The peritoneum is involved in a number of disorders that originate in the female genital tract that emerge from müllerian remnants and signify primary disorders that may mimic or even overlap with gynecologic abnormalities. Endometriosis is a mysterious disorder that can be found throughout the pelvis and beyond, and manifests in young adults as an array of nondescript changes on or near the peritoneal surface. Other müllerian rests such as endosalpingiosis and endocervicosis can be found in the submesothelial mesenchyme, and endosalpingiosis has a unique relationship to extragenital serous neoplasia. A curious overlap can be seen between these phenomena and mesothelial proliferations although the major issue for the pathologist is distinguishing them. An array of rare soft tissue or “round blue cell” tumors can manifest in the peritoneal or retroperitoneal space and, although not technically “peritoneal” in origin, they must be both distinguished from metastatic gynecologic neoplasia and assessed with a broad differential diagnosis.
Keywordsendosalpingiosis, endometriosis, endocervicosis, mesothelioma, psammocarcinoma, PEComa, gastrointestinal stromal tumor (GIST)
The practice of gynecologic pathology often entails the evaluation of abnormalities in the peritoneal cavity and determination of their relationship to the reproductive tract. This exercise requires that the pathologist distinguish which peritoneal disorders are müllerian derived versus originating from other organs. Diseases affecting the peritoneal cavity and the intra-abdominal organs include entities arising from elements native to the peritoneal cavity (secondary müllerian system, mesenchymal, and mesothelial proliferations), as well as neoplastic and non-neoplastic entities of metastatic nature, or controversial/uncertain origin. Most of these diseases affect males and females; however, this book emphasizes the disorders that occur mainly in women.
Müllerian-Derived Lesions of the Peritoneum
Ectopic Decidua (Deciduosis)
The presence of ectopic decidua in the peritoneal cavity is a relatively common finding in pregnant females, seen in up to 97% of pregnant women and focally involving the omentum in one series. It appears to be associated with a physiologic metaplastic response of the subcoelomic mesenchymal cells to the elevated levels of circulating progesterone hormone during pregnancy. Another possible explanation is that the systemic hormonal response affects preexisting foci of endometriosis and that the ectopic endometrial tissue shows an analogous response to that seen in the uterine endometrium. It usually involutes within 4 to 6 weeks postpartum.
Its occurrence in nonpregnant women is a rare event, and this diagnosis should trigger an active search for a source of hormone production, such as exogenous administration of progesterone or a hormone-producing tumor. In this setting, this benign reaction is best regarded as “pseudodecidualized” tissue.
Ectopic decidual tissue typically occurs on the surface of the pelvic organs, such as the ovarian or tubal serosal surfaces. However, involvement of the peritoneum, serosa of the gastrointestinal tract, omentum, and mesentery may also be seen. In most cases, it is an incidental finding, usually discovered during cesarean section or during another intra-abdominal operation. However, ectopic deciduosis may occasionally simulate acute abdominal emergencies, such as acute appendicitis, or may cause intra-abdominal bleeding.
Although usually a microscopic finding, if grossly evident, ectopic decidua typically appears as white, yellowish, or red small nodules located on the serosal surfaces of abdominal organs and peritoneum. Microscopically, decidua shows features similar to decidualized endometrial stroma, being composed of a well-defined collection of bland-appearing large polygonal cells with distinct cell borders, round, centrally placed nuclei, small nucleoli, and abundant eosinophilic cytoplasm ( Fig. 23.1A ).
Immunohistochemistry and Differential Diagnosis
Immunoperoxidase studies are not necessary to make the diagnosis of deciduosis. However, the main differential diagnosis is malignant mesothelioma with deciduoid features (see Fig. 23.1B ). Although the latter entity is malignant, it may show bland cytologic characteristics, closely resembling ectopic decidualized tissue. The presence of areas of the tumor showing nuclear pleomorphism and mitotic activity helps in its distinction from ectopic decidua. Moreover, the neoplastic cells in mesothelioma are positive for keratins, calretinin, and WT-1. A more detailed immunoprofile of mesothelial proliferations is discussed later in the chapter.
The clinical setting of the development of deciduoid mesothelioma is controversial; although the initial descriptions regard this malignant neoplasm as a disease of young women with no history of asbestos exposure, other authors believe that the epidemiology of this tumor follows that of conventional epithelioid mesothelioma; namely, it is a disease of older male adults.
Treatment and Prognosis
The prognosis is excellent for cases of ectopic decidua not complicated by bleeding. Surgical ablation suffices the treatment requirements. The potential for recurrence of this condition is unknown, but presumably it may recur during subsequent pregnancies.
Endosalpingiosis is defined by the presence of foci of epithelium resembling fallopian tube lining outside this anatomic location. It affects approximately 7% of the female population in the reproductive age.
Although some authors believe that endosalpingiosis may be a source of abdominal pain, it is more often an incidental finding during abdominal surgery and is frequently seen in association with other pelvic pathologic findings, such as endometriosis, leiomyomata, hydrosalpinx, and ovarian neoplasms.
Macroscopic evidence of endosalpingiosis is rarely seen involving the peritoneum, omentum, retroperitoneal and abdominal lymph nodes, wall of abdominal organs, and on the surface of pelvic organs. Most commonly, endosalpingiosis is a microscopic finding, consisting of glandular and tubular structures lined by low cuboidal ciliated epithelium ( Fig. 23.2A ).
Endosalpingiosis, as well as normal fallopian tube epithelium, stains strongly with PAX8, phospho-SMAD2, BCL2, and FOXJ1.
No endometrial stromal cells, hemosiderin deposition, or desmoplastic tissue reaction is present in association with these nests. Although these findings may raise the concern of metastasis, especially when present in a lymph node, the appearances are bland, with no mitotic figures or necrosis (see Fig. 23.2B ). Endosalpingiosis can vary in complexity (see Fig. 23.2C ) and rarely may assume a florid appearance with large cystic spaces that may mimic metastatic carcinoma.
Treatment and Prognosis
Endosalpingiosis is typically sampled during procedures for other disorders, including malignancy. Other than the fact that this entity appears to have increased in frequency in association with low-grade serous tumors, it is of no clinical consequence.
Endocervicosis is defined by the presence of ectopic endocervical-like glands (i.e., glands lined by columnar cells with mucinous cytoplasm akin to that seen in the endocervix). This condition is encountered in females of reproductive age. Although endocervicosis likely results from a metaplastic process, lesions have been repeatedly associated with a history of cesarean section, raising the possibility of implantation as an etiologic mechanism.
Endocervicosis most commonly affects the urinary bladder. Most patients present with urinary symptoms such as pain, dysuria, frequency, and hematuria, clinically mimicking a urinary bladder neoplasm or infection. Rare cases of endocervicosis have also been described in the uterine cervix, axillary lymph nodes, rectum, vagina, and small intestine. Although the condition is generally considered benign, there have been two case reports of adenocarcinoma arising in association with endocervicosis.
Endocervicosis may form large masses, measuring up to 5 cm, and thus may mimic a neoplasm. The tumor-like prominence is usually located in the posterior bladder wall or dome and may project into the bladder cavity. Microscopically, endocervical-like glands, some of which show cystic dilation, characterize this entity. The cells are columnar in appearance with evidence of mucin production (see Fig. 23.2D ). Mild atypia, as well as cilia, may be seen. In most cases, ruptured glands with extravasation of mucin into the surrounding stroma, eliciting a stromal reaction, are present. Mitoses are rare, if present at all.
The major differential diagnosis is with metastatic well-differentiated adenocarcinoma or a component of pseudomyxoma peritonei (PP), due particularly to the prominent admixture of glands and stroma. However, appreciable atypia is not present, nor is there extravasated mucin.
Treatment and Prognosis
The prognosis is excellent, and surgical excision should be curative.
Endometriosis is one of the most common gynecologic diseases, affecting 6% to 10% of American women. In patients being treated for infertility, endometriosis is much more common and can be encountered in up to 60% of cases. It is classically defined by the presence of endometrial-like epithelium and stroma outside the endometrial cavity. However, endometrial stroma may also be present in the absence of glands—so-called stromal endometriosis—which accounts for approximately 6% of cases of endometriosis.
Although endometriosis is typically seen in reproductive-age females, it has been documented across the life course, including in premenarcheal adolescents. Furthermore, approximately 70% of adolescents with pelvic pain unresponsive to medical therapy may have endometriosis; however, conservative management therapies in this age group may ultimately delay definitive diagnosis.
Most cases of endometriosis involve the pelvic organs and are associated with chronic pelvic pain (not related with the menstrual cycle), dyspareunia, dysmenorrhea, and infertility (i.e., ovarian endometriosis). When affecting peritoneal-lined organs, females with endometriosis may be asymptomatic or present with chronic, vague abdominal pain. Diagnosis depends on identification of endometriotic lesions by laparoscopy or laparotomy, with confirmatory biopsy.
Macroscopically, endometriosis might present as small dark red, black, or bluish cysts or nodules on the surface of peritoneal and pelvic organs ( Fig. 23.3A ); occasionally, the focus of endometriosis may appear whitish and be associated with adhesions. In cases of extensive involvement of the ovary, bleeding may lead to the formation a cystic mass, or endometrioma.
Histologically, endometriosis is characterized by the following:
The presence of ectopic endometrial-like glands (i.e., pseudostratified columnar glandular epithelium), which may show similar alterations when compared with the glands topically located in the uterine cavity
Spindled endometrial stroma
Hemosiderin deposition either within macrophages or in the stroma (see Fig. 23.3B )
In many instances, the classic diagnostic triad of these components is not present or the endometrial glands and stroma may be obscured by hemorrhage, foamy cells, and hemosiderin-laden macrophages such that the diagnosis may be suggested but histologic confirmation may not be possible. In other cases, endometrial stroma may be present in isolation, with no associated endometrial-like glands (“stromal endometriosis”). In some instances, the glands may be situated adjacent to other visceral structures, such as bowel mucosa (see Fig. 23.3C ). Marked (pseudo)decidual changes may obscure endometriosis during pregnancy or hormonal therapy (see Fig. 23.3D ). Histologic features described in association with stromal endometriosis include reactive mesothelial proliferation ( Fig. 23.4A and B ), inflammation, giant cell or granulomata, and myxoid changes.
Superficial Versus Deep Endometriosis
Endometriosis can be considered superficial if endometriotic foci are located less than 5 mm from the peritoneal surface. However, if the foci extend deeper than 5 mm from the surface, it can be considered deeply infiltrating. Awareness of this distinction is important, because deeply infiltrating foci of endometriosis may simulate a neoplasm, may be missed during surgical exploration, or may be incompletely excised, giving rise to possible recurrent disease. Abdominal wall endometriosis, for example, may present as a painful mass associated with a scar (e.g., cesarean section, hysterectomy scar).
Adolescent Versus Adult Endometriosis
There is growing evidence that endometriosis in adolescents differs from that seen in adulthood. Adolescent lesions tend to be subtle and transient. Laparoscopically, they frequently appear clear, red, white, or yellow-brown rather than having the classic black/blue “powder-burn” lesions that may be seen in adult endometriosis ( Fig. 23.5 ). Moreover, the histologic features of such biopsies may appear non-descript, consisting of fibrosis, calcification, or macrophages rather than endometrial glands and/or stroma as might be encountered in adults.
Complications of Endometriosis
Marked mesothelial proliferations (see Fig. 23.4A and B ) can be associated with this disorder and mimic neoplasia.
Mucinous metaplasia (see Fig. 23.4C ) may well signify a clonal process, but if it is not accompanied by complexity of growth, it is presumed benign.
Epithelial atypia (see Fig. 23.4D ) can also be found. The presence of atypia in foci of endometriosis have been associated with aneuploid DNA content and, because it has been seen in association with malignancy arising in endometriosis, some authors think nuclear atypia represents a possible precursor lesion of carcinoma. However, like mucinous metaplasia, if the atypia is not accompanied by architectural complexity (cribriforming, papillary structures), it is not considered a threat to the patient. The atypical cells have enlarged nuclei with smudgy chromatin and abundant vacuolated to eosinophilic cytoplasm. Hobnail cells with enlarged nuclei with prominent nucleoli should raise the possibility of malignancy (clear cell/papillary serous differentiation); in the latter instances, the presence of diffuse nuclear reactivity for p53 would support a neoplastic process.
The pathogenesis of endometriosis is unclear and a matter of much debate. The most accepted theory is that viable endometrial cells gain access to the peritoneum via retrograde flow through fallopian tubes during menstruation and attach to the peritoneal surface of pelvic and abdominal organs with the aid of adhesion molecules. Other theories include the possibility that endometriosis arises from metaplastic changes of the peritoneum and of the surface epithelial cells of the ovary. In addition, some authors suggest that cells composing superficial and deeply infiltrating endometriosis are distinct and are dependent on different sources of nutrition. It is suggested that superficial endometriosis would be regulated and supported by the microenvironment created by the peritoneal fluid, whereas deeply infiltrating endometriosis would be more dependent on the blood flow to the involved organ.
Treatment and Prognosis
Treatment of endometriosis, including medical or surgical therapies, is highly dependent on the presence of symptoms, being reserved mainly for symptomatic patients and those with extensive disease. Surgical options include laser coagulation and resection. Medical interventions include the use of drugs that function as estrogen antagonists, such as oral contraceptives, progesterone, danazol, and gonadotropin-releasing hormone (GnRH) agonists. Other newer approaches, such as progesterone receptor modulators, GnRH antagonists, aromatase inhibitors, tumor necrosis factor-alpha inhibitors, angiogenesis inhibitors, matrix metalloproteinase inhibitors, and estrogen receptor β-agonists are under investigation.
The prognosis is variable and related to the extent of involvement of the ovaries and peritoneal cavity by endometriosis and the depth of infiltration. Recurrence may be seen, especially in cases initially associated with extensive peritoneal or ovarian involvement or deeply infiltrating disease. In vitro fertilization may be necessary to overcome infertility associated with extensive endometriosis.
Polypoid endometriosis is a variant of endometriosis that has a tendency to mimic a neoplasm clinically, surgically, and by pathologic examination. The lesions tend to grow as polypoid masses: hence the term polypoid endometriosis , with only a subset of examples showing histologic features of polyps (i.e., prominent thick-walled vessels, fibrous stroma, irregularly spaced and cystic glands). From a historical perspective, the term polypoid endometriosis was first used by Mostoufizadeh and Scully in their description of a variant of endometriosis that shared histologic features with endometrial polyps. Since their original description, there have been only a handful of case reports, with the largest series on the subject reported by Parker et al.
In a series of 24 women, patients’ ages ranged from 23 to 78 years old (median age of 55 years old) with 60% of the patients being older than 50 years old. Slightly fewer than half of the patients were taking exogenous hormones, possibly a contributing factor to the occurrence of endometriosis in older (peri- and postmenopausal) women. Patients most commonly present with symptoms related either to a pelvic mass, vaginal mass (with associated bleeding), or large intestine obstruction. Practically any site of the abdominal cavity may be affected, with involvement of the colon, pelvic structures, vaginal mucosa, omentum, and retroperitoneum having been described in descending order of frequency. In approximately one-third of the cases, multiple sites are affected.
On gross examination, lesions may be of varying size, ranging from 0.4 to 14 cm in maximal dimension. They tend to appear as tan/brown, white/gray, or pink/red polypoid masses involving mucosal or serosal surfaces or within an endometriotic cyst ( Fig. 23.6A, C ).
Histologically, the lesions are composed of an admixture of endometriotic glands and stroma, of which the former may show varying degrees of proliferation and metaplastic change (see Fig. 23.6B and D ), including tubal, mucinous, squamous, and papillary syncytial metaplasia. The stroma typically resembles proliferative phase endometrial stroma without stromal cytologic atypia. In the majority of the cases, stromal fibrosis and numerous thick-walled vessels are present, similar to that seen in endometrial polyps. In some, a discrete endometrial polyp is present (see Fig. 23.6C and D ).
The principal differential diagnostic considerations include the distinction of polypoid endometriosis from müllerian adenosarcoma, particularly because the latter can arise from peritoneal endometriosis ( Fig. 23.7 ). Müllerian adenosarcoma can be distinguished from polypoid endometriosis by (1) the presence of stromal papillae and frondlike proliferations that project into glandular or cystic spaces, (2) mild stromal atypia (at least), and (3) periglandular cellular stromal cuffing. Also within the differential diagnosis is endometrial stromal sarcoma (ESS) with glandular differentiation, which can be distinguished from polypoid endometriosis by (1) its characteristic finger-like permeative growth pattern, (2) its propensity for lymphatic/vascular invasion, and (3) its focal presence of usually only endometrioid-type glands.
Treatment and Prognosis
Polypoid endometriosis is benign. In the series by Parker et al., follow-up in 17 (of 24) patients showed that 15 patients were alive without evidence of disease (the range of follow-up was 1 to 20 years with mean of 5.9), one patient was alive with endometriosis at 18 months, and one patient had died of unrelated causes. Similar to typical endometriosis, malignant transformation may potentially occur, with epithelial, mesenchymal, and mixed epithelial-mesenchymal tumors arising out of this lesion. Rarely, polypoid endometriosis can be the source of a well-differentiated endometrioid carcinoma, analogous to that seen in the endometrium ( Fig. 23.8 ).
Adenocarcinoma Arising in Endometriosis
Adenocarcinoma arising in the setting of ovarian endometriosis is seen in pre- or postmenopausal women and is not associated with hormone replacement therapy (HRT), whereas extraovarian adenocarcinoma arising in association with endometriosis tends to occur in postmenopausal females and has a stronger correlation with HRT. The most common histologic subtypes of adenocarcinoma encountered in these patients are endometrioid and clear cell, which account for 90% of the cancers ( Fig. 23.9 ). Similarly, cases of extrauterine ESS arising from endometriotic foci have been reported and show the typical permeative growth pattern and cytomorphologic features of those tumors that arise within the uterus.
There is little argument that extraovarian müllerian serous tumors can arise in the peritoneal cavity. Whether the origin is endometriosis or endosalpingiosis is unclear, inasmuch as it is virtually impossible to document the source, save for the occasional tumor arising in endometriosis. The rather high frequency of concurrent primary serous tumors and endosalpingiosis raises the possibility that the latter predisposes to these lesions. As discussed in later chapters, the absolute percentage of high-grade pelvic serous tumors that can be attributed to the peritoneum is unclear; the fallopian tube has been implicated in the origin of up to 45% of these tumors, including those previously assumed to be peritoneal in origin. The link between a potential extraovarian or extratubal origin for lower-grade serous tumors is more compelling, given the weak connection with the distal tube and the fact that many of these tumors do not have an obvious source in the ovarian cortex or surface epithelium. However, it is still conceivable that most of these tumors are derived from epithelium that originated in the tube, albeit present in the submesothelial mesenchyme at the time of neoplastic transformation. Whether these tumors arise directly from a “müllerianized mesothelium” is virtually impossible to either prove or refute. Thus the term primary peritoneal should not be assumed to connote an origin in mesothelium (as opposed to müllerian epithelium) per se until there is more evidence to support this.
Primary peritoneal papillary serous tumors include borderline or serous tumors of low malignant potential, as well as low- and high-grade papillary serous adenocarcinomas. Similar to the ovarian and tubal serous tumors, the borderline serous tumors afflict a younger group with a median age of 30 years old at diagnosis, whereas most patients diagnosed with papillary serous adenocarcinoma are peri- or postmenopausal, with a median age of 60 years old. Jordan et al. showed women diagnosed with primary peritoneal serous carcinoma to be significantly older than those with papillary serous carcinoma of the ovary. They found that ovarian and tubal serous carcinomas had similar patient profiles; and in contrast, patients with peritoneal carcinoma were more likely to be obese and parity increased risk. However, the expression profiles are similar albeit with differences in frequency of loss of heterozygosity (LOH) at different chromosomal loci.
Interestingly, the reported incidence of primary papillary serous carcinoma has shown a significant increase since the late 1990s, with a most accentuated elevation (more than 13% per year) in non-Hispanic and white females. The reason for this purported increase is uncertain. It is possible that this is an artifact of tumor classification (ovary vs. tube vs. peritoneal), but given the lack of knowledge about this subset of tumors, it bears further investigation.
The clinical presentation of all the primary peritoneal müllerian neoplasms is quite similar and usually characterized by symptoms related to large, frequently cystic abdominal and pelvic masses that may show involvement of multiple organs at time of diagnosis. Pain, abdominal distention, and intestinal obstruction might develop in the setting of bulky tumors. Malignant peritoneal effusions may be present. In addition, CA-125 is often elevated in patients diagnosed with primary peritoneal serous neoplasms. Radiologically, primary peritoneal serous carcinoma is characterized by the presence of ascites, and peritoneal nodules and masses that enhance with intravenous contrast material on computed tomography (CT) and magnetic resonance imaging (MRI) studies. Occasionally, calcifications, which correspond to psammoma bodies on histologic examination, may be identified. In accordance with the definition of primary peritoneal serous carcinoma, radiologic evidence of ovarian lesions is usually not identified.
The pathologist who is confronted with a primary peritoneal serous lesion must exclude several lesions, including the following:
A borderline serous tumor
Low-grade serous carcinoma, including a variant known as psammocarcinoma
High-grade serous carcinoma
Papillary serous carcinomas of the peritoneum resemble their ovarian counterparts; by definition, ovaries are uninvolved or show very limited extent of involvement (confined to surface or superficial cortex). These tumors often form large and multifocal cystic, papillary, and solid tumors, typically with seeding, and extensive involvement of the peritoneal lining and omentum may be seen at surgery. Microscopically, papillary serous adenocarcinomas are usually high-grade tumors, characterized by complex and interconnecting papillary formations lined by cuboidal cells showing moderate or marked cytologic atypia, high nuclear/cytoplasmic (N/C) ratio, cellular stratification, increased mitotic activity, including atypical figures, necrosis, and invasion of the underlying stroma ( Fig. 23.10A and B ). A specific histologic source for the tumor is difficult to establish, although careful inspection of the entire fallopian tube is important to exclude a possible total origin (see Chapter 27 ). Rarely, these tumors can be found in association with hemorrhagic cysts, suggesting an origin in endometriosis (see Fig. 23.10F ).
Although most primary peritoneal serous carcinomas are high grade, low-grade carcinomas similar to those in the ovary may be encountered, and a small subset of tumors with extensive psammoma bodies are classified as psammocarcinomas. The latter is a rare variant of papillary serous adenocarcinoma that is characterized by low to moderate nuclear grade, local invasiveness, and a somewhat more indolent behavior. Overall, these tumors appear as invasive or frankly malignant implants (see Chapter 27 )—that is, they have numerous papillary clusters in a dense fibrous tissue reaction with retraction artifact (see Fig. 23.10C and D ). Tumors placed in the borderline or low malignant potential category are distinguished from carcinoma on the basis of blander histologic features and lack of destructive invasive growth, essentially the same criteria for noninvasive implants of borderline serous neoplasia (see Chapter 27 ).
The differential diagnosis of primary peritoneal serous neoplasia includes a serous tumor arising from another site and confusion with benign ( Fig. 23.11A ) and neoplastic mesothelial proliferations (discussed later). Another potential source of confusion is a rare incidental discovery of an epithelioid trophoblastic tumor in the peritoneum. These tumors can mimic epithelial, as well as germ cell, neoplasia in the peritoneum (see Fig. 23.11B ).
Immunoperoxidase studies are ineffective in differentiating between ovarian and primary peritoneal papillary serous adenocarcinomas. In both instances, the neoplastic cells show reactivity for cytokeratins (AE-1/AE-3 and Pan-keratin), epithelial membrane antigen (EMA), B72.3, carcinoembryonic antigen (CEA), WT-1, and Leu-M1. However, immunostains might be extremely useful in the differential diagnosis with malignant mesothelioma ( Table 23.1 ). Although both neoplasms are positive for WT-1 (monoclonal antibody) and cytokeratins, calretinin is almost always exclusively expressed in benign and malignant mesothelial proliferations, whereas Ber-EP4 has 95% sensitivity and 91% specificity for carcinoma, and cytokeratin 5/6 is positive in more than 90% of mesothelioma. In addition, estrogen receptor is typically negative in mesothelioma, whereas it is positive in approximately 95% of primary peritoneal serous carcinoma. Immunostain for progesterone receptor is less reliable for this distinction, with positivity reported in 30% to 65% of serous tumors.
|Cytokeratin (AE-1/AE-3)||Claudin 4||PAX-8||Calretinin||WT-1||Cytokeratin (CK)-5/6||Estrogen Receptor||Progesterone Receptor|
|Primary peritoneal serous carcinoma||+++||+||+++||−||+++||+/−||+++||+/−|
Molecular analysis of papillary serous carcinomas arising from the peritoneal surface has led to the discovery of its association with germline mutations of BRCA-1 gene, in rates similar to those noted in ovarian counterparts. Therefore, women with known mutations of this gene should undergo thorough follow-up not only for breast and ovarian carcinomas but also for primary peritoneal papillary serous carcinomas. Also evidenced by molecular studies is the fact that primary peritoneal papillary serous carcinoma may have a multifocal origin in some cases, as substantiated by LOH at the multiple allelic loci, such as androgen receptor (AR) locus, WT-1 gene, and of 6q. LOH of AR gene is more often seen in patients harboring germline mutations of the BRCA-1 gene. Similarly to papillary serous carcinoma arising in the ovary, serous carcinomas of the peritoneal surface also showed LOH at the p53 loci, located on chromosome 17, in 75% to 100% of cases.
Treatment and Prognosis
Primary papillary serous tumors of borderline or low-grade malignant potential have a good prognosis and require conservative therapy. Biscotti and Hart showed that of 14 patients who underwent treatment, which included surgery and adjuvant chemotherapy, only one patient died of complication related to therapy. None of the patients died of disease.
Primary peritoneal high-grade papillary serous carcinoma is clinically comparable with advanced-stage ovarian papillary serous carcinomas. Therapy options include cisplatin-based chemotherapy and surgery. Surgical approach encompasses cytoreductive technique and less aggressive debulking operations. In one series, patients who underwent cytoreductive surgery appeared to have a longer overall survival, suggesting that the amount of residual disease is a prognostic factor. In another series, combination of chemotherapy and cytoreductive surgical technique had a 5-year survival of 27%. In a recently reported series of patients with advanced and recurrent ovarian and peritoneal surface papillary serous carcinomas, the prior surgical stage, completeness of cytoreduction, and response to chemotherapy before surgery were statistically significant prognostic factors.
Other Müllerian Neoplasms
Other primary müllerian neoplasms of the peritoneum include ESS, müllerian adenosarcoma (see Fig. 23.7 ), and carcinosarcoma (formerly termed “malignant mixed müllerian tumor [MMMT]”). Extrauterine ESS is discussed later in this chapter.
Extrauterine müllerian adenosarcomas are rare. Affected females are in the fifth to eighth decades of life, and tumors arise in the omentum, ovary, and pelvis. Occurrence of müllerian adenosarcoma in a 20-year-old patient has been described. Morphologically, these tumors are composed of glandular and mesenchymal elements, but only the latter is morphologically malignant. These tumors are composed of benign-appearing neoplastic glands set within a proliferation of the surrounding low-grade sarcomatous stroma, which usually resembles ESS.
Carcinosarcoma has also been described outside the uterus and in one series displayed an age range from 33 to 67 years. These tumors are characterized by proliferation of neoplastic epithelial and mesenchymal elements, both of which are unambiguously malignant. The sarcomatous element often does not show any particular line of differentiation and resembles unclassified spindle cell sarcomas; however, identifiable foci of heterologous differentiation into rhabdomyosarcomatous, chondrosarcomatous, liposarcomatous, or osteosarcomatous elements may be present. Regarding the carcinomatous element, glandular differentiation (adenocarcinoma) is most often seen, such as endometrioid and papillary serous subtypes, but squamous differentiation or undifferentiated carcinoma can also be present. Thorough search for the glandular element is required for the diagnosis in cases where the sarcomatous component is dominant; otherwise, the neoplasm is best classified as a high-grade undifferentiated sarcoma. Mitoses are frequent and necrosis is often present.
Immunoperoxidase stains are of little value in the diagnosis of adenosarcomas and carcinosarcoma. The glandular component will express cytokeratins; however, the sarcomatous component of these lesions may also be positive, with focal positivity for markers such as α-smooth muscle actin (SMA) and vimentin. The sarcomatous component may express more specific markers when heterologous elements are present (e.g., desmin and myf-4 are positive in rhabdomyosarcomatous elements). Carcinosarcomas are not typically associated with mutations in BRCA-1 or BRCA-2 , but rare cases (ovarian) have been described.
Extrauterine müllerian adenosarcoma has a poor prognosis, with three of five patients developing recurrences and metastasis in one series. Carcinosarcomas are extremely aggressive neoplasms with a likewise poor prognosis. To date, there are no large series with long-term follow-up defining therapy guidelines for these two entities; options certainly include chemotherapy, radiation, and surgery.
Mesenchymal Lesions of the Peritoneum
Smooth Muscle Neoplasms
Smooth muscle neoplasms of the peritoneal cavity encompass two main entities: leiomyoma and leiomyosarcoma. Another condition that is included under the designation of smooth muscle neoplasms is leiomyomatosis peritonealis disseminata (LPD); this entity is discussed in Chapter 20 .
To be considered a primary peritoneal neoplasm, a thorough examination of the uterus has to be performed to exclude “metastatic” disease. Leiomyomata originating in the retroperitoneum and abdomen are rare, but they unquestionably exist and are more common in females. Most often they are encountered as a tumor mass arising in the wall of the gastrointestinal tract, mainly the colon and rectum. Patients in this latter group are usually within the fifth and sixth decades, and males are more commonly affected than females. Leiomyosarcomas of the abdominal cavity are more often encountered in the retroperitoneum and show female preponderance affecting patients in the sixth and seventh decades of life.
Smooth muscle neoplasms of the abdominal cavity and retroperitoneum may be asymptomatic or present as a mass that might impinge an abdominal organ, causing obstruction. In addition, when these tumors arise from the gastrointestinal tract, they may protrude into the bowel, cause obstruction, mimic carcinoma, and lead to ulceration of the mucosa with associated gastrointestinal bleeding. Leiomyomata are usually smaller than leiomyosarcomas, which might reach large proportions.
Morcellation and Smooth Muscle Neoplasms
Recently, hysterectomy and myomectomy facilitated by power or hand morcellation have come under scrutiny due to the inadvertent morcellation of malignancies. Inadvertent morcellation of ESS, endometrial carcinoma, uterine serous carcinoma, and leiomyosarcoma have all be reported, with the overall risk of occult cancer on a morcellated specimen approaching 0.73%. When variants of leiomyoma (e.g., cellular leiomyoma, atypical leiomyoma) and STUMP are included, the rate of inadvertent morcellation rises to 1.2%.
Re-exploration in patients with STUMP or leiomyosarcoma reveals disseminated peritoneal sarcomatosis in a significant number of cases with at least one study suggesting the rate may be as high as 72.7%. Furthermore, morcellation of occult uterine leiomyosarcoma has been associated with decreased overall survival, decreased disease-free survival, and a higher risk of abdominopelvic recurrence.
Macroscopically, benign smooth muscle neoplasms (leiomyomata) usually have well-defined contours, with a firm, whorled, tan to white cut surface. Foci of hemorrhage may be present, as well as focal cystic degeneration. In cases of leiomyosarcoma, malignant features, such as necrosis and invasion of surrounding structures, are often seen. Occasionally, leiomyomata and leiomyosarcomas can be seen in close association with a vascular structure, such as the inferior vena cava, and the morphologic features are consistent with origin from the vessel wall. When the diagnosis of a leiomyosarcoma is rendered in a retroperitoneal or abdominal mass, origin from a uterine primary should be excluded.
Microscopically, these benign and malignant neoplasms are usually characterized by the typical features associated with smooth muscle neoplasms, being composed of a proliferation of spindle cells arranged in long fascicles with elongated, cigar-shaped nuclei, vesicular chromatin; variably prominent nucleoli, and moderate amounts of eosinophilic cytoplasm ( Fig. 23.12 ). Rarely, cells with epithelioid morphology are present and, exceptionally, this morphology may predominate in the neoplasm, imitating an epithelial neoplasm and often making the histologic recognition challenging. Leiomyomata can undergo several degenerative phenomena, including infarction, cystic changes, hydropic or edematous degeneration, and stromal hyalinization.
The current accepted criterion for malignancy for smooth muscle neoplasms occurring in the abdominal cavity or retroperitoneum of females is the presence of more than 10 mitoses per 50 high-power fields. Although not indicative of malignancy, hypercellularity is a worrisome feature. The presence of atypical hyperchromatic nuclei should also trigger a more extensive search for diagnostic malignant features (e.g., necrosis, mitotic activity).
Immunohistochemistry and Biomarkers
Although the morphologic features of smooth muscle neoplasms may allow for an accurate diagnosis, immunoperoxidase studies are helpful in confirming the smooth muscle origin in less typical cases or small core needle biopsies. Table 23.2 shows the immunophenotypic characteristic of mesenchymal neoplasms of the peritoneum. Smooth muscle tumors are classically positive for SMA, desmin, and h-caldesmon. The extent of expression of these markers by tumor cells varies from diffuse to focal, and this variability in expression, not surprisingly, might affect interpretation of small core needle biopsies. One should keep in mind that the morphology, if characteristic, should govern the diagnosis. Malignant tumors, for example, might have decreased expression or even lose expression of these markers. Other markers that can be expressed by smooth muscle tumors include cytokeratins and EMA, which can be encountered in up to 40% of these tumors. Estrogen and progesterone receptors are often positive in leiomyomata, occurring in reproductive-age females; however, leiomyosarcomas appear to have significantly less expression of estrogen receptor and progesterone receptor. S-100 protein, glial fibrillary acidic protein (GFAP), and c-kit are negative.
|Smooth Muscle Actin||Desmin||h-Caldesmon||CD-10||c-kit||Keratin||WT-1 *|
|Smooth muscle neoplasms||+||+||+||±||−||±|
|Low-grade endometrial stromal sarcoma (ESS)||+||±||−||+||−||−|
|Gastrointestinal stromal tumor (GIST)||±||±||±||+||−|
|Peripheral nerve sheath tumor||−||−||−||−||−|
|Desmoplastic round cell tumor||−||+||−||+||+|
Differential Diagnosis and Pitfalls
The differential diagnosis of smooth muscle tumors includes other mesenchymal neoplasms that are often encountered in the abdomen, such as gastrointestinal stromal tumor (GIST), desmoid fibromatosis, and nerve sheath tumors, such as schwannomas and malignant peripheral nerve sheath tumor (MPNST).
In GISTs, the tumor cells are uniform and show a pale eosinophilic cytoplasm with a syncytial appearance. Immunoperoxidase studies in GIST are somewhat overlapping with smooth muscle neoplasms; however, desmin is only rarely positive in GIST (fewer than 5% of the cases), whereas c-kit is characteristically positive in the majority of these tumors and negative in smooth muscle neoplasms (see Table 23.1 ). In addition, GISTs are positive for DOG-1 in more than 90% of cases, whereas smooth muscle tumors are only rarely (0.3% to 10% of cases) positive for this novel marker.
Desmoid fibromatosis shows long hypocellular fascicles composed of cells with tapered ends. Occasionally, this neoplasm may show positivity for SMA and desmin in a very focal pattern, consistent with their myofibroblastic origin; h-caldesmon is negative. In contrast to desmoid fibromatosis, smooth muscle neoplasms are negative for β-catenin.
Neoplasms of nerve sheath origin (schwannoma and MPNST) usually show fascicles formed by elongated cells with tapered nuclei and display variable positivity for S-100 protein and GFAP. They are negative for SMA and desmin. MPNST also may show loss of H3K27me3.
Treatment and Prognosis
The treatment of leiomyomata consists of simple excision. There is a small risk of recurrence. Leiomyosarcomas carry a poor prognosis with high incidence of recurrence and metastasis. The preferential sites of development of metastatic disease include lungs and liver. Therapy should include surgery with adjuvant chemotherapy and irradiation. The 5-year survival is approximately 30%.
Low-Grade Endometrial Stromal Sarcoma
Epidemiology and Clinical Features
ESS located in the abdominal cavity may be seen de novo or in association with a primary uterine ESS. The former is believed to arise from endometriotic foci, whereas the latter is due to metastasis or direct extension through the uterine wall. Regardless of the origin, primary peritoneal ESS is a rare phenomenon. The epidemiology of extrauterine ESS is similar to the primary uterine neoplasm, affecting females in the fourth and fifth decades of life. These tumors may present as a palpable mass or give rise to obstructive symptoms of other intra-abdominal organs.
The microscopic appearance of extrauterine ESS is similar to its uterine counterpart. At low magnification, one can appreciate the characteristic infiltrative growth pattern of these tumors, which invade adjacent tissues with finger-like projections.
Cytologically, they are composed of a uniform cellular proliferation of spindle cells with poorly defined cell borders, short, ovoid nuclei, inconspicuous nucleoli, and scant pale cytoplasm, recapitulating non-neoplastic endometrial stroma in the uterus. Admixed within the tumor, foamy histiocytic cells may be present. In the background, frequent small-caliber arteries, reminiscent of spiral arteries of the endometrium, are present. Mitotic figures are rare, often numbering fewer than five mitoses per 10 high-power fields. Necrosis and pleomorphism are not features of these tumors, and neoplasms showing these features are best regarded as high-grade sarcomas, rather than ESSs. Glandular and mesenchymal heterologous differentiation is occasionally seen and includes sex cord stromal elements, smooth muscle, bone, and skeletal muscle.
Immunohistochemistry and Differential Diagnosis
Similar to uterine neoplasms, extrauterine ESS may share morphologic similarities with smooth muscle neoplasms, mainly highly cellular leiomyoma and leiomyosarcoma. ESS are mainly positive for SMA, desmin, CD10, and progesterone receptor (see Table 23.2 ). In contrast, smooth muscle neoplasms are positive for desmin, SMA, and h-caldesmon.
Cytogenetically, most low-grade ESS, including metastatic and primary extrauterine tumors, are characterized by a recurrent chromosomal translocation, the t(7;17). This translocation fuses the 5′ end of JAZF-1 gene on chromosome 7p15 and the 3′ end of JJAZ-1 gene on chromosome 17q21.
Treatment and Prognosis
Uterine ESS is a low-grade neoplasm that may metastasize many years after the initial diagnosis. The preferential sites of metastatic deposits are the pelvis, intra-abdominal organs, and lungs. Hence, the presence of extrauterine ESS should trigger the search for a concurrent or prior uterine primary. The 5-year survival for uterine ESS is variable but approaches 80%. Primary extrauterine ESS is likewise a low-grade neoplasm, but few data exist regarding the response to treatment and prognostic factors. In one series, extrauterine ESS showed an intermediate behavior between uterine ESS and high-grade uterine sarcomas, with 8 of 20 patients showing tumor recurrences; 5 patients died of the disease.
Solitary Fibrous Tumor
Solitary fibrous tumor (SFT; synonyms: hemangiopericytoma, fibrous mesothelioma) occurs over a wide range of ages, but it is predominantly seen in adulthood. Males and females are equally affected. Initially SFT was believed to be a pleural-based disease; however, to date, SFT may affect several extrapleural anatomic locations, including intra-abdominal organs and peritoneum.
Frequently SFT will be an incidental finding. When symptomatic, patients will complain of a palpable mass, which is usually slowly growing, or signs and symptoms of mass effect on adjacent structures. Rarely, patients will seek medical attention because of symptoms related with hypoglycemia—also known as Doege-Potter syndrome —attributed to elevated levels of insulin-like growth factor 2 produced by tumor cells. Other systemic symptoms, such as fever and malaise, can also be seen.
Grossly, SFTs are well-circumscribed tumors with a firm, tan to white, cut surface that may reach considerably large sizes. Histologically, SFT is characterized by a proliferation of spindle cells arranged in a “patternless” pattern (with no specific appearance, such as fascicular or storiform), with alternating zones of hypocellular stroma and hypercellular areas of fibrous stroma ( Fig. 23.13 ). The neoplastic cells are small and oval to spindled with limited amount of pale cytoplasm. Scattered thick fibers of collagen and staghorn or hemangiopericytoma-like thin-walled branching vessels with hyalinization are frequently present. Most tumors show clear demarcation from the surrounding tissues, with a delicate fibrous capsule. Focal areas of adipocytic differentiation can be present (fat-forming SFT) within the tumor.
Malignant SFT comprises approximately 10% of the cases of SFT. It is characterized by hypercellularity (either diffuse or focal). Necrosis and pleomorphism may be encountered, but the single most widely accepted criterion of malignancy is the presence of more than 4 mitoses per 10 high-power microscopic fields. Often, areas of “benign”-appearing SFT are present; however, when no areas of conventional SFT are noted because of predominance of malignant-appearing, unclassified, high-grade sarcoma areas, the diagnosis of SFT is one of exclusion.
Rarely, SFT may show evidence of dedifferentiation, where conventional SFT shows abrupt transition into a morphologic high-grade neoplasm, with epithelioid, round cell, or spindle cell components. In one series, these lesions accounted for approximately 0.8% of SFT.
SFT is characterized by immunoreactivity for CD34 and variable expression of cytoplasmic O-13 (CD99). Reactivity for CD34 may be partially or entirely lost in malignant SFT and in the high-grade component of dedifferentiated SFT. Therefore, identification of conventional SFT morphology is of pivotal help in accurately diagnosing SFT. Notably, because none of the preceding immunoperoxidase stains are specific for this entity, the diagnosis relies mostly on a correct morphologic identification with immunoperoxidase staining as adjunctive support in ruling out other entities. Recently nuclear expression of STAT6 has been shown to be a highly sensitive and remarkable specific marker for SFT.
The main differential diagnosis is with synovial sarcoma, which carries a worse prognosis. Synovial sarcoma differs morphologically from SFT because it is a fascicular cellular spindle cell neoplasm that shows focal immunoreactivity for keratins and EMA. Occasionally, reactivity for O-13 and S-100 protein can be observed in synovial sarcoma. SFT should also be differentiated from malignant mesothelioma . The latter is characterized by positivity for calretinin, WT-1, and keratins. Malignant mesothelioma is negative for CD34 and STAT6.
Treatment and Prognosis
Benign SFT can be cured by local surgical excision. Occasionally, tumors may recur. Malignant SFT carries a poor prognosis and should be excised with an ample surrounding margin, possibly with consideration of adjuvant chemotherapy and radiotherapy.
Calcifying Fibrous Tumor
Calcifying fibrous tumor (CFT; synonym: calcifying fibrous pseudotumor) is a rare neoplasm that was initially described in the pediatric population in 1988 by Rosenthal and Abdul-Karim. In 1993, Fetsch et al. reported the first series of tumors and coined the calcifying fibrous pseudotumor . They observed the occurrence of this tumor in children and young adults; however, since the original description, cases affecting older adults have been described. The largest series of CFT included patients with ages ranging from 1 to 65 years old. In a recent literature review the mean age was 33.5 years.
There appears to be no gender predilection, with a male-to-female (M:F) ratio of 1 : 1. Tumor can present as a subcutaneous mass or be deep in location. The anatomic distribution of this neoplasm is wide and includes head and neck, pleura, mediastinum, inguinal region, axillary area, extremities, and intra-abdominal, including mesentery, omentum, peritoneum, and organ walls. Although most tumors are small in size, they can measure up to 25 cm. Most patients present with complaints of a mass and local pain.
Macroscopically, these tumors show defined circumscription and may have a thin fibrous capsule. Microscopically, the neoplasm is markedly hypocellular and composed of small, inconspicuous spindle cells embedded in a markedly hyalinized stroma ( Fig. 23.14 ). A characteristic finding is the presence of a nodular lymphoplasmacytic infiltrate, sometimes forming germinal centers. Stromal calcifications are present and may be irregular in shape or psammomatous, varying from focal to massive. Regardless of the macroscopic appearance, some tumors may microscopically show peripheral entrapment of small vascular elements and small peripheral nerves. Occasionally, foci resembling inflammatory myofibroblastic tumor (IMT)—hypercellularity with prominent lymphoplasmacytic inflammatory infiltrate—are present.
Immunoperoxidase studies are of little help in the diagnosis of CFT. The small spindle cells are usually positive for CD34 and may show focal expression of SMA and desmin, confirming its myofibroblastic derivation.
Because of the clinical and sometimes morphologic overlap between CFT and IMT, some authors suggest that CFT is in the spectrum of IMT, representing a “burnt-out” or sclerosing phase. Comparative immunoperoxidase studies have shown that most CFTs do not express anaplastic lymphoma kinase-1 (ALK-1), which is often expressed in IMTs (discussed later), suggesting that CFT probably represents a distinct neoplasm. There are no studies addressing cytogenetic abnormalities in CFT.
Treatment and Prognosis
In some cases of CFT, multicentricity has been noted. In addition, repeated recurrences have been reported in rare cases. There are no examples of metastatic disease. The best approach to this neoplasm should be local excision with uninvolved, albeit modest, margins. The prognosis is excellent.
Inflammatory Myofibroblastic Tumor
IMT is a fibroblastic/myofibroblastic neoplasm first recognized to be clonal by Su et al. in 1998, when three tumors were shown to have clonal cytogenetic abnormalities. Before that, the pathogenesis of IMT was controversial, and some authors believed it to represent a pseudotumor, rather than a true neoplasm, because of its rich accompanying inflammatory component.
IMT affects mainly children and young adults, although it may demonstrate quite a wide age range. The largest series published shows a median age of 9 years old. It has a slight predominance in female patients (F:M = 1.3 : 1) and is most commonly encountered in the abdomen and retroperitoneum, but other sites such as the lungs, soft tissues of the head and neck, trunk, and extremities can also be affected.
IMT often presents as an intra-abdominal tumor mass that may be present in a retroperitoneal, mesenteric, omental, or intestinal location. Not uncommonly it will be coupled with systemic symptoms, such as fever, weight loss and pain, and laboratory abnormalities (anemia, thrombocytosis, polyclonal hyperglobulinemia, and increased erythrocyte sedimentation rate).
Macroscopically, IMT has a tan, fleshy appearance because of the extensive inflammatory infiltrate, similar to the gross appearance of lymphomatous processes. Tumor size is variable; however, IMTs tend to be bulky masses when present intra-abdominally. Additionally, this neoplasm may present as multiple tumoral masses.
IMT is characterized by a fascicular proliferation of spindle cells, with indistinct cell borders, elongated nuclei, vesicular chromatin, small nucleoli, and scant amounts of pale cytoplasm. Typically, there is an accompanying component of chronic inflammation that is composed mainly of lymphocytes and plasma cells. Often, the inflammatory component may be intense and obscure the neoplastic spindle cells, imparting a pseudotumoral appearance. In addition, the prominent infiltrate of inflammatory cells also may raise the possibility of involvement by a lymphomatous process. Areas of calcification and necrosis may be seen. Rarely, IMT may show intense hyalinization with a minor inflammatory component.
In a subset of cases, atypical histologic features, characterized by hypercellularity, prominent fascicular growth pattern, herringbone architecture, necrosis, presence of ganglion-like cells, nuclear pleomorphism, and atypical mitoses, may be observed. Although in one study atypical mitoses appear to be encountered in ALK-negative tumors, the presence of atypical features does not appear to be associated with a more aggressive clinical course or development of metastatic disease.
Immunoperoxidase studies will demonstrate the myofibroblastic differentiation of the spindle cells, with focal, nonspecific positivity for α-SMA and desmin. Occasionally, the tumor cells may be positive for keratins. However, unlike other myofibroblastic proliferations, 40% to 60% of IMTs are distinguished by positive staining for ALK-1 protein that is more commonly seen in pediatric cases. Immunoperoxidase studies will also demonstrate a mixed population of T and B lymphocytes, and the polyclonal nature of the plasma cells (immunostains for immunoglobulins kappa and lambda light chains).
The expression of the ALK-1 is due to the rearrangements of chromosome 2q23, to which the ALK gene has been mapped. Translocation between chromosome 2 and various partners may be seen. Some of the reported partners in this translocation include tropomyosin-3 and -4 ( TPM-3 and TPM-4 ), clathrin heavy chain (CTLC) , cysteinyl-tRNA synthetase (CARS) , and Ran-binding protein 2 (RANBP-2) genes, all of which have been reported to exchange material with chromosome 2 in IMTs. The presence of the translocation can be suggested in conventional karyotype examination and confirmed by fluorescence in situ hybridization (FISH) utilizing a “split-apart” probe for chromosome 2.
The differential diagnosis of IMT includes nodular fasciitis (particularly if accompanied by a brisk inflammatory infiltrate), desmoid fibromatosis, CFT, and IgG-4–associated sclerosing disease (pancreatitis and retroperitoneal fibrosis). Nodular fasciitis is a benign, self-limited, subcutaneous spindle cell proliferation, which, if left untreated, regresses spontaneously. It is characterized by a bland spindle cell proliferation with variable amounts of inflammation and extravasated red blood cells. It is ALK-1 protein negative. Desmoid fibromatosis should be included in the differential of hypocellular, hyalinized IMTs. The cells composing desmoid tumors are usually more elongated. The absence of staining is not contributory; however, ALK-1 protein positivity excludes desmoid tumor, whereas expression of β-catenin is seen in approximately 70% of cases of desmoid fibromatosis. CFT is also in the differential diagnosis of hypocellular IMTs. CFTs are even less cellular and more hyalinized than IMTs. CFTs have also been shown to be negative for ALK-1 protein immunostains. IgG-4–associated sclerosing disease has to date been described in several extra- and intra-abdominal organs, including liver, gallbladder, lymph nodes, lung, salivary glands, bile ducts, and mediastinum. Autoimmune pancreatitis has been the category so far better studied and described. In approximately 8% of these patients, retroperitoneal fibrosis has also been described. Histologically, both pancreatitis and retroperitoneal fibrosis are characterized by variably sclerotic fibrous tissue with a prominent lymphoplasmacytic infiltrate and obstructive venulitis. Distinction from IMT is done by noticing the absence of a spindle cell neoplasm in the background, as well as immunoperoxidase stains, where the plasma cells in retroperitoneal fibrosis are negative for ALK-1 and positive for IgG-4.
Treatment and Prognosis
The overall prognosis is good. Local recurrence is noted in a small subset of patients (up to 20% of cases), with potential for local aggressive behavior. However, these tumors rarely give rise to metastasis.
Surgery remains the main therapeutic modality for the treatment of IMT. Chemotherapy may be used to manage aggressive and recurrent forms of the disease, decrease tumor burden, and facilitate resection. Radiation does not appear to be effective.
Gastrointestinal Stromal Tumor
GIST is an uncommon neoplasm that accounts for only 3% of all gastrointestinal neoplasms; however, this group of tumors constitutes the most common mesenchymal neoplasm of the gastrointestinal tract. These tumors are believed to originate from the interstitial cells of Cajal, the pacemaker cells for the tubular gastrointestinal tract, responsible for its peristalsis. It was not until the systematic use of immunostains for c-kit that gastrointestinal mesenchymal tumors considered in the past to be smooth muscle neoplasms (i.e., leiomyosarcoma, leiomyoma) and gastrointestinal autonomic nerve tumors (GANTs) were found to in fact represent GISTs.
GIST has no gender predilection; rarely children may be affected. Most cases arise sporadically, but in a small percentage of patients GIST may arise in the context of a syndrome, such as Carney’s triad and neurofibromatosis type 1 (NF-1). GIST may present as one of the components of Carney’s triad, which is additionally composed of (extra adrenal) paragangliomas and pulmonary chondromas. Patients affected by Carney’s triad appear to be younger than the usual population of sporadic GISTs.
GIST occurs most often in the stomach (50% of cases), followed by the small intestine and, less often, the colon and esophagus. When present outside the tubular gastrointestinal tract, such as the liver, retroperitoneum, and peritoneal or mesenteric surfaces, these tumors are believed to represent metastatic disease. However, it is not infrequent that a primary is never definitively identified, posing the possibility of an extra-gastrointestinal origin. In a recent large series of GIST cases presenting as an omental mass, approximately 20% of the patients had no evidence of a primary in the gastrointestinal tract.
These tumors are often large and well circumscribed. The cut surface is usually lobulated and homogenous, and it is well demarcated by a thin transparent fibrous pseudocapsule. Bulky masses may ulcerate into the tubular gastrointestinal tract and present with gastrointestinal bleeding. Tumors may show hemorrhage, necrosis, or cystic changes, especially after therapy with Gleevec (discussed later).
Microscopically, most cases of GIST are distinguished by a monomorphic proliferation of spindled cells arranged in short fascicles ( Fig. 23.15A ); however, partial or complete epithelioid morphology may be present in a subset of cases (see Fig. 23.15B and C ). Commonly, a combination of the two cell types is noted, either intermixed or present as distinct areas of the tumor. Most GISTs have a bland cytomorphologic appearance, with ovoid to spindled nuclei, small to inconspicuous nucleoli, and a moderate amount of palely eosinophilic cytoplasm. Cell borders are indistinct, and the cytoplasm of adjacent cells merges together forming a syncytial appearance. Occasionally, clear perinuclear punched-out cytoplasmic vacuoles can be appreciated and are a hallmark of GIST. Skeinoid fibers may be present as well, which are amorphous extracellular eosinophilic deposits of abnormal collagen. Fewer than 5% of cases of GIST have nuclear pleomorphism.
The tumors presenting as omental masses can be subdivided into two main subgroups: solitary and multiple. The group presenting as a solitary mass often shows cytomorphology similar to gastric tumors, whereas that presenting as multiple tumors resembles GIST arising in the intestine.
The majority of GISTs are reactive for c-kit, which can be cytoplasmic or dotlike positivity adjacent to the cell nucleus (see Fig. 23.15D ). Furthermore, this positivity can vary from weak to strong and from focal to diffuse. Expression of this marker was initially thought to reflect the different patterns of mutation of Kit tyrosine kinase; however, this does not appear to hold true. Notably, a small percentage of GISTs are negative for c-kit immunostains. These tumors are more often epithelioid, and the diagnosis of GIST relies on exclusion of other neoplasms. DOG-1 (also known as discovered in GIST-1) was shown to also be expressed in GIST with sensitivity and specificity superior to 95%. Interestingly, DOG-1 is somewhat superior to c-kit, because it appears to be uniformly expressed in spindle cell and epithelioid types, is expressed in a large subset of c-kit negative GISTs, and does not correlate with mutational status of kit or platelet-derived growth factor receptor-α (PDGFR-α). Other markers, which are less reliably positive in GISTs, include CD34 (60% to 70% of cases), α-SMA, and h-caldesmon. None of these are specific of GIST. In fewer than 5% of the cases, these tumors can express desmin.
The underlying pathogenesis of most cases of GIST is the constitutive activation of c-kit tyrosine kinase, which, independent of its binding to stem cell factor (SCF), will activate cell cycle pathways within the neoplastic cells, favoring proliferation and inhibiting apoptosis. In the majority of the cases (approximately 70%), this phenomenon is due to an in-frame mutation of exon 11 of the c-kit gene (chromosome 4), which encodes the juxtamembrane domain of the c-kit tyrosine kinase. The other possible mutations observed include point mutations in exons 13 and 17 and an in-frame duplication of exon 9. In a subset of cases where mutation in the kit gene cannot be detected, abnormalities in another tyrosine kinase, PDGFR-α, may be seen.
The main differential diagnosis of GIST includes desmoid fibromatosis, schwannoma, and leiomyosarcoma. Although morphologic differences between these entities exist, immunoperoxidase stains can easily confirm the diagnosis (see Table 23.2 ). The spindle cell fascicles forming desmoid tumors are longer that in GIST and the cells are more flattened, whereas the cells composing schwannomas show a more tapered cytomorphology, are usually arranged in Antoni A and Antoni B areas, and are accompanied by thick-walled, hyalinized blood vessels. In addition, schwannomas are strongly and diffusely positive for S-100 protein. In contrast to GIST, leiomyosarcomas are composed of long fascicles of spindle cells, showing plumper cells usually with more cytologic pleomorphism. Leiomyosarcomas are usually positive for desmin and SMA, and a subset also expresses h-caldesmon. Desmoid fibromatosis is composed of long fascicles of spindled cells, which show elongated nuclei with tapered ends. CD34, once believed to be specific for GIST, can be expressed in a variety of tumors. Desmin is positive in smooth muscle neoplasms and might be focally expressed in myofibroblastic neoplasms, such as desmoid fibromatosis. However, none of these tumors will express c-kit. A small subset of leiomyosarcomas (fewer than 5%) and no cases of desmoid fibromatosis or schwannoma to date have demonstrated positivity for DOG-1.
Treatment and Prognosis
In the currently accepted consensus, the prognosis of GIST is based on the combination of two pathologic parameters: mass size and number of mitoses ( Table 23.3 ). Based on these parameters, the patient can be grouped into one of four possible clinical outcome categories: very low, low, intermediate, and high risk. This system was designed because it was appreciated that tumors that in the past were classified as “benign,” based on macroscopic (i.e., small sizes) and cytomorphologic appearance, were still capable of giving rise to metastatic disease and, eventually, leading to the patient’s death.