Primary mixed large cell neuroendocrine and high grade serous carcinoma of the endometrium.

Endometrial large-cell neuroendocrine carcinoma admixed with a high-grade serous (HGS) adenocarcinoma is extremely rare with only one reported case in the literature. We present the second reported case in a 47-year-old woman who presented with abdominal pain, distension and loss of weight. On examination she had a fixed pelvic mass and vascular left vaginal mass. Imaging confirmed a 13 cm solid cystic rectouterine pelvic mass, omental disease and retroperitoneal lymphadenopathy. She underwent a modified posterior exenteration, partial posterior vaginectomy, omentectomy and Hartmanns procedure with suboptimal debulking. Histopathology revealed a stage 4B mixed carcinoma with large cell neuroendocrine (70%) and HGS carcinoma (30%). Eight cycles of adjuvant cisplatin and paclitaxel were given with a complete radiological and biochemical response after 7 months. Unfortunately, she developed widespread recurrence at 9 month and was offered second line chemotherapy.

obstetrics and gynaecology, gynecological cancer, chemotherapy, radiotherapy

Primary neuroendocrine carcinoma (NEC) of the endometrium which includes both small and large cell variants is an uncommonly reported histology. Approximately 94 cases of small cell NEC (SCNEC) have been reported in the literature and only 36 cases of large cell NEC (LCNEC) have been reported to date.1–15 Primary endometrial NEC associated with high grade serous carcinoma (HGSC) adenocarcinoma is exceedingly rare with only one case reported previously.1 Here we report the second case of a primary endometrial carcinoma with mixed LCNEC (70%) and HGSC (30%). Case presentation A 47-year-old nulliparous Filipino woman presented with a 2-month history of abdominal pain, distension, decreased appetite and 2 kg loss of weight. She did not report any vaginal bleeding and had never had a cervical screening test. She had no significant medical, surgical or family history. On examination she had a fixed solid mass to the level of the umbilicus and a vascular mass arising from the left vaginal wall. A CT of the abdomen and pelvis showed a 13 cm solid cystic rectouterine pelvic mass inseparable from uterus and ovaries, omental disease, small volume ascites and multiple enlarged pelvic and para-aortic lymph nodes (figures 1 and 2). Tumour markers were elevated with a CA 125 of 1200 U/mL, CA 19.9 of 84 U/mL and lactate dehydrogenase of 459 U/L. Her full blood count, electrolytes including calcium, liver functions tests and other tumour markers (carcinoembryonic antigen /alpha-fetoprotein/human chorionic gonadotropin were normal. Similar clinical findings were found during examination under anaesthesia (EUA). Obvious tumour involving the vagina was biopsied and the rectal mucosa appeared fixed with no obvious tumour invasion. Vaginal biopsies were reviewed in a gynaecology oncology multi-disciplinary meeting and showed a high-grade NEC of large cell type. Primary surgery followed by adjuvant chemotherapy was recommended for symptom control. Additional neuroendocrine tumour markers performed revealed a raised neuron specific enolase (40.1) but normal chromogranin (37). The patient then underwent surgery after 3 weeks with a modified supra-levator posterior exenteration, partial posterior vaginectomy and omentectomy. Intraoperative findings included 4 L of ascites, 27 cm omental cake with tumour adherent to the anterior abdominal wall, a 20 cm solid pelvic mass adherent to the uterus and pelvic peritoneum. The uterus was 14 week size with full thickness tumour invasion. Diffuse residual disease was left on the peritoneal surfaces, omentum and retroperitoneal nodes. The tumour involved the rectovaginal septum adjacent the rectal transection line and therefore a Hartmanns procedure was performed. The patient was discharged at day 10 postoperatively and represented with per-vaginal bleeding and a persistent tachycardia (3 weeks postoperative). No obvious cause for the bleeding or tachycardia was identified. CT pulmonary angiogram, abdomen and pelvis showed progressive disease with multiple new lung, liver metastases, enlarging retroperitoneal lymph node and peritoneal deposits. Investigations Histopathology Initial vaginal biopsies from the EUA showed a high-grade carcinoma with neuroendocrine differentiation of large cell type. Immunohistochemistry (IHC) was performed and the tumour cells were positive for cytokeratins MNF116, CAM 5.2 and EMA and neuroendocrine markers synaptophysin and chromogranin. In addition, there was positivity for PAX8, ER, PR, CD99 and p16. Macroscopically, the tumour appeared to diffusely infiltrate the uterus and involved the uterine serosa forming a separate posterior pelvic mass. The tumour involved both tubes and ovaries, parametria, omentum, recto-sigmoid, appendiceal serosa and two peri-colonic lymph nodes with positive ascitic fluid. Microscopically, two malignant cell populations were identified and in areas these appeared to merge. Extensive vascular invasion was seen. Mismatch repair protein IHC was normal. The main tumour cell population (70%) was composed of a poorly differentiated carcinoma with a mixed solid, nested, trabecular and focal glandular architecture. The tumour cells showed relatively monotonous round nuclei with mild to moderate cytologic atypia, small nucleoli, fine coarse chromatin, a high nuclear/cytoplasmic ratio and eosinophilic cytoplasm (figure 3). IHC demonstrated diffuse positivity for the neuroendocrine markers synaptophysin (figure 4) and chromogranin with wild type p53 staining consistent with an LCNEC. In comparison, the second tumour cell population (30%) showed marked nuclear pleomorphism with multinucleated tumour cells, numerous mitoses and abundant pale to eosinophilic cytoplasm (figure 5). This tumour component was most commonly seen in the uterus. IHC showed weak to negative staining for both synaptophysin and chromogranin, aberrant loss of p53 (null phenotype) and strong diffuse staining for WT1 (figure 6) consistent with an HGSC. The tumour appeared to be centred mainly in the uterus and the endometrium was considered to be the primary site of origin. A diagnosis of a mixed LCNEC and HGSC of endometrial origin was made. Differential diagnosis The main diagnoses considered on initial morphology were a high grade endometrioid adenocarcinoma, an HGSC, undifferentiated carcinoma, high grade neuroendocrine carcinoma, a metastatic tumour such as malignant melanoma and two separate collision tumours. No clear cell carcinoma or carcinosarcoma tumour components were seen. Tumour morphology and IHC helped to exclude most of these diagnoses. The main differential diagnosis after IHC was between a high grade endometrioid carcinoma with neuroendocrine differentiation and collision tumours. A collision tumour was considered highly unlikely as the two tumour subtypes were closely admixed with each other and shared an overlapping immunoprofile. A high grade endometrioid carcinoma can show aberrant p53 and p16 staining with nuclear pleomorphism; however, the presence of strong diffuse staining for WT1 would not be typical and is most commonly associated with an HGSC. The presence of WT1 staining in an HGSC can be seen in a significant number of cases of HGSC of endometrium and is not always associated with a tubo-ovarian origin.16 Treatment The patient commenced chemotherapy (three weekly cisplatin and paclitaxel) 4 weeks postsurgery. She had a partial radiological and biochemical response after six cycles of chemotherapy. Additional two cycles were given as she was tolerating treatment well (eight cycles total). The patient was also commenced on Tamoxifen after completing chemotherapy due to estrogen receptor (ER) positivity. Complete radiological and biochemical response was noted at 7 months (figures 7 and 8). Outcome and follow-up During routine follow-up 9 months postsurgery, examination was suspicious of recurrence in the vaginal vault. Biopsy showed tumour cells with weak chromogranin staining, positive for synaptophysin and p16. Imaging confirmed widespread recurrence at 9 months and second line chemotherapy was offered (figures 9 and 10). The most recent CA 125 level is 350 U/mL and is trending down.

Neuroendocrine tumours of endometrial origin are an uncommon entity. LCNEC and SCNEC of the endometrium represent 0.8% of endometrial cancers.17–20 Endometrial SCNEC/LCNEC tumours typically have an aggressive clinical course. The median age of women affected by these tumours is 57 and vaginal bleeding is the most common presenting symptom.1 LCNEC are known to have a high mitotic rate and be clinically aggressive, and presentation is often with advanced disease.18 The only other case of an LCNEC with a serous component (10%) was described in 2008 by MD Anderson. She was diagnosed with stage 3B disease and underwent primary surgery with hyst/bilateral salpingo-oophorectomy (BSO)/omentectomy/Para-aortic lymph node dissection (PALND). An incompletely excised vaginal lesion was treated with whole pelvic radiotherapy, brachytherapy and chemotherapy.1 This patient had no evidence of disease at follow-up at 92 months (7.6 years) post-treatment. Our patient had a raised serum neuron specific enolase (NSE) at diagnosis but as with other cases series where it is raised or within normal limits it is hard to comment on this test as a useful marker for diagnosis and follow-up in LCNEC.8 LCNEC of the endometrium present a diagnostic challenge and are likely under-reported due to its tendency to be associated with other histotypes. Admixed endometrioid adenocarcinoma makes recognition and diagnosis somewhat difficult.1 2 The NEC component can account for anywhere from 10%–95% of the tumour volume.1 IHC is helpful and neuroendocrine tumours are positive for one or more of the immunohistochemical markers chromogranin, synaptophysin and CD56. The diagnosis of LCNEC requires the expression of at least one neuroendocrine (NE) marker in addition to the presence of the histologic features associated with neuroendocrine differentiation such as nesting, trabecular or ribbon-like formations.1 Additional helpful IHC markers include pankeratin, keratin 18 (keratin cocktail), diffuse p16. These tumours tend to be PAX-8 negative and can have abnormal mismatch repair expression on IHC. This could potentially be targeted with PD-1 immunotherapy. Due to the rarity of these tumours, the gold standard of treatment is poorly defined. Endometrial LCNEC is often treated like standard endometrioid adenocarcinoma with primary surgical resection and adjuvant radiation and chemotherapy.21 22 No patient in the literature appears to have received neo-adjuvant therapy. Surgery involves hysterectomy and BSO with other procedures including lymphadenectomies and peritoneal/omental/soft tissue biopsies. Chemotherapy directed at LCNEC of the endometrium is usually etoposide/platinum based.1 However, these tumours are typically not highly chemosensitive. Some cases have been managed with a combination of chemotherapy and an octreotide similar to somatostatin.21 Typically, the prognosis for NEC is poor, due in part to the often advanced stage at diagnosis, the rapid and aggressive nature of disease and poor response to standard treatment.20 In one review of 25 cases of NEC of the endometrium (SC and LC), there was found to be a 28% 5 year survival rate. All patients who presented with stage IVB disease died of disease at 2–35 months after diagnosis (median, 9 months).1 Because LCNEC of the endometrium is extremely rare cancer, very little is known regarding optimal treatment and response. Limited data support a multi-modal therapeutic strategy with surgical resection if feasible, chemotherapy and radiation. Further research is needed to define a treatment protocol for women with NEC of the gynaecological system. Learning points. Neuroendocrine tumours of the endometrium are rare, but important to consider given their highly aggressive clinical course and unfavourable prognosis. Be mindful in cases of high grade or atypical endometrioid adenocarcinoma of the endometrium, that the diagnosis may in fact be a neuroendocrine carcinoma (NEC). NEC is commonly admixed with other endometrial histologies—immunohistochemistry has a vital role. Mismatch repair protein abnormalities may be seen in almost 50% of tumours which may have important therapeutic implications. Footnotes Contributors: LEH drafted the manuscript. ZC provided the histopathology images and revised the manuscript. KW revised the manuscript. CA revised the manuscript. Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: None declared. Patient consent for publication: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

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