tubes. The fallopian tubes are a potential passage for the transmission of pathogens, chemical and biologic, that have ascended through the genital tract from the external environment.

Inflammatory and Reactive Lesions

In adult females, most infections are ascending, as in pelvic inflammatory disease, which results in localized acute peritonitis. Acute diffuse peritonitis, characterized by a serosal fibrinopurulent exudate, is most commonly associated with perforated viscera as in appendicitis or diverticulitis and is usually bacterial or chemical in origin. In addition to the acute inflammatory reaction itself, chronic changes may occur, such as are seen in granulomatous and histiocytic reactions. In some cases, the inflammatory process leads to reactive changes.

Granulomatous Peritonitis

Both, infectious and noninfectious agents can cause granulomatous peritonitis. Among the former, Mycobacterium tuberculosis is the most common, and, less frequently, fungi and parasites. Granulomas are also induced by foreign material including keratin, by vernix caseosa or by meconium, in the form of necrotic pseudoxanthomatous nodules or as a postcautery reaction.

Tuberculosis

Tuberculous peritonitis is still encountered in the peritoneum, usually in immunosuppressed patients. It may also occur as a complication of chronic peritoneal dialysis. It may be secondary to tuberculous salpingitis or result from miliary tuberculosis. Clinically, it may manifest nonspecifically as widespread carcinomatosis. The presence of ascites, a pelvic mass, and marked elevation of serum levels of CA125 may lead to a false clinical suspicion of ovarian cancer. The granulomas are characterized by caseous necrosis and Langhans type giant cells; mycobacteria may be demonstrated by acid-fast stains or immunofluorescence techniques.

Suture Materials

Foreign-body granulomas are most commonly associated with suture material retained from prior surgical procedures. The sutures may consist of dense hyaline material in varying degrees of disintegration, or translucent threads. The foreign-body component of the granulomas can be highlighted with polarizing filters. Cellular reaction consists of macrophages, some multinucleated, and lymphocytes. There is both local fibrosis and serosal adhesions.

Surgical Glove Powder

Surgical glove powder, either talc or starch granules, is a common cause of granulomas. At laparotomy, the peritoneal granulomas may simulate carcinomatosis or tuberculosis. Usually the starch granulomas resolve within a few months, leaving no residua or only adhesions; however, some patients develop fibrosing peritonitis. Commonly, starch granulomas exhibit a typical foreign-body reaction and, less frequently, they appear as sarcoid granulomas, which lack necrosis, or tuberculoid granulomas, with necrosis, that simulate tuberculosis. The polyhedral and translucent starch granules are periodic acid–Schiff (PAS) positive and exhibit the typical Maltese cross under polarized light. Rarely, fat necrosis and rheumatoid-type necrotizing foci are identified as reactions to starch. Talc was once an important cause of granulomatous and fibrosing peritonitis because of its application as a lubricant on surgical gloves; however, its use has been discontinued. Talc is a greater irritant than starch and is poorly absorbed by some patients. Talc granulomas are of the typical foreign-body type. Multinucleated giant cells are numerous and contain pleomorphic crystal spicules readily seen with polarized light.

Contrast Media

Peritoneal granulomas may result from exposure to hysterosalpingographic contrast medium, which can be associated with a lipogranulomatous reaction. These appear as foreign-body giant cell reactions around spherical vacuoles from which lipid has been removed during processing. Lipogranulomas may become confluent and focal necrosis may occur.

Intestinal Contents

Foreign-body granulomas to intestinal contents may be seen following perforation such as in Crohn disease, diverticulitis, or malignant fistulas. These granulomas are generally confined to the serosa, but plant material and barium from a perforated colon may be identified in the wall or subserosal fat.

Cystic Teratoma (Dermoid Cyst) Rupture

Rupture of a mature cystic teratoma (dermoid cyst) is typically associated with widespread peritoneal granulomas and adhesions. The squamous cells, hairs, and sebum trigger a foreign-body reaction. This phenomenon occurs especially when the teratoma is removed by cystectomy during laparoscopic surgery. On occasion the reaction may also appear as sclerosing peritonitis and mimics a neoplasm at operation.

Keratin

Peritoneal foreign-body granulomas to keratin may be found in association with uterine or ovarian endometrioid carcinomas with squamous differentiation, or, less frequently, with squamous cell carcinomas of the cervix or atypical polypoid adenomyomas. Uterine examples are thought to result from retrograde transmission of acellular keratinous debris through the fallopian tubes ( Figure 31.1 ). Granulomas have been seen on the serosa of the adnexa, uterus, colon, and appendix. These granulomas are easily misinterpreted as metastatic carcinoma. Follow-up on these patients indicates that cell-free granulomas lack prognostic significance.

Keratin nodule in omentum. The patient had an endometrial adenocarcinoma with squamous differentiation and had received radiotherapy.

Cauterized Tissue

Foreign-body granulomatous reactions to cauterized tissue in pelvic peritoneal and ovarian biopsies are occasionally encountered in patients who have had endometriotic or other lesions treated in the weeks prior to biopsy. The lesions show central eosinophilic, focally refractile, amorphous material (representing the coagulated tissue and carbonaceous debris) palisaded by large numbers of multinucleated foreign-body giant cells and a peripheral lymphocytic infiltrate ( Figure 31.2 ). Lesions tend to hyalinize with age and may persist for many years.

Florid foreign-body granulomatous reactions to cauterized tissue.

Cesarean Delivery

Complicating cesarean delivery, the amniotic fluid contents may spill into the peritoneal cavity causing a syndrome clinically similar to bowel perforation. Amniotic fluid contains squamous cells, keratin, and sometimes lanugo hair (vernix caseosa). It may also contain meconium, which itself is composed of bile, pancreatic, and intestinal secretions. Grossly, the amniotic fluid contents appear as cheese-like yellow patches limited to the serosal layer of visceral organs. Meconium peritonitis caused by bowel perforation in utero can also be a problem in newborn infants. The hallmark of meconium peritonitis is calcification, which presumably results from the action of pancreatic enzymes.

Fibrosing Lesions

Sclerosing peritonitis is a reactive process in which a thickened fibrous or myofibromatous stroma develops on the peritoneal serosa. It is often idiopathic, although in some cases the cause is identified, such as prior peritoneal inflammation or a ruptured ovarian dermoid with spillage of the contents (see previous granulomatous reactions), chronic dialysis, or after surgical procedures.

In some cases, the sclerosing peritonitis has been described as part of a syndrome, often in association with a ‘luteinized thecoma of the ovary.’ Clinically, most of the women are young, usually under 30 years of age. Common presenting signs include abdominal enlargement and sometimes small bowel obstruction. Ascites may be present. Even when the patients have a luteinized thecoma, none has endocrine symptoms. A significant number of patients have been exposed to propranolol-type beta-blocking agents or antiepileptics.

Grossly, opaque to light-brown 1–3 mm granules or nodules appear matted together on the peritoneum or on the serosa of the involved organs. The omentum is usually indurated. Microscopic examination discloses a fibrotic process, with various chronic inflammatory cells ( Figure 31.3 ). There is usually some degree of mesothelial hyperplasia. Deeper tissues are relatively spared. Nodules are composed of moderately cellular fascicles of benign-appearing spindle cells resembling fibroblasts and myofibroblasts that contain occasional mitotic figures. In addition to cytokeratin reactivity, the cells also disclose immunoreactivity for vimentin and smooth muscle actin.

Sclerosing peritonitis. The fat lobules are surrounded by cellular fibromatous tissue.

Rarely, single or multiple fibrous nodules ranging up to 6 cm may occur in the gastrointestinal tract or mesentery in adults. Microscopically, the lesions are composed of fibro­blasts, collagen, and scattered mononuclear inflammatory cells. The fibroblastic cells show variable immunoreactivity for vimentin, CD117, muscle-specific actin, smooth muscle actin, and desmin, with negative staining for CD34 and ALK-1. These nodules have been designated as ‘fibrous pseudotumors.’

Occasionally, sclerosing lesions may be difficult to distinguish from desmoplastic mesothelioma, especially when the biopsy specimen is small. These tumors, however, are very rare in the peritoneal cavity, especially in women. Features that favor a diagnosis of mesothelioma include nuclear atypia, necrosis, organized patterns of collagen deposition (fascicular or storiform), and destructive infiltration into adjacent tissues.

Some patients with sclerosing peritonitis have been successfully treated utilizing antiestrogens and/or GnRH agonists.

Tumor-Like Lesions

Mesothelial Hyperplasia

Mesothelial hyperplasia is a common response to inflammation that occurs in any process that leads to irritation of a serosal surface, such as ascites, hernia sacs, endometriosis, pelvic inflammatory disease, or ovarian tumors. Grossly, the hyperplastic lesions may be seen at operation as multiple small nodules, but more commonly are incidental findings on microscopic examination. Microscopically, the changes range from a mild ( Figure 31.4 ) to a substantial increase in the number of mesothelial cells ( Figure 31.5 ), most of which have transformed from flat and relatively inconspicuous to cuboidal or even columnar. With marked hyperplasia, the mesothelial proliferation appears as sheets, clusters, ribbons, tubules, and sometimes as papillary formations that can be misinterpreted as metastatic adenocarcinoma ( Figure 31.6 ). Psammoma bodies are encountered occasionally and eosinophilic elongated cells resembling rhabdomyoblasts have been described.

Slight mesothelial hyperplasia of peritoneum.

Thin layer of moderately reactive mesothelium.

Reactive mesothelium. The enlarged mesothelial cells (arrow) that cover a focus of fibrous reaction superficially resemble metastatic adenocarcinoma.

Reactive mesothelial cells tend to be uniform in appearance. With minor degrees of reactivity, the nuclei are small, regular, round, or oval, and exhibit central nucleoli. The cytoplasm is eosinophilic or sometimes vacuolated and contains acid mucin (predominantly hyaluronic acid). With increasing degrees of reactivity, the nuclei enlarge and the chromatin increases. Nucleoli become more apparent and, in the extreme case, may become quite large and prominent ( Figure 31.7 ). Cells may become binucleated or multinucleated. In cytologic preparations the large macronucleoli may be mistaken as evidence for malignancy.

Markedly reactive mesothelial cells with prominent nucleoli.

The immunoprofile of normal mesothelium differs from that expected of epithelial tissue. As anticipated, it expresses cytokeratin intermediate filaments typical of epithelial cells. But it also expresses vimentin and desmin, which are indicative, respectively, of mesenchymal differentiation and specialization into muscle. In contrast, ovarian surface epithelium is immunoreactive for vimentin and desmin in fewer than half of cases. Ovarian inclusion cysts are nonreactive for vimentin and desmin, as are benign and borderline ovarian tumors. Mesothelial hyperplasia can occur within the superficial ovarian stroma overlying a borderline tumor and in such cases can be misinterpreted as invasive tumor. The differential reactivity of mesothelium (and mesothelioma) and müllerian tissue (and ovarian tumors) is discussed more fully in the following sections.

With greater degrees of injury, a layer of spindle-shaped mesenchymal cells may sometimes appear below the meso­thelial cells. In the resting state, this layer is inconspicuous, but, when stimulated, the cells may proliferate and produce a highly cellular desmoplastic tissue. Cells also express cytokeratin, vimentin, and desmin. These cells simulate myofibroblasts, and are thought to give rise occasionally to the muscular cells in the condition ‘disseminated peritoneal leiomyomatosis’ (see later).

The exuberant and sometimes pseudoinfiltrative growth that mesothelium can show, together with the increased mitotic activity that is frequently observed, may lead to a false impression of primary or metastatic carcinoma, despite the benign cytologic appearance of the cells ( Figure 31.6 ). Carcinoma cells generally demonstrate greater nuclear pleomorphism and more conspicuous mitotic activity. However, clusters of mesothelial cells are easily mistaken for metastatic carcinoma. This is true especially when mesothelial cells extensively involve sinusoids in pelvic lymph nodes either as small papillary clusters or as sheets of somewhat discohesive cells. Exuberant surface proliferations, sometimes forming sessile or polypoid nodules, can also simulate mesothelioma, a problem also encountered in the walls of hernia sacs. A useful morphologic feature that can help distinguish reactive mesothelial cell aggregates from metastatic carcinoma is their orientation at low-power magnification to one another (often in a line that can be traced for some considerable distance) ( Figure 31.6 ) and their relation to the position of the original peritoneal surface (as demonstrated by the presence of the peritoneal elastic lamina).

Organization of surface proliferative lesions and inflammatory exudates may leave adhesions of variable density, ranging from delicate strands of loose connective tissue to broad bands of dense, well-vascularized collagenous fibrous tissue. Entrapped inflammatory exudate within granulation tissue and proliferating sheets of mesothelial cells may lead to mesothelial (peritoneal) cyst formation. These may not become clinically apparent until months or years after the precipitating event.

Mesothelial hyperplasia must be distinguished from malignant peritoneal mesothelioma. The presence of necrosis, marked nuclear pleomorphism, and deep infiltration favors malignant mesothelioma. Immunostains may help in the differential diagnosis. Strong immunoreactivities for p53 and epithelial membrane antigen (EMA; nuclear and cytoplasmic, respectively) are characteristic of the cells of malignant mesothelioma but not reactive mesothelial cells; in contrast, hyperplasic mesothelial cells are usually desmin positive. Proliferative markers such as Ki-67 may also be helpful (approximately 25% vs 5% labeling index for malignant mesothelioma vs mesothelial hyperplasia, respectively). In some cases, however, the distinction between a reactive and malignant mesothelial lesion may be difficult or impossible, particularly in a biopsy samples. An apparently benign mesothelial proliferation occasionally precedes the appearance of a malignant peritoneal mesothelioma.

Mesothelial hyperplasia should also be distinguished from a borderline serous tumor of primary peritoneal origin. Grossly visible tumor, columnar cells with or without cilia, the presence of neutral mucin, and numerous psammoma bodies all favor a serous tumor. Immunohistochemical markers for epithelial differentiation may also be useful in the distinction (see Chapter 25 ).

Peritoneal Inclusion Cysts

Peritoneal inclusion cysts are unilocular or multilocular mesothelial-lined lesions that occur almost exclusively in women in the reproductive age group. They usually involve the pelvis, although may occur in other abdominal locations, including the omentum and mesentery, and are frequently associated with prior abdominal surgery. The origin of peritoneal inclusion cysts remains controversial; some authors consider them reactive lesions that develop in response to injury, whereas others favor their neoplastic nature.

Unilocular peritoneal inclusion cysts are usually incidental findings at laparotomy. Multilocular peritoneal inclusion cysts, also referred to as ‘benign cystic mesotheliomas,’ frequently form large bulky masses ( Figures 31.8–31.11 ) simulating a cystic ovarian tumor. Cysts are thin walled, contain clear proteinaceous fluid, and are lined by a single layer of flat to cuboidal, hobnail-shaped, mesothelial cells ( Figure 31.12 ) with bland nuclear features, although a degree of reactive atypia is occasionally seen. Tubal and squamous metaplasia of the mesothelial lining sometimes occurs. Inflammatory infiltrates, if present at all, are limited to sparse lymphocytic collections. The mesothelial cells are typically immunoreactive for calretinin, and less frequently positive for estrogen (ERs) or progesterone receptors (PRs), or both.

Mesothelial cyst.

Multiple small mesothelial cysts.

Multiple large mesothelial cysts.

Multicystic mesothelioma.

(A) Thin-walled mesothelial cysts in peritoneum. (B) The cyst is lined by numerous mesothelial cells. (C) Detail of the mesothelial cells.

In patients who have had peritonitis, fibrinous adhesions that are superficial to the deeper lining of normal mesothelium may develop and the underlying serosa can be mistaken for invasive serous carcinoma until attention is paid to its regularity and benign histology ( Figure 31.13 ).

(A) Serosa covered by adhesions. It is easy to mistake the normal mesothelium for serous adenocarcinoma due to its location within the peritoneal wall. (B) Detail of mesothelial inclusion.

Peritoneal inclusion cysts are confused with multilocular cystic lymphangiomas, which typically occur in children, more often in boys. Lymphangiomas are almost always localized in the mesentery of the small intestine, mesocolon, omentum, or retroperitoneum. They contain chylous material and, microscopically, show intramural lymphoid aggregates and smooth muscle, which are absent in peritoneal inclusion cysts.

Although no malignant behavior has been reported in peritoneal inclusion cysts, recurrence occurs in approximately one-half of cases from months to several years postoperatively. GnRH agonists or tamoxifen have successfully been applied to some patients.

Ovarian Remnant Syndrome

This condition exists if a patient who has had a ‘total bilateral oophorectomy’ later develops a palpable mass or experiences pelvic pain or other symptoms referable to ovarian tissue that has been left behind ( Figures 31.14 and 31.15 ). This condition is described more fully in Chapter 24 .

Ovarian remnant syndrome. Numerous corpora lutea appear surrounded by fibrous tissue.

Ovarian remnant syndrome. Ovarian tissue that was left behind at the time of oophorectomy has regrown and is functional.

Trophoblastic Implants

Finding disseminated trophoblastic implants in the peritoneum is uncommon ( Figure 31.16 ). They may occur on occasion with peritoneal pregnancy, or following laparoscopic treatment of tubal pregnancy, where the frequency has been estimated at 3.6%. Viability is suggested by rising human chorionic gonadotropin concentrations following surgery. The condition is best avoided by meticulous inspection of the abdomen after resection of the tubal pregnancy. Microscopically, the implants may show trophoblastic tissue including chorionic villi. Some implants, however, may resemble a placental site nodule.

Trophoblastic implant in peritoneum. The patient had a ruptured ectopic pregnancy.

Infarcted Appendix Epiploica

Appendices epiploicae are small polypoid processes of adipose tissue that project from the serosa of the large intestine, especially the transverse and sigmoid colon. Occasionally, they undergo torsion, infarction, and later detachment and can be found lying free within the peritoneal cavity. Typically in these cases, the center contains hyalinized fibrous tissue and often some residual adipose tissue that is mummified. The outer rim and variable portions of the core may calcify, resulting in a hard tumor-like mass ( Figure 31.17 ).

Infarcted appendix epiploica.

Granulomatous Peritonitis

Both, infectious and noninfectious agents can cause granulomatous peritonitis. Among the former, Mycobacterium tuberculosis is the most common, and, less frequently, fungi and parasites. Granulomas are also induced by foreign material including keratin, by vernix caseosa or by meconium, in the form of necrotic pseudoxanthomatous nodules or as a postcautery reaction.

Keratin

Peritoneal foreign-body granulomas to keratin may be found in association with uterine or ovarian endometrioid carcinomas with squamous differentiation, or, less frequently, with squamous cell carcinomas of the cervix or atypical polypoid adenomyomas. Uterine examples are thought to result from retrograde transmission of acellular keratinous debris through the fallopian tubes ( Figure 31.1 ). Granulomas have been seen on the serosa of the adnexa, uterus, colon, and appendix. These granulomas are easily misinterpreted as metastatic carcinoma. Follow-up on these patients indicates that cell-free granulomas lack prognostic significance.

Keratin nodule in omentum. The patient had an endometrial adenocarcinoma with squamous differentiation and had received radiotherapy.

Cauterized Tissue

Foreign-body granulomatous reactions to cauterized tissue in pelvic peritoneal and ovarian biopsies are occasionally encountered in patients who have had endometriotic or other lesions treated in the weeks prior to biopsy. The lesions show central eosinophilic, focally refractile, amorphous material (representing the coagulated tissue and carbonaceous debris) palisaded by large numbers of multinucleated foreign-body giant cells and a peripheral lymphocytic infiltrate ( Figure 31.2 ). Lesions tend to hyalinize with age and may persist for many years.

Florid foreign-body granulomatous reactions to cauterized tissue.

Tuberculosis

Tuberculous peritonitis is still encountered in the peritoneum, usually in immunosuppressed patients. It may also occur as a complication of chronic peritoneal dialysis. It may be secondary to tuberculous salpingitis or result from miliary tuberculosis. Clinically, it may manifest nonspecifically as widespread carcinomatosis. The presence of ascites, a pelvic mass, and marked elevation of serum levels of CA125 may lead to a false clinical suspicion of ovarian cancer. The granulomas are characterized by caseous necrosis and Langhans type giant cells; mycobacteria may be demonstrated by acid-fast stains or immunofluorescence techniques.

Suture Materials

Foreign-body granulomas are most commonly associated with suture material retained from prior surgical procedures. The sutures may consist of dense hyaline material in varying degrees of disintegration, or translucent threads. The foreign-body component of the granulomas can be highlighted with polarizing filters. Cellular reaction consists of macrophages, some multinucleated, and lymphocytes. There is both local fibrosis and serosal adhesions.

Surgical Glove Powder

Surgical glove powder, either talc or starch granules, is a common cause of granulomas. At laparotomy, the peritoneal granulomas may simulate carcinomatosis or tuberculosis. Usually the starch granulomas resolve within a few months, leaving no residua or only adhesions; however, some patients develop fibrosing peritonitis. Commonly, starch granulomas exhibit a typical foreign-body reaction and, less frequently, they appear as sarcoid granulomas, which lack necrosis, or tuberculoid granulomas, with necrosis, that simulate tuberculosis. The polyhedral and translucent starch granules are periodic acid–Schiff (PAS) positive and exhibit the typical Maltese cross under polarized light. Rarely, fat necrosis and rheumatoid-type necrotizing foci are identified as reactions to starch. Talc was once an important cause of granulomatous and fibrosing peritonitis because of its application as a lubricant on surgical gloves; however, its use has been discontinued. Talc is a greater irritant than starch and is poorly absorbed by some patients. Talc granulomas are of the typical foreign-body type. Multinucleated giant cells are numerous and contain pleomorphic crystal spicules readily seen with polarized light.

Contrast Media

Peritoneal granulomas may result from exposure to hysterosalpingographic contrast medium, which can be associated with a lipogranulomatous reaction. These appear as foreign-body giant cell reactions around spherical vacuoles from which lipid has been removed during processing. Lipogranulomas may become confluent and focal necrosis may occur.

Intestinal Contents

Foreign-body granulomas to intestinal contents may be seen following perforation such as in Crohn disease, diverticulitis, or malignant fistulas. These granulomas are generally confined to the serosa, but plant material and barium from a perforated colon may be identified in the wall or subserosal fat.

Cystic Teratoma (Dermoid Cyst) Rupture

Rupture of a mature cystic teratoma (dermoid cyst) is typically associated with widespread peritoneal granulomas and adhesions. The squamous cells, hairs, and sebum trigger a foreign-body reaction. This phenomenon occurs especially when the teratoma is removed by cystectomy during laparoscopic surgery. On occasion the reaction may also appear as sclerosing peritonitis and mimics a neoplasm at operation.

Keratin

Peritoneal foreign-body granulomas to keratin may be found in association with uterine or ovarian endometrioid carcinomas with squamous differentiation, or, less frequently, with squamous cell carcinomas of the cervix or atypical polypoid adenomyomas. Uterine examples are thought to result from retrograde transmission of acellular keratinous debris through the fallopian tubes ( Figure 31.1 ). Granulomas have been seen on the serosa of the adnexa, uterus, colon, and appendix. These granulomas are easily misinterpreted as metastatic carcinoma. Follow-up on these patients indicates that cell-free granulomas lack prognostic significance.

Keratin nodule in omentum. The patient had an endometrial adenocarcinoma with squamous differentiation and had received radiotherapy.

Cauterized Tissue

Foreign-body granulomatous reactions to cauterized tissue in pelvic peritoneal and ovarian biopsies are occasionally encountered in patients who have had endometriotic or other lesions treated in the weeks prior to biopsy. The lesions show central eosinophilic, focally refractile, amorphous material (representing the coagulated tissue and carbonaceous debris) palisaded by large numbers of multinucleated foreign-body giant cells and a peripheral lymphocytic infiltrate ( Figure 31.2 ). Lesions tend to hyalinize with age and may persist for many years.

Florid foreign-body granulomatous reactions to cauterized tissue.

Cesarean Delivery

Complicating cesarean delivery, the amniotic fluid contents may spill into the peritoneal cavity causing a syndrome clinically similar to bowel perforation. Amniotic fluid contains squamous cells, keratin, and sometimes lanugo hair (vernix caseosa). It may also contain meconium, which itself is composed of bile, pancreatic, and intestinal secretions. Grossly, the amniotic fluid contents appear as cheese-like yellow patches limited to the serosal layer of visceral organs. Meconium peritonitis caused by bowel perforation in utero can also be a problem in newborn infants. The hallmark of meconium peritonitis is calcification, which presumably results from the action of pancreatic enzymes.

Non-Granulomatous Histiocytic Lesions

Histiocytic infiltrates rather than discrete granulomas are occasionally found in the peritoneum. Melanin-rich histiocytes are sometimes found in cases where an ovarian dermoid cyst has ruptured. The spillage contains melanin, which the peritoneal histiocytes phagocytose. Grossly, the peritoneum may appear to be stained black or display small tumor-like nodules on its surface. Distinction of benign peritoneal melanosis from metastatic malignant melanoma is usually straightforward because of the bland nuclear features of the pigmented histiocytes and the absence of mitoses. Appropriate immunohistochemical stains can further indicate that the cells are histiocytes and not atypical melanocytes.

Occasionally, foci of endometriosis may disclose an abundance of histiocytes filled with ceroid, a wax-like, finely granular, and golden to yellow-brown pigment that is a form of lipofuscin, a lipid-containing residue of lysosomal digestion that is considered an aging or ‘wear and tear’ pigment. Ceroid is believed to be the end result of the breakdown of blood products after removal of iron. These histiocytic foci are sometimes called ‘necrotic pseudoxanthomatous nodules.’

Fibrosing Lesions

Sclerosing peritonitis is a reactive process in which a thickened fibrous or myofibromatous stroma develops on the peritoneal serosa. It is often idiopathic, although in some cases the cause is identified, such as prior peritoneal inflammation or a ruptured ovarian dermoid with spillage of the contents (see previous granulomatous reactions), chronic dialysis, or after surgical procedures.

In some cases, the sclerosing peritonitis has been described as part of a syndrome, often in association with a ‘luteinized thecoma of the ovary.’ Clinically, most of the women are young, usually under 30 years of age. Common presenting signs include abdominal enlargement and sometimes small bowel obstruction. Ascites may be present. Even when the patients have a luteinized thecoma, none has endocrine symptoms. A significant number of patients have been exposed to propranolol-type beta-blocking agents or antiepileptics.

Grossly, opaque to light-brown 1–3 mm granules or nodules appear matted together on the peritoneum or on the serosa of the involved organs. The omentum is usually indurated. Microscopic examination discloses a fibrotic process, with various chronic inflammatory cells ( Figure 31.3 ). There is usually some degree of mesothelial hyperplasia. Deeper tissues are relatively spared. Nodules are composed of moderately cellular fascicles of benign-appearing spindle cells resembling fibroblasts and myofibroblasts that contain occasional mitotic figures. In addition to cytokeratin reactivity, the cells also disclose immunoreactivity for vimentin and smooth muscle actin.

Sclerosing peritonitis. The fat lobules are surrounded by cellular fibromatous tissue.

Rarely, single or multiple fibrous nodules ranging up to 6 cm may occur in the gastrointestinal tract or mesentery in adults. Microscopically, the lesions are composed of fibro­blasts, collagen, and scattered mononuclear inflammatory cells. The fibroblastic cells show variable immunoreactivity for vimentin, CD117, muscle-specific actin, smooth muscle actin, and desmin, with negative staining for CD34 and ALK-1. These nodules have been designated as ‘fibrous pseudotumors.’

Occasionally, sclerosing lesions may be difficult to distinguish from desmoplastic mesothelioma, especially when the biopsy specimen is small. These tumors, however, are very rare in the peritoneal cavity, especially in women. Features that favor a diagnosis of mesothelioma include nuclear atypia, necrosis, organized patterns of collagen deposition (fascicular or storiform), and destructive infiltration into adjacent tissues.

Some patients with sclerosing peritonitis have been successfully treated utilizing antiestrogens and/or GnRH agonists.

Tumor-Like Lesions

Mesothelial Hyperplasia

Mesothelial hyperplasia is a common response to inflammation that occurs in any process that leads to irritation of a serosal surface, such as ascites, hernia sacs, endometriosis, pelvic inflammatory disease, or ovarian tumors. Grossly, the hyperplastic lesions may be seen at operation as multiple small nodules, but more commonly are incidental findings on microscopic examination. Microscopically, the changes range from a mild ( Figure 31.4 ) to a substantial increase in the number of mesothelial cells ( Figure 31.5 ), most of which have transformed from flat and relatively inconspicuous to cuboidal or even columnar. With marked hyperplasia, the mesothelial proliferation appears as sheets, clusters, ribbons, tubules, and sometimes as papillary formations that can be misinterpreted as metastatic adenocarcinoma ( Figure 31.6 ). Psammoma bodies are encountered occasionally and eosinophilic elongated cells resembling rhabdomyoblasts have been described.

Slight mesothelial hyperplasia of peritoneum.

Thin layer of moderately reactive mesothelium.

Reactive mesothelium. The enlarged mesothelial cells (arrow) that cover a focus of fibrous reaction superficially resemble metastatic adenocarcinoma.

Reactive mesothelial cells tend to be uniform in appearance. With minor degrees of reactivity, the nuclei are small, regular, round, or oval, and exhibit central nucleoli. The cytoplasm is eosinophilic or sometimes vacuolated and contains acid mucin (predominantly hyaluronic acid). With increasing degrees of reactivity, the nuclei enlarge and the chromatin increases. Nucleoli become more apparent and, in the extreme case, may become quite large and prominent ( Figure 31.7 ). Cells may become binucleated or multinucleated. In cytologic preparations the large macronucleoli may be mistaken as evidence for malignancy.

Markedly reactive mesothelial cells with prominent nucleoli.

The immunoprofile of normal mesothelium differs from that expected of epithelial tissue. As anticipated, it expresses cytokeratin intermediate filaments typical of epithelial cells. But it also expresses vimentin and desmin, which are indicative, respectively, of mesenchymal differentiation and specialization into muscle. In contrast, ovarian surface epithelium is immunoreactive for vimentin and desmin in fewer than half of cases. Ovarian inclusion cysts are nonreactive for vimentin and desmin, as are benign and borderline ovarian tumors. Mesothelial hyperplasia can occur within the superficial ovarian stroma overlying a borderline tumor and in such cases can be misinterpreted as invasive tumor. The differential reactivity of mesothelium (and mesothelioma) and müllerian tissue (and ovarian tumors) is discussed more fully in the following sections.

With greater degrees of injury, a layer of spindle-shaped mesenchymal cells may sometimes appear below the meso­thelial cells. In the resting state, this layer is inconspicuous, but, when stimulated, the cells may proliferate and produce a highly cellular desmoplastic tissue. Cells also express cytokeratin, vimentin, and desmin. These cells simulate myofibroblasts, and are thought to give rise occasionally to the muscular cells in the condition ‘disseminated peritoneal leiomyomatosis’ (see later).

The exuberant and sometimes pseudoinfiltrative growth that mesothelium can show, together with the increased mitotic activity that is frequently observed, may lead to a false impression of primary or metastatic carcinoma, despite the benign cytologic appearance of the cells ( Figure 31.6 ). Carcinoma cells generally demonstrate greater nuclear pleomorphism and more conspicuous mitotic activity. However, clusters of mesothelial cells are easily mistaken for metastatic carcinoma. This is true especially when mesothelial cells extensively involve sinusoids in pelvic lymph nodes either as small papillary clusters or as sheets of somewhat discohesive cells. Exuberant surface proliferations, sometimes forming sessile or polypoid nodules, can also simulate mesothelioma, a problem also encountered in the walls of hernia sacs. A useful morphologic feature that can help distinguish reactive mesothelial cell aggregates from metastatic carcinoma is their orientation at low-power magnification to one another (often in a line that can be traced for some considerable distance) ( Figure 31.6 ) and their relation to the position of the original peritoneal surface (as demonstrated by the presence of the peritoneal elastic lamina).

Organization of surface proliferative lesions and inflammatory exudates may leave adhesions of variable density, ranging from delicate strands of loose connective tissue to broad bands of dense, well-vascularized collagenous fibrous tissue. Entrapped inflammatory exudate within granulation tissue and proliferating sheets of mesothelial cells may lead to mesothelial (peritoneal) cyst formation. These may not become clinically apparent until months or years after the precipitating event.

Mesothelial hyperplasia must be distinguished from malignant peritoneal mesothelioma. The presence of necrosis, marked nuclear pleomorphism, and deep infiltration favors malignant mesothelioma. Immunostains may help in the differential diagnosis. Strong immunoreactivities for p53 and epithelial membrane antigen (EMA; nuclear and cytoplasmic, respectively) are characteristic of the cells of malignant mesothelioma but not reactive mesothelial cells; in contrast, hyperplasic mesothelial cells are usually desmin positive. Proliferative markers such as Ki-67 may also be helpful (approximately 25% vs 5% labeling index for malignant mesothelioma vs mesothelial hyperplasia, respectively). In some cases, however, the distinction between a reactive and malignant mesothelial lesion may be difficult or impossible, particularly in a biopsy samples. An apparently benign mesothelial proliferation occasionally precedes the appearance of a malignant peritoneal mesothelioma.

Mesothelial hyperplasia should also be distinguished from a borderline serous tumor of primary peritoneal origin. Grossly visible tumor, columnar cells with or without cilia, the presence of neutral mucin, and numerous psammoma bodies all favor a serous tumor. Immunohistochemical markers for epithelial differentiation may also be useful in the distinction (see Chapter 25 ).

Peritoneal Inclusion Cysts

Peritoneal inclusion cysts are unilocular or multilocular mesothelial-lined lesions that occur almost exclusively in women in the reproductive age group. They usually involve the pelvis, although may occur in other abdominal locations, including the omentum and mesentery, and are frequently associated with prior abdominal surgery. The origin of peritoneal inclusion cysts remains controversial; some authors consider them reactive lesions that develop in response to injury, whereas others favor their neoplastic nature.

Unilocular peritoneal inclusion cysts are usually incidental findings at laparotomy. Multilocular peritoneal inclusion cysts, also referred to as ‘benign cystic mesotheliomas,’ frequently form large bulky masses ( Figures 31.8–31.11 ) simulating a cystic ovarian tumor. Cysts are thin walled, contain clear proteinaceous fluid, and are lined by a single layer of flat to cuboidal, hobnail-shaped, mesothelial cells ( Figure 31.12 ) with bland nuclear features, although a degree of reactive atypia is occasionally seen. Tubal and squamous metaplasia of the mesothelial lining sometimes occurs. Inflammatory infiltrates, if present at all, are limited to sparse lymphocytic collections. The mesothelial cells are typically immunoreactive for calretinin, and less frequently positive for estrogen (ERs) or progesterone receptors (PRs), or both.

Mesothelial cyst.

Multiple small mesothelial cysts.

Multiple large mesothelial cysts.

Multicystic mesothelioma.

(A) Thin-walled mesothelial cysts in peritoneum. (B) The cyst is lined by numerous mesothelial cells. (C) Detail of the mesothelial cells.

In patients who have had peritonitis, fibrinous adhesions that are superficial to the deeper lining of normal mesothelium may develop and the underlying serosa can be mistaken for invasive serous carcinoma until attention is paid to its regularity and benign histology ( Figure 31.13 ).

(A) Serosa covered by adhesions. It is easy to mistake the normal mesothelium for serous adenocarcinoma due to its location within the peritoneal wall. (B) Detail of mesothelial inclusion.

Peritoneal inclusion cysts are confused with multilocular cystic lymphangiomas, which typically occur in children, more often in boys. Lymphangiomas are almost always localized in the mesentery of the small intestine, mesocolon, omentum, or retroperitoneum. They contain chylous material and, microscopically, show intramural lymphoid aggregates and smooth muscle, which are absent in peritoneal inclusion cysts.

Although no malignant behavior has been reported in peritoneal inclusion cysts, recurrence occurs in approximately one-half of cases from months to several years postoperatively. GnRH agonists or tamoxifen have successfully been applied to some patients.

Mesothelial Hyperplasia

Mesothelial hyperplasia is a common response to inflammation that occurs in any process that leads to irritation of a serosal surface, such as ascites, hernia sacs, endometriosis, pelvic inflammatory disease, or ovarian tumors. Grossly, the hyperplastic lesions may be seen at operation as multiple small nodules, but more commonly are incidental findings on microscopic examination. Microscopically, the changes range from a mild ( Figure 31.4 ) to a substantial increase in the number of mesothelial cells ( Figure 31.5 ), most of which have transformed from flat and relatively inconspicuous to cuboidal or even columnar. With marked hyperplasia, the mesothelial proliferation appears as sheets, clusters, ribbons, tubules, and sometimes as papillary formations that can be misinterpreted as metastatic adenocarcinoma ( Figure 31.6 ). Psammoma bodies are encountered occasionally and eosinophilic elongated cells resembling rhabdomyoblasts have been described.

Slight mesothelial hyperplasia of peritoneum.

Thin layer of moderately reactive mesothelium.

Reactive mesothelium. The enlarged mesothelial cells (arrow) that cover a focus of fibrous reaction superficially resemble metastatic adenocarcinoma.

Reactive mesothelial cells tend to be uniform in appearance. With minor degrees of reactivity, the nuclei are small, regular, round, or oval, and exhibit central nucleoli. The cytoplasm is eosinophilic or sometimes vacuolated and contains acid mucin (predominantly hyaluronic acid). With increasing degrees of reactivity, the nuclei enlarge and the chromatin increases. Nucleoli become more apparent and, in the extreme case, may become quite large and prominent ( Figure 31.7 ). Cells may become binucleated or multinucleated. In cytologic preparations the large macronucleoli may be mistaken as evidence for malignancy.

Markedly reactive mesothelial cells with prominent nucleoli.

The immunoprofile of normal mesothelium differs from that expected of epithelial tissue. As anticipated, it expresses cytokeratin intermediate filaments typical of epithelial cells. But it also expresses vimentin and desmin, which are indicative, respectively, of mesenchymal differentiation and specialization into muscle. In contrast, ovarian surface epithelium is immunoreactive for vimentin and desmin in fewer than half of cases. Ovarian inclusion cysts are nonreactive for vimentin and desmin, as are benign and borderline ovarian tumors. Mesothelial hyperplasia can occur within the superficial ovarian stroma overlying a borderline tumor and in such cases can be misinterpreted as invasive tumor. The differential reactivity of mesothelium (and mesothelioma) and müllerian tissue (and ovarian tumors) is discussed more fully in the following sections.

With greater degrees of injury, a layer of spindle-shaped mesenchymal cells may sometimes appear below the meso­thelial cells. In the resting state, this layer is inconspicuous, but, when stimulated, the cells may proliferate and produce a highly cellular desmoplastic tissue. Cells also express cytokeratin, vimentin, and desmin. These cells simulate myofibroblasts, and are thought to give rise occasionally to the muscular cells in the condition ‘disseminated peritoneal leiomyomatosis’ (see later).

The exuberant and sometimes pseudoinfiltrative growth that mesothelium can show, together with the increased mitotic activity that is frequently observed, may lead to a false impression of primary or metastatic carcinoma, despite the benign cytologic appearance of the cells ( Figure 31.6 ). Carcinoma cells generally demonstrate greater nuclear pleomorphism and more conspicuous mitotic activity. However, clusters of mesothelial cells are easily mistaken for metastatic carcinoma. This is true especially when mesothelial cells extensively involve sinusoids in pelvic lymph nodes either as small papillary clusters or as sheets of somewhat discohesive cells. Exuberant surface proliferations, sometimes forming sessile or polypoid nodules, can also simulate mesothelioma, a problem also encountered in the walls of hernia sacs. A useful morphologic feature that can help distinguish reactive mesothelial cell aggregates from metastatic carcinoma is their orientation at low-power magnification to one another (often in a line that can be traced for some considerable distance) ( Figure 31.6 ) and their relation to the position of the original peritoneal surface (as demonstrated by the presence of the peritoneal elastic lamina).

Organization of surface proliferative lesions and inflammatory exudates may leave adhesions of variable density, ranging from delicate strands of loose connective tissue to broad bands of dense, well-vascularized collagenous fibrous tissue. Entrapped inflammatory exudate within granulation tissue and proliferating sheets of mesothelial cells may lead to mesothelial (peritoneal) cyst formation. These may not become clinically apparent until months or years after the precipitating event.

Mesothelial hyperplasia must be distinguished from malignant peritoneal mesothelioma. The presence of necrosis, marked nuclear pleomorphism, and deep infiltration favors malignant mesothelioma. Immunostains may help in the differential diagnosis. Strong immunoreactivities for p53 and epithelial membrane antigen (EMA; nuclear and cytoplasmic, respectively) are characteristic of the cells of malignant mesothelioma but not reactive mesothelial cells; in contrast, hyperplasic mesothelial cells are usually desmin positive. Proliferative markers such as Ki-67 may also be helpful (approximately 25% vs 5% labeling index for malignant mesothelioma vs mesothelial hyperplasia, respectively). In some cases, however, the distinction between a reactive and malignant mesothelial lesion may be difficult or impossible, particularly in a biopsy samples. An apparently benign mesothelial proliferation occasionally precedes the appearance of a malignant peritoneal mesothelioma.

Mesothelial hyperplasia should also be distinguished from a borderline serous tumor of primary peritoneal origin. Grossly visible tumor, columnar cells with or without cilia, the presence of neutral mucin, and numerous psammoma bodies all favor a serous tumor. Immunohistochemical markers for epithelial differentiation may also be useful in the distinction (see Chapter 25 ).

Peritoneal Inclusion Cysts

Peritoneal inclusion cysts are unilocular or multilocular mesothelial-lined lesions that occur almost exclusively in women in the reproductive age group. They usually involve the pelvis, although may occur in other abdominal locations, including the omentum and mesentery, and are frequently associated with prior abdominal surgery. The origin of peritoneal inclusion cysts remains controversial; some authors consider them reactive lesions that develop in response to injury, whereas others favor their neoplastic nature.

Unilocular peritoneal inclusion cysts are usually incidental findings at laparotomy. Multilocular peritoneal inclusion cysts, also referred to as ‘benign cystic mesotheliomas,’ frequently form large bulky masses ( Figures 31.8–31.11 ) simulating a cystic ovarian tumor. Cysts are thin walled, contain clear proteinaceous fluid, and are lined by a single layer of flat to cuboidal, hobnail-shaped, mesothelial cells ( Figure 31.12 ) with bland nuclear features, although a degree of reactive atypia is occasionally seen. Tubal and squamous metaplasia of the mesothelial lining sometimes occurs. Inflammatory infiltrates, if present at all, are limited to sparse lymphocytic collections. The mesothelial cells are typically immunoreactive for calretinin, and less frequently positive for estrogen (ERs) or progesterone receptors (PRs), or both.

Mesothelial cyst.

Multiple small mesothelial cysts.

Multiple large mesothelial cysts.

Multicystic mesothelioma.

(A) Thin-walled mesothelial cysts in peritoneum. (B) The cyst is lined by numerous mesothelial cells. (C) Detail of the mesothelial cells.

In patients who have had peritonitis, fibrinous adhesions that are superficial to the deeper lining of normal mesothelium may develop and the underlying serosa can be mistaken for invasive serous carcinoma until attention is paid to its regularity and benign histology ( Figure 31.13 ).

(A) Serosa covered by adhesions. It is easy to mistake the normal mesothelium for serous adenocarcinoma due to its location within the peritoneal wall. (B) Detail of mesothelial inclusion.

Peritoneal inclusion cysts are confused with multilocular cystic lymphangiomas, which typically occur in children, more often in boys. Lymphangiomas are almost always localized in the mesentery of the small intestine, mesocolon, omentum, or retroperitoneum. They contain chylous material and, microscopically, show intramural lymphoid aggregates and smooth muscle, which are absent in peritoneal inclusion cysts.

Although no malignant behavior has been reported in peritoneal inclusion cysts, recurrence occurs in approximately one-half of cases from months to several years postoperatively. GnRH agonists or tamoxifen have successfully been applied to some patients.

Ovarian Remnant Syndrome

This condition exists if a patient who has had a ‘total bilateral oophorectomy’ later develops a palpable mass or experiences pelvic pain or other symptoms referable to ovarian tissue that has been left behind ( Figures 31.14 and 31.15 ). This condition is described more fully in Chapter 24 .

Ovarian remnant syndrome. Numerous corpora lutea appear surrounded by fibrous tissue.

Ovarian remnant syndrome. Ovarian tissue that was left behind at the time of oophorectomy has regrown and is functional.

Supernumerary or Accessory Ovaries

Supernumerary ovaries are ectopic ovaries located at some distance from the eutopic ovary. It is rare but occasional cases have been reported in the peritoneal cavity. This condition is described more fully in Chapter 23 .

Splenosis

Nodules of splenic tissue, usually less than 1 cm in diameter, are randomly distributed in the peritoneal cavity. The etiology is trauma, most commonly a motor vehicle accident, which has resulted in splenic rupture. Splenosis is generally asymptomatic but may cause abdominal or pelvic pain simulating endometriosis, or produce intestinal obstruction due to the development of adhesions. Splenosis may be encountered as an incidental finding or mistakenly interpreted as endometriosis, benign or malignant vascular tumors, or metastatic cancer.

Trophoblastic Implants

Finding disseminated trophoblastic implants in the peritoneum is uncommon ( Figure 31.16 ). They may occur on occasion with peritoneal pregnancy, or following laparoscopic treatment of tubal pregnancy, where the frequency has been estimated at 3.6%. Viability is suggested by rising human chorionic gonadotropin concentrations following surgery. The condition is best avoided by meticulous inspection of the abdomen after resection of the tubal pregnancy. Microscopically, the implants may show trophoblastic tissue including chorionic villi. Some implants, however, may resemble a placental site nodule.

Trophoblastic implant in peritoneum. The patient had a ruptured ectopic pregnancy.

Infarcted Appendix Epiploica

Appendices epiploicae are small polypoid processes of adipose tissue that project from the serosa of the large intestine, especially the transverse and sigmoid colon. Occasionally, they undergo torsion, infarction, and later detachment and can be found lying free within the peritoneal cavity. Typically in these cases, the center contains hyalinized fibrous tissue and often some residual adipose tissue that is mummified. The outer rim and variable portions of the core may calcify, resulting in a hard tumor-like mass ( Figure 31.17 ).

Infarcted appendix epiploica.

Mesothelial Neoplasms

Well-Differentiated Papillary Mesothelioma

A rare form of peritoneal mesothelioma is the well-differentiated papillary mesothelioma. Most patients are of reproductive age, although an occasional patient has been postmenopausal. Also encountered in males, less common sites include the tunica vaginalis testis, pericardium, and pleura. These tumors are typically asymptomatic and often found incidentally at operation. Grossly, they are usually multiple, broad-based, wart-like excrescences that are polypoid or slightly nodular. Color and texture are similar to ovarian cortical tissue but sometimes firmer. They are generally small, usually measuring less than 2 cm in diameter. An occasional tumor is solitary.

On microscopic examination, the neoplasm consists of relatively thick papillae composed of dense fibrous or hyalinized tissue covered by a single layer of cytologically benign, small flattened to cuboidal cells ( Figure 31.18 ). Nuclei are bland, with a low nuclear grade ( Figure 31.19 ). Mitoses are rare, usually under 1, but may be as high as 3, mitotic figures per 10 HPFs. The diagnosis should be made with caution, as malignant mesotheliomas may have foci that, viewed in isolation, resemble this tumor. These lesions can usually be reliably distinguished from serous epithelial tumors, since the architecture of the latter discloses feathery irregular clusters of cells in which the nuclei are far more atypical and higher grade. Psammoma bodies may be encountered in rare cases. These tumors are nearly always benign, but rare tumors have acted aggressively.

Well-differentiated peritoneal mesothelioma.

Detail of well-differentiated peritoneal mesothelioma.

Diffuse Malignant Mesothelioma

Peritoneal diffuse malignant mesotheliomas are much less common than their pleural counterparts, accounting for about 10% of all malignant mesotheliomas. Only one-third of these tumors occur in middle-aged or postmenopausal women and they must be distinguished from the more prevalent serous adenocarcinomas, including those arising from the peritoneum itself and those metastatic from an ovarian or fallopian tube primary. The survival rate for women with malignant mesothelioma is worse than that for women with serous adenocarcinoma, and the treatment of the two diseases currently differs.

Clinical manifestations usually are nonspecific and include ascites, abdominal discomfort, digestive disturbances, and weight loss. Ascites is present in most cases, and cytologic examination of the ascitic fluid may be diagnostic in some cases. The diagnosis, however, usually requires laparotomy or laparoscopy and biopsy. While most malignant mesotheliomas are highly aggressive, some peritoneal malignant mesotheliomas pursue a more indolent course. It is generally stated in the literature that asbestos exposure is uncommon in women with peritoneal mesothelioma. In one (2003) population-based study of peritoneal malignant mesotheliomas, 29% of 96 men had asbestos-related jobs whereas none of 113 women had occupational or environmental risk factors. In fact, men with peritoneal mesotheliomas typically have had a heavier burden and more prolonged exposure to asbestos than men with pleural mesotheliomas. Most males with peritoneal malignant meso­theliomas reported in the literature survived less than 2 years after diagnosis, although there have been occasional long-term survivors. A study of peritoneal malignant mesotheliomas in women, however, found that 40% of the patients survived longer than 4 years. The histopathologic subtype (see later) is of prognostic significance, as biphasic peritoneal malignant mesotheliomas are associated with a much shorter survival than pure epithelial tumors and deciduoid mesotheliomas are usually rapidly fatal. Increasing nuclear and nucleolar size has been shown to correlate with shorter survival in epithelial tumors. Also, p16 loss independently correlates with increased risk of death according to one study, while another failed to identify any morphologic features that differentiated those cases with a highly aggressive course from indolent ones. Two studies have identified a number of favorable prognostic factors including an age less than 60 years, low nuclear grade, low mitotic index, minimal residual disease after cytoreduction, and lack of deep invasion.

Pathology

Tumors may extensively involve and diffusely thicken the peritoneum and the serosa of the various abdominal and pelvic organs and typically consist of multiple nodules measuring less than 1.5 cm in greatest dimension. Some tumors incite a striking desmoplastic reaction. On microscopic examination, most tumors have only an epithelial component, which usually has a tubulopapillary to focally solid pattern. The epithelial variant of malignant mesothelioma has polygonal or cuboidal cells with moderately abundant eosinophilic cytoplasm ( Figures 31.20 and 31.21 ). The tumor cells usually resemble mesothelial cells, with a more or less constant nuclear : cytoplasmic ratio and only mild to moderate nuclear atypia ( Figures 31.22–31.24 ); in some cases, however, the nuclei become larger and more bizarre as the cytoplasmic volume increases. Mitotic figures usually are present but are not numerous. In rare cases, the cytoplasm is abundant, amphophilic, and glassy, mimicking an exuberant ectopic decidual reaction (so-called ‘deciduoid mesothelioma’) ( Figure 31.25 ). Psammoma bodies are found in approximately one-third of cases ( Figure 31.26 ), but are usually less common than in serous tumors. Unlike pleural mesotheliomas, sarcomatoid or fibrous variants are extremely rare. Intra-abdominal lymph nodes may be involved.

Diffuse malignant mesothelioma.

Diffuse malignant mesothelioma, detail.

Diffuse malignant mesothelioma. Individual cells have central oval–round uniform nuclei and abundant eosinophilic cytoplasm.

Diffuse malignant mesothelioma in which the regular-sized cells are arranged in glandular and tubular structures.

Diffuse malignant mesothelioma in which the cells display a more or less constant nuclear : cytoplasmic ratio and only mild to moderate nuclear atypia.

Diffuse malignant mesothelioma in which the tumor cells exhibit abundant, amphophilic cytoplasm mimicking an ectopic decidual reaction (so-called ‘deciduoid mesothelioma’).

Diffuse malignant mesothelioma with numerous psammoma bodies.

Differential Diagnosis

The two types of lesions that are most difficult to distinguish from diffuse malignant mesothelioma are florid mesothelial hyperplasia and serous adenocarcinoma, whether the latter is primary in the peritoneum or metastatic from the ovary or another site. In contrast to hyperplasia, malignant meso­thelioma often has grossly visible nodules, necrosis, and conspicuous large cytoplasmic vacuoles, and may have severe nuclear pleomorphism. Destructive tissue invasion should be sought as an important indicator of malignancy. Reactive mesothelial cells generally have smaller nuclei than those of malignant mesothelioma.

The diagnosis that results in substantially differing treatment plans is the high-grade serous adenocarcinoma. Psammocarcinoma and low-grade serous carcinoma with abundant psammoma bodies are readily distinguished from mesothelioma, in which psammoma bodies are few when they are present. Mesothelial cells tend to be uniform, polygonal, and have moderate to extensive amounts of eosinophilic cytoplasm. Adenocarcinomas, in contrast, tend to have columnar cells, occasional cells with bizarre nuclear features, and variable numbers of psammoma bodies. Complicating the distinction, it is now recognized that malignant mesotheliomas can on rare occasion arise within the ovary ( Table 31.1 ).

Table 31.1

Malignant Mesothelioma versus Serous Carcinoma: Differential Diagnosis

Feature	Malignant Mesothelioma	Serous Carcinoma
Clinical
History of asbestos exposure	Often positive	None
Diffuse peritoneal tumor mass	Yes	Usually dominant ovarian
Responsive to therapy	Rapidly fatal and unresponsive	Some respond
Histologic
Sarcomatoid and adenomatoid foci	Present	Absent
Columnar cells	Rare	Numerous
Psammoma bodies	Rare	Often present
Nuclei	Round	Oval or elongate
Mucins (scanty)	Cytoplasmic acid mucin	Apical neutral mucin
Ultrastructural
Microvilli	Abundant	Usually sparse
Cilia	Never numerous	Often numerous
Intracytoplasmic lumina	Common	Uncommon
Apical ‘snouts’	Rare	Common

 

Immunohistochemistry is important in establishing the proper diagnosis. Differential immunoreactivities for mesothelioma and serous carcinoma are shown in Table 31.2 . Calretinin, a 29 kDa calcium-binding protein, is present in nearly all epithelial mesotheliomas ( Figure 31.27 ), but rarely in adenocarcinomas. Both mesothelioma and adenocarcinoma are immunoreactive for low molecular weight cytokeratins. Cytokeratin (CK) 5/6 is usually expressed by mesotheliomas, but seldom by adenocarcinomas. Vimentin and desmin are commonly detected in mesotheliomas. Once, it was believed that vimentin expression favored a diagnosis of mesothelioma, but it is now known that this intermediate filament is seen in normal and neoplastic cells of both epithelial and mesenchymal origin. Moreover, keratins and vimentin are commonly coexpressed by adenocarcinomas of müllerian type. CA125, an antigen initially identified in cell lines of ovarian serous adenocarcinomas, can be expressed by mesotheliomas. Thus, no single immunohistochemical stain is diagnostic in the separation of peritoneal malignant mesothelioma from adenocarcinoma, and a panel of antibodies should be interpreted in conjunction with the H&E and mucin stains.

Table 31.2

Immunohistochemical Panel to Differentiate Mesothelioma from Serous Carcinoma ^a

	Percentage Positive
	Mesothelioma	Serous Carcinoma
h-Caldesmon	>90%	5%
Calretinin	>90%	10% b
CK panel (AE1/AE3 and CAM 5.2)	>90%	100%
CK5/6	>90%	25% b
D2-40	>90%	20%
EMA	>80%	100%
Thrombomodulin	50–75%	5% b
Desmin	40%	Negative
Vimentin	25%	35%
CA125	15–30%	95%
MOC-31	5% b	95%
S-100	0–10%	33–85%
Ber-EP4	0–10% b	100%
Leu-M1 (CD15)	0–10%	65%
Carcinoembryonic antigen (CEA)	>5%	15%
Placental-like alkaline phosphatase (PLAP)	>5%	65%
B72.3	>5%	85%
CA19.9	>5%	67%
ER	>5%	95%
PR	>5%	65%

 

Note: Mesothelial cells showing reactive atypia show an identical immunophenotype to malignant mesothelioma (with the exception of EMA immunoreactivity).

a The percentages for serous carcinoma of ovary and serous carcinoma primary in the peritoneum are essentially identical.

b Trace to focally positive.

Diffuse malignant mesothelioma, calretinin immunoreaction.

Adenomatoid Tumor

Adenomatoid tumors are benign neoplasms of mesothelial origin, encountered most often in the fallopian tubes where frequently they are sieve like or multicystic. In contrast, they are also found subserosally in the uterine corpus near the fallopian tube, where they more usually simulate leiomyomas. They are seldom encountered elsewhere in the peritoneal cavity (see Chapter 21 ). Clinically, they are asymptomatic, and rarely recur after adequate excision. Grossly, adenomatoid tumors are usually solitary, less than 2 cm in diameter and have a white-gray appearance. Microscopically, multiple small slit-like or ovoid spaces are lined by a single layer of cells. Nuclear atypia is absent or minimal, and mitotic figures are rarely seen.

Well-Differentiated Papillary Mesothelioma

A rare form of peritoneal mesothelioma is the well-differentiated papillary mesothelioma. Most patients are of reproductive age, although an occasional patient has been postmenopausal. Also encountered in males, less common sites include the tunica vaginalis testis, pericardium, and pleura. These tumors are typically asymptomatic and often found incidentally at operation. Grossly, they are usually multiple, broad-based, wart-like excrescences that are polypoid or slightly nodular. Color and texture are similar to ovarian cortical tissue but sometimes firmer. They are generally small, usually measuring less than 2 cm in diameter. An occasional tumor is solitary.

On microscopic examination, the neoplasm consists of relatively thick papillae composed of dense fibrous or hyalinized tissue covered by a single layer of cytologically benign, small flattened to cuboidal cells ( Figure 31.18 ). Nuclei are bland, with a low nuclear grade ( Figure 31.19 ). Mitoses are rare, usually under 1, but may be as high as 3, mitotic figures per 10 HPFs. The diagnosis should be made with caution, as malignant mesotheliomas may have foci that, viewed in isolation, resemble this tumor. These lesions can usually be reliably distinguished from serous epithelial tumors, since the architecture of the latter discloses feathery irregular clusters of cells in which the nuclei are far more atypical and higher grade. Psammoma bodies may be encountered in rare cases. These tumors are nearly always benign, but rare tumors have acted aggressively.

Well-differentiated peritoneal mesothelioma.

Detail of well-differentiated peritoneal mesothelioma.

Diffuse Malignant Mesothelioma

Peritoneal diffuse malignant mesotheliomas are much less common than their pleural counterparts, accounting for about 10% of all malignant mesotheliomas. Only one-third of these tumors occur in middle-aged or postmenopausal women and they must be distinguished from the more prevalent serous adenocarcinomas, including those arising from the peritoneum itself and those metastatic from an ovarian or fallopian tube primary. The survival rate for women with malignant mesothelioma is worse than that for women with serous adenocarcinoma, and the treatment of the two diseases currently differs.

Clinical manifestations usually are nonspecific and include ascites, abdominal discomfort, digestive disturbances, and weight loss. Ascites is present in most cases, and cytologic examination of the ascitic fluid may be diagnostic in some cases. The diagnosis, however, usually requires laparotomy or laparoscopy and biopsy. While most malignant mesotheliomas are highly aggressive, some peritoneal malignant mesotheliomas pursue a more indolent course. It is generally stated in the literature that asbestos exposure is uncommon in women with peritoneal mesothelioma. In one (2003) population-based study of peritoneal malignant mesotheliomas, 29% of 96 men had asbestos-related jobs whereas none of 113 women had occupational or environmental risk factors. In fact, men with peritoneal mesotheliomas typically have had a heavier burden and more prolonged exposure to asbestos than men with pleural mesotheliomas. Most males with peritoneal malignant meso­theliomas reported in the literature survived less than 2 years after diagnosis, although there have been occasional long-term survivors. A study of peritoneal malignant mesotheliomas in women, however, found that 40% of the patients survived longer than 4 years. The histopathologic subtype (see later) is of prognostic significance, as biphasic peritoneal malignant mesotheliomas are associated with a much shorter survival than pure epithelial tumors and deciduoid mesotheliomas are usually rapidly fatal. Increasing nuclear and nucleolar size has been shown to correlate with shorter survival in epithelial tumors. Also, p16 loss independently correlates with increased risk of death according to one study, while another failed to identify any morphologic features that differentiated those cases with a highly aggressive course from indolent ones. Two studies have identified a number of favorable prognostic factors including an age less than 60 years, low nuclear grade, low mitotic index, minimal residual disease after cytoreduction, and lack of deep invasion.

Pathology

Tumors may extensively involve and diffusely thicken the peritoneum and the serosa of the various abdominal and pelvic organs and typically consist of multiple nodules measuring less than 1.5 cm in greatest dimension. Some tumors incite a striking desmoplastic reaction. On microscopic examination, most tumors have only an epithelial component, which usually has a tubulopapillary to focally solid pattern. The epithelial variant of malignant mesothelioma has polygonal or cuboidal cells with moderately abundant eosinophilic cytoplasm ( Figures 31.20 and 31.21 ). The tumor cells usually resemble mesothelial cells, with a more or less constant nuclear : cytoplasmic ratio and only mild to moderate nuclear atypia ( Figures 31.22–31.24 ); in some cases, however, the nuclei become larger and more bizarre as the cytoplasmic volume increases. Mitotic figures usually are present but are not numerous. In rare cases, the cytoplasm is abundant, amphophilic, and glassy, mimicking an exuberant ectopic decidual reaction (so-called ‘deciduoid mesothelioma’) ( Figure 31.25 ). Psammoma bodies are found in approximately one-third of cases ( Figure 31.26 ), but are usually less common than in serous tumors. Unlike pleural mesotheliomas, sarcomatoid or fibrous variants are extremely rare. Intra-abdominal lymph nodes may be involved.

Diffuse malignant mesothelioma.

Diffuse malignant mesothelioma, detail.

Diffuse malignant mesothelioma. Individual cells have central oval–round uniform nuclei and abundant eosinophilic cytoplasm.

Diffuse malignant mesothelioma in which the regular-sized cells are arranged in glandular and tubular structures.

Diffuse malignant mesothelioma in which the cells display a more or less constant nuclear : cytoplasmic ratio and only mild to moderate nuclear atypia.

Diffuse malignant mesothelioma in which the tumor cells exhibit abundant, amphophilic cytoplasm mimicking an ectopic decidual reaction (so-called ‘deciduoid mesothelioma’).

Diffuse malignant mesothelioma with numerous psammoma bodies.

Differential Diagnosis

The two types of lesions that are most difficult to distinguish from diffuse malignant mesothelioma are florid mesothelial hyperplasia and serous adenocarcinoma, whether the latter is primary in the peritoneum or metastatic from the ovary or another site. In contrast to hyperplasia, malignant meso­thelioma often has grossly visible nodules, necrosis, and conspicuous large cytoplasmic vacuoles, and may have severe nuclear pleomorphism. Destructive tissue invasion should be sought as an important indicator of malignancy. Reactive mesothelial cells generally have smaller nuclei than those of malignant mesothelioma.

The diagnosis that results in substantially differing treatment plans is the high-grade serous adenocarcinoma. Psammocarcinoma and low-grade serous carcinoma with abundant psammoma bodies are readily distinguished from mesothelioma, in which psammoma bodies are few when they are present. Mesothelial cells tend to be uniform, polygonal, and have moderate to extensive amounts of eosinophilic cytoplasm. Adenocarcinomas, in contrast, tend to have columnar cells, occasional cells with bizarre nuclear features, and variable numbers of psammoma bodies. Complicating the distinction, it is now recognized that malignant mesotheliomas can on rare occasion arise within the ovary ( Table 31.1 ).

Table 31.1

Malignant Mesothelioma versus Serous Carcinoma: Differential Diagnosis

Feature	Malignant Mesothelioma	Serous Carcinoma
Clinical
History of asbestos exposure	Often positive	None
Diffuse peritoneal tumor mass	Yes	Usually dominant ovarian
Responsive to therapy	Rapidly fatal and unresponsive	Some respond
Histologic
Sarcomatoid and adenomatoid foci	Present	Absent
Columnar cells	Rare	Numerous
Psammoma bodies	Rare	Often present
Nuclei	Round	Oval or elongate
Mucins (scanty)	Cytoplasmic acid mucin	Apical neutral mucin
Ultrastructural
Microvilli	Abundant	Usually sparse
Cilia	Never numerous	Often numerous
Intracytoplasmic lumina	Common	Uncommon
Apical ‘snouts’	Rare	Common

 

Immunohistochemistry is important in establishing the proper diagnosis. Differential immunoreactivities for mesothelioma and serous carcinoma are shown in Table 31.2 . Calretinin, a 29 kDa calcium-binding protein, is present in nearly all epithelial mesotheliomas ( Figure 31.27 ), but rarely in adenocarcinomas. Both mesothelioma and adenocarcinoma are immunoreactive for low molecular weight cytokeratins. Cytokeratin (CK) 5/6 is usually expressed by mesotheliomas, but seldom by adenocarcinomas. Vimentin and desmin are commonly detected in mesotheliomas. Once, it was believed that vimentin expression favored a diagnosis of mesothelioma, but it is now known that this intermediate filament is seen in normal and neoplastic cells of both epithelial and mesenchymal origin. Moreover, keratins and vimentin are commonly coexpressed by adenocarcinomas of müllerian type. CA125, an antigen initially identified in cell lines of ovarian serous adenocarcinomas, can be expressed by mesotheliomas. Thus, no single immunohistochemical stain is diagnostic in the separation of peritoneal malignant mesothelioma from adenocarcinoma, and a panel of antibodies should be interpreted in conjunction with the H&E and mucin stains.

Table 31.2

Immunohistochemical Panel to Differentiate Mesothelioma from Serous Carcinoma ^a

	Percentage Positive
	Mesothelioma	Serous Carcinoma
h-Caldesmon	>90%	5%
Calretinin	>90%	10% b
CK panel (AE1/AE3 and CAM 5.2)	>90%	100%
CK5/6	>90%	25% b
D2-40	>90%	20%
EMA	>80%	100%
Thrombomodulin	50–75%	5% b
Desmin	40%	Negative
Vimentin	25%	35%
CA125	15–30%	95%
MOC-31	5% b	95%
S-100	0–10%	33–85%
Ber-EP4	0–10% b	100%
Leu-M1 (CD15)	0–10%	65%
Carcinoembryonic antigen (CEA)	>5%	15%
Placental-like alkaline phosphatase (PLAP)	>5%	65%
B72.3	>5%	85%
CA19.9	>5%	67%
ER	>5%	95%
PR	>5%	65%

 

Note: Mesothelial cells showing reactive atypia show an identical immunophenotype to malignant mesothelioma (with the exception of EMA immunoreactivity).

a The percentages for serous carcinoma of ovary and serous carcinoma primary in the peritoneum are essentially identical.

b Trace to focally positive.

Diffuse malignant mesothelioma, calretinin immunoreaction.

Pathology

Tumors may extensively involve and diffusely thicken the peritoneum and the serosa of the various abdominal and pelvic organs and typically consist of multiple nodules measuring less than 1.5 cm in greatest dimension. Some tumors incite a striking desmoplastic reaction. On microscopic examination, most tumors have only an epithelial component, which usually has a tubulopapillary to focally solid pattern. The epithelial variant of malignant mesothelioma has polygonal or cuboidal cells with moderately abundant eosinophilic cytoplasm ( Figures 31.20 and 31.21 ). The tumor cells usually resemble mesothelial cells, with a more or less constant nuclear : cytoplasmic ratio and only mild to moderate nuclear atypia ( Figures 31.22–31.24 ); in some cases, however, the nuclei become larger and more bizarre as the cytoplasmic volume increases. Mitotic figures usually are present but are not numerous. In rare cases, the cytoplasm is abundant, amphophilic, and glassy, mimicking an exuberant ectopic decidual reaction (so-called ‘deciduoid mesothelioma’) ( Figure 31.25 ). Psammoma bodies are found in approximately one-third of cases ( Figure 31.26 ), but are usually less common than in serous tumors. Unlike pleural mesotheliomas, sarcomatoid or fibrous variants are extremely rare. Intra-abdominal lymph nodes may be involved.

Diffuse malignant mesothelioma.

Diffuse malignant mesothelioma, detail.

Diffuse malignant mesothelioma. Individual cells have central oval–round uniform nuclei and abundant eosinophilic cytoplasm.

Diffuse malignant mesothelioma in which the regular-sized cells are arranged in glandular and tubular structures.

Diffuse malignant mesothelioma in which the cells display a more or less constant nuclear : cytoplasmic ratio and only mild to moderate nuclear atypia.

Diffuse malignant mesothelioma in which the tumor cells exhibit abundant, amphophilic cytoplasm mimicking an ectopic decidual reaction (so-called ‘deciduoid mesothelioma’).

Diffuse malignant mesothelioma with numerous psammoma bodies.

Differential Diagnosis

The two types of lesions that are most difficult to distinguish from diffuse malignant mesothelioma are florid mesothelial hyperplasia and serous adenocarcinoma, whether the latter is primary in the peritoneum or metastatic from the ovary or another site. In contrast to hyperplasia, malignant meso­thelioma often has grossly visible nodules, necrosis, and conspicuous large cytoplasmic vacuoles, and may have severe nuclear pleomorphism. Destructive tissue invasion should be sought as an important indicator of malignancy. Reactive mesothelial cells generally have smaller nuclei than those of malignant mesothelioma.

The diagnosis that results in substantially differing treatment plans is the high-grade serous adenocarcinoma. Psammocarcinoma and low-grade serous carcinoma with abundant psammoma bodies are readily distinguished from mesothelioma, in which psammoma bodies are few when they are present. Mesothelial cells tend to be uniform, polygonal, and have moderate to extensive amounts of eosinophilic cytoplasm. Adenocarcinomas, in contrast, tend to have columnar cells, occasional cells with bizarre nuclear features, and variable numbers of psammoma bodies. Complicating the distinction, it is now recognized that malignant mesotheliomas can on rare occasion arise within the ovary ( Table 31.1 ).

Immunohistochemistry is important in establishing the proper diagnosis. Differential immunoreactivities for mesothelioma and serous carcinoma are shown in Table 31.2 . Calretinin, a 29 kDa calcium-binding protein, is present in nearly all epithelial mesotheliomas ( Figure 31.27 ), but rarely in adenocarcinomas. Both mesothelioma and adenocarcinoma are immunoreactive for low molecular weight cytokeratins. Cytokeratin (CK) 5/6 is usually expressed by mesotheliomas, but seldom by adenocarcinomas. Vimentin and desmin are commonly detected in mesotheliomas. Once, it was believed that vimentin expression favored a diagnosis of mesothelioma, but it is now known that this intermediate filament is seen in normal and neoplastic cells of both epithelial and mesenchymal origin. Moreover, keratins and vimentin are commonly coexpressed by adenocarcinomas of müllerian type. CA125, an antigen initially identified in cell lines of ovarian serous adenocarcinomas, can be expressed by mesotheliomas. Thus, no single immunohistochemical stain is diagnostic in the separation of peritoneal malignant mesothelioma from adenocarcinoma, and a panel of antibodies should be interpreted in conjunction with the H&E and mucin stains.

Diffuse malignant mesothelioma, calretinin immunoreaction.

Miscellaneous Primary Tumors

Intra-Abdominal Desmoplastic, Small Round Cell Tumor

Desmoplastic small, round cell tumor is the descriptive designation for a rare, undifferentiated, and highly aggressive tumor that, with few exceptions, involves the peritoneal serosa and contiguous organs such as the kidney and ovary. It usually appears during adolescence and early adulthood, with a mean age of 25 years, but occasionally may be found in older women. It is far more common in men than in women. The prognosis is poor.

Grossly, most tumors are bulky abdominal masses that have spread diffusely over the peritoneal surface with prominent involvement of the tunica vaginalis or the ovaries, mimicking a primary testicular or ovarian tumor. The characteristic microscopic pattern is nests of ‘small, blue cells’ embedded in a desmoplastic fibrous stroma ( Figure 31.28 ). The tumor cells are uniform with scanty cytoplasm and indistinct cell borders ( Figure 31.29 ). About one-third of tumors exhibit a wider range of morphologic features, principally as spindle-shaped cells with epithelioid to focally sarcomatoid arrangements. Mitotic figures are numerous and foci of necrosis are usually present. Invasion of vascular spaces is common but lymph node involvement is rare.

Desmoplastic small, round cell tumor. Nests of ‘small, blue cells’ embedded in a desmoplastic fibrous stroma.

Desmoplastic small, round cell tumor. The tumor cells are uniform with scanty cytoplasm and indistinct cell borders.

Virtually all tumors are CK positive (CK monoclonal antibodies CAM 5.2, AE1/AE3), but lack CK20 expression, indicative that they are not of large intestinal origin. Roughly four-fifths are also reactive with antibodies to EMA, neuron-specific enolase, desmin (with paranuclear dot-like reactivity) ( Figure 31.30 ), and vimentin, suggestive that there is both epithelial and mesenchymal (divergent) differentiation. Between two-fifths and two-thirds of tumors express Ber-EP4, CD57 (Leu-7), CD15 (Leu-M1), and CA125, suggestive that the tumor is not mesothelial in origin. Wilms’ tumor (WT1) protein is detected immunohistochemically in 90% of cases. Most other common immunohistochemical stains lack reactivity in most cases. Electron microscopic examination shows the tumor cells have mesenchymal–fibroblastic features.

Desmoplastic small, round cell tumor. Desmin immunoreaction.

Coexpression of epithelial and mesenchymal antigens distinguishes the desmoplastic small, round cell tumor from other small round and blue cell tumors occurring in this age group. These antigenic properties have challenged the popular notion that the intra-abdominal desmoplastic small round cell tumor is a ‘blastomatous’ tumor derived exclusively from the primitive mesothelium.

Desmoplastic small round cell tumor exhibits a 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, which appears to be unique for this tumor. The translocation results in a loss of three specific amino acids and appears to have an oncogenic effect. Other translocation patterns have also been described. The fusion protein that is produced seems to function as a potent activator of transcription, suggesting that the Wilms’ tumor gene gains function as a result of the fusion. Thus, the fusion gene seems to function as a dominant oncogene in this disease.

After initial treatment (aggressive surgical debulking and postoperative chemotherapy, external beam radiotherapy, or both), there may be an initial response, but more than 99% of patients die of tumor progression.

Solitary Fibrous Tumor of Peritoneum (‘Fibrous Mesothelioma’)

Solitary fibrous tumors, previously called ‘fibrous mesotheliomas,’ are primitive tumors composed of fibroblasts and primitive mesenchymal cells that can manifest multidirectional differentiation. They are rare tumors found most often in the pleura, but do occur occasionally in the peritoneum. Most patients remain well after tumor excision, although occasional neoplasms have acted aggressively.

Grossly, the tumors vary in size from 1 cm to over 20 cm in diameter ( Figure 31.31 ). They are usually solitary and appear encapsulated by fibrous tissue. Microscopically, tumors are composed of spindle cells in a markedly collagenized stroma, often with abundant blood vessels, in a hemangiopericytoma-like pattern ( Figure 31.32 ). Tumor cells may have fascicular, cord-like, and irregular arrangements and are found interspersed in strands in between thick collagen bundles. Nuclei are often vesicular and the nucleoli inconspicuous. Mitoses are rare.

Solitary benign fibrous mesothelioma (‘solitary fibrous tumor’). The cut surface appears multinodular and fleshy.

Solitary benign fibrous mesothelioma (‘solitary fibrous tumor’). The tumor is composed of spindle cells arranged in a hemangiopericytoma-like pattern.

Tumor cells are reactive for vimentin but not for CK. CD34, a sialylated transmembrane glycoprotein found initially in endothelial cells and myeloid progenitor cells, is usually demonstrable. CD31, a platelet endothelial cell adhesion molecule, is not. In contrast, desmoplastic meso­theliomas, tumors in the differential diagnosis, are reactive for CK but not for CD34.

Inflammatory Myofibroblastic Tumor

This lesion has also been referred to as inflammatory pseudotumor or plasma cell granuloma. Most tumors arise in the lung, mesentery, omentum, or retroperitoneum. The abdominal lesions are usually found in the mesentery of patients younger than 20 years of age who present with a mass, fever, weight loss, anemia, thrombocytosis, and polyclonal hypergammaglobulinemia. Microscopic examination reveals myofibroblastic spindle cells, mature plasma cells, and small lymphocytes. The spindle cells often show positive cytoplasmic immunoreactivity for ALK-1, with associated chromosomal translocations detected in approximately 50% of cases. Inflammatory myofibroblastic tumors are regarded as neoplasms of low-grade or intermediate biologic behavior, which can be associated with favorable outcome, but have a tendency for local recurrence and a low risk of distant metastasis. ALK-negative tumors are more likely to be associated with metastases.

Intra-Abdominal Desmoplastic, Small Round Cell Tumor

Desmoplastic small, round cell tumor is the descriptive designation for a rare, undifferentiated, and highly aggressive tumor that, with few exceptions, involves the peritoneal serosa and contiguous organs such as the kidney and ovary. It usually appears during adolescence and early adulthood, with a mean age of 25 years, but occasionally may be found in older women. It is far more common in men than in women. The prognosis is poor.

Grossly, most tumors are bulky abdominal masses that have spread diffusely over the peritoneal surface with prominent involvement of the tunica vaginalis or the ovaries, mimicking a primary testicular or ovarian tumor. The characteristic microscopic pattern is nests of ‘small, blue cells’ embedded in a desmoplastic fibrous stroma ( Figure 31.28 ). The tumor cells are uniform with scanty cytoplasm and indistinct cell borders ( Figure 31.29 ). About one-third of tumors exhibit a wider range of morphologic features, principally as spindle-shaped cells with epithelioid to focally sarcomatoid arrangements. Mitotic figures are numerous and foci of necrosis are usually present. Invasion of vascular spaces is common but lymph node involvement is rare.

Desmoplastic small, round cell tumor. Nests of ‘small, blue cells’ embedded in a desmoplastic fibrous stroma.

Desmoplastic small, round cell tumor. The tumor cells are uniform with scanty cytoplasm and indistinct cell borders.

Virtually all tumors are CK positive (CK monoclonal antibodies CAM 5.2, AE1/AE3), but lack CK20 expression, indicative that they are not of large intestinal origin. Roughly four-fifths are also reactive with antibodies to EMA, neuron-specific enolase, desmin (with paranuclear dot-like reactivity) ( Figure 31.30 ), and vimentin, suggestive that there is both epithelial and mesenchymal (divergent) differentiation. Between two-fifths and two-thirds of tumors express Ber-EP4, CD57 (Leu-7), CD15 (Leu-M1), and CA125, suggestive that the tumor is not mesothelial in origin. Wilms’ tumor (WT1) protein is detected immunohistochemically in 90% of cases. Most other common immunohistochemical stains lack reactivity in most cases. Electron microscopic examination shows the tumor cells have mesenchymal–fibroblastic features.

Desmoplastic small, round cell tumor. Desmin immunoreaction.

Coexpression of epithelial and mesenchymal antigens distinguishes the desmoplastic small, round cell tumor from other small round and blue cell tumors occurring in this age group. These antigenic properties have challenged the popular notion that the intra-abdominal desmoplastic small round cell tumor is a ‘blastomatous’ tumor derived exclusively from the primitive mesothelium.

Desmoplastic small round cell tumor exhibits a 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, which appears to be unique for this tumor. The translocation results in a loss of three specific amino acids and appears to have an oncogenic effect. Other translocation patterns have also been described. The fusion protein that is produced seems to function as a potent activator of transcription, suggesting that the Wilms’ tumor gene gains function as a result of the fusion. Thus, the fusion gene seems to function as a dominant oncogene in this disease.

After initial treatment (aggressive surgical debulking and postoperative chemotherapy, external beam radiotherapy, or both), there may be an initial response, but more than 99% of patients die of tumor progression.

Solitary Fibrous Tumor of Peritoneum (‘Fibrous Mesothelioma’)

Solitary fibrous tumors, previously called ‘fibrous mesotheliomas,’ are primitive tumors composed of fibroblasts and primitive mesenchymal cells that can manifest multidirectional differentiation. They are rare tumors found most often in the pleura, but do occur occasionally in the peritoneum. Most patients remain well after tumor excision, although occasional neoplasms have acted aggressively.

Grossly, the tumors vary in size from 1 cm to over 20 cm in diameter ( Figure 31.31 ). They are usually solitary and appear encapsulated by fibrous tissue. Microscopically, tumors are composed of spindle cells in a markedly collagenized stroma, often with abundant blood vessels, in a hemangiopericytoma-like pattern ( Figure 31.32 ). Tumor cells may have fascicular, cord-like, and irregular arrangements and are found interspersed in strands in between thick collagen bundles. Nuclei are often vesicular and the nucleoli inconspicuous. Mitoses are rare.

Solitary benign fibrous mesothelioma (‘solitary fibrous tumor’). The cut surface appears multinodular and fleshy.

Solitary benign fibrous mesothelioma (‘solitary fibrous tumor’). The tumor is composed of spindle cells arranged in a hemangiopericytoma-like pattern.

Tumor cells are reactive for vimentin but not for CK. CD34, a sialylated transmembrane glycoprotein found initially in endothelial cells and myeloid progenitor cells, is usually demonstrable. CD31, a platelet endothelial cell adhesion molecule, is not. In contrast, desmoplastic meso­theliomas, tumors in the differential diagnosis, are reactive for CK but not for CD34.

Inflammatory Myofibroblastic Tumor

This lesion has also been referred to as inflammatory pseudotumor or plasma cell granuloma. Most tumors arise in the lung, mesentery, omentum, or retroperitoneum. The abdominal lesions are usually found in the mesentery of patients younger than 20 years of age who present with a mass, fever, weight loss, anemia, thrombocytosis, and polyclonal hypergammaglobulinemia. Microscopic examination reveals myofibroblastic spindle cells, mature plasma cells, and small lymphocytes. The spindle cells often show positive cytoplasmic immunoreactivity for ALK-1, with associated chromosomal translocations detected in approximately 50% of cases. Inflammatory myofibroblastic tumors are regarded as neoplasms of low-grade or intermediate biologic behavior, which can be associated with favorable outcome, but have a tendency for local recurrence and a low risk of distant metastasis. ALK-negative tumors are more likely to be associated with metastases.

Other Tumors

A variety of tumors arise rarely in the peritoneum. Their histogenesis is not always certain. Of the less rare tumors, adenosarcomas are often associated with endometriosis. Carcinosarcomas have also been described, as have the stromal sarcomas and rhabdomyosarcomas. Pure epithelial tumors, such as clear cell adenocarcinoma, have been described, also in association with endometriosis. Any tumor usually associated with an endometrial origin could well have arisen in extrauterine endometriosis. This subject is discussed more fully in Chapter 22 .

Metastatic Tumors

Pseudomyxoma Peritonei

Pseudomyxoma peritonei is a clinical term that refers to the accumulation of jelly-like mucus in the pelvis or abdominal cavity (‘gelatinous ascites’) resulting from peritoneal spread of a low-grade mucinous tumor, usually of the appendix and less commonly of other intestinal locations. Unilateral or bilateral ovarian involvement is common in these cases ( Figure 31.33 ). The ovarian and appendiceal tumors may present simultaneously or metachronously.

Mucinous cystic ovarian tumor associated with pseudomyxoma peritonei and a similar appendiceal tumor. Note the presence of mucin deposits on the surface of the cyst.

(Reproduced with permission from Prat J. Pathology of the ovary. Philadelphia: Saunders; 2004. p. 83–109.)

Pathology

Pseudomyxoma peritonei is a disease of MUC2-expressing goblet cells, which secrete voluminous quantities of mucin in a ratio of mucin : cells exceeding 10 : 1. During the operation, it is critical for the surgeon to inspect and remove the appendix. Usually, the appendix will be enlarged ( Figure 31.34 ) or adherent to the omentum, but in some cases it appears grossly normal and the primary tumor is found only after a thorough histologic evaluation ( Figure 31.35 ).

Mucinous appendiceal tumor (mucocele) associated with pseudomyxoma peritonei and bilateral ovarian mucinous tumors.

(Reproduced with permission from Prat J. Pathology of the ovary. Philadelphia: Saunders; 2004. p. 83–109.)

Mucinous appendiceal tumor associated with pseudo­myxoma peritonei and bilateral ovarian mucinous tumors.

(Reproduced with permission from Prat J. Ovarian tumors of borderline malignancy (tumors of low malignant potential): a critical appraisal. Adv Anat Pathol 1999;6:247–74.)

The mucinous deposits may have several histologic appearances. The mucus may be acellular (‘mucinous ascites’) or may contain mucinous epithelial cells ( Figure 31.36 ). The mucinous material often contains inflammatory cells, mesothelial cells, and, if present for some time, may display capillaries and fibroblasts indicating that organization has occurred. If epithelial cells are present, the degree of nuclear atypia (variously described as low grade or high grade, or alternatively as benign, borderline, or malignant) should be indicated in the report, as well as whether the mucin dissects into tissues with a fibrous response or is merely on the surface. The finding of occasional mitoses or lack of cytoplasmic mucin suggests that the tumor is of at least borderline malignancy. Alternatively, the presence of cribriform pattern or signet-ring cells warrant a diagnosis of adenocarcinoma.

Pseudomyxoma peritonei associated with mucinous tumors of the appendix and ovaries. Note the presence of tumor cells floating in pools of mucin dissecting through the fat.

(Reproduced with permission from Prat J. Pathology of the ovary. Philadelphia: Saunders; 2004. p. 83–109.)

Patients in whom the tumor appears benign ( Figures 31.37–31.39 ) or borderline (peritoneal ‘adenomucinosis’) usually have a more favorable clinical course than those in whom the tumor appears histologically malignant (peritoneal carcinomatosis). Nevertheless, the former tumors may lead to significant morbidity and mortality (10 year survival rate of 45%) and their designation as low-grade mucinous carcinomas has recently been proposed.

Pseudomyxoma peritonei. Multiple clusters and tumor cells are present in the mucinous material.

Pseudomyxoma peritonei, high magnification. Clusters of tumor cells are present in the mucin.

Clusters of intestinal-type epithelium in pseudo­myxoma peritonei.

The secondary ovarian tumors are commonly bilateral and typically show surface involvement ( Figure 31.40 ) and/or the presence of pools of mucin dissecting through the ovarian stroma (pseudomyxoma ovarii) ( Figure 31.41 ). These features are in contrast to those of ovarian borderline tumors of intestinal type, which are usually unilateral and only occasionally associated with pseudomyxoma peritonei.

Mucinous ovarian tumor associated with a similar mucinous tumor of the appendix pseudomyxoma peritonei. Ovarian surface involvement.

(Reproduced with permission from Prat J. Pathology of the ovary. Philadelphia: Saunders; 2004. p. 83–109.)

Mucinous ovarian tumor associated with mucinous tumor of the appendix and pseudomyxoma peritonei. Pools of mucin dissecting through the ovarian stroma (pseudomyxoma ovarii).

(Reproduced with permission from Prat J. Pathology of the ovary. Philadelphia: Saunders; 2004. p. 83–109.)

Pathogenesis

The origin of pseudomyxoma peritonei has been a matter of debate. Historically, most of these tumors were thought to be ovarian in origin, especially when the associated ovarian tumor was of large size or had the appearance of a mucinous borderline tumor. Over two decades ago opinions began to shift toward the appendix as the site of origin in most cases. Based on genetic analyses, most cases are now believed to be of appendiceal origin, and more specifically from goblet cells expressing MUC2. A recent review has gone so far as to state, ‘pseudomyxoma peritonei almost never results from a ruptured primary ovarian neoplasm, but often produces secondary borderline-like ovarian tumors’ ( Figure 31.42 ). In an exceptional case, however, pseudomyxoma peritonei can arise from the rupture of a mucinous tumor of intestinal type that has arisen in ovarian teratomas.

Mucinous ovarian tumor associated with pseudo­myxoma peritonei and a similar appendiceal tumor. The tumor resembles a mucinous borderline tumor of the ovary.

(Reproduced with permission from Cuatrecasas et al.)

Specific CK panels have been employed to distinguish ovarian mucinous tumors from gastrointestinal mucinous tumors. Tumors of müllerian origin are usually reactive for CK7 but not CK20, whereas tumors of lower intestinal origin have findings that generally are reversed, i.e., CK20 reactivity but generally not for CK7. Most cases of pseudo­myxoma peritonei show reaction patterns consistent with an appendiceal origin.

Molecular genetic studies in synchronous ovarian and appendiceal tumors associated with pseudomyxoma peritonei have revealed a concordance of K-ras mutational pattern in both tumors in each patient ( Figure 31.43 ). These findings suggest their clonal nature and supports that, in the light of the clinicopathologic data, the appendix is the most likely origin.

Mucinous ovarian tumors associated with mucinous tumors of the appendix and pseudomyxoma peritonei. Mutational pattern studied by RFLP-PCR. MWM, molecular weight marker, 10 bp DNA Ladder (Life Technologies Inc., Gaithersburg, MD); UNCUT, undigested 65 bp DNA amplified PCT product. Lane 15, CAPAN 2: positive control (CAPAN 2 cell line). Cases 1–6 are underlined. The mutational band (52 bp) for codon samples in five of the six cases (cases 2–6). The 40 bp fragment represents the normal allele.

(Reproduced with permission from Cuatrecasas et al.)

Prognosis and Treatment

Patients with pseudomyxoma peritonei containing epithelial cells that are benign or borderline appearing usually have a protracted clinical course. The 5 and 10 year survival rates are 75% and 68%, respectively. In contrast, when the epithelial cells of the pseudomyxoma peritonei appear malignant (peritoneal carcinomatosis), the clinical course is more aggressive and approximately 90% of patients die within 3 years. Cytoreductive surgery at initial presentation and repeated palliative debulking, mucolytic agents, chemotherapy and/or radiotherapy have done relatively little to modify the natural history of this disease.

Gliomatosis Peritonei

Gliomatosis peritonei is a rare condition in which peritoneal implants composed largely or exclusively of fully mature glial tissue are found in the abdominal cavity, usually in association with a solid ovarian teratoma, which can be mature or immature. Tears in the capsule of the ovarian tumor have been identified, suggesting a mechanism by which the gliomatous tissue leaks into the abdominal cavity ( Figure 31.44 ). Nevertheless, a molecular genetic study has suggested that glial implants may also arise by metaplasia of pluripotent peritoneal stem cells.

Gliomatosis peritonei. Multiple nodules of mature glial tissue are implanted within omental adipose tissue.

At the time of laparotomy, either when the ovarian tumor is discovered or subsequently, implants in the peritoneum are found to be composed of glial tissue only ( Figures 31.44 and 31.45 ). Occasionally, other teratomatous elements are identified. Microscopic implants should be graded separately from the ovarian tumor, and this will determine whether subsequent therapy is needed. Usually, the implants are grade 0 or 1 ( Figure 31.45 ). In some cases, they are grade 2 or 3. Although most patients with this condition do well, recurrences have been recorded as well as subsequent malignant transformation. This condition is described more fully in the section on ovarian teratomas in Chapter 29 . Gliomatosis peritonei has also been reported in a patient with a ventriculoperitoneal shunt.

Gliomatosis peritonei. Uniform glial cells, all highly differentiated (grade 0), show an extensive neurofibrillary background.

Strumosis Peritonei

Strumosis peritonei is a rare condition in which nodules found singly or throughout the omentum are composed largely of well-differentiated thyroid tissue. The lesion most likely represents a metastatic or implanted form of malignant struma ovarii. Most cases occur in association with a solid ovarian teratoma or a struma ovarii. Nodules may be several millimeters to centimeters in size and grossly, on cut section, resemble colloid ( Figure 31.46 ). Microscopically, the thyroid tissue may resemble a macrofollicular adenoma ( Figure 31.47 ). Like gliomatosis peritonei, a defective capsule has been found in most cases with ‘implants’ from the ovary, suggesting a mechanism of spread into the abdominal cavity. While some patients with the condition do well, recurrence is unpredictable and some patients have had a clinically more aggressive course. This condition is described more fully on ovarian teratomas in Chapter 29 .

Strumosis peritonei.

Strumosis peritonei with macrofollicular appearance.

Pseudomyxoma Peritonei

Pseudomyxoma peritonei is a clinical term that refers to the accumulation of jelly-like mucus in the pelvis or abdominal cavity (‘gelatinous ascites’) resulting from peritoneal spread of a low-grade mucinous tumor, usually of the appendix and less commonly of other intestinal locations. Unilateral or bilateral ovarian involvement is common in these cases ( Figure 31.33 ). The ovarian and appendiceal tumors may present simultaneously or metachronously.

Mucinous cystic ovarian tumor associated with pseudomyxoma peritonei and a similar appendiceal tumor. Note the presence of mucin deposits on the surface of the cyst.

(Reproduced with permission from Prat J. Pathology of the ovary. Philadelphia: Saunders; 2004. p. 83–109.)

Pathology

Pseudomyxoma peritonei is a disease of MUC2-expressing goblet cells, which secrete voluminous quantities of mucin in a ratio of mucin : cells exceeding 10 : 1. During the operation, it is critical for the surgeon to inspect and remove the appendix. Usually, the appendix will be enlarged ( Figure 31.34 ) or adherent to the omentum, but in some cases it appears grossly normal and the primary tumor is found only after a thorough histologic evaluation ( Figure 31.35 ).

Mucinous appendiceal tumor (mucocele) associated with pseudomyxoma peritonei and bilateral ovarian mucinous tumors.

(Reproduced with permission from Prat J. Pathology of the ovary. Philadelphia: Saunders; 2004. p. 83–109.)

Mucinous appendiceal tumor associated with pseudo­myxoma peritonei and bilateral ovarian mucinous tumors.

(Reproduced with permission from Prat J. Ovarian tumors of borderline malignancy (tumors of low malignant potential): a critical appraisal. Adv Anat Pathol 1999;6:247–74.)

The mucinous deposits may have several histologic appearances. The mucus may be acellular (‘mucinous ascites’) or may contain mucinous epithelial cells ( Figure 31.36 ). The mucinous material often contains inflammatory cells, mesothelial cells, and, if present for some time, may display capillaries and fibroblasts indicating that organization has occurred. If epithelial cells are present, the degree of nuclear atypia (variously described as low grade or high grade, or alternatively as benign, borderline, or malignant) should be indicated in the report, as well as whether the mucin dissects into tissues with a fibrous response or is merely on the surface. The finding of occasional mitoses or lack of cytoplasmic mucin suggests that the tumor is of at least borderline malignancy. Alternatively, the presence of cribriform pattern or signet-ring cells warrant a diagnosis of adenocarcinoma.

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1. Vagina
2. Ovarian Mucinous Tumors
3. Metastatic Tumors of the Ovary
4. Cervical Benign and Non-Neoplastic Conditions

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