Neuroendocrine carcinoma of the endometrium is a “rare bird” and solid rules coming from reference centers are hard to find in literature.

However, there have only been 3 series and 90 cases of NECa in literature to date: the three largest series that fulfil the current WHO diagnostic criteria for endometrial NECa had 10, 16 and 25 cases.

The largest case series comes from MD Anderson Cancer Center and it took 15 years to collect 24 patients ^[3].

Endometrial NECa arises predominantly in the sixth and seventh decades, like other cancers arising from uterine epithelium, usually with AUB-M (FIGO, PALM-COEIN) and even paraneoplastic syndromes have been described (retinopathy, Cushing, …) ^[4].

Data in literature are scarce to encourage generalizations; consequently no reliable guidelines for diagnosis and treatment are established.
Imaging does not allow histological distinction since all endometrial cancers tend to present similarly: CT can show an hyperintense enhancing with or without central zones of low attenuation suggesting necrosis, while MRI may note heterogenic lesions with deep myometrial infiltration, low to moderate signal on T2 and hypo-intensity relative to the hyperintense enhancing myometrium on dynamic contrast-enhanced sequences ^[5].

Therefore, it is uncommon to come across this tumour in our clinical practice and it is also quite easy to miss the diagnosis when it comes to the pathologist.

1. Kurman et al. divide neuroendocrine tumors of the corpus uteri into two categories: low-grade neuroendocrine tumors (carcinoid tumors; Grade 1) and high-grade neuroendocrine tumors (Grade 3) which includes small cell NECa (SCNECa) and large cell NECa (LCNECa) ^[6].

Macroscopically they usually produce bulky masses with variable myometrial invasion, although SCNECa and LCNECa differ for their histopathology. Indeed, SCNECa resembles small cell carcinoma of the lung and is made up of ovoid, oat-cells with condensed nuclei and scant cytoplasm with frequent nuclear molding. It may arise with different growth patterns (diffuse, trabecular, nested or rosette-like). At the same time, the main feature of LCNECa are large polygonal cells with hyperchromatic nuclei arranged in well demarcated nests or trabeculae. There is high mitotic index per HPF and geographic necrosis with a single case in literature without necrosis.

Vascular invasion with or without nodes involvement is typically present.

SCNECa may react for chromogranin A, synaptophysin, CD-56, vimentin and cytokeratins. It should be acknowledged, however, that Tafe and Bartosch proposed that this diagnosis should require the expression of two NE markers and/or more than 20% of positivity.

MMR protein abnormalities may be seen in almost 50% of tumors. A patchy or diffused positivity for p16 (FISH for HRHPV), PAX-8, CD117 and TTF-1 (rare) is also reported, although those are not required for diagnosis. Also remember that PNETs are commonly synaptophysin positive but chromogranin negative ^[3].

Expression of neuroendocrine markers is reported in 62.5% of FIGO grade 3 non-NECa endometrioid carcinoma, which behave more aggressively with deep myometrial invasion, metastasis and decreased survival. ^[7]

However, a small percentage of SCNECa cases show distinctive histologic features of small cell carcinoma without any typical immunohistochemical evidence of neuroendocrine differentiation ^[8].

In this regard, we report the case of a woman who came to our institution in September 2020, hospitalized for the clinical suspect of locally invasive cervical tumor and liver metastasis (IVB FIGO). The patient was 63 years old, gravida 1, para 1, menopause 15 years before.

We performed cervical biopsy and needle biopsy of the liver nodules.

The histopathological study demonstrated:

“Histological and immunohistochemical analysis: The histological analysis showed multiple endocervical fragments, almost completely infiltrated by solid and trabecular clusters of malignant cells, with high mitotic count (>20/10HPF) and extensive necrosis.

The microscopical examination of liver nodule biopsy revealed similar histological features.

Proliferative index (Ki67-positive neoplastic cells) was about 80%.

Immunoistochemically, the neoplastic cells showed positivity only for CK-CAM5.2 and negativity for synaptophysine, chromogranin A, CD56, CK7, TTF-1, CDX2, ER, PgR, p63, p40 and HepPar-1.

Although the neoplasm was chromogranin A and synaptophysine negative, the morphological aspect and the clinical features of the disease (paraneoplastic hypercalcemia) were likely to suggest the diagnosis of small cell neuroendocrine carcinoma.”

The patient did not receive chemotherapy and died two months after the diagnosis.

Therefore, recognizing this neoplasia remains difficult due to its incidence (less than 1% of endometrial cancers) and its tendency to be intermingled with other histotypes.

Fifty to 80% of SCNECa are mixed with serous or endometrioid histotypes, so it can be misinterpreted as dedifferentiated carcinoma ^[1]. When compared to mixed type of endometrial SCNEC, prognosis of a pure type was reported to be worse ^[9].

We cannot assess whether there is a dedifferentiation of epithelial component or there are two distinct populations ab initio.

The diagnosis usually comes from consultation to a referral center for uncommon/unknown histological features; in literature, frequent misdiagnosis has been reported with: grade 3 endometrioid or serous carcinoma, PNETs, atypical carcinoid, carcinosarcoma, metastasis of breast carcinoma.
Most cases arose in advanced stages with an advanced to early stage ratio of 1.3:1 or 1.8:1. It is an aggressive disease with mean survival (FIGO stage I to IV) of about 12 months, however there is a subset of cases with endometrial NECa surviving more than 5 years ^[3]. SCNECa and the presence of a predominant NECa component seem to be good prognostic items.

Although there is no evidence that radical surgery has an impact in the course of the disease, primary surgical cytoreduction with total hysterectomy, salpingo-oophorectomy, omentectomy and pelvic lymphadenectomy is usually performed as the first step in the management of these tumors. Complete surgery provided better outcomes compared to incomplete surgery ^[10].

If we consider the experience coming from MDACC to choose the best adjuvant regiment ever, we can find there is no evidence-based, univocal indication: patients responded to platinum (plus etoposide, cyclophosphamide, 5-fluorouracil, streptozocin or paclitaxel) with or without radiation therapy, although others underwent radiation therapy alone. Partial responses to octreotide have been reported. For FIGO stage I-II disease radical hysterectomy with pelvic lymph node dissection followed by adjuvant chemoradiation with concurrent cisplatin and etoposide is usually performed. Chemoradiation followed by additional chemotherapy with a goal of six total cycles is an option for locally advanced disease. Hoskins et al. reported that chemoradiation with etoposide/cisplatin (EP) along with pelvic radiation resulted in successful treatment of stage IA-IVB disease ^[11].

Consequently, the optimal management still remains unclear. Oncologists may consider prescribing neoadjuvant chemotherapy when a preoperative diagnosis of uterine NEC is possible, given the poor prognosis even after radical surgery.

These malignancies are extremely rare, thus management is often extrapolated from small and large cell carcinomas of the lung (cisplatin, carboplatin, etoposide or cyclophosphamide) ^[12;13].