Rare large cell neuroendocrine tumor of the endometrium: A case report and review of the literature

Abstract

INTRODUCTION

Large cell neuroendocrine carcinoma (LCNEC) of the endometrium is a rare malignancy with an aggressive course. Although data is limited to case reports, the prognosis appears to be poor, similar to other type II uterine cancers. A total of 12 cases of LCNEC of the uterus have been published to date.

PRESENTATION OF CASE

A 71 year-old woman presented with postmenopausal vaginal bleeding. Endometrial biopsy was non-diagnostic for LCNEC. She underwent surgical debulking and staging of a 22 cm endometrial tumor with omental metastasis and positive lymph nodes. Her final FIGO stage was IVB.

DISCUSSION

We summarize all prior case reports of LCNEC of the endometrium and discuss the definition, presentation, imaging and surgical management. The pathology with immunohistochemical review, adjuvant therapy and prognosis of LCNEC of the endometrium are also reviewed.

CONCLUSION

Pathologic findings and immunohistochemistry are essential in making a diagnosis of LCNEC of the endometrium. Primary debulking and surgical staging is typically performed, but if a diagnosis of LCNEC can be made preoperatively with immunohistochemistry, surgeons should consider neoadjuvant chemotherapy due to its high grade histology and aggressive course. Otherwise adjuvant chemotherapy is usually given. Even with early stage disease, the prognosis seems poor. Due to the rarity of this aggressive malignancy, more data is needed to establish incidence.

1. Introduction

Large cell neuroendocrine carcinoma (LCNEC) of the endometrium is a rare malignancy with an aggressive course. Although data is limited to case reports, the prognosis appears to be poor, similar to other type II uterine cancers. A total of 12 cases of LCNEC of the uterus, not including ours, have been published in the English literature (Table 1).^1–7 Here we discuss the clinical course of a 71 year-old woman with widely metastatic disease.

Table 1.

Large cell neuroendocrine tumor of the endometrium.

Case	Year	Author	Age	Surgery	Stage	Histology	Treatment	Immunoprofile positivity	Outcome (months)
1	2004	Erhan	52	TAH, BSO	ICa	Pure LCNEC	RT, Cis, Eto	NSE SNP	DOD 3
2	2007	Mulvany	50	TAH, BSO, OMY, LN	IIIC	Pure LCNEC	RT, Cis, Eto	NSE SNP	AWD 12
3	2007	Mulvany	80	TAH, BSO, LN	ICa	LCNEC + endometrioid	NFT	NSE CGA	DOD 5
4	2007	Mulvany	77	TAH, BSO	IIBa	LCNEC + endometrioid	RT	NSE SNP CGA CD56	DOD 23
5	2007	Mulvany	79	TAH, BSO, omental bx, peritoneum	IIIA	LCNEC + endometrioid	RT	NSE CGA CD56	AWD 2
6	2007	Mulvany	88	TAH, BSO, LN	IIIC	LCNEC + SCNEC + endometrioid	RT	NSE CGA CD56	AWD 1
7	2008	Albores-Saavedra	42	RH	ICa	Pure LCNEC	Cis, Eto	SNP CGA CD56	AWD 9
8	2010	Terada	40	TAH, BSO, PLND, OMY	IB	LCNEC + sarcomatoid	None	SNP CD56	AWD 16
9	2011	Deodhar	70	TAH, BSO, OMY	1B	Pure LCNEC	Cis, Eto	SNP CGA CD56	AWD 6
10	2011	Shahibi	59	TAH, BSO, OMY, PPALND, APPY	IIIC2	Pure LCNEC	Carbo, Taxol, RT. Doxil. Cis, Eto, Oct	NSE SNP CGA CD56	DOD 12
11	2012	Makihara	73	None	IVB	Pure LCNEC	NFT	NSE SNP CGA	DOD 1
12	2012	Makihara	73	TAH, BSO, OMY, PPALND	IIIC1	Pure LCNEC	Cis, Iri	SNP CGA CD56	AWD 13
13	2013	Present case	71	RH, BSO, OMY, PPALND	IVB	Pure LCNEC	Planned Cis, Eto, Oct	SNP CGA CD56	DOD 1

TAH = Total abdominal hysterectomy, BSO = Bilateral salpingoophorectomy, OMY = Omentectomy, RH = Radical hysterectomy, PLND = Pelvic lymph node dissection, PPALND = Pelvic and paraaortic lymph node dissection, APPY = Appendectomy, RT = Radiotherapy, NFT = No further treatment, Cis = Cisplatin, Eto = Etoposide, Carbo = Carboplatin, Oct = Octreotide, Doxil = Pegelated doxorubicin, Iri = Irinotecan, NSE = Neural-specific enolase, SNP = Synaptophysin, CGA = Chromogranin A, DOD = Dead of disease, AWD = Alive with disease

^a1998 FIGO staging.

2. Case presentation

A 71 year-old Caucasian female, with a BMI of 44, presented with her first episode of postmenopausal vaginal bleeding. She underwent an endometrial biopsy which revealed extensive necrosis and apoptosis. Tumor cells were diffusely positive for vimentin, desmin, and Ki67, while negative for AE1/AE3, CD10 and SMA. The differential diagnosis from biopsy included undifferentiated sarcoma, poorly differentiated adenocarcinoma and malignant mixed mullerian tumor.

MRI revealed a uterus measuring 19.5 cm × 13.1 cm × 12.3 cm with complete loss of usual myometrial architecture with increased T2 signal at the infiltrative lesion (Fig. 1A–D). The mass appeared to involve the entire myometrium and appeared to extend along the right fallopian tube surrounding a 7.4 cm myoma lying in the broad ligament. The endometrial echo was thickened to 3.5 cm containing heterogeneous debris. No definite extension to parametria was seen on MRI. A 3.1 cm × 2.5 cm left external iliac lymph node was enlarged along with a 1.9 cm × 2.4 cm paraaortic node, which both appeared concerning for metastasis.

Fig. 1.

Sagittal (A) and coronal (B) T2 weighted images without fat saturation through the pelvis demonstrates abnormal diffusely infiltrative high T2 signal throughout the myometrium with loss of the normal architecture. Rounded mass lesions with decreased T2 signal within the myometrium represent leiomyomas. Heterogeneous signal within the endometrial canal is likely debris. Axial diffusion weighted images (C) and axial T2-weighted images with fat saturation (D) redemonstrated diffusely infiltrative process with increased signal one restricted diffusion images suggestive of a hypercellular state restricting the motion of water molecules. The process can be seen to extend along the broad ligament on the left surrounding a broad ligament leiomyoma.

Two weeks later, the patient underwent an exploratory laparotomy, radical hysterectomy, debulking of a retroperitoneal tumor, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, bilateral ureterolysis, omenectomy, and resection of the posterior bladder wall with repair. Intraoperatively, a large primary tumor approximately 25 cm in size extruded from the uterus and involved the small bowel mesentery with bulky lymph nodes measuring up to 4 cm No gross residual disease was noted at the end of the procedure.

On gross pathologic exam, the uterus weighed 2120 g and measured 22 cm in widest diameter. The endometrial cavity was filled with necrotic-hemorrhagic material and showed a friable, polypoid mass attached to the anterior fundus (Fig. 2A). The tumor involved the full thickness of the myometrium as well as the cervix, bilateral ovaries and tubes. The upper vagina and bilateral parametria were also infiltrated by tumor and lymphovascular space invasion was present. One of 18 pelvic lymph nodes and one of 13 paraaortic lymph nodes were positive for metastasis. The omentum was diffusely infiltrated by tumor. Her final FIGO stage was IVB due to omental involvement.

Fig. 2.

(A) Uterus and cervix shows marked thickened, yellow-tan, fleshy walls and a subserosal, calcified nodule on the upper side. The endometrial cavity is filled with necrotic and hemorrhagic debris. (B) Sheets of the tumor cells. H&E 100×. (C) Tumor cells are arranged in sheets without a defined border. Individual cells are large with high nuclear/cytoplasmic ratios, prominent nucleoli, and amphophillic cytoplasm. Numerous mitotic figures and apoptotic bodies are seen, as well as multiple, interspersed areas of necrosis. H&E 400×.

Microscopically, the tumor was poorly differentiated (Fig. 2B and C). Immunohistochemical stains confirmed the diagnosis of a large cell neuroendocrine carcinoma of the endometrium (Table 2). Synaptophysin, chromogranin A (CGA), and CD56 were diffusely and strongly positive neuroendocrine markers. P53 and P16 revealed 70–90% staining with 3+ intensity, estrogen receptor (ER) was negative, progesterone receptor (PR) was positive (Fig. 3).

Table 2.

IHC profile of present case.

Antibody	Marker for	Results
CK7	Cytokeratin 7	Negative
AE1/3	Cytokeratin AE-1/AE-3 cocktail	Negative
EMA	Epithelial membrane antigen	Negative
CK8/18	CAM 5.2 Ck, LMW	Negative
VIMENTIN	Vimentin	Focal positive
CD10	CD10	Negative
SYN	Synaptophysin	Diffuse strongly positive
CHRO	Chromogranin	Diffuse positive
CD56	CD56	Diffuse strongly positive
P53	Oncoprotein	70%; 3+
P16	Dysplastic epithelial cell	90%; 3+
ER	Estrogen receptor	Negative
PR	Progesterone receptor	70%; 2+
S100	S100	Negative
HMB45	Human melanoma	Focal positive
MYOGENIN	Myogenin	Negative
DESMIN	Desmin	Negative
CD45	CD45	Negative
CD3	T cell	Negative
CD20	B cell	Negative
CD138	Plasma cell	Negative

Fig. 3.

Positive immunohistochemical stains (Synaptophysin, Chromogranin, CD56, P53, P16 and PR).

Postoperatively, the patient's course was complicated by a superficial wound infection and separation. She was treated with antibiotics, discharged home, and was planned to receive combination chemotherapy with etoposide, cisplatin and octreotide. On the 32nd post-operative day, she expired due to recurrent malignant ascites and acute renal failure secondary to her malignancy.

3. Discussion

3.1. Definition

LCNEC is an extremely rare malignancy of the uterus, most often found in the cervix and/or ovaries and more commonly of the small cell neuroendocrine type. The WHO defines small-cell carcinoma as an undifferentiated carcinoma with cellular and nuclear features which include small-sized cells, scant cytoplasm, hyperchromatic, finely granular and molded nuclei and inconspicuous nuclei.⁴ In contrast, large cell carcinoma is defined as undifferentiated large cells that lack cytologic and architectural features of small cell carcinoma and glandular or squamous differentiation.⁴ More simply, LCNEC are defined as malignant tumors composed of large cells that show neuroendocrine differentiation.⁶ All reported large cell carcinomas of the uterus have contained neuroendocrine features.

3.2. Presentation

The median age at diagnosis for all cases of endometrial LCNEC is 71 years (range 40–88 years). In the current case, the 71-year old patient presented with postmenopausal vaginal bleeding as was common among all prior reports. On endometrial sampling, the biopsy was not suggestive of a neuroendocrine carcinoma; the usual differential diagnosis for such a specimen includes type 2 tumors such as undifferentiated carcinoma or mesenchymal tumors such as sarcoma or mixed mullerian tumor based on immunohistochemical staining.

3.3. Imaging

Preoperatively, imaging was obtained to evaluate for metastatic disease. Preoperative MRI, performed without intravenous gadolinium secondary to the patient's renal function, demonstrated diffuse abnormal infiltrative myometrial signal throughout the uterus with loss of the normal uterine architecture. This diffusely infiltrative process extended along the broad ligament to the left adnexa and demonstrated restricted diffusion suggestive of a hypercellular process. Conglomerate right external iliac lymphadenopathy and paraaortic lymphadenopathy also with restricted diffusion was present. These findings were suggestive of a uterine sarcoma.

In another report by Makihara et al., the MRI findings of LCNEC seem to mimic MRI findings found in other poorly differentiated endometrial adenocarcinomas and uterine sarcomas.⁷ A gynecologic exam, endometrial sampling and MRI should be included in the initial workup of a suspected uterine LCNEC.

3.4. Surgical management

The most common initial management of LCNEC is cytoreductive surgery, based on prior published reports. Typically, a hysterectomy and bilateral salpingo-ophorectomy are performed at minimum. In one reported case where a biopsy confirmed widely metastatic disease, the patient did not undergo surgery and died.⁷ A post-mortem autopsy then confirmed LCNEC of the uterus.⁷ Although several case reports have noted an early stage at the time of surgery, many of these patients went on to have distant metastasis and/or rapid recurrence. In cases where only TAH and BSO were performed without lymph node dissection, stage III disease may have been missed. Though there is no surgical standard for this rare histology, most patients will undergo hysterectomy presumed high grade sarcoma or carcinoma that is in fact LCNEC. If a LCNEC can feasibly be diagnosed on a preoperative endometrial biopsy or curettage specimen, providers may want to consider neoadjuvant therapy versus primary surgery as is done in advanced cases of ovarian cancer. Although complete surgical staging with omentectomy and pelvic and paraaortic lymphadenectomy is required for accurate staging of uterine cancer, treating physicians may want to asses the patient's response to chemotherapy first, since surgery has not been proven to be entirely beneficial in most cases.

3.5. Pathology

Because LCNEC can sometimes be mixed with other histological types, they can be easily dismissed as poorly differentiated endometrioid carcinomas and are likely underreported. Histogenically, LCNEC of the uterus most likely arises from neuroendocrine cells of the endometrium.¹ Grossly, the typical finding is a polypoid mass confined to the endometrium in stage 1 disease.^1–5 The pathologic features typically include high grade scant stroma, ulceration, extensive tumor necrosis, and a trabecular, organoid, palisading or rosette-like growth pattern.^1–3,5 In the majority of cases, the following cellular features of abundant cytoplasm with a granular eosinophilic or basophilic appearance, large nuclei, small but frequent nucleoli and mitotic rates > 10 per 10 HPF were observed.^1–7

3.6. Immunoprofile

The most useful tool for diagnosing uterine LCNEC is the immunohistochemical profile. Neuroendocrine differentiation in LCNEC of the uterus can be confirmed by staining for synaptophysin, chromogranin and CD56. A summary of previous reports suggests that two of the three tumor markers may confirm a diagnosis of LCNEC. Cervical LCNEC may express neuroendocrine markers with approximately 25 to 38% of cases expressing chromogranin and synpatophysin.^9–12 In the present case, the tumor was diffusely strongly positive for all three markers. Earlier case reports suggest that neuron-specific enolase (NSE) may be a sensitive marker but may not be as useful for diagnosis.^1,2,7

3.7. Adjuvant therapy

In previous reports on uterine LCNEC, adjuvant chemotherapy^1–3,5–7 and/or radiation^1,2,6 was either performed or planned. There is limited data to guide treatment for LCNEC of the uterus or cervix. No prospective trials exist for uterine LCNEC or even for SCNEC of the cervix. Currently there is no consensus as to the optimal management of these tumors. Like LCNEC of the cervix, LCNEC of the endometrium requires a multi-modality approach. Most physicians will favor surgery, followed by chemotherapy, radiation or both. The patient in this report was optimally debulked to no gross residual disease, but she still recurred within one month of surgery and succumbed to her disease. Octreotide, a synthetic somatostatin analog, was planned for the patient in the present case. Two other case reports have reported its use for neuroendocrine tumors, one case demonstrating a partial response and the other with progression of disease.^6,13 Given this aggressive course and poor prognosis, perhaps surgeons who are able to preoperatively diagnose LCNEC of the endometrium should consider neoadjuvant chemotherapy and/or therapy with octreotide prior to surgery. Platinum and Etoposide based chemotherapy is generally used as adjuvant therapy, and this data is largely extrapolated from SCNEC of the lung since data for cervical and uterine neuroendocrine tumors is limited.¹⁴

3.8. Prognosis

Even for early stages, LCNEC of the endometrium appears to have an aggressive course with a strong propensity for distant metastasis and rapid recurrence. No prognostic data is available for LCNEC of the uterus or cervix. The best available survival data is from small cell neuroendocrine carcinoma (SCNEC) of the cervix. One small, retrospective study showed that the estimated 3-year progression free survival (PFS) and overall survival (OS) rates for cervical SCNEC were 22% and 30%, respectively⁸. The median time to progression was 9.1 months and the extent of disease was the only significant prognostic factor.⁸ In the same study, patients who received platinum-based chemotherapy had both a 3-year recurrence-free survival (RFS) and a 3-year overall survival (OS) of 83%.⁸ In patients who did not receive chemotherapy, the RFS and OS were 0% and 20%, respectively.⁸ In our review of all reported cases of uterine LCNEC, six out of 13 patients died of their disease. Of these six, only two received chemotherapy and four were dead of disease by five months, two of whom were early stage (IC) at diagnosis (Table 1). Of the seven patients who are reported to be alive with LCNEC, four received platinum-based chemotherapy, two received radiotherapy only, and one received no further treatment (Table 1). Of all 13 reported cases, eight patients presented with advanced FIGO stage III or IV disease. Based upon these reported cases, there may be some benefit to chemotherapy in LCNEC. Again, providers may consider administering neoadjuvant chemotherapy when a preoperative diagnosis of uterine LCNEC is possible, given the poor prognosis of the disease even after surgical debulking.

3.9. Classification

Endometrial LCNEC is a rare entity which is often likely under-reported and misdiagnosed. When LCNEC of the uterus is diagnosed, whether treatment should proceed as suggested in earlier reports is questionable. Although the data on LCNEC is limited, endometrial LCNEC appears to behave very aggressively, akin to type II uterine cancers. In brief, type II cancers of the endometrium typically present in older-aged, postmenopausal women, are unrelated to unopposed estrogen, have P53 mutations, have poorly-differentiated and non-endometrioid histology, present with stage 3 or 4 disease, and have an unfavorable prognosis.^15,16 All of the above were true of the patient in the present case. Most, if not all, of these same elements were also found in the 12 other cases of endometrial LCNEC listed in this review (Table 1).

4. Conclusion

The presentation of endometrial LCNEC can mimic uterine sarcoma with postmenopausal or abnormal uterine bleeding. Pre-operative imaging with MRI can be useful in assessing the extent of disease. Cytoreductive debulking and surgical staging is typically performed for diagnostic and staging accuracy. Common pathological findings and a typical immunohistochemistry profile (synptophysin, chromogranin and CD56) are paramount in making a diagnosis of uterine LCNEC. In theory, a diagnosis of LCNEC may be made preoperatively with immunohistochemistry. If this is the case, surgeons may consider neoadjuvant chemotherapy with etoposide and a platinum agent followed by surgical cytoreduction. Adjuvant therapy should consist of a similar regimen, although prognosis even with early stage disease and adjuvant therapy appears to be poor. LCNEC of the endometrium behaves similarly to other type II uterine cancers and should be classified as such. Due to the rarity of this aggressive malignancy, more data is needed to establish incidence. Clinicians are urged to report any new cases and may need to rely on case reports and reviews to guide treatment.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Funding

None.

Ethical approval

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Author contributions

My-Linh Nguyen is the primary author of manuscript, data collection, drafting of full article, final approval. Liying Han involved in drafting of the following manuscript sections: case presentation, pathology, immunoprofile, concession of images and final approval. Anjoinette Minors involved in data collection, drafting of the following manuscript sections: Introduction, Definition, editing of full article. Stuart Bentley-Hibbert involved in drafting of the following manuscript sections: Case presentation, Imaging; concession of images and final approval. Tana Pradhan involved in drafting of the following manuscript sections: Case presentation, Surgical management, Adjuvant treatment; classification and final review. Tarah Pua and Tana Pradhan involved in drafting of the following manuscript sections: Case presentation, Surgical management, Adjuvant treatment; classification and final review. Sean Tedjarati is primary surgeon for present case and involved in drafting of the following manuscript sections: Case presentation, Surgical management, Adjuvant treatment; classification and final approval.