MNAC is a typical rare malignancy which arises from the mesonephric remnant located in the female genital tract[1]. It was found mostly in the cervix [3] and rarely in the vagina [26] and uterine corpus[31]. These carcinomas have unique histologic and immunohistochemical characteristics. MNAC often presented varable histologic grown patterns from microscopic field to field within the same tumor, and as a result may be under-evaluated and misdiagnosed[4].The characteristic morphologic pattern include tubulocystic, retiform, papillary, ductal, sex cord, glomeruloid and solid components, the lumens contain dense periodic acid Schiff positive eosinophilic secretions[9, 11, 35]. Due to its rarity, these histologic patterns can easily be mistaken for a variety of other neoplasms to the unsuspecting pathologist. There may be a characteristic immunophenotype with consistent positive staining for GATA3 and PAX-8 as well as negativity staining for steroid hormone receptors, both the ER and PR [39, 44, 47]. The staining for TTF1 is usually diffuse, and there is a luminal positivity for CD10 in the majority of cases.[48]
UB-MNAC is rare, and the diagnosis of UB-MNAC can be challenging, especially on biopsy materials and frozen sections. Morphologic differential diagnoses of UB-MNAC include cervical mesonephric adenocarcinoma with involvement of the uterine corpus and different morphological subtypes of endometrial adenocarcinomas. The distinction of a “true” cervical mesonephric adenocarcinoma depends on the tumor being located entirely or predominantly within the cervix or the uterine corpus. This can be determined by a detailed analysis of the hysterectomy specimen or preoperatively by a topographic evaluation of the imaging findings on CT and/or MRI[21]. To distinguish the UB-MNAC from other types of endometrial adenocarcinomas, such as clear cell carcinoma, endometrioid carcinoma, serous carcinoma, the characteristic grown pattern mentioned above and the classic immunohistochemical stains should be considered together. But by now, there are no antibodies that can distinguish UB-MNAC from Müllerian carcinomas.
The question about a real UB-MNAC has been raised by McFarland et al, who described a series of corpus mesonephric-like adenocarcinomas (MLAC) arising in the endometrium and infiltrating into the myometrium[21]. Given that these uterine cases appeared to arise from the endometrium rather than being located predominantly in the myometrium where the mesonephric remnant was supposed to be located in theory, these authors proposed that UB-MNAC do not actually arise from mesonephric remnants, but could arise from Mullerian structures and differentiate along a mesonephric pathway, and this tumor should be described as a ‘mesonephric-like” adenocarcinoma rather than MNAC.
To better understand this, we reviewed all the published cases of UB-MNAC or MLAC, and summarized them in supplementary table1. As shown in Table1, totally, 53 cases of UB-MNAC or MLAC, including the present three cases, have been reported by now, but only 46 patients had detailed clinical information. Generally, the patients with UB-MNAC or MLAC ranged in age from 31 to 91 years (mean, 59.8 years). The tumors measured 1.5 to 9.0 cm (mean, 5.3 cm) in size. Most of the patients complained of vaginal bleeding (27,58.4%).9 cases showed an elevated CA125 level, accounting for 19.6%, while the other 16 cases had a normal CA125 level. 23 cases (50%) were FIGO stage I, 5 cases (10.9%) were stage II,10 cases (21.7%) were stage III, and 7cases (15.2%) were stage IV. Only 7 cases were diagnosed as MNAC by D&C before operation, while 12 cases (26.1%) had be mistaken as EC. They all received operation therapy, but exact operation varied from TH + BSO to TH + BSO + PLND + PALND, depending on the stage and the patient general well beings. 20 cases, that was 43.4%, received postoperative therapy, either chemotherapy or radiotherapy or both. 15 cases (32.6%) showed metastasis, usually to lung(12cases,26.1%). Among them, 30 cases are arising from the endometrium, and /or infiltrating into the myometrium layer, accounting for 65.2%, while other 10 cases (21.7%) were completely confined in the myometrium layer, without endometrium involved. Respectively, evidence of mesonephric remnant was only found in 3(5.6%) cases, with two cases in our hospital found mesonephric remnant around the tumor, and the other one found mesonephric remnant in the cervix(summarized in supplementary table1).Notably, the tumors of the three cases were all arising from the myometrium, without endometrium involved. These three cases, especially the two cases in our hospital, which found mesonephric remnants around the tumor raised our interesting about whether these mesonephric or mesonephric-like adenocarcinomas arising from different parts of the uterine corpus have the same pathogenesis.
Table 1
Characteristics of patients with UB-MNAC or MLAC
Characteristics
|
n(%)
|
Total number
|
46
|
Mean age(range)
|
59.8(31 ~ 91)
|
Symptoms
|
Vaginal bleeding
|
27(58.7)
|
Abdominal pain
|
2 (4.3)
|
Pollakiuria
|
1 (2.2)
|
None
|
2 (4.3)
|
NA
|
16(30.4)
|
CA125
|
Elevated
|
9 (19.6)
|
Normal level
|
16(34.8)
|
NA
|
21(45.7)
|
Size(cm)
|
Mean size(range)
|
5.3(1.5-9.0)
|
Stage
|
I
|
23(50.0)
|
II
|
5 (10.9)
|
III
|
10(21.7)
|
IV
|
7 (15.2)
|
NA
|
1 (2.2)
|
D&C
|
MNAC
|
7 (15.2)
|
EC
|
12(26.1)
|
AC
|
2 (4.3)
|
CS
|
2 (4.3)
|
None
|
2 (4.3)
|
NA
|
21(45.8)
|
Location
|
Myometrium
|
10(21.7)
|
Endometrium, Myometrium Involved
|
30(65.2)
|
NA
|
6 (13.1)
|
Operation
|
TH
|
1 (2.2)
|
TH + BSO
|
8 (17.4)
|
TH + BS0 + PLND
|
6 (13.0)
|
TH + BSO + OMT
|
1 (2.2)
|
TH + BS0 + PLND + PALND
|
12(26.1)
|
TH + BS0 + PLND + PALND + OMT
|
1 (2.2)
|
TH + BS0 + PLND + PALND + OMB
|
1 (2.2)
|
TH + BSO + PLND + PALND + OMT + APD
|
1 (2.2)
|
NA
|
15(32.6)
|
Post operation therapy
|
None
|
9 (19.6)
|
CT
|
11(23.9)
|
RT
|
3 (6.5)
|
CT + RT
|
6 (13.0)
|
NA
|
17(37.0)
|
Metastasis
|
None
|
15(32.6)
|
Lung
|
12(26.1)
|
Lymph node
|
3 (6.5)
|
NA
|
16(34.8)
|
|
Abbreviation: UB-MNAC: uterus body Mesonephric adenocarcinoma; MLAC: mesonephric-like adenocarcinoma; NA: not available; D&C: dilatation and curettage; EC: endometrioid carcinoma; AC: adenocarcinoma; CS: carcinosarcoma; TH :total hysterectomy; BSO: bilateral salpingo-oophorectomy; PLND: pelvic lymph node dissection; PALND: para-aorta lymph node dissection;OMT:omentectomy;OMB:omentalbiopsy;APD:appendectomy;CT:chemotherapy;RT:Radiotherapy; |
To have a better understanding of this, we further analyzed the clinical characteristics and the survival rate of the two subgroup cases. Known that the MLAC arising from the endometrium had identical morphologic and immunohistochemical features with the UB-MNAC as the published literature indicated [21], our analyzed results showed the two subgroups most clinical characteristics were also identical (Table2), such as the age(60.6 ± 1.8 & 55.2 ± 4.3,P = 0.19),symptoms(most cases were presented with vaginal bleeding), stages(P = 0.19),and metastasis rate (P > 0.99)and metastasis site(a tendency to metastasize to the lung). Notably, 81.3% cases rising from the endometrium had normal CA125 level, while those originating from the myometrium had a higher elevated CA125 level (P = 0.03). This result was in consistent with the Kaplan-Meier survival analysis, which indicated that the cases from the myometrium layer had a poorer prognosis (Fig. 4, P = 0.11,). But this need more data, because the longest follow-up time was only 56 months as reported and the cases were limited so far.
Table 2
Correlation between different tumor location and various clinicopathological features of patients with UB-MNAC
Tumor Originate Location
|
Endometrium
|
Myometrium
|
P value
|
Number
|
30
|
10
|
Age
|
60.6 ± 1.8,
|
55.2 ± 4.3
|
0.19
|
Stage
|
I
|
18(60.0)
|
4(44.4)
|
0.61
|
II
|
3(10.0)
|
2(22.2)
|
III
|
6(20.0)
|
1(11.1)
|
IV
|
3(10.0)
|
2(22.2)
|
CA125
|
Normal
|
13(81.3)
|
3(33.3)
|
0.03*
|
Elevated
|
3(18.7)
|
6(66.7)
|
Tumor size
|
≤ 5
|
16(66.7)
|
4(40.0)
|
0.25
|
༞5
|
8(33.3)
|
6(60.0)
|
Therapy
|
Operation
|
8(42.1)
|
1(10.0
|
0.08
|
Operation + others
|
11(57.9)
|
9(90.0)
|
Metastasis
|
Yes
|
10(47.6)
|
4(44.4)
|
> 0.99
|
No
|
11(52.4)
|
5(55.6)
|
|
By reviewing the literatures, we found that some theories do exist for the MLAC, one is the secondary trans-differentiation from Müllerian type carcinomas. The theory appears to be supported on a molecular basis. In the first sizeable series investigating the molecular alterations in MNAC, the authors showed that MLAC, similar to MNAC, are characterized by recurrent KRAS mutations, frequently PIK3CA mutations, and lack of PTEN mutations.PIK3CA mutations are mutations which have not been identified in MNAC previously [46] and PTEN and PIK3CA mutations are common in endometrial carcinomas, present in up to 95% of endometrial microsatellite instable and POLE mutated tumors[44]. These molecular features demonstrate biological overlap with carcinomas of both mesonephric and Mullerian (endometrioid) differentiation. Besides, one recent report presented a patient with coexisting endometrial MLAC and low-grade endometrioid carcinoma[40], which was treated using medroxyprogesterone acetate therapy, resulting in recurrence of MLAC alone. Another recently published two papers presented two ovarian adenocarcinomas with combined low-grade serous and mesonephric morphologies, also suggest a Müllerian Origin for some Mesonephric Carcinomas.[22, 24]Given the previously documented association with endometriosis (ovarian neoplasms)[24] and the prominent endometrial involvement (uterine corpus neoplasms)[21], these tumors are best regarded as of Mullerian origin and representing adenocarcinomas which differentiate along mesonephric lines.
From the cases we presented in this study, we suggest that UB-MNAC arising from different part of the uterus have different pathogenesis, and may have different prognosis though they may have identical morphology and immunophenotype as well as other clinical characteristic. The tumor arise from the myometrium should be referred as “true” mesonephric carcinomas which is originated from the mesonephric remnant in the uterine wall, though in most cases, mesonephric remnants could not be found. That may be because of the overgrowth of the tumor. and those located in the endometrium layer are better to be diagnosed as “mesonephric-like” carcinomas, which may undergo mesonephric transformation of Müllerian adenocarcinoma. To date, only 53 cases of UB-MNAC or MLAC, including the present cases, have been reported. It might because many cases had been misdiagnosed as Müllerian adenocarcinoma. To better understand the pathogenesis and biological behavior, it is necessary to collect sufficient MNAC cases for clinicopathological and molecular study by keeping in mind the possible presence and classic histological features of MNAC or MLAC in the uterine corpus.