Serosal Membranes

Serosal Membranes

Jon H. Ritter

John D. Pfeifer

  • I. INTRODUCTION. The serosal membranes are derived from the mesoderm, and form the visceral and parietal surfaces of the pleural cavity, peritoneal cavity, pericardium, and tunica vaginalis testis. Histologically, the serosal membranes consist of a single layer of flat mesothelial cells that rest on a basement membrane, below which is a poorly delimited connective tissue layer. The parietal surfaces of the serosal membranes are perforated by numerous narrow stomas, the so-called lymphatic lacuna, that connect with the extensive lymphatic plexus which drains the enclosed cavities. Under an electron microscope, mesothelial cells show characteristic long, slender surface microvilli; their demonstration can be used to support a mesothelial origin for a neoplasm that is indeterminate by other histopathologic methods.


    • A. Biopsy samples, from procedures performed for diagnosis or in the context of staging procedures, are usually small tissue fragments in the range of 1 to 5 mm in maximal dimension. Detailed gross descriptions are unnecessary, although documentation of the number and size of the fragments is important to ensure that they are adequately represented on the slides. The tissue should be submitted in its entirety, and three hematoxylin and eosin (H&E) stained levels should be examined microscopically.

    • B. Excision specimens, from procedures performed for benign or malignant diseases, include tissue from pleural decortication procedures (stripping procedures to remove thick visceral pleural peels that encase the lung and decrease ventilatory function), debulking procedures, and resections. The aggregate size of the tissue should be described, as well as its color and texture. The presence of gross lesions should also be documented. Gross abnormalities should be thoroughly sampled. When no gross lesions are identified, as a general rule, at least one section per centimeter of aggregate tissue should be submitted for microscopic examination.


    • A. Acute serositis

      • 1. Acute pleuritis is usually infectious in origin and is most commonly associated with pneumonia. Gram-positive bacteria are most commonly isolated, although a wide variety of pathogens can be responsible. Spontaneous bacterial pleuritis occurs occasionally in patients who have cirrhosis. Autoimmune pleuritis, although sterile, can produce clinical and pathologic findings that resemble infectious pleuritis.

      • 2. Acute peritonitis is usually associated with a perforated viscus. If it is due to gastric, biliary, or pancreatic rupture, it has a chemical etiology; on the other hand, if it is due to intestinal rupture, it has a bacterial etiology. Spontaneous bacterial peritonitis also occurs, usually in children, immunocompromised patients, or patients with cirrhosis. Localized acute peritonitis is a feature of pelvic inflammatory disease.

      • 3. Acute pericarditis can have an infectious etiology or can be a manifestation of autoimmune disease.

    • B. Granulomatous serositis can present in a number of different patterns; studding of the serosa by innumerable small nodules can be especially worrisome clinically for disseminated tumor.

      • 1. Infectious. Although special stains can often demonstrate the offending pathogen, microbiologic cultures are a more sensitive and specific method for identification of the causative organism. Common causes include mycobacteria, fungi (including Histoplasma, Cryptococcus, and Coccidioides), and parasites (including Schistosoma, Echinococcus, and Ascaris).

      • 2. Noninfectious etiologies include a reaction to foreign material from a prior surgical procedure (such as starch granules and sutures) or from a perforated organ. In women, additional causes include retrograde introduction of foreign material through the fallopian tube (e.g., douche fluid, lubricants, radiographic contrast agents), and spillage of amniotic fluid following a Cesarean section.

        Peritoneal granulomas can form as a response to implants of keratin produced by a neoplasm of the female reproductive tract, including mature cystic teratoma, endometrioid adenocarcinoma with squamous differentiation (of either endometrial or ovarian origin), squamous cell carcinoma of the cervix, or even atypical polypoid adenomyoma of the uterus. Microscopically, laminated deposits of keratin (sometimes including the so-called ghost squamous cells) are present in the granulomas, but in the absence of viable tumor, these granulomas have no prognostic significance.

      • 3. Autoimmune causes include Crohn disease and sarcoidosis.

      • 4. Meconium peritonitis in a neonate can lead to a serosal granulomatous reaction.

    • C. Mesothelial Hyperplasia is commonly seen in response to chronic serosal injury. Microscopically, hyperplasia has a number of different patterns, including solid, tubular, trabecular, papillary, or tubulopapillary, and often shows limited extension into the underlying connective tissue (e-Fig. 11.1).* The hyperplastic cells are often disbursed in linear, parallel, or thin layers in associated organizing fibrinous tissue. Cytologically, mild-to-moderate nuclear pleomorphism is present, and mitotic figures and even occasional multinucleated cells can be identified.

      Given these architectural and cytologic features, mesothelial hyperplasia can be difficult to distinguish from well-differentiated diffuse malignant mesothelioma (DMM), especially epithelioid mesothelioma. The distinction is based on the degree of cellular proliferation and atypia. Mesothelioma should be suspected when deep infiltration of the underlying soft tissue is present, or when areas of necrosis are present. Knowledge of the clinical setting can be used to guide the diagnosis, although it is well established that slowly growing mesothelioma can initially present as a lesion that cannot be distinguished from mesothelial hyperplasia.

    • D. Metaplasias are predominantly a feature of the peritoneal serosal surfaces in women. Most originate from the so-called secondary Müllerian system, which by convention includes the pelvic and lower abdominal mesothelium and underlying mesenchyme. The close embryologic relationship of the mesothelium in these areas and the Müllerian ducts (which arise from invaginations of coelomic epithelium) provides an explanation for the fact that many of the metaplasias produce tissues that are a normal component of the female reproductive tract.

      • 1. Endometriosis is thought to arise via a metaplastic process, through retrograde implantation of menstrual endometrium (the so-called metastatic theory), or as a developmental anomaly. Rare cases of pleural endometriosis have been reported, as have cases of endometriosis in men who have been
        treated with long-term estrogen therapy (usually in the setting of adenocarcinoma of the prostate).

        When endometriosis develops in association with the viscera, such as the wall of the intestine, adjacent to the ureter, the wall of the bladder, and so on, it can clinically present with signs and symptoms that resemble malignancy. Microscopically, the findings include endometrial glands and stroma, often associated with chronic inflammation, hemosiderin laden macrophages, dense fibrosis, and adhesions (e-Fig. 11.2). Since a number of different malignancies, most commonly endometrioid adenocarcinoma and clear cell adenocarcinoma, can develop in endometriosis, areas of endometriosis in biopsy and excision specimens must be carefully examined.

      • 2. Endosalpingiosis typically occurs in women during their reproductive years. Microscopically, multiple dilated cysts lined by a single layer of fallopian tube-type epithelium are present. The lack of endometrial-type stroma distinguishes endosalpingiosis from endometriosis.

      • 3. Endocervicosis, consisting of benign glands with an endocervical type epithelium, and squamous metaplasia, are both rare. Both occur in women, and are primarily metaplasias of the peritoneal mesothelium.

      • 4. Ectopic decidual reaction is an incidental finding in women who are pregnant or on high-dose progestogen therapy. Most lesions are not evident grossly, but when they are, they consist of small gray-white nodules which may be hemorrhagic, and often stud the peritoneal surfaces. Microscopically, the metaplasia involves the submesothelial stroma, and consists of large epithelioid cells with prominent cell borders and abundant amphophilic cytoplasm (e-Fig. 11.3) morphologically identical to the cells comprising the decidual reaction characteristic of the fallopian tube, cervix, and upper vagina in pregnant women. Diagnostic difficulty can arise on the rare occasions when the decidual cells assume a signet-ring appearance.

      • 5. Walthard nests, usually found on the serosal surfaces of the fallopian tubes or in the mesovarium as yellow-white nodules, are usually only several millimeters in the greatest dimension. They may show cystic change, and are usually lined by mesothelial cells that have undergone transitional (urothelial) metaplasia.

      • 6. Disseminated peritoneal leiomyomatosis (leiomyomatosis peritonealis disseminata) is an uncommon multifocal proliferation of smooth muscle-like cells that is thought to represent a hormone-induced metaplasia of the multipotential submesothelial mesenchymal cells of the peritoneum. Grossly, it appears as widely scattered nodules that often suggest metastatic malignancy. Microscopically, the lesion is characterized by cytologically bland, benign spindle cells centered in the submesothelial connective tissue (e-Fig. 11.4). A conservative approach to treatment is indicated, since the condition tends to spontaneously regress.

    • E. Fibrosis

      • 1. Pleura

        • a. Reactive pleural fibrosis is usually a consequence of prior inflammation or surgery. Often, the fibrosis is associated with formation of dense adhesions. Because reactive mesothelial cells are entrapped within the fibrous tissue, careful microscopic examination with knowledge of the clinical history is required to avoid over-interpretation as mesothelioma.

        • b. Pleural plaques, which primarily occur on the parietal pleura of the thoracic cavity, are raised, discrete, white to gray-white lesions that range from several millimeters to over 6 cm in diameter. When pleural plaques are bilateral, they are almost always related to prior asbestos exposure, even very low fiber levels. Causes of unilateral plaques include asbestos,
          as well as any process that features pleural chronic effusions. Microscopically, they consist of pauci-cellular dense collagenous connective tissue with a basket-weave pattern, sometimes associated with overlying organizing fibrinous deposits. Asbestos bodies are essentially never seen within the plaques. Mesothelial cells are not a prominent component of the lesion; any significant cellularity in a putative pleural plaque should raise concern for desmoplastic mesothelioma. Finally, since mesothelioma and plaques may occur in the same individual, it is not uncommon for blind biopsies to sample plaques; in this setting, additional biopsies are indicated if there is strong clinical suspicion for a pleural malignancy.

        • c. Diffuse visceral pleural fibrosis has a number of etiologies. It is a feature of several occupational exposures (e.g., silicosis), and occurs as an advanced hypersensitivity reaction, as a component of connective tissue diseases, and as a sequela of bacterial pneumonia (especially as a result of empyema). Grossly, diffuse visceral pleural fibrosis may be difficult to distinguish from desmoplastic mesothelioma. Microscopically, the fibrosis does not infiltrate the subjacent soft tissue and has a zonated appearance, with more cellular areas near the surface while the deeper tissues tend to be more paucicellular; mesothelioma has the reverse pattern. Nonetheless, careful microscopic examination, often accompanied by immunohistochemical studies, can be required to exclude mesothelioma.

      • 2. Peritoneum

        • a. Reactive peritoneal fibrosis is usually a consequence of recurrent bouts of peritonitis (often associated with long-term peritoneal dialysis), decompensated cirrhosis, or surgery, and is often associated with formation of dense adhesions. As is true with reactive pleural fibrosis, reactive mesothelial cells entrapped within the fibrous tissue must not be overinterpreted as mesothelioma.

        • b. Localized plaques, composed of dense hyalinized fibrous tissue, are frequent incidental findings on the splenic capsule.

        • c. Sclerosing peritonitis is due to hyperplasia of submesothelial mesenchymal cells, and manifests as diffuse sheets of white, thickened visceral peritoneum that encase the small bowel and also involve the diaphragmatic, hepatic, and splenic peritoneum. Known etiologies include peritoneal dialysis, infections, autoimmune disorders, therapy with the beta adrenergic blocker practolol, and the carcinoid syndrome. Many cases are idiopathic.

    • F. Cysts

      • 1. Emphysematous bulla are the most frequent cystic lesion that involves the pleural cavity.

      • 2. Peritoneal inclusion cysts characteristically occur in the peritoneal cavity in women of reproductive age (although they also rarely occur in males, and also rarely occur in the pleural cavity). They are usually incidental findings at the time of surgery, and consist of single or multiple, thin-walled, translucent, unilocular cysts lined by a single layer of bland, flattened mesothelial cells.

      • 3. The so-called pericardial cyst is the most common cyst associated with the pericardium. It can achieve dimensions of 15 cm or more. Microscopically, it is lined by bland mesothelial cells.

    • G. Splenosis is an incidental finding, and usually represents implantation of splenic tissue as a result of traumatic splenic rupture. Grossly, innumerable red-blue nodules ranging from several millimeters to over 5 cm in diameter are scattered widely through the abdomen.

    • H. Eosinophilic peritonitis arises in the context of a variety of medical diseases including childhood atopy, autoimmune disorders (especially collagen vascular
      diseases), and the hypereosinophilic syndrome. It also occurs in association with lymphoma and metastatic carcinoma. Other causes include a ruptured hydatid cyst, and in association with peritoneal dialysis.


    • A. Adenomatoid tumor is of mesothelial origin, and usually arises in the peritoneum, also rarely from the pleura. It most commonly involves the serosal surfaces of the uterus or fallopian tubes, or paratesticular regions. Grossly, the tumor usually forms a tan 1 to 2 cm well-circumscribed nodule. Microscopically, the tumor is composed of tubular and slit-like spaces lined by a single layer of flattened cuboidal cells with bland cytology (e-Fig. 11.5). The cells are immunopositive for cytokeratin, calretinin, WT1, and vimentin expression, but immunonegative for factor VIII-related antigen and CD31 expression, a profile that can be used to distinguish the tumor from metastatic carcinoma and vascular tumors. Adenomatoid tumor is clinically asymptomatic and complete excision is the appropriate management.

    • B. Multicystic peritoneal inclusion cyst usually arises in the pelvis in women and is typically associated with lower abdominal pain. It forms a palpable mass adherent to the pelvic organs that can grossly be indistinguishable from a cystic ovarian tumor, although a subset of cases arises in the upper abdominal cavity, in a hernia sac, or even in the retroperitoneum. Most cases are associated with a history of previous abdominal operation, endometriosis, or pelvic inflammatory disease (Obstet Gynecol Surg. 2009;64:321).

      Microscopically, the neoplasm consists of numerous thin-walled cysts lined by a single layer of bland, flat-to-cuboidal mesothelial cells. The septa and walls between the cysts are composed of loose fibrovascular connective tissue. The constitutive cells are immunophenotypically identical to other mesothelial cell lesions.

      Some confusion exists regarding the proper classification of multicystic peritoneal inclusion cyst, as demonstrated by the fact that the lesion is also known as multicystic mesothelioma. Tumors in which the mesothelium has bland cytologic features with no significant atypia have an indolent course (Cancer. 1989;64:1336), although very rare cases may progress to conventional malignant mesothelioma (Am J Surg Pathol. 1988;12:737; J Surg Oncol. 2002;79:243). However, cases in which the cysts are lined, even focally, by markedly atypical mesothelial cells and/or that harbor areas of conventional malignant mesothelioma are best considered low-grade mesotheliomas from the outset (see below).

  • V. MALIGNANT PLEURAL NEOPLASMS. The World Health Organization (WHO) classification of tumors of the pleura is shown in Table 11.1.

    • A. Mesothelial

      • 1. Diffuse malignant mesothelioma (DMM). The WHO recommends the terminology DMM when referring to malignant neoplasms arising from mesothelial cells. The association of the tumor with asbestos exposure is well established (Ann Occup Hyg. 2000;44:565). There is usually a long latency period between asbestos exposure and the onset of mesothelioma, usually 30 to 40 years. While sequences from the highly oncogenic SV40 virus have been reported in some cases (Clin Lung Cancer. 2003;5:177), an association with latent viral infection has yet to be established. Rare cases may be related to therapeutic radiation exposure or chronic pleural infections.

        Patients with mesothelioma usually present with dyspnea, chest wall pain, and a significant pleural effusion. Constitutional symptoms include weight loss, malaise, chills, sweats, weakness, and fatigue. While the tumor may begin as multiple small nodules on the parietal and visceral pleura, it eventually encases the lung, invades the soft tissue of the chest wall, and often extends into the mediastinum with encasement of the pericardial sac
        and other midline structures. DMM of the pleura remains a lethal disease, with essentially 100% mortality. Selected early stage cases may benefit from extrapleural pneumonectomy and aggressive adjuvant therapy, although the role for therapy other than supportive care is controversial. The staging scheme for pleural DMM is shown in Table 11.2.

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Oct 20, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Serosal Membranes

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