Diseases of the Peritoneum
This chapter considers the wide range of nonneoplastic and neoplastic lesions that involve the peritoneum, and in some cases the retroperitoneal lymph nodes, of females. The first half of the chapter covers inflammatory lesions, tumor-like lesions (including mesothelial hyperplasia), mesothelial neoplasms, miscellaneous primary tumors, and metastatic tumors. The final half of the chapter is devoted to a large group of lesions that exhibit müllerian differentiation on microscopic examination and share a potential origin from the secondary müllerian system, the prototypical example of which is endometriosis.
Acute diffuse peritonitis, characterized by a serosal fibrinopurulent exudate, is most commonly associated with a perforated viscus and is usually bacterial or chemical (bile or gastric or pancreatic juice) in origin. The lipases in pancreatic juice typically produce fat necrosis. Spontaneous bacterial peritonitis occurs most often in children and in adults who are immunocompromised or have cirrhosis of the liver (Weinstein et al. 1978), with proton pump inhibitor use a potential risk factor in cirrhotic patients (Min et al. 2014). Rare infectious causes of acute peritonitis include Candida (Bayer et al. 1976), Actinomycetes, and amoebas (Kapoor et al. 1972). Recurrent attacks of acute peritonitis are an almost constant feature of familial Mediterranean fever (recurrent polyserositis) (Sohar et al. 1967). Localized acute peritonitis may be associated with infection (or infarction) of specific organs, as in pelvic inflammatory disease.
A variety of infectious and noninfectious agents can cause granulomatous peritonitis. The peritoneum may be studded with nodules, which can mimic disseminated tumor at operation. The diagnosis rests on the histologic, and, in some cases microbiologic, identification of the causative agent.
Tuberculous peritonitis, which is increasing in frequency, particularly among immunosuppressed patients, may be secondary to spread from a focus within the abdominopelvic cavity or be a manifestation of miliary spread (Koc et al. 2006). The granulomas are characterized by caseous necrosis and Langhans type giant cells; Mycobacteria may be demonstrated by acid-fast stains or immunofluorescence methods. Rarely, granulomatous peritonitis is a complication of fungal infections, including histoplasmosis, coccidioidomycosis, and cryptococcosis, and parasitic infestations, including schistosomiasis, oxyuriasis, echinococcosis, ascariasis, and strongyloidiasis.
Foreign material, typically recognizable on histologic examination, can elicit a granulomatous reaction on the peritoneum. Starch granules from surgical gloves, douche fluid, and lubricants typically incite a granulomatous and fibrosing peritonitis; in occasional cases, the inflammatory reaction may be of tuberculoid type with caseous necrosis (Nissim et al. 1981). The periodic acid–Schiff- (PAS) positive starch granules exhibit a characteristic Maltese cross configuration under polarized light. Talc was once an important cause of granulomatous and fibrosing peritonitis because of its use as a lubricant on surgical gloves, and talc-induced peritonitis has also been described in drug abusers. Other iatrogenic causes of granulomatous peritonitis include cellulose and cotton fibers from surgical pads and drapes, microcrystalline collagen hemostat (Avitene) (Park et al. 1981), and oily materials such as hysterosalpingographic contrast medium, which can be associated with a lipogranulomatous reaction. In one described case, a foreign body reaction to Surgicel™ resulted in a pelvic mass that mimicked recurrent ovarian cancer (Deger et al. 1995).
Spillage of amniotic fluid at Cesarean section, with its content of vernix caseosa (keratin, squames, sebum, and lanugo hair) and meconium (bile, pancreatic, and intestinal secretions), produces a granulomatous peritonitis (George et al. 1995). Meconium peritonitis caused by bowel perforation in utero can also be a problem in newborn infants. In contrast to vernix caseosa peritonitis, calcification rather than granulomatous inflammation dominates the microscopic picture, which in some cases is associated with striking radiographic findings. In boys, the process may involve the tunica vaginalis and result in a tumor-like scrotal mass (Forouhar 1982). Rare cases of meconium peritonitis are associated with disseminated intravascular spread of the meconium.
Nongranulomatous Histiocytic Lesions
Peritoneal collections of mucicarmine-positive histiocytes have also been described in association with topical administration of oxidized regenerated cellulose, a hemostatic agent (Tang et al. 2009). The cytoplasm of these cells is PAS positive, diastase resistant, CD68 positive, and S-100 and cytokeratin negative.
Reactive peritoneal fibrosis, often accompanied by fibrous adhesions, is a common sequela of prior peritoneal inflammation and a frequent complication of a surgical procedure. The fibrosis can on occasion take the form of well-circumscribed fibrous nodules. Some reactive peritoneal fibrous lesions may contain spindle cells that are immunoreactive for vimentin, smooth muscle actin, and cytokeratin, referred to as multipotential subserosal cells (Bolen et al. 1986). It has also been postulated that under pathologic conditions, mesothelial cells undergo transition to myofibroblasts, resulting in fibrous peritoneal adhesions (Sandoval et al. 2016). Rarely, reactive fibrous proliferations of the peritoneum can form tumor-like nodules, in contrast to the more widespread peritoneal thickening of sclerosing peritonitis. In one case of an ovarian mucinous cystadenocarcinoma, several nodules composed of moderately cellular fascicles of benign-appearing spindle cells resembling fibroblasts and myofibroblasts that contained occasional mitotic figures were found in the cul-de-sac and serosal aspect of the tumor. Some of the spindle cells had the immunoprofile of the multipotential subserosal cells noted earlier. We refer to these lesions as peritoneal fibrous nodules (Clement 1995).
Reactive nodular fibrous pseudotumor is a term that has been applied to single or multiple lesions ranging up to 6 cm involving the gastrointestinal tract or mesentery in adults; some have been associated with bowel wall infiltration, but all have had a benign clinical course (Yantiss et al. 2003). Microscopically, the lesions are composed of a low to moderate cellular proliferation of fibroblasts, collagen, and mononuclear inflammatory cells that are usually sparse. 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. Sclerosing mesenteritis (mesenteric panniculitis, mesenteric lipodystrophy) usually occurs as a localized mass in the small bowel mesentery and is characterized by variable fibrosis, inflammation, and fat necrosis (Emory et al. 1997). Sclerosing mesenteritis may also rarely develop in IgG4-related disease, characterized by numerous IgG4-positive plasma cells and obliterative phlebitis (Minato et al. 2012).
In occasional cases, it may be difficult to differentiate between markedly reactive peritoneal fibrosis and a desmoplastic mesothelioma lacking frankly sarcomatoid areas, particularly in a small biopsy specimen. These tumors, however, are very rare in the peritoneal cavity, especially in women. Features favoring a diagnosis of mesothelioma include nuclear atypia, necrosis, organized patterns of collagen deposition (fascicular, storiform), and infiltration of adjacent tissues (Mangano et al. 1998).
Rare Types of Peritonitis
Eosinophilic peritonitis is seen rarely in cases of eosinophilic gastroenteritis and the hypereosinophilic syndrome (Adams and Mainz 1977). Isolated cases of eosinophilic ascites have been associated with childhood atopy, peritoneal dialysis, vasculitis, lymphoma or metastatic carcinoma, and ruptured hydatid cysts (Adams and Mainz 1977). Rare cases of peritonitis may be secondary to peritoneal involvement by collagen vascular diseases, including systemic lupus erythematosus and Degos disease.
In florid examples, solid, trabecular, tubular, papillary, or tubulopapillary patterns (Figs. 10 and 11) and limited degrees of extension of the mesothelial cells into the underlying reactive fibrous tissues or the walls of ovarian tumors, endometriotic cysts, and peritoneal inclusion cysts (see below) may be seen (“mural mesothelial proliferation”). Incorporation into the ovarian tissue and true lymphovascular space involvement have also been described (Oparka et al. 2011). The cells are often focally disposed in linear, sometimes parallel, thin layers, separated by fibrin or fibrous tissue (Fig. 12). The mesothelial cells may have cytoplasmic vacuoles containing acid mucin (predominantly hyaluronic acid) or, less commonly, exhibit marked cytoplasmic clearing. Superimposed deciduoid change (“deciduoid mesothelial hyperplasia”), especially in nodal mesothelial cells, can be a pitfall in the distinction from metastatic tumor (Stewart 2013). Mild to moderate nuclear pleomorphism, mitotic figures, and occasional multinucleated cells may be seen. Psammoma bodies are encountered in occasional cases, and, rarely, eosinophilic strap-shaped cells resembling rhabdomyoblasts have been described. Variable numbers of admixed histiocytes may also be present (nodular mesothelial/histiocytic hyperplasia) (Michal et al. 2016).
The major differential diagnosis is with peritoneal malignant mesothelioma (PMM). The presence of grossly visible nodules, necrosis, conspicuous large cytoplasmic vacuoles, marked nuclear pleomorphism, and deep infiltration favor PMM over mesothelial hyperplasia (Churg et al. 2006). Some of these features, however, such as marked nuclear atypia, are not always present or may be present only focally within a PMM. Immunostains may facilitate the differential diagnosis. Immunoreactivity for p53, epithelial membrane antigen (EMA), insulin-like growth factor 2 messenger RNA-binding protein (IMP)-3, glucose transporter (GLUT)-1, XIAP, and high expression of EZH2 are characteristics of the cells of PMMs but not hyperplastic mesothelial cells; reactive mesothelial cells, in contrast to PMMs, tend to be desmin-positive (Attanoos et al. 2003; Chang et al. 2014; Shen et al. 2009; Shi et al. 2011; Shinozaki-Ushiku et al. 2017). Loss of BAP1 immunoreactivity, particularly in combination with homozygous deletion of 9p21 and p16 by fluorescent in situ hybridization, is highly characteristic of malignant mesothelioma, whereas these alterations have not been observed in reactive mesothelial proliferations (Churg et al. 2016; Cigognetti et al. 2015; Ito et al. 2015; Kawai et al. 2016; Sheffield et al. 2015; Shinozaki-Ushiku et al. 2017).
Despite these differential features, in occasional cases the distinction between a hyperplastic and malignant mesothelial lesion may be difficult or impossible, particularly in a biopsy specimen. If the lesion in question is a PMM, follow-up usually reveals its nature within several months because of its typical rapid growth. In contrast, an atypical mesothelial proliferation occasionally persists for years without an apparent cause. An apparently benign, otherwise typical mesothelial proliferation, however, occasionally precedes the appearance of a PMM (Churg et al. 2006). Some cases of “atypical mesothelial hyperplasia” evolving into PMM, however, likely represent PMM ab initio (Padmanabhan et al. 2003).
The differential diagnosis of mesothelial hyperplasia also includes atypical proliferative/borderline serous tumors of primary peritoneal or ovarian origin. Grossly visible ovarian or peritoneal tumor, columnar cells with or without cilia, the presence of intracellular or extracellular neutral mucin, and numerous psammoma bodies all favor a serous tumor. Immunohistochemical markers for epithelial differentiation (see section on Malignant Mesothelioma) may also be of value in the differential diagnosis.
Peritoneal Inclusion Cysts
Peritoneal inclusion cysts typically occur in the peritoneal cavity of women in the reproductive age group, but may develop over a wide age range (McFadden and Clement 1986; Ross et al. 1989; Veldhuis et al. 2013). Rarely, they occur in males and in the pleural cavity. Unilocular peritoneal inclusion cysts are usually incidental findings at laparotomy in the form of single or multiple, small, thin-walled, translucent, unilocular cysts that may be attached or lie free in the peritoneal cavity. Occasionally, they may involve the round ligament simulating an inguinal hernia (Harper et al. 1986). The cysts have a smooth lining and contents that vary from yellow and watery to gelatinous. Although most of these unilocular mesothelial cysts are probably reactive in origin, some of those located in the mesocolon, mesentery of the small intestine, retroperitoneum, and splenic capsule may be developmental (Ross et al. 1989).
A history of a prior abdominal operation (most common), pelvic inflammatory disease, endometriosis, inflammatory bowel disease, radiotherapy, or abdominal trauma, or combinations thereof, was present in 70% and 84% of patients in two series (Ross et al. 1989; Veldhuis et al. 2013), suggesting a role for inflammation in the pathogenesis of the cysts. An inflammatory pathogenesis is also supported by the occurrence of cases in which the dividing line between florid adhesions associated with inflammation and a MPIC may be difficult. With rare exceptions, there has been no association with asbestos exposure. Follow-up examinations have not disclosed malignant behavior in cases that we consider MPICs, but in as many as one half of these, the lesions have recurred from months to many years postoperatively (Ross et al. 1989). It is likely, however, that at least some of these “recurrences” are the result of newly formed postoperative adhesions. Some patients have responded favorably to treatment with GnRH agonists, tamoxifen, or oral contraceptives (Sawh et al. 2003; Yokoyama et al. 2014). For these reasons, we prefer the designation multilocular peritoneal inclusion cyst to benign cystic mesothelioma for such lesions, until there is convincing evidence for their neoplastic nature.
MPICs are confused most often with multilocular cystic lymphangiomas. In contrast to MPICs, the latter typically occur in children, more frequently in boys. In addition, they are usually extrapelvic, being almost always localized to the mesentery of the small intestine, omentum, mesocolon, or retroperitoneum. Their contents may be chylous, and on histologic examination lymphoid aggregates and smooth muscle, which are rare findings in MPICs, are typically present within their walls. In problematic cases, immunohistochemical stains are useful in distinguishing endothelial from mesothelial cells. Another lesion that merits consideration in the differential diagnosis of MPICs is the rare multicystic adenomatoid tumor. In contrast to MPICs, the latter typically involve the myometrium, contain foci of typical adenomatoid tumor, and lack prominent numbers of inflammatory cells. A detailed discussion of other lesions in the differential diagnosis of MPICs has been presented elsewhere (Ross et al. 1989).
Splenosis, which results from the implantation of splenic tissue, is typically an incidental finding at laparotomy or autopsy months to years after splenectomy for traumatic splenic rupture (Carr and Turk 1992). A few to innumerable, red-blue, peritoneal nodules, ranging from punctate to 7 cm in diameter, are scattered widely throughout the abdominal cavity and, less commonly, over the pelvic cavity. The intraoperative appearance may mimic endometriosis, benign or malignant vascular tumors, or metastatic cancer.
Peritoneal Keratin Granulomas
Infarcted Appendix Epiploica
This benign tumor of mesothelial origin, adenomatoid tumor, rarely arises from extragenital peritoneum, such as the omentum or mesentery, but is much more commonly encountered within the fallopian tube and myometrium (see chapters “Mesenchymal Tumors of the Uterus” and “Diseases of the Fallopian Tube and Paratubal Region”) and, in the male, the epididymis.
Well-Differentiated Papillary Mesothelioma
Well-differentiated papillary mesotheliomas (WDPMs) of the peritoneum are uncommon lesions (Chen et al. 2013; Churg et al. 2014; Daya and McCaughey 1990; Goldblum and Hart 1995; Malpica et al. 2012). Eighty percent of the cases have occurred in women, who are usually of reproductive age; occasional patients are postmenopausal. WDPMs are usually an incidental finding at operation, but rare cases have been associated with abdominal pain or ascites. Occasional patients, including two who were sisters, have had possible exposure to asbestos, but the association may be incidental (Daya and McCaughey 1990).
With the exception of one case that appeared to evolve into a diffuse malignant mesothelioma, follow-up studies suggest that most WDPMs are associated with benign or indolent behavior. Recurrences are rare; in one study, only 1 of 26 patients developed a recurrence of WDPM, after an interval of 46.5 months from the original diagnosis (Malpica et al. 2012). Occasional examples, however, have persisted for as many as 29 years (Daya and McCaughey 1990). Several patients with WDPM have died, although the adjuvant therapy used in such cases possibly was a contributory factor (Daya and McCaughey 1990). In a recent study of 20 WDPMs with invasive foci, most occurred in the female peritoneum and were often multifocal (Churg et al. 2014). Five cases tested for p16 deletion were negative, but two thirds had abnormal karyotypes. Recurrences developed in eight patients (40%), including one patient who died of disseminated disease (but without histologic confirmation of the recurrent tumor). Thus, WDPMs, when multifocal or with invasive foci, warrant clinical follow-up.
Peritoneal malignant mesotheliomas (PMMs) are much less common than similar tumors in the pleural cavity and account for only 10–20% of all mesotheliomas (Baker et al. 2005; Goldblum and Hart 1995; Kerrigan et al. 2002). These tumors are particularly rare in women, in whom most malignant papillary neoplasms of the peritoneum are extraovarian papillary serous carcinomas (see section “Lesions of the Secondary Müllerian System”).
Historically, most PMMs occurred in middle-aged to elderly males, but a recent study found an equal male to female ratio (Liu et al. 2014); occasional PMMs occur in young adults or children. The patients typically present with nonspecific manifestations, including abdominal discomfort and distension, digestive disturbances, and weight loss. Ascites is present in the majority of cases, and cytologic examination of the ascitic fluid may be diagnostic of PMM in some cases. The diagnosis, however, usually requires laparotomy or laparoscopy and biopsy. PMMs may rarely present within a hernia or hydrocele sac; as a retroperitoneal, umbilical, intestinal, or pelvic tumor; or as cervical or inguinal lymphadenopathy (Sussman and Rosai 1990). Rarely there is prominent ovarian involvement, the intraoperative appearance mimicking that of a primary ovarian tumor with peritoneal spread (Clement et al. 1996b).
More than 80% of the patients in one large series had a history of asbestos exposure, but most of them were identified because of an occupational exposure to asbestos. In contrast, two series of PMMs in women found no association with a history of asbestos exposure (Goldblum and Hart 1995; Kerrigan et al. 2002). Asbestos fibers, however, have been identified with special techniques in some of these women (Heller et al. 1999). Aside from asbestos, radiation, chronic inflammation, organic chemicals, and nonasbestos mineral fibers may be etiologic agents in some cases.
Most males with PMMs reported in the literature survived less than 2 years after diagnosis, although there have been occasional long-term survivors. A study of PMMs in women (Kerrigan et al. 2002), however, found that 40% of the patients survived longer than 4 years. Increasing nuclear and nucleolar size has been shown to correlate with shorter survival in epithelial tumors (Ceruto et al. 2006). The histopathological subtype (see below) is of prognostic significance, as biphasic PMMs are associated with a much shorter survival than pure epithelial tumors (Ceruto et al. 2006); deciduoid mesotheliomas are usually rapidly fatal (Shia et al. 2002). PMMs with low WT-1 expression (≤25% positive tumor cells), loss of p16 expression, homozygous deletion of p16/CDKN2A, and hemizygous loss of the neurofibromatosis type 2 gene have also been associated with unfavorable prognosis (Krasinskas et al. 2010; Scattone et al. 2012; Singhi et al. 2016). A number of favorable prognostic factors have been identified, including an age less than 60 years, low nuclear grade, low mitotic count, an absence of deep invasion, and low genomic copy number aberrations (Chirac et al. 2016; Feldman et al. 2003; Krasinskas et al. 2016; Liu et al. 2014; Nonaka et al. 2005). A two-tier grading system for epithelioid PMMs, utilizing a combined score for nuclear atypia and mitotic count, has shown that patients with low-grade tumors have a longer overall survival than those with high-grade tumors (Valente et al. 2016). Current therapeutic regimens of cytoreductive surgery (optimally debulked with minimal or no residual disease) and hyperthermic intraperitoneal chemotherapy have obtained some improvement in long-term survival rates (Alexander et al. 2013; Lee et al. 2013).
The differential diagnoses of PMM with atypical mesothelial hyperplasia (see section “Mesothelial Hyperplasia”) and of desmoplastic PMM versus reactive fibrosis (see section “Peritoneal Fibrosis”) have been previously discussed. Rarely, PMM may form multiloculated cysts, but, in contrast to multilocular peritoneal inclusion cyst, are at least focally lined by markedly atypical mesothelial cells, and areas of conventional PMM may be disclosed with thorough sampling. A frequently problematic lesion in the differential diagnosis is adenocarcinoma with diffuse peritoneal involvement, including metastatic adenocarcinomas (see section “Metastatic Tumors”) and adenocarcinomas of primary peritoneal origin, of which the majority are papillary serous carcinomas morphologically identical to those arising in the fallopian tube or ovary (see section “Lesions of the Secondary Müllerian System”). Features favoring a diagnosis of PMM include a prominent tubulopapillary pattern, polygonal cells with moderate amounts of eosinophilic cytoplasm, only mild to moderate nuclear atypia, a paucity of mitotic figures, and the presence of acid mucin (alcianophilic material) rather than neutral (PASD) mucin. Most PMMs are immunoreactive for cytokeratin 5/6, WT-1, and calretinin (Fig. 30b) and usually lack immunoreactivity for a variety of “epithelial” antigens, including claudin-4, carcinoembryonic antigen (CEA), B72.3, Leu-M1 (CD 15), MOC-31, and Ber-EP4. In addition, positive immunoreactivity for PAX-8, PAX-2, and estrogen receptors favors serous carcinoma; positive staining with calretinin, cytokeratin 5/6, podoplanin, and D2–40, as well as loss of BAP-1, favors PMM, but these markers are less discriminatory as they may be positive in a minor proportion of serous carcinomas (Andrici et al. 2016; Barneston et al. 2006; Chapel et al. 2017; Comin et al. 2007; Joseph et al. 2017; Ordonez 2005b, 2013b). One study found that an h-caldesmon+/calretinin+/estrogen receptor–/Ber-EP4– immunophenotype strongly favors PMM over serous carcinoma (Comin et al. 2007). However, no single immunohistochemical stain is diagnostic in the separation of PMM from adenocarcinoma, and the results of a panel of antibodies should be interpreted in conjunction with the hematoxylin and eosin (H&E) and mucin stains.
“Deciduoid” PMMs must be distinguished from an ectopic decidual reaction involving the peritoneum. Prominent nucleoli, often brisk mitotic activity, and cytokeratin immunoreactivity in the deciduoid tumors exclude an ectopic decidual reaction.
One study (Lin et al. 1996) reported peritoneal epithelioid hemangioendotheliomas or epithelioid angiosarcomas that have mimicked PMM. Features that suggested the diagnosis of PMM in some of the cases included epithelioid cells in a tubulopapillary pattern and the presence of reactive or neoplastic spindle cells resulting in a focal biphasic pattern. Variable degrees of vascular differentiation and immunoreactivity of the neoplastic cells for endothelial antigens (and negative or weak cytokeratin staining) excluded the diagnosis of PMM. Perivascular epithelioid cell tumor (PEComa) can rarely arise in the mesentery (see Chapter 10, “Mesenchymal Tumors of the Uterus”), and diffuse peritoneal involvement may mimic mesothelioma (Folpe et al. 2005; Salviato et al. 2006).
Miscellaneous Primary Tumors
Intra-abdominal Desmoplastic Small Round Cell Tumor
This rare tumor (desmoplastic small round cell tumor, DSRCT) is of uncertain histogenesis, but it may ultimately prove to be a primitive tumor of mesothelial origin (“mesothelioblastoma”) (Lae et al. 2002; Ordi et al. 1998; Ordonez 1998a, b; Young et al. 1992). Although most of the tumors are intra-abdominal, similar tumors have also been described in the pleura and rarely at a distance from a mesothelium-lined surface (parotid gland, tentorium, and hand). DSRCTs exhibit 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 that appears to be unique for this tumor (Ordi et al. 1998). This fusion results in the expression of the EWS/WT1 chimeric transcript detectable by reverse transcriptase polymerase chain reaction (PCR). The EWS/ERG fusion gene characteristic of Ewing’s sarcoma/peripheral neuroectodermal tumors has been found in rare DSRCTs, suggesting some overlap between the two groups of tumors.
DSRCTs have a strong male predilection (M:F ratio, 4:1) and are most common in adolescents and young adults (range, 5–76 years) who usually have abdominal distension, pain, and a palpable abdominal, pelvic, or scrotal mass, sometimes in association with ascites. Some patients have had an elevated serum level of CA-125 or neuron-specific enolase (NSE). Laparotomy typically discloses variably sized but usually large, intra-abdominal masses associated with smaller peritoneal “implants” of similar appearance. The tumor is sometimes confined to the pelvis, and prominent involvement of the tunica vaginalis or the ovaries may mimic a primary testicular or ovarian tumor (Young et al. 1992). The retroperitoneum is involved in some cases. One tumor appeared to originate within the liver.
After initial treatment (debulking and postoperative chemotherapy, irradiation, or both), there may be an initial response, but more than 90% of patients die of tumor progression. Recent studies have advocated complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy to optimized local disease control (Msika et al. 2010). The bulk of the tumor tends to remain within the peritoneal cavity, although extraabdominal metastases occur in some patients.
On gross examination, the tumors, which may reach 40 cm in maximal dimension, have smooth or bosselated outer surfaces and firm to hard, gray-white, focally myxoid, and necrotic sectioned surfaces. Direct invasion of intra-abdominal or pelvic viscera may occur.
Architectural features noted in a minority of cases, which can occasionally predominate and lead to diagnostic problems, include tubules, glands (sometimes with luminal mucin), cysts, papillae, anastomosing trabeculae, cords of cells mimicking lobular breast carcinoma, adenoid cystic-like foci, and only a sparse desmoplastic stroma. Cytologic features noted in a minority of cases, which can occasionally predominate, include spindle cells; cells with abundant eosinophilic or clear cytoplasm, which may create a biphasic pattern; signet-ring-like cells; and cells with marked nuclear pleomorphism which may include bizarre nuclei (Ordonez 1998a). Invasion of vascular spaces, especially lymphatics, is a common feature. Lymph nodes are occasionally involved by tumor.
Immunohistochemical and Ultrastructural Findings
The usual immunoreactivity for epithelial (low molecular weight cytokeratins, epithelial membrane antigen [EMA]), neural/neuroendocrine (neuron-specific enolase [NSE], CD57/Leu-7), and muscle (desmin) markers, as well as vimentin, suggests divergent differentiation. Desmin and vimentin immunoreactivity is typically paranuclear and globular and is particularly intense in the rhabdoid cells. Immunoreactivity for a wide variety of other antigens has been present in a variable proportion of cases, including most with nuclear staining for the C-terminal of Wilms’ tumor protein (WT1) (Lae et al. 2002; Ordonez 1998b; Zhang et al. 2003). Ultrastructural variability suggests a range of differentiation, with cell junctions of various types, paranuclear intermediate cytoplasmic filaments, and basal lamina surrounding the nests of tumor (Ordonez 1998b).
The typical age of the patient, the absence of an extraperitoneal primary tumor, the distribution of the tumor, and its typical microscopic features and immunoprofile facilitate the distinction from other malignant small blue cell tumors in most cases. Distinction of DSRCT from blastemal-predominant Wilms’ tumor may be problematic, as the former may show atypical staining patterns due to full-length or variant transcripts (Murphy et al. 2008) and the latter can exhibit paranuclear desmin and cytokeratin positivity (Arnold et al. 2014). Cyclin D1 immunohistochemistry may be helpful to discriminate DSCRT (negative or <5% tumor cells positive) from Ewing sarcoma/primitive peripheral neuroectodermal tumor (strong positive nuclear staining in >50% tumor cells) (Magro et al. 2017). Identification of the unique reciprocal translocation is diagnostic and may be essential in problem cases.
Solitary Fibrous Tumor
Although once referred to as fibrous mesotheliomas, these tumors are now designated solitary fibrous tumors and are believed to originate from submesothelial fibroblasts (Brunnemann et al. 1999; Young et al. 1990). The clinical and pathologic features are similar to their much more common pleural counterparts, including immunoreactivity for CD34 and lack of immunoreactivity for cytokeratin, an immunoprofile that is useful in distinguishing these tumors from desmoplastic mesotheliomas (Brunnemann et al. 1999). Typical tumors are clinically benign. One peritoneal solitary fibrous tumor that was focally sarcomatous was clinically malignant (Fukunaga et al. 1996).
Inflammatory Myofibroblastic Tumor
Day et al. reviewed the features of seven cases of abdominal “inflammatory pseudotumor” (Day et al. 1986), a lesion that has also been referred to as plasma cell granuloma or, more recently, inflammatory myofibroblastic tumor (Pettinato et al. 1990). Various anatomical locations have been reported, but most tumors arise in the lung, mesentery, omentum, or retroperitoneum. The abdominal lesions are typically encountered in patients younger than 20 years of age, often in the first decade, who present with a mass, fever, growth failure or weight loss, hypochromic anemia, thrombocytosis, and polyclonal hypergammaglobulinemia. Laparotomy typically reveals a solid mesenteric mass that on microscopic examination consists of 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 generally a low risk of distant metastasis. Coffin et al. (2007) recently reported that abdominopelvic tumors had a higher rate of recurrence relative to other anatomical sites and that ALK-negative tumors were more likely to be associated with distant metastases.
Calcifying Fibrous Tumor
The rare lesion known as calcifying fibrous tumor, initially considered a pseudotumor, is likely neoplastic, with a predilection for children and young adults but which can occur over a wide age range and in a variety of anatomical sites including the subcutaneous or deep soft tissues and the pleura (Nascimento et al. 2002; Sigel et al. 2001). In the peritoneum, the calcifying fibrous tumor is usually an incidental finding involving the visceral peritoneum of the small intestine or stomach. The tumors are often small (less than 5 cm) but can be larger and sometimes multiple. Microscopically, they are hypocellular, composed of bland spindle cells, hyalinized collagen, a chronic lymphoplasmacytic inflammatory infiltrate, and psammomatous or dystrophic calcifications. The spindle cells are typically CD34-positive and ALK-negative, the latter regarded as evidence that these lesions are distinct from the inflammatory myofibroblastic tumor; rare cells may show positive staining with muscle actin and desmin (Nascimento et al. 2002; Sigel et al. 2001). A recent review of 157 patients reported a 10% recurrence rate and no patient deaths (Chorti et al. 2016).
Omental–Mesenteric Myxoid Hamartoma
The omental–mesenteric myxoid hamartoma designation was applied by Gonzalez-Crussi et al. (1983) to a lesion in infants characterized by multiple omental and mesenteric nodules composed of plump mesenchymal cells in a myxoid, vascularized stroma. The diagnosis of the referring pathologists was usually that of some type of sarcoma, but the follow-up was uneventful. The lesions may be hamartomatous or a variant of inflammatory myofibroblastic tumor.
The majority of intra-abdominal sarcomas are of non-peritoneal origin and arise in the retroperitoneum or gastrointestinal tract; they include leiomyosarcomas, liposarcomas, and gastrointestinal stromal tumors and are not discussed further here. Rarely, malignant vascular tumors may arise from the peritoneum (epithelioid hemangioendothelioma, epithelioid angiosarcoma) and are briefly discussed above in the differential diagnosis with malignant mesothelioma (Lin et al. 1996).
Gestational Trophoblastic Disease
Rarely, gestational trophoblastic disease (including placental site trophoblastic tumor, hydatidiform mole, and choriocarcinoma) may arise in the peritoneum, presumably secondary to an intra-abdominal pregnancy.
Pseudomyxoma peritonei, which is a clinical term referring to the presence of masses of jelly-like mucus in the pelvis and often the abdomen, is usually a result of peritoneal spread from a typically low-grade mucinous neoplasm, usually originating within the appendix or, less commonly, from a primary tumor elsewhere in the gastrointestinal tract. Ovarian involvement is common in such cases, and this topic is discussed in detail in chapters “Surface Epithelial Tumors of the Ovary” and “Metastatic Tumors of the Ovary”.
Lesions of the Secondary Müllerian System
These peritoneal lesions are characterized by müllerian differentiation on microscopic examination and share an origin from the so-called secondary müllerian system, that is, the pelvic and lower abdominal mesothelium and the subjacent mesenchyme of females (Lauchlan 1972). The müllerian potential of this layer is consistent with its close embryonic relation to the müllerian ducts that arise by invagination of the coelomic epithelium. Displacement of coelomic epithelium and subcoelomic mesenchyme during embryonic development could account for the presence of identical lesions within the pelvic and abdominal lymph nodes. The origin of many of these lesions, however, is not known with certainty, and other proposed histogenetic mechanisms are discussed where appropriate.
Lesions of the secondary müllerian system include those containing endometrioid, serous, and mucinous epithelium, simulating normal or neoplastic endometrial, tubal, and endocervical epithelium. The metaplastic potential of the pelvic peritoneum also includes differentiation toward cells of transitional (urothelial) type, exemplified most commonly by Walthard nests. Proliferation of the subjacent mesenchyme may accompany epithelial differentiation of the mesothelium or may give rise to a variety of pure mesenchymal lesions composed of endometrial stromal-type cells, decidua, or smooth muscle.
Endometriosis in Usual Sites
Endometriosis is defined as the presence of endometrial tissue outside the endometrium and myometrium. Usually both epithelium and stroma are seen, but occasionally the diagnosis of endometriosis can be made when only one component is present, as discussed below.
Etiology and Pathogenesis
Two theories have been proposed for the pathogenesis of endometriosis: (1) metastases of endometrial tissue to its ectopic location (metastatic theory) and (2) metaplastic development of endometrial tissue at the ectopic site (metaplastic theory). The metastatic theory explains the majority of cases, but a metaplastic origin likely accounts for occasional cases in which metastatic spread of endometrial tissue is unlikely or impossible (see following).
Sampson (1927) proposed that endometriosis was caused by reflux of endometrial tissue through the fallopian tubes by a process of retrograde menstruation, with subsequent implantation and growth on peritoneal surfaces. Implantation of menstrual endometrium has also been proposed to explain endometriosis within surgical scars, on traumatized cervical and vaginal mucosa, and within perineal and vulvar scars following vaginal delivery. Passage of refluxed menstrual endometrium from the peritoneal cavity through diaphragmatic defects, diaphragmatic lymphatics, or both may explain pleural endometriosis.
Observations supporting the menstrual implantation hypothesis include the following: (1) endometriotic lesions are most common in areas closest to the tubal ostia and occur in a distribution that appears dependent on gravity and uterine position (Ishimaru and Masuzaki 1991); (2) lateral predisposition of ovarian endometriomas, which are more commonly left-sided than right-sided, is a phenomenon attributed to reduced flow of peritoneal fluid due to the presence of the sigmoid colon in the left pelvis (Sznurkowski and Emerich 2008); (3) retrograde menstruation through the fallopian tubes is a common physiologic process, occurring in 90% of menstruating women with patent tubes (Halme et al. 1984); (4) endometriosis is more common in women with early menarche, heavy menstrual flow, long menstrual flow (greater than 7 days), and frequent menses (cycle less than 27 days); (5) breastfeeding has an inverse association with risk of endometriosis (at least partially attributable to postpartum amenorrhea) (Farland et al. 2017); (6) menstrual endometrium is viable, capable of growth in tissue culture and after subcutaneous or intrapelvic injection (D’Hooghe et al. 1995); (7) endometriosis is more frequent in females with congenital obstruction to menstrual flow (Olive and Henderson 1987); and (8) endometriosis may follow uteropelvic or utero-abdominal wall fistulas in experimental animals and humans.
Although endometriosis in some scars may be a result of menstrual implantation, endometriosis within scars after uterine operations may be secondary to intraoperative implantation of endometrial tissue (Chatterjee 1980; Steck and Helwig 1966). Supporting this theory is the greater frequency of scar endometriosis after abdominal hysterotomy than after Cesarean section in some studies, consistent with the greater viability of transplanted early-pregnancy endometrium compared to late-pregnancy endometrium. Also, the occurrence of endometriosis within an episiotomy scar is much higher if uterine curettage is performed immediately after delivery than in patients without postdelivery curettage (Paull and Tedeschi 1972).
The presence of endometriosis in distant sites (e.g., lungs, extremities, and brain) is most easily explained by hematogenous spread from the uterus. Similarly, endometriosis within lymph nodes is likely a result of lymphatic spread. Evidence supporting the origin of endometriosis from lymphatic or hematogenous spread includes (1) the presence of normal endometrial tissue within endothelium-lined spaces as an incidental histologic finding within the myometrium, most often associated with adenomyosis; (2) the presence of intraluminal vascular involvement in rare endometriotic lesions; (3) the presence of intravascular or perivascular trophoblastic tissue and “decidua” as an incidental microscopic finding within the lungs of pregnant patients (Jelihovsky and Grant 1968); (4) the occurrence of pulmonary endometriosis almost exclusively in women who have had prior uterine operations that could predispose to the embolization of endometrial tissue; (5) the experimental production of pulmonary endometriosis by intravenous injection of endometrial tissue in rabbits; and (6) the observations that tumor cells, blood, dye, and radiographic material can migrate from the pelvis to the umbilicus by retrograde lymphatic flow. Perineural spread may be an alternate mechanism to account for rare cases of endometriosis that involve the nervous system (Siquara de Sousa et al. 2015).
The origin of pelvic endometriosis by a process of metaplasia from the pelvic peritoneum is consistent with the putative müllerian potential of this tissue, which, as noted earlier, has been referred to as the secondary müllerian system (Lauchlan 1972). Evidence for the metaplastic theory includes (1) the demonstration of endometriosis in subjects in whom metastasis of normally situated endometrium could not occur or is highly unlikely, such as those with Turner’s syndrome and pure gonadal dysgenesis who are amenorrheic and have hypoplastic uteri (Peress et al. 1982), and in males, (2) the experimental induction of peritoneal endometriosis adjacent to millipore filters that contain endometrial tissue but that prevent cellular transfer, (3) the observation that autologous endometrial implants in rabbits degenerate but are associated with the subsequent development of endometriosis in adjacent tissues, and (4) the juxtaposition of endometriosis with other putative metaplastic lesions of the peritoneum, such as diffuse peritoneal leiomyomatosis (Guarch et al. 2001).
Other Etiologic Factors
Endometriosis is an idiopathic disease in most patients, and why only a minority of females are affected despite the common occurrence of retrograde menstruation is unknown. The unique microenvironment of the pelvic peritoneum and the pathogenetic mechanisms that may facilitate survival, implantation, and proliferation of endometriotic tissue have garnered recent attention. These include altered cellular and immune response to peritoneal injury and inflammation, with aberrant activation of macrophages and promotion of angiogenesis, and increased expression of key extracellular matrix proteoglycans in the endometriotic peritoneum (Capobianco et al. 2017; Tani et al. 2016). Some potential etiologic factors have been discussed (congenital obstruction, iatrogenic implantation); others are summarized in the following section.
Familial and Genetic Factors
Several studies concluded that the prevalence of endometriosis is greater in mothers and sisters of women with endometriosis than in the mothers and sisters of their husbands (Lamb et al. 1986; Simpson et al. 1980). Lamb et al. (1986) calculated the overall risk for first-degree relatives to be 4.9%. Genetic studies suggest a polygenic mode of inheritance (influenced by several different genes) or one that is multifactorial (a result of interaction between genetic and environmental factors). In opposition to the foregoing, Houston et al. (1988) concluded that there were methodologic flaws in these studies and that an inherited tendency to endometriosis has not yet been substantiated. Recently, genetic markers that may impart an increased risk of endometriosis have been identified by genome-wide association studies (Fung et al. 2015).
Molecular genetic analysis has elucidated a number of intriguing theories regarding the pathogenesis of endometriosis (Bulun 2009). By microarray analysis, Wu et al. (2006) have shown that in patients with endometriosis, the ectopic and eutopic endometria have different gene expression profiles. Putative endometrial progenitor/stem cells, which are thought to reside in the basalis endometrium and possibly in the bone marrow, have been characterized by in vitro and in vivo assays (Sasson and Taylor 2008). It has been shown that patients with endometriosis shed significantly more basalis layer during menstruation compared with normal controls, supporting the hypothesis that endometriotic implants develop from endometrial progenitor/stem cells, which are in turn derived from retrograde menstrual flow, known to be higher in women with endometriosis (Halme et al. 1984; Leyendecker 2002; Sasson and Taylor 2008).
Because endometriosis occurs almost exclusively in women of reproductive age, hormonal factors may play an etiologic role. The rare examples of endometriosis in phenotypic females with gonadal dysgenesis and in males have usually been associated with the use of exogenous estrogens (Martin and Hauck 1985; Peress et al. 1982). Similarly, smoking and exercise, which are inversely correlated with endogenous estrogen levels, appear to be protective factors for the development of endometriosis. In a large epidemiologic study, factors associated with an increased risk of endometriosis included low body weight, alcohol use, and certain menstrual characteristics (early menarche, short cycle length, and heavy menstrual cycles) (Matalliotakis et al. 2008).
It has been suggested that the progestational milieu of pregnancy may inhibit the development of endometriosis. Many studies have indicated that endometriosis is more likely to occur in women who have delayed pregnancy and is less common in multiparous women (Redwine 1987). Similarly, in some studies, patients with endometriosis are much less likely to have used oral contraceptives than similar patients without endometriosis.
Some studies have found an increased frequency of the luteinized unruptured follicle syndrome (LUFS) in patients with endometriosis. In normal women, the ruptured corpus luteum releases its progesterone-rich fluid into the peritoneal cavity. It has been postulated that this fluid may inhibit implantation and growth of refluxed endometrial fragments at the time of menstruation (Koninckx et al. 1980). In patients with LUFS, a corpus luteum is formed, but rupture and fluid release do not occur, resulting in lowered luteal-phase levels of progesterone in the peritoneal fluid (Koninckx et al. 1980). This local hormonal imbalance may be critical in allowing endometrial cells to implant on the peritoneum. Other studies, however, have shown no difference in the luteal-phase peritoneal fluid hormone values in women with and without endometriosis.
One study has demonstrated a reduced T lymphocyte-mediated cytotoxicity to autologous endometrial cells and a decreased lymphocyte stimulation response to autologous endometrial antigens in patients with endometriosis (Steele et al. 1984). The degree of depressed cellular immunity was directly proportional to the severity of the disease. The authors of this study suggested that certain cell-mediated immune mechanisms that may be operative in limiting the growth of endometriotic tissue may be impaired in patients with endometriosis. A recent study found a significant decrease in activated regulatory T cells from endometrioma and eutopic endometrium, in comparison to endometrium from women without endometriosis, providing additional evidence for a dysregulated immune response in the pathogenesis of endometriosis (Tanaka et al. 2017). Other authors have suggested that the growth of endometriotic implants may be stimulated by activated macrophages. Estrogen receptor positivity has been demonstrated in endometriotic macrophages, and, in murine models, estradiol stimulated macrophage–nerve interactions (Greaves et al. 2015). It has been shown that local production of interleukin 4, a cytokine involved in the Th2 immune response, induces proliferation of endometriotic stromal cells (OuYang et al. 2008). Cyclooxygenase-2, which is involved in the biosynthesis of prostaglandin E2, is highly expressed in ectopic endometria relative to eutopic endometria and is thought to play a promotory role in the development of endometriosis (Banu et al. 2008).
The highest risk of the disease has traditionally been considered to be in the upper socioeconomic levels of developed societies, especially among women who delay pregnancy, although, according to Houston, these associations have not been proven statistically (1988). Although endometriosis was once considered to be more common in Caucasians, studies showing a similar frequency of the disease in Asians and Africans cast doubt on this view.
The true prevalence of endometriosis is unknown as many patients are asymptomatic; estimates for the prevalence of the disease in women of reproductive age are 10–15%. Prevalence figures, however, have varied widely, depending on the population studied and the method of diagnosis (clinical, operative, or pathologic). Similarly, a study of the incidence rates of pelvic endometriosis in white females of reproductive age in Rochester, Minnesota (USA), found that the overall incidence of the disease more than doubled (from 108.8 to 246.9 cases per 100,000 person-years) as the definition of a case was extended from histologically confirmed cases to clinically and surgically diagnosed cases (Houston et al. 1987).
More than 80% of affected patients are in the reproductive age group. In one study, the age-specific incidence rates increased in successive age groups through age 44 and then declined for women 45–49 years (Houston et al. 1987). Less than 5% of cases occur in postmenopausal women, and in these patients the disease is frequently not diagnosed premenopausally (Kempers et al. 1960). Endometriosis can be clinically significant in this age group, with 20–30% of affected patients requiring operative management (Kempers et al. 1960; Punnonen et al. 1980). In some postmenopausal patients with endometriosis, an association with obesity and endometrial carcinoma has been noted, suggesting that hyperestrinism may play a role, but in other series, a majority of patients have had no obvious exogenous or endogenous source of estrogen (Kempers et al. 1960). Chronic endometritis has been shown to be more prevalent in women with endometriosis (38.5% of patients vs. 14.1% without endometriosis) (Cicinelli et al. 2017). Almost 10% of patients with endometriosis are adolescents (Chatman and Ward 1982). Endometriosis was found at laparoscopy in approximately 50% of teenage patients with dysmenorrhea or chronic pelvic pain in three studies (Chatman and Ward 1982). In some studies, adolescents with endometriosis have a particularly high frequency of a congenital obstruction to menstrual flow.
Symptoms and Signs
The recurrent cyclic menstrual, inflammatory, and fibrotic changes within the endometriotic lesions are likely responsible for most of the symptomatology of endometriosis, although there is often no direct relationship between the extent of the disease and the severity of the symptoms (Chatman and Ward 1982). An exception to the foregoing applies to women with deeply infiltrating endometriosis, a clinical term used for patients with deep pelvic pain, usually in the form of severe dyspareunia and dysmenorrhea, which is often associated with rectovaginal lesions or involvement of the bowel, ureter, or bladder (Cornillie et al. 1990). One study has shown significant reduction in painful symptoms obtained with complete surgical excision of deep lesions (Chopin et al. 2005). Hormonal responsiveness of the lesions as judged histologically also does not correlate with symptoms, and microscopic examination of symptomatic endometriosis in postmenopausal patients typically reveals atrophic changes (Kempers et al. 1960). Age generally does not appear to affect disease severity in most studies (Houston et al. 1988). An exception to the foregoing is one study in which women in the age group of 26–52 years had less extensive disease than women 16–25 years of age (Redwine 1987). A higher frequency of nulliparity in the younger women appeared to account for part of this difference (Houston et al. 1988). Another study found that endometriosis in postmenopausal patients was morphologically less extensive and less active in appearance relative to endometriosis in premenopausal women, but that the endometriotic foci retained the same immunoprofile by estrogen and progesterone receptor immunostaining (Cumiskey et al. 2008).
The typical symptoms that are attributed to pelvic endometriosis are acquired dysmenorrhea; lower abdominal, pelvic, and back pain; dyspareunia; irregular bleeding; and infertility. Infertility is present in up to 30% of women with endometriosis, although the putative association between mild endometriosis and infertility has been challenged and remains controversial. The subject of endometriosis-related infertility has been reviewed elsewhere (Gupta et al. 2008) and is not considered in detail here. Potential pathogenetic factors include tubal factors (adhesions, luminal obstruction), ovarian factors (anovulation, luteal-phase dysfunction, LUFS), immune factors (antiendometrial antibodies), peritoneal factors (increased prostaglandins, increased macrophages), and an increased risk of spontaneous abortion.
Pelvic examination may reveal tender nodules in the cul-de-sac and uterosacral ligaments; tender, semifixed, cystic ovaries; and a fixed, retroverted uterus. The rectovaginal septum may also be tender and indurated. The endometriotic lesions frequently enlarge and become more painful during menses. The clinical manifestations also vary according to the site of the endometriosis, as is discussed later in this chapter. As the clinical manifestations of endometriosis are frequently nonspecific, vary widely between patients, and may be absent in a high proportion of patients, a definitive diagnosis requires direct visualization by laparoscopy (or laparotomy) and, ideally, biopsy. Hormonal suppression and surgical ablation remain the commonly employed therapeutic modalities, and while treatment of endometriosis is not discussed here, it is important to note that with advances in the understanding of the pathogenesis of endometriosis, future methods may include molecular-targeted drug therapies such as cyclooxygenase inhibitors and immunomodulators in an attempt to minimize the need for surgical intervention (Bulun 2009; Gupta et al. 2008).
A number of studies have stressed that endometriotic foci, especially early ones, are frequently nonpigmented and may have a wide variety of laparoscopic appearances, including clear, white, and red lesions (Jansen and Russell 1986; Martin et al. 1989). Sequential laparoscopic examinations indicate that nonpigmented endometriotic implants eventually evolve into the typical pigmented lesions (Jansen and Russell 1986). Even in patients with laparoscopically typical disease, biopsy may yield only nondiagnostic tissue, and, thus, in the opinion of some authors, diagnosis and treatment should not always depend on microscopic confirmation (Chatman and Zbela 1987). Other authors have found that 25% of laparoscopically atypical lesions prove to be endometriosis on histological examination and therefore advocate that all lesions suggestive of endometriosis, both typical and atypical, should be excised if eradication is the surgical objective (Albee et al. 2008). In another study, only 50% of all laparoscopic biopsies from clinically suspicious foci were proven microscopically to be endometriosis (Walter et al. 2001).
Laparoscopically detectable defects or “pockets” involving the pelvic peritoneum are frequently associated with, and likely caused by, endometriosis. In one study, 80% of women with pelvic peritoneal defects had endometriosis, and, in another, the endometriotic foci were often located along the edges of the defects. Conversely, 18–28% of women with endometriosis had peritoneal defects (Redwine 1989).
Levels of serum CA-125 may be elevated in patients with endometriosis, and concentrations correlate with both the severity and the clinical course of the disease (Santulli et al. 2015). The serum test has low sensitivity, however, and is not appropriate for general screening purposes. In contrast, CA-125 levels have acceptable sensitivities and very high specificities in populations with a relatively high prevalence of the disease and are useful in monitoring response to treatment.
A wide range of blood biomarkers have been investigated to potentially aid in the nonsurgical diagnosis of endometriosis, including antiendometrial antibodies, but in a recent large meta-analysis, none were found to be of sufficient sensitivity and specificity to support routine clinical application (Nisenblat et al. 2016).
Effects of Pregnancy
Although rare cases of endometriosis undergo permanent regression during pregnancy, the ameliorative effect of pregnancy noted in many cases of endometriosis is only temporary. The behavior of endometriosis during pregnancy is extremely variable among different patients and between one pregnancy and another in the same patient. During pregnancy, visible endometriotic lesions frequently undergo initial enlargement, with occasional ulceration and bleeding, followed by shrinkage. In most sites, there is a decrease in the associated pain.
A rare complication of endometriosis during pregnancy is intrapartum or postpartum rupture of the lesion, most probably caused by a softening of the lesion secondary to stromal decidualization, pressure from the expanding uterus, or both. Rupture occurs most frequently in the ovaries or bowel, typically resulting in perforation and an acute abdomen. Rarely, hemoperitoneum, sometimes fatal, is caused by hemorrhage from decidualized endometriotic lesions at term.
Massive, sometimes serosanguineous, ascites can occur in patients with pelvic endometriosis; a right pleural effusion is also present in one third of such patients (Muneyyirci-Delale et al. 1998). If one or both ovaries are involved, the operative findings may simulate those of an ovarian carcinoma. The pathogenesis of the ascites is not clear. Possible sources include production by endometriotic cysts, irritated peritoneal mesothelial cells, or the ovarian serosa (Meigs-like syndrome). Other rare complications include hemorrhage from an endometriotic focus and spontaneous rupture of ovarian endometriotic cysts, resulting in an acute abdomen.
Gross Features of Peritoneal and Ovarian Endometriosis
Sites of endometriosis
Large bowel, small bowel, appendix
Uterine ligaments (uterosacral, round, broad)
Mucosa of the cervix, vagina, and fallopian tubes
Soft tissues, breast
Skin (scars, umbilicus, vulva, perineum, inguinal region)
Upper abdominal peritoneum
Peritoneum of the uterus, tubes, rectosigmoid, ureter, bladder
Omentum, pelvic lymph nodes
Stomach, pancreas, liver
Urethra, kidney, prostate, paratesticle
Sciatic nerve, subarachnoid space, brain
Typical Microscopic Findings
Endometriosis that involves smooth muscle in the uterine ligaments or the walls of hollow viscera differs significantly in its appearance from that of endometriosis in the ovaries and the peritoneal surfaces. In the former, there is typically a striking proliferation of the indigenous smooth muscle, often resulting in a firm, solid, tumor-like mass. The appearance is similar to that of adenomyosis with secondary striking myometrial hypertrophy.
Unusual Microscopic Findings
Metaplastic Glandular Changes
Unusual Hormonal Changes
Hyperplastic Glandular Changes
Necrotic Pseudoxanthomatous Nodules
Rare Miscellaneous Findings
Rare examples of endometriosis have been encountered in intimate association with foci of peritoneal leiomyomatosis, glial implants of ovarian teratomas, and nodules of splenosis. Perineural and vascular invasion can occur rarely in otherwise typical, benign endometriotic lesions, findings that may incorrectly suggest the diagnosis of malignancy (Roth 1973).
Microscopic examination of the fallopian tubes in patients with endometriosis has revealed nonspecific chronic salpingitis in as many as one third of cases (Czernobilsky and Silverstein 1978). A less common lesion, so-called pseudoxanthomatous salpingitis or pseudoxanthomatous salpingiosis, characterized by infiltration of the tubal mucosa by pseudoxanthoma cells, is almost always associated with pelvic endometriosis (Czernobilsky and Silverstein 1978; Clement et al. 1988).
Ultrastructural, Histochemical, and Steroid Receptor Studies
Endometriotic glands typically exhibit ultrastructural features that represent a response, but an incomplete one, to the prevailing hormonal milieu of the particular phase of the menstrual cycle. In contrast to eutopic endometrial glands, it is usually not possible to date the glands precisely within the secretory phase because of marked interglandular and intraglandular variability. Ultrastructural examination of endometriotic tissue following danazol treatment shows either arrest of the endometriotic glandular epithelium in the early proliferative phase or disorganization of the epithelial cells with atrophic changes.
Estrogen (ER) and progesterone receptors (PR) are present in the endometriotic glands and stroma but usually in lower concentrations than in eutopic endometrium (Bur et al. 1987). In a variable number of cases, one or both receptors are absent. Moreover, the normal variation in the quantity of both receptors exhibited by eutopic endometrium during the menstrual cycle is diminished or absent within foci of endometriosis (Lessey et al. 1989). Differences in receptor concentrations between eutopic endometrium and endometriotic epithelium in response to danazol have also been noted. No correlation has been found between receptor levels and severity of symptoms.
In summary, the findings of these studies are consistent with the incomplete and variable hormonal response of endometriotic foci observed on microscopic examination. They indicate a greater degree of autonomy of endometriotic tissue from the mechanisms controlling eutopic endometrium and may explain the failure of hormonal therapy in some patients (Metzger et al. 1991).
Endometriosis may be accompanied by, and should be distinguished from, endosalpingiosis, which is characterized by glands lined by benign tubal-type epithelium, unassociated with endometrial stroma or the usual histiocytic inflammatory reaction of endometriosis (see section “Endosalpingiosis”). A misdiagnosis of endosalpingiosis or, if in the ovary, an epithelial inclusion gland (see chapter “Nonneoplastic Lesions of the Ovary”) is likely when the endometriotic stroma is sparse or obscured by hemorrhage (see Fig. 39).
Necrotic pseudoxanthomatous nodules should be distinguished from other ovarian and peritoneal necrotic nodules, such as infectious granulomas and isolated palisading granulomas of the ovary (see chapter “Nonneoplastic Lesions of the Ovary”), and, as noted earlier, peritoneal granulomas related to diathermy (Clarke and Simpson 1990). Such lesions, in addition to having characteristic features, lack the numerous pseudoxanthoma cells that are typical of endometriotic lesions.
Rare low-grade endometrial stromal sarcomas (ESSs) contain numerous benign-appearing or atypical endometrial glands, to the extent that confusion with endometriosis may occur (Clement and Scully 1992). Indeed, it is likely that at least some cases referred to as aggressive endometriosis are examples of ESS with prominent glandular differentiation. These tumors, however, in contrast to typical endometriosis, contain foci of more typical ESS devoid of glands, and, in some cases, prominent mitotic activity of the stromal cells, sex cord-like elements, and prominent vascular invasion.
A diagnosis of adenosarcoma was initially considered in some cases of polypoid endometriosis. Adenosarcomas, in contrast to polypoid endometriosis, are characterized by a stromal component that usually exhibits dense periglandular cellularity, atypia (albeit mild in many cases), intraglandular papillae, and increased mitotic activity.
Cervical and Vaginal Endometriosis
Superficial endometriosis of the uterine cervix is more common than is generally appreciated (Baker et al. 1999; Clement et al. 1990; Gardner 1966). The predilection for sites of trauma and the usual absence of associated pelvic endometriosis suggest implantation as the most likely pathogenetic mechanism. The condition may be an incidental finding in an asymptomatic patient or be associated with premenstrual or postcoital spotting or menorrhagia. The solitary or multiple lesions typically involve the ectocervix; endocervical lesions have been described only rarely. The endometriotic foci appear as friable, ecchymotic streaks, patches, nodules, or cysts measuring from 1 mm to 2 cm in diameter. Rare lesions have been puckered secondary to fibrosis within the lesion, or papillary, simulating a carcinoma. In patients who have had a recent cone biopsy or extensive cautery, the entire transformation zone may be involved (Ismail 1991). Before menses, the lesions typically enlarge and change from bright red to blue; during menses they may rupture, leaving an irregular ulcer. Because a punch biopsy may yield nondiagnostic tissue due to the size of the lesion (which is frequently small), tissue crushing, and fragmentation, aspiration cytology may be useful in establishing the diagnosis. Cervical endometriosis may be the source of abnormal gland cells identified on cervicovaginal smears (Szyfelbein et al. 2004).
In contrast to superficial cervical endometriosis, deep cervical endometriosis is usually an extension of cul-de-sac involvement in association with more widespread pelvic endometriosis. It may be palpable as deep, firm nodules or cysts in the posterior wall of the cervix (Gardner 1966). The diagnosis is made by biopsy or pathologic examination of the hysterectomy specimen. The differential diagnosis includes downgrowth of adenomyosis from the uterine corpus.
The term “tubal endometriosis” has been applied to at least three different unrelated lesions of the fallopian tube. The most common type is serosal or subserosal endometriosis, typically associated with endometriosis elsewhere in the pelvis; the myosalpinx is usually not involved.
The third type of endometriosis involving the fallopian tube has been designated postsalpingectomy endometriosis. It occurs in the tip of the proximal tubal stump, typically 1–4 years following tubal ligation (Rock et al. 1981). It is closely related to, and may be associated with, salpingitis isthmica nodosa. The lesion is analogous to uterine adenomyosis, consisting of endometrial glands and stroma extending from the endosalpinx into the myosalpinx and frequently to the serosal surface. Hysterosalpingography or India ink injection of the specimen may show tuboperitoneal fistulous tracts; postligation pregnancies are a rare complication. Postsalpingectomy endometriosis has been documented in 20–50% of tubes examined following ligation. The frequency of this complication is increased with the electrocautery method of ligation, with short proximal stumps, and with increasing postligation intervals.
Intestinal involvement has been documented in as many as 37% of patients with endometriosis undergoing laparotomy (Williams and Pratt 1977), although the average frequency appears to be approximately 12%. In the majority of such cases, the involvement is confined to the serosa or subserosa and is unassociated with clinical manifestations referable to the intestinal tract. In contrast, from 0.7% to 2.5% of patients with endometriosis require bowel resection for symptomatic lesions (Prystowsky et al. 1988). In some series, as many as half the patients with symptomatic intestinal endometriosis have no extraintestinal involvement; the endometriotic nature of the intestinal lesions in such cases is more likely to be unrecognized preoperatively or at the time of laparotomy. Misdiagnosis is also common in postmenopausal patients because of a decreased index of suspicion, even though the intestine is one of the more common sites of clinically significant endometriosis in this age group (Kempers et al. 1960). As many as 7% of patients with symptomatic intestinal endometriosis are postmenopausal.
Intestinal sites of involvement include, in descending order of frequency, the rectum and sigmoid, the appendix, the terminal ileum, the cecum, and other parts of the large and small bowel, including Meckel’s diverticulum (Yantiss et al. 2001). In one large study (Prystowsky et al. 1988), 15% of patients had more than one site of involvement. The presenting symptoms include, alone or in combination, acute or chronic abdominal pain, diarrhea, constipation, hematochezia, and decrease in stool caliber. Although the frequently catamenial nature of the symptoms may suggest the correct diagnosis, the clinical presentation can mimic acute appendicitis, bowel obstruction due to adhesions or a hernia, a neoplasm, or even inflammatory bowel disease. Endoscopic and radiographic studies typically demonstrate an extramucosal stenosing lesion; endoscopic biopsies are usually of no diagnostic value.
A complication of intestinal endometriosis is perforation, which is usually associated with pregnancy; a marked decidual reaction is typically seen with the endometriotic stroma in such cases. Other complications include volvulus, intussusception, acute appendicitis, appendiceal mucocele, intramural hematoma, and the development of a malignant neoplasm (see below) (Mostoufizadeh and Scully 1980; Yantiss et al. 2000).
Urinary Tract Endometriosis
Urinary tract involvement has been documented at laparotomy from 16% to 20% of patients with endometriosis (Redwine 1987; Williams and Pratt 1977). In most of these cases, the endometriosis is found on the serosa of the urinary bladder or that overlying the ureter and is without local clinical manifestations. Similarly, high-volume intravenous urography has demonstrated subtle, clinically insignificant abnormalities in 15% of women with proven pelvic endometriosis before therapy. In contrast, only 0.5–1% of patients with endometriosis have clinically significant urinary tract involvement; approximately 30% of such patients ultimately require nephrectomy for a hydronephrotic or nonfunctioning kidney. Most reported cases of urinary tract endometriosis have involved the ureters or urinary bladder (with approximately equal frequency), although in one large recent study, 95% and 14% of patients had ureteral and bladder involvement, respectively (Knabben et al. 2015). The kidneys and urethra are involved much less commonly. Urinary tract involvement is usually associated with endometriosis elsewhere in the pelvis, although the symptoms relating to the urinary tract may be the initial or sole manifestations of the disease in such patients (Stanley et al. 1965). In some series, however, as many as half the patients with ureteral involvement have disease restricted to the ureter and the adjacent uterosacral ligament (Kane and Drouin 1985). Patients with renal endometriosis typically do not have endometriosis elsewhere, suggesting an embolic, likely blood-borne, origin.
One third to one half of the affected patients are over 40 years of age, and almost 5% of the patients are postmenopausal, some of whom had received estrogen replacement therapy. A preoperative diagnosis may be suspected by the catamenial nature of the symptoms, which include suprapubic or flank pain, frequency, urgency, dysuria, and hematuria; chills and fever secondary to a urinary tract infection have been the presenting symptoms in occasional cases. A tender suprapubic or flank mass may be palpable. Many patients, however, particularly those with ureteric involvement, have nonspecific manifestations or present with a silent obstructive uropathy, occasionally complicated by hypertension, renal failure (in cases of bilateral involvement), or both (Kane and Drouin 1985; Stanley et al. 1965). In patients with bladder involvement, urography may reveal a filling defect; a stricture in the lower ureter with hydroureter and hydronephrosis or a nonfunctioning kidney is the typical urographic finding in those with ureteral involvement. All seven patients with ureteral endometriosis in one study had hydroureter, in most cases accompanied by hydronephrosis, two with superimposed pyelonephritis (Al-Khawaja et al. 2008). Endoscopy may confirm vesical or even ureteral involvement, and the lesions may exhibit catamenial enlargement, darkening, and bleeding. Endoscopy and biopsy, however, are often nondiagnostic (Stanley et al. 1965).
Symptomatic endometriosis of the bladder is usually a result of mural involvement, and the lesions are typically located on the trigone, the floor of the bladder, or low on the posterior wall (Stanley et al. 1965). Involvement is rarely confined to the lateral walls, the dome, or the ureterovesical junction. Gross examination typically reveals a solitary, blue, red, gray, or brown multicystic mass that thickens the wall and sometimes projects into the bladder lumen; the lesions have ranged from several millimeters to 14 cm in diameter. The mucosa is usually intact, but occasionally may be ulcerated and bleeding, particularly during menses. Histologic examination reveals fibrosis and proliferation of the muscularis around the foci of endometriosis; the lamina propria was also involved in 60% of the cases in one study (Stanley et al. 1965). Obstruction of both ureteric orifices, vesicocolic fistula, and malignant transformation have been rare complications.
On gross examination, endometriosis of the kidney is typically a solitary, well-circumscribed, hemorrhagic, solid and cystic mass that focally replaces the renal parenchyma; the lesions in the ten reported cases measured from 1.5 to 13 cm in diameter. In occasional cases, polypoid masses have projected into the renal pelvis. Foci of the smooth muscle have been found admixed with the endometriotic tissue on microscopic examination in some of the cases.
Only rare cases of urethral endometriosis have been described, usually involving a urethral diverticulum (Chowdhry et al. 2004).
The majority of the reported cases of cutaneous endometriosis have occurred within surgical scars (Chatterjee 1980; Horton et al. 2008; Kazakov et al. 2007; Minaglia et al. 2007; Steck and Helwig 1966) and rarely within needle tracts or associated with ventriculo- or lumboperitoneal shunts (Healey and McCluggage 2012); the remainder are spontaneous. Both types are associated with pelvic endometriosis in only a minority of cases (Chatterjee 1980; Steck and Helwig 1966). Because scar-related endometriosis typically occurs after operations on the uterus or fallopian tubes, the site most commonly involved is the lower abdominal wall; the umbilicus is involved less commonly. Similarly, most cases of endometriosis of the lower vagina, vulva, Bartholin’s gland, perineum, and perianal region involve areas of obstetric or surgical trauma, most commonly episiotomy scars (Chatterjee 1980; Gardner 1966; Paull and Tedeschi 1972; Steck and Helwig 1966). The overall frequency of post-Cesarean scar endometriosis was 0.08% in one study, and the authors hypothesized that an increased risk of incisional endometriomas may result from failure to close the parietal and visceral peritoneum with sutures (Minaglia et al. 2007). Scar-related cases occur less commonly after nongynecologic procedures, such as an appendectomy or inguinal hernia repair (Steck and Helwig 1966). Spontaneous cutaneous endometriosis typically involves the umbilicus and, less commonly, the inguinal and perianal regions (Steck and Helwig 1966).
The most common symptoms are those relating to a cutaneous mass or nodule that, in the scar-related cases, appears weeks to years following surgery (Horton et al. 2008; Steck and Helwig 1966); the average postoperative interval from the time of Cesarean section in the study cited above was 3.2 years (Minaglia et al. 2007). In a more recent study of 65 patients with abdominal wall endometriosis, the time from initial surgery (usually Cesarean section) to presentation ranged from 1 to 32 (median 7) years (Ecker et al. 2014). A catamenial increase in size and tenderness, and occasionally bleeding from the lesion, suggest the diagnosis. Patients with perianal lesions may have involvement of the external sphincter producing anorectal pain and irritation simulating an anal fistula, abscess, or thrombosed hemorrhoid. Umbilical endometriosis may simulate an umbilical hernia on physical examination. The lesions occasionally recur following excision; the recurrence rate of 445 cases of abdominal wall endometriosis after surgical excision was 4.3% (Horton et al. 2008).
The association of abdominal scar-related endometriosis and episiotomy scar-related endometriosis with uterine operations and episiotomies, respectively, suggests implantation of endometrial tissue as the most likely pathogenesis. The risk of implantation appears to be much higher after hysterotomy than after Cesarean section or vaginal delivery, suggesting that the decidua of late pregnancy has a reduced ability to implant. When curettage is performed immediately after vaginal term delivery, however, the frequency of endometriosis in the episiotomy scar becomes much higher (Paull and Tedeschi 1972). In nonpregnant patients, implantation of endometrium during endometrial curettage or spontaneous implantation of menstrual endometrium has also been implicated in occasional cases of scar-related endometriosis. Lymphatics have been demonstrated between the pelvis and umbilicus that may explain cases of spontaneous endometriosis in the latter site. Rare cases of clear cell carcinoma arising in abdominal scar-associated endometriosis have been reported (Shalin et al. 2012).
Noncutaneous, non-nodal inguinal endometriosis, secondary to involvement of the extraperitoneal portion of the round ligament, occurs in less than 1% of patients with endometriosis (Candiani et al. 1991). The usual presentation is that of a painful, typically right-sided, hernia-like inguinal mass, with catamenial exacerbation in some cases. In approximately one third of the reported cases, an inguinal hernia may also be present. The lesion can impinge on the pubic tubercle and mimic arthritis, bursitis, or tendinitis. Rarely, endometriosis in the inguinal region has also been described in inguinal or femoral hernia sacs or the canal of Nuck (Quagliarello et al. 1985). In the largest available series of inguinal endometriosis, the age range was 20–53 (mean 35) years, and the correct diagnosis was suspected preoperatively in 31% of patients; 5 of the 42 patients had a prior history of endometriosis (Mourra et al. 2015). No malignant transformation was found in any of the cases, and one patient developed a recurrence 3 years postoperatively. All four patients who underwent concurrent laparoscopy were found to have ovarian endometriomas. The authors noted that inguinal endometriosis was an incidental finding in 20% of cases and advocated histopathologic examination of hernia sac tissue in women (Mourra et al. 2015).
Endometriosis of the Lymph Nodes
Lymph node involvement by endometriosis is uncommon, and many examples reported as such, particularly in the older literature, are lymph nodes involved by benign müllerian (usually endosalpingiotic) glands devoid of an endometrial stromal component. The involved lymph nodes may be visibly or palpably enlarged at operation. On microscopic examination, in contrast to glandular inclusions, endometriotic foci are characterized by a more central location within the node, an endometrial stromal component, and the frequent presence of erythrocytes and pseudoxanthoma cells. Endosalpingiosis and endometriosis may coexist, however, in the same lymph node. As in other sites, decidual transformation of the endometriotic stroma has been encountered during pregnancy. One case of decidualized intranodal endometriosis has been reported in a postmenopausal woman on hormonal replacement therapy (Kim et al. 2015a). As previously noted, one case of intranodal endomyometriosis has been reported.
Pathologically documented cases of endometriosis involving the lungs or pleura are rare. Some reported examples interpreted as pulmonary endometriosis have taken the form of microscopic foci of “decidua” found at autopsy in pregnant or recently pregnant women. Most such lesions would likely be interpreted by current criteria as foci of embolic intermediate trophoblast, although one case of bona fide deciduosis of the lung has been documented (Flieder et al. 1998). Many cases of purported pleuropulmonary endometriosis have been diagnosed solely on the basis of clinical manifestations or in conjunction with nonspecific histologic or cytologic findings. Coverage here is based on the 38 pathologically documented cases of thoracic endometriosis in the literature, 21 of which were pleural and 17 of which were parenchymal (Flieder et al. 1998), and from a recent retrospective study of 18 patients with histologically confirmed, thoracic endometriosis-related pneumothorax (Ghigna et al. 2015).
The affected patients are usually in the reproductive age group, although rare patients are postmenopausal. The clinical manifestations of pleural endometriosis usually differ from those associated with parenchymal involvement. In the former, the characteristic presentation is one of recurrent catamenial shortness of breath related to catamenial pneumothorax, typically right-sided. In the aforementioned study, 18 (7.3%) of 246 women who underwent surgery for spontaneous pneumothorax were found to have thoracic endometriosis (Ghigna et al. 2015). Less common presentations include recurrent right-sided, typically hemorrhagic effusions, hemoptysis, or catamenial pain. Chest X-rays usually reveal a pneumothorax or, occasionally, a hemothorax, a pleural effusion, or a pleural lesion. Coexistent intra-abdominal endometriosis has been demonstrated in approximately one third of cases, although in another one third of cases, its presence or absence was not confirmed. In contrast, patients with parenchymal endometriosis typically present with catamenial hemoptysis or blood-tinged cough; other patients are asymptomatic and the lesion is an incidental radiographic finding. Chest X-ray typically shows a nodule, infiltrates, or opacification of an entire lobe (Flieder et al. 1998). Only one patient has had documented peritoneal endometriosis, although in most patients the peritoneum has not been visualized. The majority of patients with parenchymal endometriosis have had prior uterine operations.
Pleural endometriosis is almost invariably confined to the right side; one case with bilateral involvement has been reported. The lesions are typically multiple and dark red or blue nodules or cysts on the diaphragmatic pleura; parietal, visceral, and pericardial pleural surfaces are also affected less commonly. Associated pathologic changes have included diaphragmatic fenestrations in 50% of the cases and occasionally pleural blebs. In half of the pneumothorax-associated cases, the diaphragmatic and pleural lesions were composed of endometriotic stroma only, which was often scant, and recognition was facilitated by immunohistochemical staining for hormone receptors and CD10 (Ghigna et al. 2015). Parenchymal endometriotic lesions are typically solitary, tan to gray, focally hemorrhagic nodules or thin-walled cysts measuring up to 6 cm in diameter. Several lesions have been subpleural or have involved the bronchial walls and lumina. Parenchymal lesions lack the almost exclusively right-sided location of pleural endometriosis; one case had a bilateral miliary distribution. In additional contrast to pleural lesions, associated diaphragmatic fenestrations have not been described.
The clinicopathologic differences between pleural endometriosis and parenchymal endometriosis of the lung suggest that they differ in their histogenesis. The distribution of the parenchymal lesions and their strong association with prior uterine trauma strongly suggest an embolic origin. In contrast, most if not all pleural lesions are likely a result of passage of endometriotic tissue from the peritoneal cavity through diaphragmatic defects or diaphragmatic lymphatics, consistent with the right-sided predominance of both structures. The catamenial pneumothorax in these patients, and in those with catamenial pneumothorax unassociated with pleural endometriosis, may be related to the diaphragmatic defects that allow the passage of air from the peritoneal into the pleural cavity. The escape of air from defects in the visceral pleura produced by the endometriotic lesions or from preexistent blebs is another possible explanation for the pneumothorax in these patients. It has been suggested that prostaglandins produced by eutopic endometrium or endometriotic tissue at the time of the menses may predispose to alveolar rupture.
Soft Tissue and Skeletal Endometriosis
Rarely, typical endometriomas have occurred in skeletal muscle or deep soft tissues in distant sites. The presentation is usually that of a mass associated with catamenial pain, tenderness, and enlargement. The involved sites have included the trapezius, extensor carpi radialis, thumb, biceps femoris, thigh, and the knee. A unique endometrioma occurred in the breast of a patient with a 2-year history of catamenial bloody nipple discharge (Moloshok and Ivanko 1984). Rare pelvic endometriotic cysts have eroded lumbar vertebrae, causing catamenial lumbar pain.
Upper Abdominal Endometriosis
Endometriotic implants may occasionally occur on the omentum; omental endometriosis was only one eighth as common as omental endosalpingiosis in one study (Zinsser and Wheeler 1982). Rarely, endometriotic implants may involve the peritoneal surfaces of the liver or the diaphragm. As with pleural diaphragmatic involvement, implants on the peritoneal side of the diaphragm have occasionally been associated with diaphragmatic defects and catamenial pneumothorax. Rare endometriomas of the epigastrium, the tail of the pancreas, and the liver parenchyma have been reported.
Endometriosis of the Nervous System
Based on a recent comprehensive literature review of 378 cases of neural involvement in endometriosis, 97% involved the peripheral nervous system, most frequently the sacral plexus and sciatic nerve, of which the vast majority presented with catamenial sciatica (Siquara de Sousa et al. 2015). Some cases have been associated with a visible peritoneal evagination attached to the involved portion of the nerve (“pocket sign”). Thirteen cases of central nervous system involvement have been reported, most involving the conus medullaris or cauda equina, and associated with catamenial back pain or lower extremity weakness and paresthesia. Both patients with cerebral (frontal or parietal lobe) endometriomas and one patient with gait disturbance from cerebellar involvement presented with headache; one developed subarachnoid hemorrhage and the other a generalized seizure (Siquara de Sousa et al. 2015).
Endometriosis in Males
Rare examples of endometriosis have been described in men receiving long-term estrogen therapy for prostatic carcinoma. With the exception of one case involving the abdominal wall (Martin and Hauck 1985), the sites of involvement have been confined to the genitourinary tract, specifically the urinary bladder, prostate, and paratesticular region (Young and Scully 1986). The two paratesticular lesions were endomyometriotic in composition.
Neoplasms Arising from Endometriosis
One study evaluating consecutive cases of endometriosis found that a malignant tumor was associated with ovarian and pelvic endometriosis in 4% and 10% of cases, respectively (Stern et al. 2001). However, exact frequencies of malignancy arising from pelvic endometriosis in the general population are not known, as some tumors likely overgrow and obliterate the endometriotic foci from which they arose (Mostoufizadeh and Scully 1980). Coexistence of endometriosis and a müllerian-type tumor is not definitive evidence that the tumor has arisen from the endometriosis, unless merging of the two lesions is histologically identified. In most cases, the term “endometriosis-associated” tumor is preferable. For stage I epithelial ovarian cancers, up to 30% have associated ovarian endometriosis, with an even higher frequency for endometrioid and clear cell carcinomas. Studies to determine putative precursor lesions in such cases have shown that hyperplastic changes (“atypical endometriosis,” discussed above), similar to those that arise in eutopic endometrium, may occur in endometriotic lesions. Such morphologic findings may be observed in the setting of endogenous or exogenous estrogenic stimuli or tamoxifen therapy (see Fig. 46). Atypical ovarian endometriosis was found in approximately 60% of endometriosis-associated carcinomas, but in only 2% of cases of ovarian endometriosis not associated with carcinoma (Fukunaga et al. 1997). Some endometriotic lesions, including atypical endometriosis, and the synchronous carcinoma share similar molecular genetic alterations, including phosphatase and tensin homolog (PTEN), PIK3CA, and AT-rich interaction domain 1A (ARID1A) gene mutations, loss of heterozygosity (LOH), and overexpression of p53 (Akahane et al. 2007; Ayhan et al. 2012; Matsumoto et al. 2015; Sato et al. 2000). Of note, in a recent intriguing study, somatic mutations were detected in glandular epithelium from deep infiltrating endometriosis, without associated malignancy, in 19 of 24 (79%) cases, and of these, 5 harbored cancer driver mutations (including ARID1A, PIK3CA, KRAS, and PPP2R1A) (Anglesio et al. 2017).
Molecular alterations in endometriosis-associated neoplasms have been reviewed in detail elsewhere (Lu et al. 2015; Maeda and Shih 2013; Wei et al. 2011) and are briefly summarized here. Immunohistochemical loss of ARID1A, a tumor suppressor gene, has been identified in tumor cells and contiguous endometriotic epithelium in two thirds of ovarian endometrioid and clear cell carcinoma cases (Ayhan et al. 2012). In addition, ARID1A mutations have been identified in 46% and 30% of endometrioid and clear cell carcinomas, respectively, in correlation with loss of BAF250a expression (Wiegand et al. 2010). The latter finding was also demonstrated in clear cell carcinoma and adjacent atypical endometriosis, with concurrent upregulation of hepatocyte nuclear factor-1β and loss of estrogen and progesterone receptors (Kato et al. 2006; Xiao et al. 2012). Other stepwise changes that have been identified in endometriotic epithelium and contiguous clear cell carcinoma include overexpression of Skp2, a cell cycle regulator, and elevation of Ki67 proliferative index (Yamamoto et al. 2010). Stepwise decreases in levels of LINE-1 methylation, expression of DNA mismatch repair (MMR) proteins, and microsatellite instability have been observed in endometriosis and the associated ovarian carcinoma (Fuseya et al. 2012; Senthong et al. 2014). Furthermore, one study (Lu et al. 2012) has proposed that selective screening for Lynch syndrome may be justified, as loss of MMR protein expression was also found in 10% of patients with endometriosis-associated ovarian carcinomas. Mutations in exon 3 of the β-catenin (CTNNB1) gene have been found in 60% and 73% of ovarian endometrioid carcinomas and associated atypical endometriosis, respectively, whereas PIK3CA mutations were detected in approximately one third of ovarian endometrioid and clear cell carcinomas (Matsumoto et al. 2015).
From the foregoing, it is apparent that endometriosis-associated ovarian clear cell and endometrioid carcinoma share at least some molecular genetic alterations, but a mutually exclusive, histotype-specific genetic profile has not yet been elucidated. It has recently been proposed that ovarian endometrioid carcinoma may arise from a secretory cell precursor, whereas those of clear cell type may be derived from ciliated cells, based on highly differential tumor expression of secretory and ciliated cell markers, shared with eutopic and ectopic endometrium (Cochrane et al. 2017).
It has been shown that women with carcinomas arising in endometriosis tend to be younger (and premenopausal), obese, and have a history of unopposed estrogens, in comparison to women with uncomplicated endometriosis (Zanetta et al. 2000). Furthermore, endometriosis-associated tumors are more often lower grade and lower stage; some studies have demonstrated a better prognosis than similar tumors without associated endometriosis (Erzen et al. 2001), but others have found no significant survival difference independent of stage (Noli et al. 2013). Approximately 75% of tumors complicating endometriosis arise within the ovary. The most common extraovarian site is the rectovaginal septum; less frequent sites include the vagina, colon and rectum (Yantiss et al. 2000), urinary bladder, and other sites in the pelvis and abdomen. In some cases, there is a history of prolonged unopposed estrogen replacement therapy (Yantiss et al. 2000). As previously noted, hyperplastic and metaplastic changes within the endometriosis may precede or be found synchronously with the neoplasm. Tumors arising in endometriosis in unusual sites are more likely to be misdiagnosed than similar tumors arising in ovarian endometriosis, such as an endometrioid adenocarcinoma arising in colonic endometriosis being mistaken for a primary colonic adenocarcinoma (see below), an error that could result in inappropriate staging and treatment (Yantiss et al. 2000).
Peritoneal Endometrioid Lesions Other Than Endometriosis
Benign glands lined by endometrial epithelium (but lacking endometrial stroma) with the peritoneal distribution of endosalpingiosis occasionally occur (Lauchlan 1972); some may represent foci of endometriosis in which the stromal component has undergone atrophy. Benign endometrioid peritoneal “implants” lacking an endometrial stromal component have also been reported in association with an atypical proliferative/borderline ovarian endometrioid tumor (Russell 1979). The peritoneal lesions were interpreted as having arisen directly from the peritoneum.
A variety of extrauterine, extraovarian, pelvic, or retroperitoneal neoplasms of endometrioid type occur in the absence of demonstrable endometriosis. These tumors have generally been considered to arise directly from the mesothelium or submesothelial stroma, or possibly from foci of endometriosis that have been obliterated by the tumor. They have included endometrioid cystadenofibroma and cystadenocarcinoma, endometrioid stromal sarcoma, homologous and heterologous types of carcinosarcoma (malignant mixed Mullerian tumor), and Mullerian adenosarcoma.
Peritoneal Serous Lesions
Serous lesions of the peritoneum include those that are nonneoplastic (endosalpingiosis) and neoplastic, which are morphologically analogous to their ovarian counterparts.
Endosalpingiosis typically refers to the presence of benign glands lined by tubal-type epithelium involving the peritoneum and subperitoneal tissues; the term may also be used to refer to similar glands within retroperitoneal lymph nodes (see section “Benign Intranodal Glands of Müllerian Type”). This disorder occurs almost exclusively in females, typically during their reproductive years, with a mean age of 29.7 years in one study (Zinsser and Wheeler 1982), although occasional cases have been described in postmenopausal women. Endosalpingiosis is almost always an incidental finding at either the time of operation or more commonly on microscopic examination. In a retrospective study, endosalpingiosis was found in 12.5% of surgically removed omenta, but this figure doubled when omenta were examined more thoroughly in a prospective study by these same investigators (Zinsser and Wheeler 1982). Endosalpingiosis may be detected as multiple fine pelvic calcifications on X-ray examination or as psammoma bodies within cul-de-sac fluid, peritoneal washings (Sidaway and Silverberg 1987), the lumen of the fallopian tube, or cervical Papanicolaou smears (Kern 1991).
An origin from the secondary müllerian system is favored by most investigators, but the association of endosalpingiosis with chronic salpingitis implicates implantation of sloughed tubal epithelium as a possible histogenetic mechanism in some cases (Zinsser and Wheeler 1982). A similar association with serous atypical proliferative/borderline tumors suggests that some endosalpingiotic foci may represent tumor implants that have undergone maturation (Vang et al. 2013). Intralymphatic spread of tubal epithelial cells has also been proposed (Russell et al. 2016). Endosalpingiosis in the absence of residual tumor at the time of second-look laparotomy in patients with ovarian epithelial neoplasms does not justify additional treatment (Copeland et al. 1988).
The term atypical endosalpingiosis has been applied to endosalpingiotic lesions in which there is cellular stratification, including cellular buds, cribriform patterns, and varying degrees of cellular atypia, occurring in the absence of a serous atypical proliferative/borderline tumor (SBT). Such lesions may also merge histologically with peritoneal SBT (see next section). Bell and Scully (1990) use the latter term if the “lesions composed of tubal-type epithelium exhibit papillarity, tufting, or detachment of cell clusters.. .. even when they arise on a background of endosalpingiosis.” Endosalpingiotic glands should be differentiated from mesonephric remnants, which are common incidental microscopic findings in the region of the fallopian tube. Mesonephric tubules are typically located more deeply than endosalpingiosis and characteristically have a collar of smooth muscle under the epithelial lining, which is typically a single layer of nonciliated, low columnar to cuboidal cells. Rare extraovarian atypical proliferative/borderline and malignant serous tumors have been shown to arise from endosalpingiosis (Carrick et al. 2003; McCoubrey et al. 2005).
Peritoneal Serous Tumors
The full spectrum of serous neoplasms arising within the ovary may also arise directly from the extraovarian peritoneum. These tumors are considered only briefly here because their clinicopathologic features closely resemble those of their tubal and ovarian counterparts. Primary peritoneal serous atypical proliferative/borderline tumors are usually associated with widespread extraovarian peritoneal involvement and normal-sized ovaries that are free of disease or which have only very minimal surface involvement (Bell and Scully 1990; Biscotti and Hart 1992). The most common presenting features in patients with these tumors, who are typically under the age of 35 years (range, 16–67), are infertility and chronic pelvic or abdominal pain. Many cases, however, are discovered incidentally at laparotomy for other conditions. At operation, focal or diffuse miliary granules, fibrous adhesions, or both involve the pelvic peritoneum and omentum and, less commonly, the abdominal peritoneum. Microscopic examination reveals superficial tumor that resembles noninvasive epithelial or desmoplastic implants of borderline serous tumors of ovarian origin. Coexistent endosalpingiosis has been found in 85% of cases. The prognosis of peritoneal serous atypical proliferative/borderline tumors is favorable; approximately 85% of patients have had no clinically persistent or progressive disease on follow-up. In rare cases, transformation to an invasive low-grade peritoneal serous carcinoma (LGPSC) may occur, although, in a proportion of these, the invasive tumor may have been present but not sampled at the time of the initial operation.
Typical peritoneal serous carcinomas have high-grade nuclear features (Ben-Baruch et al. 1996; Truong et al. 1990) with an intraoperative appearance that of widespread peritoneal tumor associated with ovaries of normal size, mimicking a diffuse malignant mesothelioma or peritoneal carcinomatosis associated with an unknown primary tumor. In some series, the patients have had an average age that is a decade older than patients with similar tumors of ovarian origin. Some tumors have occurred in women who had had bilateral oophorectomy performed as prophylactic treatment for BRCA-related familial ovarian cancer (Casey et al. 2005).The risk of peritoneal serous carcinoma in BRCA1 mutation carriers is about 4% at 20 years after prophylactic salpingo-oophorectomy (Casey et al. 2005; Finch et al. 2006).
Rare extraovarian serous tumors take the form of localized, typically cystic masses, usually within the broad ligament and less commonly within the retroperitoneum. Serous papillary cystadenomas and adenofibromas, serous atypical proliferative/borderline tumors, and serous carcinomas have been described in these sites (Aslani et al. 1988; Aslani and Scully 1989; Ulbright et al. 1983).
Endocervicosis (Including Müllerianosis)
Extraovarian Mucinous Tumors
Peritoneal Transitional, Squamous, Clear Cell, and Non-Epithelial Lesions
Peritoneal Decidual Reaction
Clinical and Operative Findings
An ectopic decidual reaction similar to that seen in the lamina propria of the fallopian tube, cervix, and vagina may also be seen within the submesothelial stroma of the peritoneal cavity. Frequent sites of ectopic decidua include the submesothelial stroma of the fallopian tubes, uterus and uterine ligaments, appendix and omentum, and within pelvic adhesions. Rare sites have included the serosal surfaces of the diaphragm, liver, spleen, and renal pelvis.
Submesothelial decidua is typically an incidental microscopic finding, but florid lesions may be visible at the time of Cesarean section or postpartum tubal ligation as multiple, gray to white, focally hemorrhagic nodules or plaques studding the peritoneal surfaces and simulating metastatic malignancy (Adhikari and Shen 2013). Several cases have been associated with massive, occasionally fatal, intraperitoneal hemorrhage during the third trimester, labor, or the puerperium. Appendiceal deciduosis may also mimic acute appendicitis during pregnancy (Chai and Wijesuriya 2016). Other rare clinical presentations include hydronephrosis and hematuria secondary to renal pelvic involvement.
Diffuse Peritoneal Leiomyomatosis
Diffuse peritoneal leiomyomatosis is a rare disorder characterized by the presence of multiple submesothelial nodules of cytologically benign smooth muscle, frequently associated with uterine leiomyomas and, rarely, ovarian leiomyomas. The nodules are generally considered to arise from multipotential submesothelial mesenchymal cells. This disorder is discussed elsewhere (see chapter “Mesenchymal Tumors of the Uterus”).
Benign Intranodal Glands of Müllerian Type
Benign glands of müllerian type are most commonly encountered within the pelvic and para-aortic lymph nodes of females (Horn and Bilek 1995; Kheir et al. 1981) and less often in inguinal and femoral lymph nodes. Because these glands are almost always incidental microscopic findings in lymph nodes removed in cases of pelvic carcinoma, their reported frequency, which has varied from 2% to 41%, depends on the number of lymph nodes removed and the extent of the histologic sampling. Almost all the patients have been adults, although rare examples have been reported in children. In males, the presence of similar glands has been recorded rarely within lymph nodes in the pelvis, abdomen, and mediastinum (Gallan and Antic 2016). Although typically without clinical or intraoperative manifestations, rare examples of lymph nodes containing müllerian-type glands have been associated with a false-positive lymphangiogram, ureteral obstruction secondary to lymph node enlargement, or visible enlargement at the time of operation.
In a number of patients, intranodal glandular inclusions have been accompanied by endosalpingiosis of the peritoneum, salpingitis isthmica nodosa, or acute and chronic salpingitis (Kheir et al. 1981). Other patients have had coexistent ovarian serous tumors, which have been benign, atypical proliferative/borderline tumors, or carcinomas (Prade et al. 1995).
Examples of intranodal glandular inclusions lined by benign endometrioid epithelium, mucinous epithelium of endocervical or goblet cell type, or metaplastic squamous epithelium have been reported (Lauchlan 1972; Mills 1983).
In most cases the distinction between glandular inclusions and metastatic adenocarcinoma is not difficult unless a primary ovarian serous atypical proliferative/borderline tumor is present, in which case the distinction may be difficult or impossible. Features favoring a benign diagnosis include a capsular or interfollicular location of the glands, lining cells of multiple types including ciliated forms, a lack of significant cellular atypia and mitotic activity, and an absence of a desmoplastic stromal reaction. Complicating the differential diagnosis is the very rare development of atypical proliferative/borderline or frankly malignant change in müllerian glandular inclusions in the lymph nodes. This diagnosis is suggested in cases in which the intranodal neoplasm merges with the foci of atypical endosalpingiosis. Awareness that estrogen receptor-positive endosalpingiosis can occur in axillary lymph nodes will avoid the potential misdiagnosis of metastatic breast carcinoma (Corben et al. 2010). Positivity for PAX8, WT-1, and hormone receptors has also been demonstrated in rare cases of nodal endosalpingiosis identified in men who underwent pelvic lymphadenectomy for prostatic or urothelial carcinoma (Gallan and Antic 2016). Intranodal nests of benign squamous epithelium should not be mistaken for metastatic squamous cell carcinoma. Features favoring a benign diagnosis include bland cytologic features, lack of mitotic activity, and, in some cases, an origin within benign glands.
Intranodal Ectopic Decidua
- Attanoos RL, Griffin A, Gibbs AR (2003) The use of immunohistochemistry in distinguishing reactive from neoplastic mesothelium. A novel use for desmin and comparative evaluation with epithelial membrane antigen, p53, platelet-derived growth factor-receptor, P-glycoprotein and bcl-2. Histopathology 43:231–238PubMedCrossRefPubMedCentralGoogle Scholar
- Ayhan A, Mao T, Tamer S et al (2012) Loss of ARID1A expression is an early molecular event in tumor progression from ovarian endometriotic cyst to clear cell and endometrioid carcinoma. Mod Pathol 22:1310–1315Google Scholar
- Bransilver BR, Ferenczy A, Richart RM (1974) Brenner tumors and Walthard cell nests. Arch Pathol Lab Med 98:76–86Google Scholar
- Ceruto CA, Brun EA, Chang D et al (2006) Prognostic significance of histomorphologic parameters in diffuse malignant peritoneal mesothelioma. Arch Pathol Lab Med 130:1653–1661Google Scholar
- Chang S, Oh MH, Ji SY et al (2014) Practical utility of insulin-like growth factor II mRNA-binding protein 3, glucose transporter 1, and epithelial membrane antigen for distinguishing malignant mesotheliomas from benign mesothelial proliferations. Pathol Int 64:607–612PubMedPubMedCentralGoogle Scholar
- Chapel DB, Husain AN, Krausz T et al (2017) PAX8 expression in a subset of malignant peritoneal mesotheliomas and benign mesothelium has diagnostic implications in the differential diagnosis of ovarian serous carcinoma. Am J Surg Pathol 41:1675–1682. [Epub ahead of print]PubMedCrossRefPubMedCentralGoogle Scholar
- Churg A, Cagle PT, Roggli VL (2006) Tumors of the serosal membranes, Atlas of tumor pathology, ser IV. Armed Forces Institute of Pathology, Washington, DCGoogle Scholar
- Comin CE, Saieva C, Messerini (2007) h-caldesmon, calretinin, estrogen receptor, and Ber-EP4: a useful combination of immunohistochemical markers for differentiating epithelioid peritoneal mesothelioma from serous papillary carcinoma of the ovary. Am J Surg Pathol 31:1139–1148PubMedCrossRefGoogle Scholar
- Elmore LW, Sherman ME, Seidman JD et al (2000) p53 expression and mutational status of primary peritoneal micropapillary serous carcinoma (abstract). Mod Pathol 13:124AGoogle Scholar
- Goldblum J, Hart WR (1995) Localized and diffuse mesotheliomas of the genital tract and peritoneum in women. A clinicopathological study of nineteen true mesothelial neoplasms, other than adenomatoid tumors, multicystic mesotheliomas and localized fibrous tumors. Am J Surg Pathol 19:1124–1137PubMedCrossRefGoogle Scholar
- Kawai T, Tominaga S, Hiroi S et al (2016) Peritoneal malignant mesothelioma (PMM), and primary peritoneal serous carcinoma (PPSC) and reactive mesothelial hyperplasia (RMH) of the peritoneum. Immunohistochemical and fluorescence in situ hybridization (FISH) analyses. J Clin Pathol 69:706–712PubMedCrossRefGoogle Scholar
- Kazakov DV, Ondic O, Zamecnik M et al (2007) Morphological variations of scar-related and spontaneous endometriosis of the skin and superficial soft tissue: a study of 71 cases with emphasis on atypical features and types of müllerian differentiations. J Am Acad Dermatol 57:134–146PubMedCrossRefGoogle Scholar
- McCluggage WG, Oliva E, Herrington CS et al (2003) CD10 and calretinin staining of endocervical glandular lesions, endocervical stroma and endometrioid adenocarcinomas of the uterine corpus: CD10 positivity is characteristic of, but not specific for, mesonephric lesions and is not specific for endometrial stroma. Histopathology 43:144–150PubMedCrossRefGoogle Scholar
- Michal M, Kazakov DV, Dundr P et al (2016) Histiocytosis with raisinoid nuclei: a unifying concept for lesions reported under different names as nodular mesothelial/histiocytic hyperplasia, mesothelial/monocytic incidental cardiac excrescence, intralymphatic histiocytosis, and others. A report of 50 cases. Am J Surg Pathol 40:1507–1516PubMedCrossRefPubMedCentralGoogle Scholar
- Muneyyirci-Delale O, Neil G, Serur E et al (1998) Endometriosis with massive ascites. Obstet Gynecol 69:42–46Google Scholar
- Nisenblat V, Bossuyt PM, Shaikh R et al (2016) Blood biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev 5:CD012179Google Scholar
- Sato N, Tsunoda H, Nishida M et al (2000) Loss of heterozygosity on 10q.23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cysts of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res 60:7052–7056PubMedPubMedCentralGoogle Scholar
- Seidman JD, Zhao P, Yemelyanova A (2011) “Primary peritoneal” high-grade serous carcinoma is very likely metastatic from serous tubal intraepithelial carcinoma: assessing the new paradigm of ovarian and pelvic serous carcinogenesis and its implications for screening for ovarian cancer. Gynecol Oncol 120:470–473PubMedCrossRefGoogle Scholar