Pure large cell neuroendocrine carcinoma (LCNEC) of the ovary is an exceptionally rare occurrence. Previous reports of LCNEC in the ovary have primarily been associated with other epithelial carcinomas or teratomas [2–6]. To date, including our case, only 26 cases of pure LCNEC of the ovary have been reported.
The diagnosis of LCNEC relies heavily on the morphological characteristics of the tumor. These features include the presence of neuroendocrine tumor structures such as organoid, trabecular, palisading, and/or rosette formations. The tumor cells typically exhibit vesicular chromatin, prominent nucleoli, abundant eosinophilic cytoplasm, and brisk mitotic activity (usually more than 10 mitoses per 2 mm^2), three times of the diameter of lymphocytes, which is the distinguishing morphology differentiated LCNEC from small cell neuroendocrine carcinoma (SCNC). Additionally, necrosis is often observed in LCNEC cases [1]. The presented case in this study exhibited the typical morphological features consistent with LCNEC.
Immunohistochemical analysis of the LCNEC tumor cells revealed positive staining for at least one of the neuroendocrine markers, such as CgA, syn, NSE, and CD56. Conversely, the tumor cells were typically negative for PAX8, WT1, vimentin, estrogen receptor (ER), progesterone receptor (PR), and epithelial membrane antigen (EMA). The p53 protein exhibited a wild-type pattern, while the nuclear stains for SMARCB1/INI-1 and SMARCA4 were retained [1–8]. Based on the histopathological and immunohistochemical features, the final diagnosis was established as pure LCNEC of the ovary.
In terms of immunochemotherapy, it holds promise for identifying treatment targets. Expression of HER2 and PD-L1 in cancer cells has been associated with favorable outcomes in certain patients. For instance, PD-L1 expression has been observed in 22.3% of LCNEC lung cancer samples [9]. However, in the present study, these markers were examined through staining and were found to be negative.
The main differential diagnosis of LCNEC includes high-grade serous carcinoma. In LCNEC, the neuroendocrine markers typically exhibit diffuse positivity, with at least one marker showing diffuse staining, which aids in the diagnosis [1]. Though in some cases, neuroendocrine markers can also be expressed in high-grade serous carcinoma, they would be focal, and the WT-1 would be diffusely expressed in high grade serous carcinoma and p53 is mutated type [7–10]. In challenging cases, the morphological features characteristic of LCNEC should be given primary consideration for an accurate diagnosis.
pLCNEC in the ovary is a very rare occurrence. To the best of our knowledge, only 25 cases have been reported in English literature. Molecular examination has been limited in these cases, with only two cases undergoing such analysis and one of them was with a heterozygous germline mutation of BRCA2 exon 17, c.7976G > A, p.(Arg2659Lys), and a deleterious somatic mutation in TP53, c.600delT, p.(Leu201Cysfs*46); while the other case showed pathogenic mutations in TERT and TP53, without BRCA1/2 mutations identified [2, 6]. In the present case, BRCA1 exon 20 c.5332 + 1G > A splice site mutation and cnLOH were found. The c.5332 + 1G > a splice site mutation of the BRCA1 gene is predicted to affect normal splicing and result in loss of protein function. The cnLOH observed in the gene copy number variation analysis may contribute to the development of ovarian cancer [11–12].
Studies on LCNEC in other parts of the body are also limited but have identified molecular characteristics. Kim et al. did gene sequencing research in 467 cases of lung LCNEC and categorized the tumors into SCLC-LCNEC (TP53/RB1 co-mutated) and NSCLC-LCNEC (wild type for TP53 or RB1) [13]. Rekhtman et al. found TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%) in LCNECs, classifying them into SCLC-like (TP53 + RB1 co-mutation/loss), NSCLC-like, and other SCLC-type subtypes [14].
Yaghmour et al. studied 46 cases of neuroendocrine tumors of the ovary and 58 cases of small cell carcinoma of the lung by using NGS and Sanger sequencing (a 47-gene panel), revealed that TP53 mutations in 25% of small cell carcinoma (1/4) patients, BRCA2 mutations in 50% of small cell carcinoma (1/2) patients. There were no LCNEC in their series [15]. Our case had no TP53 or RB1 mutation.
In the case of multiple tumors occurring simultaneously, gene analysis can help determine their common origin by identifying a common molecular profile. Additionally, gene mutations can aid in selecting targeted therapies or predicting prognosis. TP53 mutations have been associated with poor prognosis and early recurrence, while patients with BRCA gene mutations may benefit from PARP therapy [16]. However, further comprehensive studies are needed to deepen our understanding of these molecular characteristics and their clinical implications.
Surgical removal of the tumor is the primary treatment option for eligible patients with pure LCNEC of the ovary. Chemotherapy regimens commonly include paclitaxel, platinum, docetaxel, carboplatin, or cisplatin [2–8]. However, previous studies have reported poor treatment responses and dismal prognoses in LCNEC cases [3–4]. It has been observed that different molecular profiles of LCNEC tumors may respond differently to chemotherapy regimens. For example, patients with RB1 wild-type tumors showed worse response to paclitaxel + etoposide regimen compared to GTP regimen (platinum + gemcitabine or taxanes) (overall survival was 5.6 vs. 9.6 months) [17].
Despite the historically poor prognosis associated with LCNEC, it is interesting to note that among the 26 reported cases of pLCNEC, only 20% of patients died of progressive cancer within 2–20 months. This suggests a potential for better prognoses in these cases, but further research is needed to investigate the factors influencing the outcomes of pLCNECs.
The presence of BRCA1/BRCA2 mutations in LCNEC tumors may provide a therapeutic target for clinicians, as these tumors may exhibit sensitivity to platinum-based chemotherapy and PARP inhibitors [18]. Patients with BRCA1/BRCA2 germline or somatic mutations, like the case described, could potentially benefit from targeted and more precise therapies.
In conclusion, pure LCNECs of the ovary are extremely rare, and their molecular characteristics, biological behavior, and optimal treatment approaches are still not well understood. Establishing an international tumor bank for these tumors may prove to be a valuable resource in addressing these knowledge gaps and advancing research in this field.