Clinicopathological Characteristics of Microscopic Tubal Intraepithelial Metastases from Adenocarcinoma and Small Cell Neuroendocrine Carcinoma of the Uterine Cervix

Discussion

Herein, we presented five cases of cervical carcinoma that metastasized to the fallopian tube and described their detailed clinical and pathological aspects, including histological features and immunostaining results of the tubal metastases. Despite the small number of cases, we focused on the various histological subtypes of cervical carcinoma: HPV-associated endocervical adenocarcinoma of usual and mucinous types, HPV-independent endocervical adenocarcinoma of gastric type, and SCNEC. We demonstrated that the tubal metastatic tumors were confined within the mucosa and spread along the surface. In all cases, the adnexa appeared grossly unremarkable, and there was no ovarian metastasis. Instead, the fallopian tubes exhibited microscopic IEMs, which were distributed over not only the distal but also the middle and proximal portions of the tube. Four of the five patients showed extension into the upper vagina and parametrium, which was not identified in the preoperative imaging studies.

From the pathologists’ point of view, tubal metastases from cervical carcinomas should be distinguished from various tubal conditions: STIC, high-grade serous carcinoma (HGSC), and other non-neoplastic lesions, including Arias– Stella reaction, tubal hyperplasia, secretory cell outgrowth (SCOUT), and metaplastic changes (28). The colonization of metastatic tumor cells on the tubal mucosa can mimic primary tubal neoplasm. High-grade nuclear atypia, including loss of polarity, enlargement, hyperchromasia, moderate-to-severe pleomorphism, prominent nucleoli, apoptotic bodies, and increased mitotic activity, is a sign that is suggestive of malignancy and may be a characteristic of both metastatic tumor and STIC (28). In other words, the degree of architectural or cytological atypia cannot be used as the key criteria for differentiating metastatic lesions from STIC. Papillary tufting and slit-like glandular spaces indicate the possibility of STIC but are inconclusive. There are some differences in histological features between IEM and STIC. Firstly, unlike metastatic lesions, the majority of STIC arises from the fimbria (29). Secondly, as the metastatic tumor cells closely resemble the primary tumor, morphological consistency between the primary and metastatic tumors can help to differentiate between tubal metastasis and STIC. Usual-type endocervical adenocarcinoma (case 1) shows numerous apically situated mitotic figures and basally situated apoptotic debris appreciable at scanning magnification (28, 30). Tumors with mucinous components, including mucinous-type (case 2) and gastric-type (cases 3 and 4) endocervical adenocarcinoma, show intracytoplasmic mucin and may have some goblet cells, both of which are not seen in STIC. The tumor cell nuclei of SCNEC (case 5) display frequent molding, salt-and-pepper chromatin pattern, marked pleomorphism, inconspicuous nucleoli, and brisk mitotic activity (31). HGSCs present typically as grossly evident mass-forming lesions with ovarian involvement and tubal stromal invasion. The Arias–Stella reaction can occur in the tubal epithelium of pregnant women, generating a similar morphology to that seen in the endometrium. This benign condition can be distinguished from malignant lesions based on clinical information about a recent pregnancy. Tubal hyperplasia primarily occurs in patients with estrogen-producing tumors or in response to inflammatory diseases such as pelvic inflammatory disease and endometriosis (32). Histologically, tubal hyperplasia shows several features, including a cribriform, back-to-back tubular epithelium, or microcystic sieve-like growth pattern, that induce suspicion of a neoplastic condition (33). However, there is an absence of both high-grade nuclear atypia and atypical mitotic figures. SCOUT is a rare condition, which may look distinct from the adjacent tubal epithelium. SCOUT lacks block p16 positivity and high-grade cytological atypia and shows wild-type p53 immunostaining pattern.

The metaplastic change of the tubal epithelium is a benign, reactive cytoplasmic alteration. The commonest type is mucinous metaplasia, whereas transitional and squamous metaplasias are less common. In patients with malignant tumors showing mucinous differentiation, it is often difficult for pathologists to determine whether the tubal lesion is a metastatic lesion or mucinous metaplasia. Few studies have investigated mucinous metaplasia of the fallopian tube. Wong et al. (34) reported 23 cases of tubal mucinous metaplasia, and only one of them was identified in a patient with colonic carcinoma. The authors suggested that, as mucinous cytoplasmic alterations of the tubal epithelium are observed in patients who do not have a malignant tumor, these changes represent a metaplastic process. Furthermore, they stated that the incidence of tubal mucinous metaplasia remains unknown, and is probably underreported. Moreover, there are no reliable immunohistochemical markers for tubal mucinous metaplasia because its immunophenotype was seldom investigated. Unlike metastatic mucinous carcinoma, mucinous metaplasia lacks cytological atypia and mitotic activity, and tends to coexist with other metaplastic changes and chronic inflammation. Nevertheless, the possibility of neoplastic transformation of tubal mucinous metaplasia should be considered when atypical mucinous glandular proliferation is associated with cytological and architectural atypia.

Immunostaining can guide the differential diagnosis of challenging intraepithelial lesions of the fallopian tube. WT1 is the first marker to be included in the immunostaining panel. STIC shows uniform positivity for WT1, whereas WT1 expression was absent in all five cases of metastatic cervical carcinoma. A mutant p53 immunostaining pattern is another requisite feature for diagnosing STIC. Most endocervical adenocarcinomas, particularly HPV-associated tumors, demonstrate wild-type p53 expression pattern, which helps to distinguish metastatic lesions from STIC. However, one potential pitfall that is worthy of mention is that either p53 over-expression or complete absence of p53 immunoreactivity is observed in a significant proportion of gastric-type endocervical adenocarcinoma, and this could lead to the misdiagnosis of the tubal involvement by an endocervical adenocarcinoma, such as STIC (36). In this study, we noted that both cases (cases 3 and 4) of gastric-type endocervical adenocarcinoma exhibited diffuse and strong nuclear p53 immunoreactivity (p53 over-expression) in both primary and tubal metastatic tumors. Correlation with the cervical findings and the mucinous features could result in an accurate diagnosis. p16 immunoreactivity is a reliable surrogate marker for HPV-associated endocervical adenocarcinoma, wherein the tumor cells show horizontally continuous, strong staining in almost all tumor cell nuclei. However, similar to p53 expression, this block positivity for p16 can be a misleading clue. Although the majority of STICs show generally negative or non-block p16 immunoreactivity (36), a small subset of STICs is diffusely and strongly positive for p16 regardless of high-risk HPV infection. In this situation, HPV in situ hybridization (ISH) is useful for recognizing the distribution of HPV within the tumor cells. HPV ISH is negative in STICs because HPV infection is irrelevant to STICs.

In addition, endometrioid tubal intraepithelial neoplasia (ETIN), also known as atypical endometrioid proliferation of the fallopian tube, should be included in the differential diagnosis of tubal intraepithelial lesions. In a recent study by Hecht et al. (35) who reported four cases of ETIN, the authors observed ETIN in <1% of the hysterectomy specimens that were examined. ETIN is a focal and microscopic lesion that shows atypical glands with endometrioid cytomorphology that resembles endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia. Similar to metastatic lesions, ETIN consists of cells with nuclear atypia, including hyperchromasia, pleomorphism, loss of polarity, and prominent nucleoli. In addition to these features, ETIN exhibits pale, oval nuclei and abundant cytoplasm with apical cytoplasmic vacuoles, which can mimic metastatic endocervical adenocarcinoma. Nuclear expression of β-catenin lends support to a diagnosis of ETIN rather than to a diagnosis of metastasis.

Intraepithelial spread of metastatic tumor cells has been described in other gynecological organs. The best recognized is vulvar intraepidermal metastases by colorectal and urothelial carcinomas, that is, secondary vulvar Paget disease (36). Metastatic tumors may involve the tubal surface epithelium by any of the following potential mechanisms: 1) extension of tumor deposits along the parametrium or serosal surface into the fimbrial mucosa (transperitoneal spread); 2) transuterine/transtubal spread of exfoliated tumor cells; 3) lymphovascular spread; and 4) direct extension. Two or more mechanisms may be involved in the tubal metastases. The transuterine/transtubal route has been suggested as a mode of spread of endocervical adenocarcinoma (37, 38). Of note, considering that all cases in this study extensively involved the endomyometrium, the most likely mechanism for the metastasis is that exfoliated tumor cells might spread along the uterine corpus into the isthmic portion of the tube. Furthermore, although the transperitoneal spread is suspected by the presence of parametrial extension in all cases, the metastatic tumors skipped the ovaries and peritoneum and involved the tubes only.

Data on the clinical significance of tubal IEM from cervical carcinomas are very limited, and we found no relevant literature on this issue. In our series, tubal IEMs were detected in cases with at least locally advanced disease, and all had pelvic lymph node metastases. One case had distant metastases at the time of surgery, and three of the remaining four cases developed metachronous distant metastases during the follow-up period. The mode of tumor spread within the gynecological organs is considered to affect the prognosis, as there are two contrasting biological forms of these: one in which a generally indolent tumor spreads transtubally, and another wherein aggressive disease spreads via conventional routes of dissemination (12). The spread of transuterine/transtubal metastases to the fallopian tube may not be an independent prognostic factor, but could represent an incidental finding that can be seen in locally advanced disease, especially in cases with endomyometrial involvement.

Neuroendocrine tumors are rare at all locations in the female genital tract (39). Tubal involvement of high-grade neuroendocrine carcinoma of gynecological origin has been mentioned in only a few reports in the literature (39, 40). In a recent case report, primary ovarian large cell neuroendocrine carcinoma (LCNEC) secondarily spread to the tubal mucosa (39). The pathological diagnosis of ovarian LCNEC in a 72-year-old woman was rendered based on a typical neuroendocrine histology and positive immunoreactivities for neuroendocrine markers. The metastatic tumor involved the tubal mucosa with STIC-like and pagetoid growth patterns. To the best of our knowledge, our case is the first reported case of tubal IEM of primary cervical SCNEC. Based on the theory that the tubal intraepithelial carcinoma with expression of neuroendocrine markers and absence of WT1 suggests a precursor of primary neuroendocrine carcinoma of the fallopian tube (39), the possibility of intraepithelial involvement of primary tubal neuroendocrine tumors or a neuroendocrine component of another histological subtype exists. However, the advanced stage of disease at the time of diagnosis and the simultaneous presence of distant metastases support the possibility of a metastasis rather than that of a precursor of an independent primary tumor.

In summary, we described the clinicopathological characteristics of tubal IEMs of cervical carcinomas. Although ovarian metastasis was absent, all tubal metastatic tumors were detected microscopically and measured ≤2 mm in their greatest dimension. Tubal metastases from the cervical carcinoma should be distinguished from various tubal conditions including STIC, HGSC, and other non-neoplastic lesions. As the metastatic tumor resembles the primary tumor, morphological consistency between the primary and metastatic tumors can help to distinguish tubal metastasis from STIC. Moreover, immunostaining helps guide the differential diagnosis for challenging intraepithelial lesions of the fallopian tube. One of the possible mechanisms of tubal metastasis is transuterine/transtubal spread of exfoliated tumor cells. We believe that sharing the details of our clinical experience with tubal IEM will be of great help to further the pathologist’s understanding of this rare condition and to establish an accurate diagnosis.