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. Author manuscript; available in PMC: 2022 Apr 1.
Published in final edited form as: Am J Surg Pathol. 2021 Apr 1;45(4):498–506. doi: 10.1097/PAS.0000000000001612

Clinicopathologic Characteristics of Mesonephric Adenocarcinomas and Mesonephric-like Adenocarcinomas in the Gynecologic Tract: A Multi-Institutional Study

Jennifer Pors 1,*, Sheila Segura 2,*, Derek S Chiu 3, Noorah Almadani 1, Hezhen Ren 1, Daniel J Fix 2, Brooke E Howitt 4, David Kolin 5, W Glenn McCluggage 6, Jelena Mirkovic 7, Blake Gilks 1,8, Kay J Park 2,*, Lynn Hoang 1,8,*
PMCID: PMC7954854  NIHMSID: NIHMS1635322  PMID: 33165093

Abstract

Mesonephric and mesonephric-like adenocarcinomas are uncommon neoplasms of the gynecologic tract that have until recently been poorly understood. Although their morphological, immunohistochemical, and molecular profiles have been recently defined, little is known about their clinical behavior. Small studies have demonstrated inconsistent findings and no large studies have examined the clinical behaviour of these adenocarcinomas. In this multi-institutional study, representing the largest and most stringently defined cohort of cases to date, we examined the clinicopathologic features of 99 mesonephric and mesonephric-like adenocarcinomas (30 mesonephric adenocarcinomas (MA) of the uterine cervix, 44 mesonephric-like adenocarcinomas (MLA) of the endometrium, and 25 MLA of the ovary). Only tumors with characteristic mesonephric morphology and either immunohistochemical or molecular support were included. Our results demonstrate that the majority of mesonephric neoplasms presented at advanced stage (II-IV) (15/25 [60%] MA of cervix, 25/43 [58%] MLA of endometrium, and 7/18 [39%] MLA of ovary). The majority (46/89 [52%] overall) (12/24 [50%] MA of cervix, 24/41 [59%] MLA of endometrium, and 10/24 [42%] MLA of ovary) developed recurrences, most commonly distant (9/12 [75%] MA of cervix, 22/24 [92%] MLA of the endometrium, and 5/9 [56%] MLA of the ovary). The 5-year Disease Specific Survival (DSS) was 74% (n=26) for MA of cervix, 72% (n=43) for MLA of endometrium, and 71% (n=23) for MLA of ovary. Our results confirm that mesonephric neoplasms are a clinically aggressive group of gynecologic carcinomas that typically present at an advanced stage, with a predilection for pulmonary recurrence.

Keywords: Mesonephric carcinoma, mesonephric-like carcinoma, clinical presentation, prognosis, immunohistochemistry

INTRODUCTION

Mesonephric and mesonephric-like adenocarcinomas are uncommon neoplasms of the gynecologic tract that have, until recently, been underrecognized and poorly understood. Mesonephric adenocarcinomas (MA) are human papillomavirus (HPV)-independent neoplasms of the uterine cervix. Mesonephric-like adenocarcinoma (MLA) are a recently defined group of adenocarcinomas of the ovary and endometrium. This entity was described in 2016 in a study coauthored by one of us (WGM)1 and will be included in the upcoming 2020 World Health Organization (WHO) Classification of Female Genital Tumors.

Currently, little is known about the clinical behavior of these rare tumors. Most studies are case reports or small case series, which have demonstrated inconsistent findings; some suggest that MA are more indolent than Mullerian-adenocarcinomas2 while other studies of MLAs conclude that they have a worse prognosis, presenting at higher stages and with frequent recurrences3–5. Some of the discrepancy in reported clinical behavior likely stems from the challenge of diagnosing MA and MLA by morphology, as these tumors are known to demonstrate varied architecture, including tubular, ductal, solid, papillary, sex cord-like and retiform, and a component of spindle cells may be also present2,6. There is often marked heterogeneity with an admixture of architectural patterns within an individual neoplasm and while this may be useful in diagnosis, it may also result in misdiagnosis as one of a variety of other tumor types, especially on a small biopsy specimen. Only within the last 5 years have useful, although not entirely specific, immunohistochemical markers and molecular alterations been demonstrated in these neoplasms. MA and MLA are often GATA3 positive7,1,8, TTF1 positive (particularly MLA)9,1, calretinin positive8, they exhibit luminal staining with CD10, and they are usually estrogen receptor (ER) negative or at the most focally positive (especially MLA)9,1. Distinct molecular aberrations have been defined, with both MA and MLA classically demonstrating mutations in KRAS and NRAS10–12, and a subset of MLA additionally demonstrating mutations in PIK3CA and ARID1A, among others3,5,11,13.

Building on the recent work of others, who have demonstrated the unique immunohistochemical profile and molecular alterations of MA and MLA, we aimed to better characterize the clinical behavior of these rare tumors. Specifically, the primary goal of this multi-institutional study was to examine the clinicopathologic features of a rigorously defined, large cohort of mesonephric neoplasms of the uterine cervix, endometrium and ovary, and compare them to other gynecologic Mullerian adenocarcinomas.

METHODS

MAs and MLAs were retrieved from the Anatomical Pathology Departments at Vancouver General Hospital (VGH), Memorial Sloan Kettering Cancer Center, Stanford University Hospital, Belfast Health and Social Care Trust, Sunnybrook Health Sciences Centre, and Brigham and Women’s Hospital. Additional cases were obtained from the BC Cancer Registry Database. The hematoxylin and eosin slides were reviewed by subspecialty trained gynecologic pathologists (LH, KP, DK, WGM, JM, BH) who have previously published on these neoplasms. Cases were included if they showed characteristic morphologic features of mesonephric adenocarcinoma as well as either immunohistochemical confirmation (positive for at least one of GATA3, TTF1, CD10 [luminal], calretinin AND negative/focal positivity for ER), or molecular confirmation (KRAS mutations)14,15. The immunohistochemical staining was performed at the various laboratories to which the authors are affiliated using standardised validated local protocols8,7,5. Tumors were subclassified into MA of the uterine cervix and MLA of the endometrium or ovary.

The following clinical and pathologic features were recorded: age at diagnosis, presenting symptom, biopsy result and date, type and date of surgery, tumor size, FIGO stage, lymph node metastasis, presence or absence of recurrences, date and site of recurrences, and the date and status at last follow-up. The overall survival (OS) for each patient was calculated from the date of diagnosis to the date of last known follow-up or death. The disease-specific survival (DSS) was calculated from the date of diagnosis to the date of last known follow-up or death secondary to the tumor. The progression-free survival (PFS) was calculated from the date of diagnosis to the date of recurrence or, if there was no recurrence, the date of last known follow-up or death. The 5-year OS, DSS and PFS were also calculated. Cases with at least 2 years of follow-up were plotted on Kaplan Meier survival curves.

The OS, DSS and PFS of the endometrial MLA were compared to a publicly available database of endometrial carcinomas from the Cancer Genome Atlas (TCGA; https://www.cbioportal.org/)16. As no large multi-institutional database of endocervical adenocarcinomas was publicly available, the cervical neoplasms from Vancouver General Hospital were compared to a local cohort of HPV-associated (HPVA) and non-mesonephric HPV-independent (HPVI) endocervical adenocarcinomas. The hazards ratio (HR), 95% confidence intervals (95% CI), and log-rank p-values were calculated. There were no local databases, or publicly available multi-institutional databases, of ovarian carcinomas for comparison.

RESULTS

A total of 129 cases were initially identified, of which ninety-nine cases met our inclusion criteria and were entered in this study. Almost all ([91%] 90/99) had supportive immunohistochemical confirmation (positive for at least one of GATA3, TTF1, CD10 [luminal], calretinin AND negative/focal positivity for ER), except for 3 cervical MA, 1 endometrial MLA and 5 ovarian MLA which had KRAS mutation confirmation. Overall, the study group consisted of 30 MA of the cervix, 44 MLA of the endometrium, and 25 MLA of the ovary. Overall there were 18 cases from Vancouver General Hospital/BC Cancer Registry Database, 48 from Memorial Sloan Kettering Cancer Center, 19 from Brigham and Women’s Hospital, 4 from Stanford Hospital, 7 from Belfast Health and Social Care Trust, and 3 from Sunnybrook Health Sciences Centre. Six MA of the cervix11, 10 MLA of the endometrium5,11,13,17, and 4 MLA of the ovary11,8 have been published previously. The clinicopathologic features are summarized in Figure 1.

FIGURE 1.

FIGURE 1.

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Summary of clinicopathologic features of mesonephric neoplasms. Abbreviations: ND: not done; AUB: abnormal uterine bleeding; PMB: postmenopausal bleeding; APP: abdominal or pelvic pain; Cx: cervical; AGC: atypical glandular cells; Dx: diagnosis.

Mesonephric Adenocarcinomas of the Cervix (n=30)

The mean age at diagnosis for patients with cervical MA was 59 years (median: 60.5, range from 30 to 81) and the most common presenting symptom was vaginal bleeding (40% presented with postmenopausal bleeding [PMB], 34% with abnormal uterine bleeding [AUB]). Cervical MA was detected by Papanicolaou (pap) test in 10% of cases, as atypical glandular cells (AGC). A small proportion (3%) presented with a cervical mass. The remainder were diagnosed incidentally, during workup for fibroids (7%), pelvic pain (3%), or other incidental cause (3%). MA of the cervix was diagnosed correctly on initial biopsy in only 10% of cases (2 of 21).

60% (15 of 25) of cervical MA, where clinical details were available, presented at advanced stage (FIGO stage II-IV) and 28% (4/14) presented with lymph node metastases. Half of the cases (12/24) were associated with recurrences, most commonly to distant sites ([75%] 9/12), frequently to the lungs ([56%] 5 of 9). Other sites of recurrence included the vagina ([33%] 4/12), abdomen ([17%] 2/12), liver ([8%] 1/12), bowel ([8%] 1/12), and omentum/peritoneum ([8%] 1/12). Follow-up for all ranged from 0 to 204 months (mean: 51 months). The 5-year PFS was 60%, the 5-year OS/DSS was 74%.

On univariate analysis, stage (I/II compared with III/IV) was associated with a trend for association with OSS and DS but did not reach statistical significance (p=0.05772). Age, tumor size and lymph node status were not statistically significant for OS, DSS, nor PFS (p>0.09). On multivariate analysis, stage (I/II compared with III/IV) was significant for PFS (p=0.0442) independent of age, tumor size and lymph node status; but not for DSS or OS (p>0.185).

The OS, DSS, and PFS of VGH cases of cervical MA (n=6) were compared with a cohort of cervical adenocarcinomas from VGH (n=91) with at least 2 years follow-up (Figure 2). When MA was compared to HPVA, HPVA had better OS (HR: 0.112, 95% CI: 0.028–0.458, p<0.001), DSS (HR: 0.066, 95% CI: 0.009–0.472, p<0.001) and PFS (HR: 0.182, 95% CI: 0.036–0.917, p=0.00653). No differences were detected between MA and non-mesonephric HPVIA.

FIGURE 2.

FIGURE 2.

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Kaplan- Meier overall survival (OS) (A) and progression-free survival (PFS) (B) analysis for mesonephric carcinoma of the cervix versus other cervical adenocarcinomas from the same institution. Abbreviations: CI: confidence interval; HR: hazard ratio; HPVA: human papilloma virus associated; HPVI: human papilloma virus independent; MA: mesonephric adenocarcinoma.

Mesonephric-like Adenocarcinomas of the Endometrium (n=44)

The mean age at diagnosis for patients with MLA of the endometrium was 60 years (median: 61, range from 28 to 91) and the most common presenting symptom was vaginal bleeding (30/36 [83%] presented with PMB and 3/36 [8%] presented with AUB). The remaining MLA were diagnosed incidentally (1/36 [3%] in a case of uterine prolapse, 1/36 [3%] during an infertility work-up, and 1/36 [3%] with uterine fibroids). MLA were initially correctly diagnosed on biopsy in 32% (10/31) of cases.

58% (25/43) of patients with MLA of the endometrium presented at advanced stage (FIGO stage II-IV). 32% of patients (11/34) presented with lymph node metastases. 59% (24/41) of cases were associated with recurrence, most commonly to distant sites ([92%] 22/24), most frequently to the lungs (14/22 [64%]). Other sites of recurrence were the pelvis ([21%] 5/24), liver ([13%] 3/24), vagina ([13%] 3/24), brain ([8%] 2/24), spleen ([8%] 2/24), abdomen ([8%] 2/24), omentum ([4%] 1/24), peritoneum ([4%] 1/24), abdominal wall ([4%] 1/24), and vertebrae ([4%] 1/24). Follow-up ranged from 1 to 130 months (mean: 44 months). The 5-year PFS was 27.5% and the 5-year OS/DSS was 72%.

On univariate analysis, stage (I/II compared with III/IV) was statistically significant for OS and DSS (p= 0.00182) but not PFS (p=0.73207). Age, tumor size and nodal metastasis were not statistically significant for OS, DSS, nor PFS (p> 0.17544). On multivariate analysis, stage (I/II compared with III/IV) was significant for DSS and OS (p=0.00347) independent of age and tumor size, but not for PFS (p> 0.86409).

The OS, DSS, and PFS of endometrial MLA with at least 2 years follow-up (n=31) was compared with that of other endometrial adenocarcinomas available through TCGA database (68 FIGO grade 1 endometrioid, 70 FIGO grade 2 endometrioid, 123 FIGO grade 3 endometrioid, 81 serous and 50 carcinosarcomas)16 (Figure 3). Uterine carcinosarcomas had worse OS (HR: 4.692, 95% CI: 2.067–10.653, p<0.001) and DSS (HR: 4.774, 95% CI: 2.085–10.932, p<0.001) compared to MLA. FIGO grade 1 endometrioid carcinomas had better OS (HR: 0.125, 95% CI: 0.026–0.6, p<0.001) and FIGO grade 1 and 2 endometrioid carcinomas had better DSS (HR: 0–0.129, 95% CI: 0.027–0.622, p<0.001). The PFS was worse for MLA compared to FIGO grade 1, 2 and 3 endometrioid carcinomas (p<0.001).

FIGURE 3.

FIGURE 3.

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Kaplan- Meier overall survival (OS) (A) and progression-free survival (PFS) (B) analysis for mesonephric-like endometrial carcinoma versus other endometrial carcinomas from TCGA endometrial database. Abbreviations: CI: confidence interval; HR: hazard ratio. MMMT: malignant mixed Mullerian tumor; EEC: endometrioid endometrial adenocarcinoma (grade 1, 2, 3); MLA: mesonephric-like adenocarcinoma.

Mesonephric-like Adenocarcinomas of the Ovary (n=25)

The mean age at diagnosis for MLA of the ovary was 61 years (median 61, range from 36 to 81) and the most common presenting symptom was pelvic pain (10/23 [43%]). The remainder presented with AUB/PMB (4/23 [17%]), abdominal distention/bloating (4/23 [17%]), or were discovered incidentally (5/23 [22%]). Ovarian biopsies were rare and no cases of MLA of ovary were correctly diagnosed on biopsy (0/3 [0%]).

39% (7/18) of patients with MLA of the ovary presented at advanced stage (FIGO stage II-IV). 43% of patients (3/7) presented with lymph node metastases. 42% (10/24) of cases were associated with recurrences, most commonly to distant sites ([56%] 5/9). The most common sites of recurrence were the lungs (40% [2/5]), omentum (40% [2/5]), followed by the liver (20% [1/5]), iliopsoas (20% [1/5]), pubic bone (20% [1/5]), perihepatic region (20% [1/5]), mesentery (20% [1/5]), and peritoneum (20% [1/5]). Follow-up ranged from 1 to 1346 months (mean: 101 months). The 5-year PFS was 68% and the 5-year OS/DSS was 71%.

On univariate and multivariate analyses, no features were statistically significant for OS, DSS, PFS (p=0.18599 and p=0.13054, respectively).

DISCUSSION

In this multi-institutional study, we examined the clinicopathologic features of 99 mesonephric and mesonephric-like adenocarcinomas (30 MA of the cervix, 44 MLA of the endometrium, and 25 MLA of the ovary). Based on stringently defined inclusion criteria, and by far the largest cohort of cases published to date, we found that these are aggressive, and difficult to detect adenocarcinomas, which often present at high-stage and have frequent distant recurrences, with a distinct propensity for the lung recurrences.

Cervical MAs are not routinely detected by screening. Only 10% of MA of the cervix in our study were detected on a Papanicolaou (pap) test, as atypical glandular cells (AGC). Their infrequent detection by pap test has been previously described18 and is likely due, in part to their origin in the lateral walls of the cervix from mesonephric remnants19 rather than at the squamocolumnar junction.

In addition, only a small number ([22%] 12/55) of MA and MLA as a whole were correctly diagnosed by pathologists on biopsy. There are several possible explanations, including the uncommon nature of these neoplasms, their variety of architectural patterns mimicking other neoplasms and the fact that MLA is relatively recently described neoplasm and may not be known to some pathologists. Alternatively, some authors have hypothesized that MLA derive from Mullerian, rather than mesonephric, structures and differentiate along mesonephric lines; this hypothesis resulted in the term MLA17. If MLA are actually of Mullerian origin, with subsequent mesonephric transdifferentiation, it is plausible that MLA shares a common precursor with other Mullerian neoplasms, such as endometrial atypical hyperplasia.

Unlike MA of the cervix, MLA of the endometrium appear to arise from the endometrium rather than the myometrium, where residual mesonephric remnants would theoretically reside, and have not been found to be associated with mesonephric remnants17. In fact, mesonephric remnants in the myometrium are vanishingly rare and none of the authors of this paper can recall having seen a convincing example, and to our knowledge none have been reported in the literature. Furthermore, MLA exhibit molecular aberrations in KRAS, frequently, like MA, and a subset also have mutations in PIK3CA and ARID1A, like endometrioid adenocarcinomas3,5,11,13. In addition, several cases of MLA, especially in the ovary but also in the endometrium, have been shown to coexist with prototypical Mullerian neoplasms, further suggesting the possibility of Mullerian origin in at least a subset of these tumors. In fact, given the overlap between MLA and Mullerian carcinoma, it has been debated whether MLA represents a distinct clinical entity or is a subtype of Mullerian carcinoma, such as endometrioid adenocarcinoma (discussed in more detail below). Recently, one endometrial MLA was reported in association with a low-grade endometrioid adenocarcinoma, each with their expected morphology and immunophenotype and with a KRAS mutation20. Similarly, one of the authors of the current study (WGM) reported an ovarian neoplasm with distinct regions of MLA, serous borderline tumor and low-grade serous carcinoma, each with their expected morphology and immunophenotype, and a shared KRAS mutation21. In that study, a strong association was shown between ovarian MLA and benign Mullerian lesions, especially endometriosis; in 8 of 11 cases of MLA there was either endometriosis or adenomas/ adenofibromas within the same ovary21. Chapel et al12 reported a case of an ovarian neoplasm with components of MLA and serous borderline/low grade serous carcinoma regions, with a shared NRAS mutation. To date, no systematic review for precursor lesions in MLA of the endometrium has been conducted and this is an area worthy of future study.

Three patients in our current study with MAs had endometrial hyperplasia on biopsy (two as complex atypical hyperplasia (CAH), and one as simple hyperplasia without atypia). Two biopsies were available for review, and we confirmed that one definitively represented conventional CAH (which was ER positive and GATA3 negative), while the case reported as simple hyperplasia was a misdiagnosed cervical MA (GATA3 positive and ER negative)(Figure 4). Although it is possible that this may have represented an incidental or unrelated process, it raises the possibility that at least some cases of mesonephric adenocarcinoma may arise from CAH, a premalignant Mullerian lesion.

FIGURE 4.

FIGURE 4.

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The classic architectural patterns of mesonephric carcinoma are tubular (A) and glandular (B). Two patients in our study had reported histories of endometrial hyperplasia. Upon review, one case, which was originally diagnosed as simple hyperplasia, was reclassified as an incipient focus of mesonephric carcinoma (C) with concordant GATA 3 positivity (focal) (D) and ER negativity (E), while the second was confirmed to be complex atypical hyperplasia bordering on low grade endometrioid endometrial carcinoma (F), with concordant GATA3 negativity (G) and ER positivity (H), suggesting a possible Mullerian origin in a subset of mesonephric neoplasms.

Despite the well-known propensity for confusion of MA with clear cell carcinoma, the latter also referred to historically as “mesonephroma” in the literature22,23,24, most endometrial MLA in our study were mistaken for low-grade endometrioid adenocarcinoma. This is not surprising given that the various architectural patterns characteristic of mesonephric neoplasms may also occur in endometrioid adenocarcinomas. Review of the literature revealed cases reported as endometrioid endometrial adenocarcinoma which may actually represent MLA. In 2014, before MLA was described, in a study coauthored by one of us (WGM), Ervine et al reported a series of 4 cases of endometrioid endometrial adenocarcinoma with aggressive behavior25. These tumors were either PAX8 or ER positive, and similar to MLA, they were all TTF1 positive, with all patients developing recurrences in the lung. TTF1 positivity has been noted in approximately 8% (0–22%) of endometrioid endometrial adenocarcinomas26,27,28,25,29,30, and has been recognized as a poor prognostic feature for endometrioid adenocarcinoma25, again raising the possibility that some of these TTF1 positive endometroid adenocarcinomas might actually be MLA.

Although mesonephric neoplasms are difficult to diagnose, their accurate identification is important due to their relatively poor prognosis. More than half of MA and MLAs from all sites (55% [47/86]) presented at stage II or higher. Furthermore, more than half of all MA and MLAs (52% [46/89] developed recurrences, most commonly (80% [36/45]) to distant sites, with a distinct propensity for recurrence in the lung (58% (21/36) of distant recurrences overall, and 46% (21/46) of recurrences overall). The majority of cases of MA of the cervix (5/9 [56%]) and MLA of the endometrium (14/22 [64%]) recurred in the lungs, consistent with what has been previously reported31,5,3,13,32,10,1,33,34,35. By contrast, fewer ovarian MLA (2/8 [25%]) recurred in the lungs, and, to our knowledge, no lung recurrences have been documented in the literature in these neoplasms1,13,21. The incidence of lung metastasis is much lower (<5% overall) in non-mesonephric endometrial carcinomas36,37 and endocervical carcinomas in general38.

The distinction between MLA and low-grade endometrioid adenocarcinoma is clinically important, as our study compared the outcome of MLA to TCGA endometrial carcinoma database16 and demonstrated that endometrial MLA have worse OS and DSS compared to low-grade endometrioid with a behavior more similar to high-grade endometrioid endometrial adenocarcinoma. This parallels the findings by Euscher et al., who, in the only other significant study with follow-up in MLA of the uterus, studied 23 of these neoplasms and found that the median PFS was 18.2 months (median PFS was 21 months in our study), which was significantly lower compared to 183 months for low-grade endometrioid adenocarcinoma and 67.1 months for serous carcinoma35. Thus, all authors agreed that MLA should be regarded as high-grade tumors and not graded, similar to serous carcinomas and clear cell carcinomas.

When we directly compared cases of cervical MA from Vancouver General Hospital with a cohort of local HPVA and HPVI cervical adenocarcinomas, we found that MA had worse OS, DSS and PFS compared to HPVA cervical adenocarcinomas. Given the small cohort size, we were not able to adequately compare the behaviour of cervical MA to specific HPVI adenocarcinomas, such as gastric-type adenocarcinoma. However, data available in the literature suggests that gastric-type adenocarcinoma remains the most aggressive cervical adenocarcinoma overall. The 5-year DSS of cervical MA in our study was 74%, compared to previously published 5-year DSS of 42% (n=38)39 and 30% (n=16)40 for cervical gastric-type adenocarcinomas.

Although there is no available multi-institutional database for direct comparison, data available in the literature suggests that ovarian MLA has a relatively worse prognosis than endometrioid and clear cell ovarian carcinomas. The 5 year OS of ovarian MLA in our study was 71%, compared to 85% for endometrioid and clear cell ovarian carcinoma in a large study of ovarian neoplasms41.

Interestingly, we observed a difference between OS/DSS and PFS in all cohorts of mesonephric neoplasms, whereby the PFS was disproportionately worse than OS/DSS. This was also noted by Euscher et al35. It appears that although most patients with mesonephric neoplasms develop distant recurrences, the rate of death from disease does not parallel this trend. There are several possible explanations. First, the higher rate of recurrences may be a reflection of tertiary care cancer center practice, as all institutions in this study represent major cancer referral centers. Second, it is possible that the disease course of MA/MLA may be lengthy, similar to low-grade serous carcinoma, and additional long-term follow-up may be needed to confirm the expected diminished survival due to distant disease, as has been previously hypothesized2.

As discussed, our study showed that MLA of the endometrium and MA of the cervix exhibit distinct clinical behaviors, with a worse outcome than low-grade endometrial endometrioid adenocarcinoma and HPVA cervical adenocarcinoma. It still remains unclear whether MLA represents a distinct clinicopathological entity, or whether it is a variant of another tumor type, such as endometrioid adenocarcinoma. To accurately prove the lineage, more sophisticated analytic technologies, such as methylation profiling, would have to be used. If MLA do fall under the umbrella of endometrioid adenocarcinoma, they may be unsuitable for inclusion into molecular prognosticator systems in endometrial cancer, such as ProMisE, especially since they almost never exhibit TP53 mutations or microsatellite instability5,42.

We acknowledge that this study did not perform stage-matched comparisons and thus we cannot comment whether the differences in clinical prognosis are independent of stage.

In conclusion, our multi-institutional study investigating the clinical behavior of 99 mesonephric neoplasms demonstrated that they have a relatively poor prognosis, and typically present at high stage, with a distinct propensity for lung recurrences. The histogenesis and place in tumor classification for MLA is still debated, but based on their clinical behavior, they warrant distinction as a separate entity in the gynecologic tract.

Footnotes

Conflicts of Interest and Source of Funding: None declared

Disclosure: None.

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