Ovarian seromucinous carcinoma: an independent epithelial ovarian cancer?

The 2014 WHO Classification of Tumors of the Female Reproductive Organs introduced a new category of ovarian neoplasm designated seromucinous tumors [3]. The recognition of this distinctive group is an important addition to the classification of epithelial ovarian tumors. To the best of our knowledge, in 1976 when Fox and Langley introduced the term seromucinous tumor to describe a tumor composed of endocervical type mucinous epithelium and serous-type cells [2]. Then in 1988 Rutgers and Scully divided similar appearing borderline tumors into two categories. One was composed of pure endocervical-type epithelium and another one was composed of a mixture of endocervical-type mucinous, serous, endometrioid and indifferent cells with abundant eosinophilic cytoplasm [6, 7]. Later, in 1993 Hendrickson and Kempson resurrected the term “seromucinous tumor” that a term that Shappell adopted in 2002 [8]. The previous studies were almost described the OSMCs from the pathologic aspects, and our study is firstly comparing OSMC with other EOCs to prove that OSMC is different with OEC from clinical perspective.

OSMC has similar clinical characteristics to OMC. Most OSMCs, like OMC, appear as large lumps, so a majority of OSMC are stage I or II. In our series, the prognosis of OSMC is correlated with stages. In general, patients at earlier stage have a better prognosis except case 7. The PFS of this case in OSMC is 2.5 months. One possible reason is that the grade of the lesion is three. This may be the reason of its resistance to chemotherapy. The patient received multiple chemotherapy regimens, but still died in December 26, 2017. As for biomarker, 50% cases’ ratio of CA125 to CEA of OSMC is less than 25 in OSMC, while OEC is 9% and OSC is 33.3%, but OMC is 58%. In ovarian cancer, about 5-15% of all ovarian malignancies are metastases from another malignancy. The majority of these metastases have a gastrointestinal origin, but also metastases from breast, skin or other gynaecological origin occur [9]. The ratio of CA125 and CEA differentiates better between EOC and ovarian metastases from gastrointestinal neoplasms than one of these markers alone [10]. A previous study also showed a sensitivity of 73% and specificity of 63% when a cut-off value for the CA125/CEA ratio of 25 was used compared to a sensitivity of 78% and specificity of 50% for CA125 alone to distinguish EOC and gastrointestinal neoplasms and a cut-off value of 25 has demonstrated high accuracy, and thus it has been used in clinical practice [11, 12]. OMC usually performs he biological characteristics of gastrointestinal neoplasms, so we often use the ratio of CA125 and CEA to distinguish OMC and other EOCs. In our study, more than 50% cases’ ratio of CA125 to CEA is less than 25 both in OSMC and OMC. Another point is that OMC is usually very large primary tumors that generate symptoms while the disease is still localized to the ovary [13]. And in 12 OMSC cases, about 66.7% cases are because of a pelvic mass. These all may suggest that OSMC has some biological characteristics of OMC.

In matched cohort the prognosis of OSMC is probably closer to that of OMC and different with OEC(p = 0.03). The prognosis for OEC is better than other EOCs. A potential explanation is that most OEC diagnosed at an early stage. In matched cohort, the prognosis for OSC is better than OSMC, but when change the OSC patients in 2015, the prognosis for OSC become worse. One possible reason is that most cases of the OSC in the matched cohort are early stage and lower grade, but High-grade serous carcinoma was diagnosed more often in higher stage in a natural year, and this did affect prognosis. In the whole cohort, the prognosis was not significantly related to the type of EOCs.

Histologically, our results show that firbo-oedematous papillae, squamous metaplasia, mucous epithelium in this model of the cervical canal and small nipples are the unique pathological characteristics of OSMCs. On the previous studies, the background of endometriosis was found in 36% of the cases, with ectopic endometrium and serous carcinoma transition visible in some tumors. But in our study, endometriosis was not found in any of the cases, even if we focused on past medical history of patients, we cannot find endometriosis in one case.

As for the immunophenotype of OSMC, the phenotype of gastrointestinal and mucinous tumors is quite different from that of OSMC [14]. Gastrointestinal and mucinous tumors often express markers of gastrointestinal differentiation: CK20 and CDX2, while OSMC expressed the markers of Mullerian epithelium: ER, PR, CA125, mesothelin. Moreover, PAX-8 was strongly expressed in OSMC, which was different from mucinous tumors but similar to serous tumors. In our study, OSMC also expressed the markers of Mullerian epithelium and PAX-8 was strongly expressed.

At present, there are few studies on the molecular characteristics of OSMC. The ARID1A gene is reported to be mutated in half of clear cell ovarian cancers and 30% of endometrioid cancers [15, 16]. In a study of 32 patients with OSC, the mutations included KRAS, PIK3CA, PTEN, and ARID1A [17]. And a study in 2020 demonstrated a distinct mutational landscape of OSMC in which (1) KRAS is invariably mutated, (2) PIK3CA is frequently mutated, and (3) TERT promoter mutations and DNA mismatch repair deficiencies are absent [4]. So from a molecular point of view, OSMC is probably not belong to OEC and its molecular signature is more like OSC. Because of the time span of our cases, molecular testing was not performed.

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