Origins of retroperitoneal mucinous tumors may be primordial germ cells and Walthard cell nests like ovarian mucinous tumors. Primary retroperitoneal mucinous carcinomas have immunohistochemical staining patterns similar to those of ovarian mucinous tumors [109], and mucinous tumors develop in both women and men, as well as teratoma that is of germ cell origin. The migration of primordial germ cells in the embryo starts from the dorsal wall of the yolk sac. Then primordial germ cells migrate into the midgut and hindgut, passing through the dorsal mesentery into the gonadal ridges. Thus, mucinous tumors can arise from primordial germ cells that stopped anywhere in the retroperitoneal space. Mucinous carcinomas arising from a retroperitoneal mature cystic teratoma have been reported [110,111].
5.2. Serous Carcinoma
The pathogenesis of retroperitoneal serous carcinomas appears to be associated with endosalpingiosis. Although endosalpingiosis and endometriosis occur concurrently in 34% of endosalpingiosis cases
[100][117], endosalpingiosis is not a variant of endometriosis as they have different clinical presentations
[100][117]. Endosalpingiosis is not significantly associated with infertility or chronic pain and its incidence increases with age
[101][118], with 40% of endosalpingiosis cases being postmenopausal
[100][117].
Endosalpingiosis, as well as retroperitoneal serous carcinomas, can be divided into non-nodal and nodal lesions. Non-nodal endosalpingiosis is observed in the peritoneum and subperitoneal tissues
[100][117]. In the peritoneal cavity, endosalpingiosis is observed in the ovary, fallopian tube, uterus, omentum, small bowel, and sigmoid colon
[100][117]. Its prevalence is 7.6% in women undergoing laparoscopic surgery for gynecologic conditions
[102][119].
The pathogenic mechanism of endosalpingiosis remains unclear. Two major theories are postulated, namely, the tubal escape theory and the Müllerian metaplasia theory
[103][104][92,123]. In the tubal escape theory, shed tubal epithelium either implants on the peritoneal surface or disseminates via lymphatics into a lymph node
[104][123]. Tubal epithelia are easily sloughed off by tubal inflammation, tubal lavage, or salpingectomy
[105][122]. In the Müllerian metaplasia theory, latent cells present in ectopic locations outside the Müllerian tract (fallopian tube, endometrium, endocervix) retain the capacity for forming benign tubal-type glands
[103][92]. Endosalpingiosis that arises from the embryological remnant of the Müllerian duct may be an origin of retroperitoneal serous carcinoma, especially in men
[104][123].
Endosalpingiosis appears to be a latent precursor to low-grade pelvic serous carcinomas
[106][124] and prone to neoplastic transformation, as it represents cancer driver mutations that are observed in ovarian low-grade serous tumor
[107][125]. Endosalpingiosis is associated with ovarian and uterine cancers
[108][80].
Although low-grade serous tumor and high-grade serous carcinoma are two distinct diseases, low-grade serous carcinoma may transform into high-grade serous carcinoma in rare cases
[109][110][111][129,130,131]. A morphologic continuum between the low-grade tumors and high-grade carcinoma was observed in four cases
[109][129]. The same mutation of
KRAS was found in both the serous borderline tumor and the high-grade serous carcinoma components of the tumor in two cases
[109][129].
Serous carcinoma and endosalpingiosis can develop in men
[25][104][25,123]. These lesions may originate from Müllerian cell rests remaining after regression of the Müllerian duct. During fetal development, before the secretion of anti-Müllerian hormone by the fetal testes, the Müllerian ducts develop in male fetuses
[112][133]. Thus, Müllerian tissue may remain in a male body. Endometriosis can also develop in men who had been treated with prolonged estrogen therapy for prostate cancer or diagnosed as cirrhosis
[113][114][134,135].
5.3. Endometrioid Carcinoma
Retroperitoneal endometrioid carcinoma appears to arise from endometriosis of the urinary tract and lymph nodes. Endometrioid tumors are the majority of extragonadal endometriosis-associated carcinomas
[115][138]. Tumors arising in endometriosis are predominantly low-grade and confined to the site of origin
[115][138]. Pelvic surgery may affect the development of retroperitoneal endometrioid carcinoma.
Endometrioid carcinoma may also arise in the lymph nodes and it appears to develop from nodal endometriosis. Endometriosis is believed to disseminate via the lymphatic system
[116][141]. Metastatic endometriosis lesions in pelvic sentinel lymph nodes were present in women with ovarian and/or pelvic endometriosis
[117][142]. Interestingly, both of the patients who developed endometrioid carcinoma in the pelvic lymph nodes had Lynch syndrome
[33][34][33,34]. Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, i.e.,
MLH1,
MSH2,
MSH6, and
PMS2, related to an increased risk of developing colorectal, endometrial, and ovarian cancers
[118][143]. Thus, the malignant transformation of endometriosis in the lymph nodes in women with Lynch syndrome may be likely to occur.
5.4. Clear Cell Carcinoma
Clear cell carcinoma is another endometriosis-associated carcinoma and may arise in both retroperitoneal endometriosis and lymph nodes. A case who underwent supracervical hysterectomy and bilateral salpingo-oophorectomy and received 4 years of estrogen therapy developed clear cell carcinoma arising in retroperitoneal endometriosis
[35]. This case may also suggest that estrogen replacement may be a risk factor for developing endometriosis-associated cancer
[119][139].
5.5. Carcinosarcoma
Retroperitoneal carcinosarcoma, as well as uterine carcinosarcoma
[96][108], may derive from serous or endometrioid carcinoma. In ovarian carcinosarcoma, frequently encountered epithelial components are serous, endometrioid, or undifferentiated carcinomas
[120][155]. Of the three retroperitoneal carcinosarcomas, one was associated with endometriosis that is known to be associated with the development of endometrioid carcinoma
[41].
6. Retroperitoneal Carcinoma as a Part of Carcinoma of Unknown Primary
Part of carcinomas of unknown primary may be a primary retroperitoneal carcinoma. Carcinoma of unknown primary represents a heterogeneous group of metastatic tumors for which a standard diagnostic work-up fails to identify the site of origin at the time of diagnosis
[121][157]. Patients with carcinoma of unknown primary are categorized into two prognostic subgroups according to their clinicopathologic characteristics. The majority of patients with carcinoma of unknown primary (80–85%) belong to unfavorable subsets. In this subset, two prognostic groups are identified according to LDH level and the performance status
[122][123][158,159]. The favorable risk cancer subgroup (15–20%) includes patients with neuroendocrine carcinomas of unknown primary.
Carcinoma in the lymph node diagnosed as a carcinoma of unknown primary may be a primary carcinoma that derives from endosalpingiosis or endometriosis in the node. Serous carcinomas in the inguinal node have been reported
[124][125][161,162]. In addition, atypical hyperplasia with noninvasive, well-differentiated endometrioid carcinoma and high-grade serous carcinoma within a focus of endometriosis in an inguinal mass in a young woman has been reported
[126][163]. In addition, cases with a primary tumor regressing spontaneously and lymph node metastasis remaining may be diagnosed as a carcinoma of unknown primary.
7. Conclusions
Although many hypotheses are proposed, the exact pathogenesis of retroperitoneal carcinomas remains to be elucidated. Retroperitoneal carcinomas may not originate in the coelomic epithelium but in the Müllerian epithelium, as well as ovarian carcinomas
[127][176]. The secondary Müllerian system, which refers to the presence of Müllerian epithelium outside the indigenous locations, has been proposed
[128][177] and this system may be an origin of ovarian carcinomas
[129][178], endometriosis
[130][179], endosalpingiosis
[131][180], and retroperitoneal carcinomas
[9][31][44][53][9,31,45,54]. However, this notion remains unverified
[127][176]. Coelomic metaplasia may have been considered the most plausible hypothesis of retroperitoneal carcinogenesis, but direct evidence may not exist to support this theory at present. However, as ovarian serous carcinomas originate from both fallopian tube epithelium and ovarian surface epithelium
[78][82][83][84,88,89], there is a possibility that retroperitoneal carcinomas develop directly from the abdominal and pelvic peritoneum that invaginates into the retroperitoneal space.
Endosalpingiosis and endometriosis are both involved in the development of ovarian, peritoneal, and retroperitoneal carcinomas
[86][106][107][132][133][134][81,95,124,125,181,182]. Nevertheless, the pathogenesis of these diseases, in particular endosalpingiosis, is poorly understood. Although endosalpingiosis resembles tubal epithelium, it is associated with the development of not only serous tumors, but also mucinous carcinomas
[132][81]. Endosalpingiosis may be a hereditary disease, similar to endometriosis
[135][183], as endosalpingiosis is associated with
BRCA mutation
[106][124]. In addition, patients with endosalpingiosis had lower overall survival than patients with endometriosis
[132][81]. Are shed epithelial cells of the fallopian tube a cause of endosalpingiosis and/or a precursor of both peritoneal and retroperitoneal carcinomas? If so, what is the difference between cells that become a peritoneal carcinoma and those that become a retroperitoneal carcinoma? Further studies on the pathogenesis of retroperitoneal, peritoneal, and ovarian carcinomas are necessary, as well as on endosalpingiosis and endometriosis.