The Peritoneum

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The Peritoneum

Chapter Outline

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.1 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.1

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.2


Tuberculous peritonitis is still encountered in the peritoneum, usually in immunosuppressed patients.3 It may also occur as a complication of chronic peritoneal dialysis.4 It may be secondary to tuberculous salpingitis or result from miliary tuberculosis. Clinically, it may manifest nonspecifically as widespread carcinomatosis.5 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.3,6 The granulomas are characterized by caseous necrosis and Langhans type giant cells; mycobacteria may be demonstrated by acid-fast stains or immunofluorescence techniques.

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,7,8 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.


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.11 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.11

Cesarean Delivery

Complicating cesarean delivery, the amniotic fluid contents may spill into the peritoneal cavity causing a syndrome clinically similar to bowel perforation.12,13 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.14 Grossly, the amniotic fluid contents appear as cheese-like yellow patches limited to the serosal layer of visceral organs.15 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.9 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.16

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.’2,17,18

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,19,20 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),10,21 chronic dialysis,2226 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.’2732 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.27,30

Rarely, single or multiple fibrous nodules ranging up to 6 cm may occur in the gastrointestinal tract or mesentery in adults.32 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.’32

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.3335 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.

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.

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 cells33 (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.36 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).37

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.38 Immunostains may help in the differential diagnosis. Strong immunoreactivities for p5339 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.40 Proliferative markers such as Ki-67 may also be helpful (approximately 25% vs 5% labeling index for malignant mesothelioma vs mesothelial hyperplasia, respectively).41 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.38,42

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.43 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 31.831.11) 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.44

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).

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.45 GnRH agonists or tamoxifen have successfully been applied to some patients.44


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.47 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.4850

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%.51,52 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.

Mesothelial Neoplasms

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.55 An occasional tumor is solitary.55

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.56 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.57,58

Diffuse Malignant Mesothelioma

Peritoneal diffuse malignant mesotheliomas are much less common than their pleural counterparts, accounting for about 10% of all malignant mesotheliomas.59 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.60 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.61 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,60 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 tumors62 and deciduoid mesotheliomas are usually rapidly fatal.63,64 Increasing nuclear and nucleolar size has been shown to correlate with shorter survival in epithelial tumors.62 Also, p16 loss independently correlates with increased risk of death according to one study,65 while another failed to identify any morphologic features that differentiated those cases with a highly aggressive course from indolent ones.66 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.67,68


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 31.2231.24); in some cases, however, the nuclei become larger and more bizarre as the cytoplasmic volume increases.69 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).56,70 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.56,60,68,71 Intra-abdominal lymph nodes may be involved.

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