Controversies in the Management of Mesonephric and Mesonephric-Like Adenocarcinomas of the Female Genital Tract.

To date, there are no completed prospective therapeutic studies in patients with mesonephric or mesonephric-like adenocarcinoma of gynecologic origin. Due to the rarity of these tumors, it is very difficult to study a large enough population of patients to assess efficacy of treatments and subsequent survival outcomes. As such, retrospective cohort studies have provided most of the information used to guide the treatment of patients with these tumors. Even then, these retrospective studies include no more than 100 patients with mesonephric or mesonephric-like adenocarcinoma. Moreover, with tissue of origin from cervix or uterus/ovary, subsets of patients with specific tissue of origin who receive particular treatment regimens become too small to draw concrete conclusions. Currently, there are 2 ongoing trials investigating novel therapeutics for the treatment of this these rare tumors. A phase II single-institution study ( NCT05787561 ) is assessing the dual MEK/RAF inhibitor avutometinib in combination with the FAK inhibitor defactinib in patients with recurrent mesonephric or mesonephric-like adenocarcinoma of gynecologic origin. In addition, a phase I/II study ( NCT0592293 ) is investigating intraperitoneal delivery of TROP2-CAR/IL-15 transduced cord blood-derived natural killer cells for patients with recurrent or progressive ovarian, pancreatic, or mesonephric-like adenocarcinoma [ 45 ]. Continued clinical trial development and multi-institutional collaboration are necessary to accrue enough patients with these rare tumors to enable further expansion and development of efficacious treatment regimens.

Mesonephric and mesonephric-like adenocarcinomas response to adjuvant treatment, and specifically platinum treatment, is a point of study and controversy. Historically, due to their aggressive nature, mesonephric and mesonephric-like adenocarcinomas were thought to not respond to systemic chemotherapy options, and so surgery has remained the mainstay for treatment. In 2003, Montagut et al. published a case report of a patient with recurrent mesonephric-like adenocarcinoma of the uterine corpus with a good response to carboplatin and paclitaxel systemic treatment [ 39 ]. In addition, they reported on 10 patients with recurrent mesonephric-like adenocarcinoma, 6 of whom demonstrated response to salvage treatment with chemotherapy [ 39 ]. While the salvage treatment regimens differed for each patient, platinum was included for most patients with good response [ 39 ]. These data generated hypotheses regarding the efficacy of platinum-doublet treatment in patients with recurrent mesonephric or mesonephric-like adenocarcinoma. In a large cohort of 81 patients with mesonephric or mesonephric-like adenocarcinoma, Praiss et al. reported response rates to systemic treatment in 24 patients with evaluable recurrent disease [ 4 ]. The response rate for patients with recurrent mesonephric-like adenocarcinoma of uterine origin who received platinum-doublet treatment was 78% (7 of 9; 1 complete response, 6 partial responses) [ 4 ]. The response rate for those with recurrent mesonephric-like adenocarcinoma of ovarian origin who received platinum-doublet treatment was 75% (3 of 4; 1 partial response, 2 stable disease) [ 4 ]. Only 1 patient had recurrent mesonephric adenocarcinoma and received platinum-doublet treatment; their best response was stable disease and they subsequently demonstrated progression of disease after 5 months [ 4 ]. While these data do not provide insight into the efficacy of adjuvant systemic treatment after upfront surgery, they may indicate better response to platinum-doublet treatment for those with recurrent mesonephric-like adenocarcinoma than what has previously been described. Aside from platinum-doublet treatment, mesonephric and mesonephric-like adenocarcinomas demonstrate poor response to other systemic treatments [ 40 ]. Endocrine agents and poly (ADP-ribose) polymerase (PARP) inhibitors are often not effective, as mesonephric and mesonephric-like adenocarcinomas do not commonly express estrogen or progesterone receptor by immunohistochemistry and are not associated with BRCA mutations or homologous recombination deficiency [ 14 , 40 – 42 ]. Data regarding the use of immunotherapy in patients with mesonephric and mesonephric-like adenocarcinomas are limited [ 40 , 43 ]. Praiss et al. described 3 patients with recurrent mesonephric-like adenocarcinoma of uterine origin who received immunotherapy, with best response of progression of disease [ 4 ]. Notably, all 3 tumors had mismatch repair-proficient tumors and/or low tumor mutational burden [ 4 ]. One patient in their cohort had recurrent mesonephric adenocarcinoma (positive for programmed death-ligand 1 on immunohistochemistry) and had stable disease on immunotherapy for 22 months [ 4 ]. Aside from immunotherapy, 2 patients with recurrent mesonephric-like adenocarcinoma of uterine origin received either temsirolimus or anti-hormonal therapy, and both had a best response of stable disease [ 4 ]. These findings indicate a need for continued development and assessment of targeted treatment options for patients with these rare tumors [ 40 ].

Because mesonephric adenocarcinoma originates in the cervix and mesonephric-like adenocarcinoma can originate from uterine or ovarian tissue (often associated with endometriosis), treatment plans are controversial with regards to treating as a unified mesonephric disease or treating by tissue of origin [ 27 , 28 ]. For example, a patient with early-stage mesonephric adenocarcinoma might follow the treatment paradigm of early-stage cervical cancer, ie, upfront surgical resection followed by possible adjuvant radiation. In contrast, a patient with early-stage mesonephric-like adenocarcinoma of the ovary may undergo upfront surgical resection of the tumor followed by adjuvant platinum-doublet chemotherapy, consistent with an ovarian cancer paradigm. Similar treatment paradigms and systemic chemotherapy regimens are used for the treatment of small-cell carcinoma, a rare neuroendocrine tumor, regardless of site of origin (lung, uterine cervix, prostate) [ 29 , 30 ]. Data regarding treatment and prognostic outcomes for patients with mesonephric and mesonephric-like adenocarcinomas are based largely on published case reports/series and only a few literature reviews [ 27 , 28 , 31 , 32 ]. Dierickx et al. published a case report and literature review of cervical mesonephric adenocarcinoma, which included 40 previously published cases [ 27 ]. Of 39 cases described, 70% were diagnosed at stage I after primary surgery, and most patients did not receive adjuvant treatment: 5 patients received postoperative adjuvant radiotherapy and only 1 patient, whose tumor had mixed histology with a spindle cell component, received chemotherapy. The authors did not note any differences in disease recurrence between those who did and did not receive adjuvant therapy; however, with such small numbers, the authors were unable to draw any conclusions about appropriate treatment paradigms for patients with mesonephric adenocarcinoma [ 27 ]. Horn et al. similarly published a case series with literature review on mesonephric-like adenocarcinoma of the uterine corpus [ 28 ]. They identified 40 patients, 52.4% of whom presented with locally advanced disease [ 28 ]. Almost all patients were treated with upfront surgical management including hysterectomy and bilateral salpingo-oophorectomy with or without lymph node dissection [ 28 ]. Postoperative adjuvant treatment included a range of radiation therapy (vaginal brachytherapy and/or abdominal radiation), chemotherapy alone, or chemoradiation [ 28 ]. After a mean follow-up time of 24.7 months (range, 3–144.5), 48.6% of patients showed no evidence of disease, 12.5% died of disease, and 40% were alive with evidence of disease [ 28 ]. To our knowledge, there are even fewer case reports/series or literature reviews reporting on mesonephric-like adenocarcinoma of ovarian origin [ 33 , 34 ]. Outside of the gynecologic tract, mesonephric and mesonephric-like adenocarcinomas of non-gynecologic origin are exceedingly rare. They have been reported primarily in the urethra, bladder, prostate, and periprostatic tissue arising from mesonephric remnants, bland, tubular structures with luminal eosinophilic secretions with the capacity to undergo hyperplastic proliferation [ 35 – 37 ]. The first case of mesonephric carcinoma of genitourinary origin was described in 1968, and involved the urethra [ 38 ]. Between 1973 and 2018, fewer than 40 cases of mesonephric adenocarcinoma involving the urethra and bladder were reported, most of which occurred in females [ 36 ]. However, a study from 2021 indicated that the term “mesonephric” had likely been inaccurately applied in many prior studies reporting on mesonephric adenocarcinoma of the urinary tract, which were likely Mullerian-derived carcinomas, in particular clear cell adenocarcinomas [ 37 ]. In this report, 2 cases of primary mesonephric adenocarcinoma (Wolffian-derived) of the urethra were described, in which tumors displayed nuclear pleomorphism with heterogeneous tubular, solid and ductal growth patterns, spindle and clear cell morphologies, neoplastic tubules with luminal eosinophilic material, and fewer hobnailed cells. One of the two cases noted the presence of mesonephric remnants. Consistent with mesonephric adenocarcinomas of female genital tract origin, both cases were positive on immunohistochemistry staining for PAX8, GATA3, and CD10 (luminal), negative for estrogen receptor and prostate-specific antigen, and displayed the reverse GATA3 and TTF1 staining pattern previously described [ 23 ]. One tumor had a genomic profile consistent with mesonephric adenocarcinoma of the female genital tract, including a KRAS G12D mutation. Ultimately, with limited data available, it is difficult to determine the most effective treatment paradigms for patients with mesonephric or mesonephric-like adenocarcinoma. Based on the available case reports/series and literature reviews, most patients undergo upfront surgical management of the tissue of origin [ 27 , 28 ]. Upfront surgery provides optimal diagnostic tissue and allows the ability to clear local tumor. The role of adjuvant treatment paradigms after surgery remains largely dictated by standard practice for treatment based on the site of disease origin. Given similar histologic and molecular underpinnings, mesonephric and mesonephric-like adenocarcinomas may one day be treated as a unified disease process.

Ultimately, mesonephric and mesonephric-like adenocarcinomas of the gynecologic tract are a rare subset of tumors with nearly ubiquitous somatic KRAS mutations and aggressive behavior. Routine next-generation sequencing is helpful in the diagnosis of this otherwise difficult-to-diagnosis and under-represented histology. Given the lack of prospective data available, treatment response rates remain largely unknown, but patients with metastatic disease have been shown to respond to platinum-based treatment. Currently, surgical treatment paradigms are based on the site of origin (cervix, uterine, ovary). Surveillance with thoracic imaging is necessary, as recurrent disease is most often located in the lungs. Finally, treatment regimens utilizing the molecular underpinnings of MAPK pathway alterations are being studied in phase I and II trials. Further multi-institutional trials are necessary to elucidate additional therapies for these rare tumors.

Mesonephric and mesonephric-like adenocarcinomas of the gynecologic tract are rare, aggressive cancers that share histologic appearance and nearly universal mitogen-activated protein kinase (MAPK) alteration, most commonly KRAS mutations [ 1 – 5 ]. Mesonephric adenocarcinoma of the cervix is a human papillomavirus-independent adenocarcinoma that originates from mesonephric (Wolffian) duct remnants within the deep cervical wall [ 6 – 11 ]. In contrast, mesonephric-like adenocarcinoma arises in the uterine corpus, ovary, para-adnexal soft tissue, or vagina, and does not have Wolffian duct remnant origins but rather is thought to arise from transdifferentiation of Mullerian epithelium, including endometriosis [ 1 , 12 – 15 ]. Regardless of their tissue of origin, mesonephric and mesonephric-like adenocarcinomas are histologically and molecularly similar. A recent methylation study showed co-clustering of mesonephric and mesonephric-like adenocarcinomas, distinct from clusters of other gynecologic cancers, suggesting that mesonephric-like adenocarcinoma have true mesonephric differentiation [ 16 , 17 ]. Both mesonephric and mesonephric-like adenocarcinomas can display architectural heterogeneity, often within the same tumor. Typical patterns include tubular, glandular, papillary, solid, spindled, and glomeruloid, all lined by cuboidal to columnar cells with uniform, round to ovoid nuclei with open chromatin resembling the classic “Orphan Annie eye” seen in papillary thyroid carcinoma. Because of this morphologic variation, mesonephric and mesonephric-like adenocarcinomas are often mistaken for other more common entities, like endometrioid, clear cell, or low-grade serous tumors. This, compounded by their rarity, results in mesonephric and mesonephric-like adenocarcinomas being often under-recognized [ 18 ]. Moreover, its mimicry of other neoplasms and frequent presentation with mixed histologies further complicates the diagnostic process [ 19 , 20 ]. In a retrospective review of 81 patients with mesonephric or mesonephric-like adenocarcinoma, approximately 70% of tumors had mixed histology [ 4 ]. As such, immunohistochemistry can be helpful in the diagnosis of these challenging tumors [ 18 , 21 ]. Mesonephric-like adenocarcinomas are often positive for GATA3 and TTF-1, while negative or focally positive for estrogen receptor and progesterone receptor [ 11 , 14 , 22 – 25 ]. In contrast, cervical mesonephric adenocarcinoma is typically positive for GATA3, with flat negative estrogen receptor and progesterone receptor, while TTF-1 is infrequently expressed [ 16 ]. In a large cohort of 694 patients, including 8 with mesonephric adenocarcinomas, 5 with mesonephric-like adenocarcinomas, 585 with endometrial cancers, and 96 with cervical adenocarcinomas, Pors et al. compared the efficacy of GATA3 and TTF-1 compared to traditional markers, CD10, and calretinin in distinguishing mesonephric and mesonephric-like adenocarcinomas from other endometrial and cervical carcinomas [ 23 ]. GATA3 demonstrated the highest sensitivity and specificity (91% and 94%, respectively), compared with TTF-1 (45% and 99%, respectively), CD10 (73% and 83%, respectively), and calretinin (36% and 89%, respectively) [ 23 ]. While GATA3 was the best overall marker for mesonephric and mesonephric-like adenocarcinomas, the authors concluded that it may not be helpful to distinguish mesonephric and mesonephric-like adenocarcinomas from Mullerian carcinosarcomas [ 23 ]. They also demonstrated an inverse staining pattern between GATA3 and TTF-1, which may be helpful in small biopsies with negative GATA3 but high suspicion of mesonephric or mesonephric-like adenocarcinoma [ 23 ]. They also noted that TTF-1 was more often positive in mesonephric-like adenocarcinoma (100%) than mesonephric adenocarcinoma (13%), suggesting potential biological differences between the tumors. Many subsequent studies have looked at the immunohistochemical expression profile of mesonephric-like adenocarcinoma, and while in general these tumors tend to be estrogen receptor and progesterone receptor negative and express some amount of GATA3 and/or TTF-1, there is significant variation in individual tumors, and no single immunohistochemical test is definitive. In fact, there is currently no widely accepted gold standard diagnostic criteria for mesonephric-like adenocarcinoma. Beyond standard histologic diagnosis, molecular profiling of these tumors almost ubiquitously demonstrates MAPK pathway alterations, specifically in KRAS [ 2 , 4 , 16 , 26 ]. In a cohort of 36 patients, da Silva et al. performed genomic sequencing on primary and metastatic mesonephric and mesonephric-like adenocarcinomas and found 100% (8 of 8) of mesonephric adenocarcinomas harbored a KRAS mutation, while 89% (25 of 28) of mesonephric-like adenocarcinomas harbored a KRAS mutation [ 2 ]. Among the 3 mesonephric-like adenocarcinomas without a KRAS mutation, 2 had an NRAS mutation and 1 had a BRAF mutation [ 2 ]. Praiss et al. demonstrated similar findings, with 96% (25 of 26) of patients with mesonephric or mesonephric-like adenocarcinoma harboring an MAPK pathway alteration [ 4 ]. On copy number analysis, da Silva et al. also demonstrated frequent gains of chromosomes 1q and 10 in both mesonephric adenocarcinoma (87% 1q; 50% chromosome 10) and mesonephric-like adenocarcinoma (89% 1q; 43% chromosome 10) [ 2 ]. Because mesonephric and mesonephric-like adenocarcinomas are rare tumors, they often go unrecognized on pathology. To help with pathologic diagnosis, we recommend expert pathologic review of cases that are suspected to be mesonephric or mesonephric-like adenocarcinoma. Immunohistochemical staining with GATA3, TTF-1, calretinin, estrogen receptor, and progesterone receptor are helpful to further elucidate a diagnosis of mesonephric and mesonephric-like adenocarcinomas. Importantly, performance of next-generation sequencing for identification of MAPK alterations (including KRAS, NRAS, and BRAF ) can aid in the diagnosis of mesonephric and mesonephric-like adenocarcinomas.

After initial surgery or treatment, there is a paucity of data available to guide surveillance methodology. Clinicians most likely follow surveillance guidelines specific to the tissue of origin for mesonephric or mesonephric-like adenocarcinoma. However, because these tumors display aggressive and unique behaviors, they may warrant alternative surveillance methods [ 40 ]. Importantly, the limited available data suggest a long first progression-free survival interval. Praiss et al. reported a median initial progression-free survival of 33 months in a cohort of 36 patients who received all treatment at their institution [ 4 ]. However, once recurrent, they reported a median second progression-free survival of 8.3 months [ 4 ]. Alongside other published reviews, it appears mesonephric and mesonephric-like adenocarcinomas may have a latency period until first recurrence, but then once recurrent, the disease process is more aggressive [ 1 , 3 , 12 , 13 , 27 , 28 , 44 ]. This suggests a crucial role for surveillance in the initial disease-free interval. The most common site of recurrence for patients with mesonephric or mesonephric-like adenocarcinoma is the lungs [ 3 , 4 ]. Pors et al. reported that 75% of patients with mesonephric adenocarcinoma, 92% with mesonephric-like adenocarcinoma of the uterus, and 56% with mesonephric-like adenocarcinoma of the ovary experienced distant metastases [ 1 ]. Among patients with distant metastases, the lung was the most common site, with 56%, 64%, and 40% of patients, respectively, experiencing metastases to the lung. Praiss et al. similarly found the lung as the most common site of recurrence, with 48% (28 of 58) of patients experiencing recurrence in the lungs. With this high rate of distant metastases, specifically to the lung, we recommend that surveillance imaging include the chest, such as with computed tomography imaging of the chest, abdomen, and pelvis.