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Year : 2022  |  Volume : 65  |  Issue : 4  |  Page : 918-920
High-grade mixed neuroendocrine non-neuroendocrine neoplasm of the gastroesophageal junction: A rare case report and review of literature

1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India

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Date of Submission07-Feb-2021
Date of Decision07-Aug-2021
Date of Acceptance24-Aug-2021
Date of Web Publication21-Oct-2022


Mixed neuroendocrine non-neuroendocrine neoplasm (MiNeN) is a recently described entity of the esophagus in the latest (fifth) edition of WHO Classification of Digestive System Tumors. It is often a difficult pathological diagnosis, especially in small preoperative biopsies. We herein report a case of high-grade MiNeN of gastroesophageal junction diagnosed as a squamous cell carcinoma in preoperative biopsy and subsequently as a high-grade MiNeN in esophagogastrectomy specimen comprising areas of mucoepidermoid carcinoma and large-cell neuroendocrine carcinoma (NEC). This report accentuates the importance of deeper multisite preoperative biopsies as the management is completely different in a MiNeN from esophageal squamous cell carcinoma.

Keywords: ATRX, gastroesophageal junction, mixed neuroendocrine non-neuroendocrine neoplasms, mucoepidermoid carcinoma, neuroendocrine carcinoma

How to cite this article:
Sulaiman M, Agarwal S, Mandal A, Kumar S, Das P. High-grade mixed neuroendocrine non-neuroendocrine neoplasm of the gastroesophageal junction: A rare case report and review of literature. Indian J Pathol Microbiol 2022;65:918-20

How to cite this URL:
Sulaiman M, Agarwal S, Mandal A, Kumar S, Das P. High-grade mixed neuroendocrine non-neuroendocrine neoplasm of the gastroesophageal junction: A rare case report and review of literature. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Dec 7];65:918-20. Available from:

   Introduction Top

According to Globocan 2018, esophageal cancer (EC) is the seventh most common cancer (3.2%) in the world and the sixth most common cause of cancer-related mortality (5.3%). EC accounts for approximately 3.2% of all the newly diagnosed gastrointestinal tract (GIT) malignancies.[1] Squamous cell carcinoma (SCC) and adenocarcinoma are the two most common histological subtypes, of which 90% are SCC, widely seen in the landscapes of Asia, Africa, and Eastern European countries.[2] An esophageal neuroendocrine carcinoma (NEC) is relatively unusual and contributes to 0.4%–5.9% of all ECs.[3] Although mixed neuroendocrine non-neuroendocrine neoplasm (MiNeN) has been illustrated in various organs, a very limited number of cases had been reported in the esophagus. MiNeN is an aggressive esophageal malignancy and is often missed in small preoperative biopsies, making management decisions difficult. Identification of both the components of this tumor is of utmost importance in preoperative biopsy samples as treatment depends on diagnostic accuracy. Due to its rarity in the esophagus, a diagnosis of MiNeN may not be considered in differentials when working up a gastroesophageal junction (GEJ) tumor. Herein, we report a case of a high-grade MiNeN at the GEJ initially diagnosed as SCC in the preoperative biopsy. The patient underwent six cycles of neoadjuvant chemotherapy, followed by radical McKeown esophagectomy, without much tumor regression in the operated specimen.

   Case History Top

A 50-year-old male presented with painless progressive dysphagia for the last 8 months. Contrast-enhanced computed tomography (CECT) showed a circumferential growth involving a length of 6.8 cm from the level of carina to the distal third of the esophagus [Figure 1]. Biopsy was taken and the lesion was preoperatively diagnosed as an SCC at a private health care center. The report was reviewed at AIIMS and a report stating features consistent with SCC was given. Subsequently, he underwent six cycles of carboplatin–paclitaxel-based chemotherapy, followed by McKeown esophagectomy. Histopathological evaluation revealed the presence of a malignant tumor comprising of areas of high-grade mucoepidermoid carcinoma and a large-cell NEC, the latter involving approximately 40% of the tumor area [Figure 2]a, [Figure 2]b, [Figure 2]c. The mucoepidermoid area predominantly consisted of SCC-like areas, connected with the overlying esophageal stratified squamous epithelium, with foci of glandular and goblet cell differentiation. The NEC component comprised sheets, lobules, and acini of tumor cells showing moderate nuclear pleomorphism and foci of comedo necrosis. Brisk atypical mitotic figures were noted in the latter [Figure 2]d. These two tumor areas were intimately mixed at places. The mucoepidermoid component was immunopositive for P40 and focally for CEA. The glandular differentiated area was positive for CK7 and CEA. The NEC component was positive for synaptophysin, focally for chromogranin, and diffusely for p53. Ki67 labeling index was approximately 90% in the hotspot areas of the NEC component [Figure 2]e, [Figure 2]f, [Figure 2]g, [Figure 2]h, [Figure 2]i. The tumor was negative for TTF-1 and CK20. Thus, a histological diagnosis of high-grade MiNeN of the esophagus (yPT3N0cM0) was made, as per the description by La Rosa S, 2016.[4] In the resected post-neoadjuvant chemotherapy specimen, overall tumor necrosis was limited to <10% of the tumor area. To determine the biological behavior of the tumor and for the prognostication, we performed α-thalassemia/mental retardation syndrome X-linked (ATRX) protein analysis using IHC, which showed diffuse positivity in tumor cells [Figure 2]j.
Figure 1: Contrast-enhanced computed tomography (CECT) chest study; the mediastinal window shows circumferential wall thickening of the esophagus (black arrow) just below the carina and abutting the descending thoracic aorta with no encasement

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Figure 2: Low-power photomicrograph from the GEJ tumor shows a subepithelial tumor mass comprising definite intermixing of areas showing glandular (black arrow) and large-cell neuroendocrine carcinomatous differentiation (blue arrows) [a and b, a: ×20, b: ×40]. Further, in some areas, squamous cell carcinomatous differentiation (black arrow) was noted in addition to the large-cell NEC (blue arrow) [c: ×40]. The NEC component shows large pleomorphic cells with brisk mitotic activities (arrows) [d: ×200]. The glandular tumor areas are positive for CK7 (black arrow), whereas the squamoid area is positive for P40 stain (black arrows). The NEC cells are negative for both Ck7 and P40 stains (blue arrow) [e and f: ×100]. The NEC cells are also positive for synaptophysin (arrows) and p53 [g and h; g: ×40, h: ×100]. Ki67 proliferation index was 90% in the area showing NEC differentiation (black arrow) than in the adjacent areas of squamous differentiation (blue arrow) [i: ×100]. The NEC cells show nuclear positivity for ATRX stain (arrows) [j: ×100]

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   Discussion Top

According to recent WHO classification 2017, MiNeNs are defined as neoplasms in which neuroendocrine and non-neuroendocrine (adenocarcinoma or SCC) component exceeds 30% of the total tumor population, originally described as MANEC in the older 2010 WHO classifications of tumors.[5] Rosa et al.,[4] in 2016, adopted the term “mixed neuroendocrine–non-neuroendocrine neoplasm (MiNeN)” to integrate these morphologically heterogeneous groups of neoplasms showing different traits in their clinical behavior in comparison to pure epithelial tumors demanding unique treatment strategies. MiNeN is less frequently metastatic than “pure” high-grade NEC of small- or large-cell type and shows better survival than its pure NEC counterpart.[6]

Recent genomic studies have provided cognizance of the molecular pathway of NETs and hold promise to speculate the outcome.[7] Chou et al.[8] demonstrated that loss of ATRX or death-domain-associated protein (DAXX) proteins are independently associated with a poor outcome in pancreatic NETs. Not many studies are available in the published literature implicating the role of ATRX and DAXX genes in NETs of GIT except the pancreas; thus, further evaluation is required. Diffuse ATRX positivity in the NEC component of the index case helped us to confirm its malignant behavior.

The management of esophageal malignancy depends on various factors such as depth of tumor invasion, nodal or distant metastasis, and surgical resectability. Combined modality chemoradiation followed by surgery is the preferred treatment of EC in patients eligible for such therapy.[9] Preoperative chemotherapy with the use of cisplatin and 5-fluorouracil followed by radical surgery became the standard treatment protocol for resectable, clinical stage II, or III ECs, as was given in this patient.[10] Even in an operable case, adjuvant chemotherapy is part of the treatment as it may provide a better outcome than surgery alone.[10] However, the treatment of MiNeN has not been unified yet due to the rarity and heterogeneity. In many centers, the same treatment protocol is followed for MiNeN and pure NEC as the prognosis and survival outcomes are nearly similar.

   Conclusion Top

We herein report a rare case of high-grade MiNeN of the distal esophagus comprising high-grade mucoepidermoid and large-cell NEC components, which was misinterpreted as SCC in preoperative biopsies, followed by six cycles of carboplatin–paclitaxel-based chemotherapy and esophagogastrectomy with no significant tumor regression. This case highlights the importance of multifocal deep preoperative biopsies to enable pathologists to identify different components of the tumor and make a correct preoperative diagnosis so that appropriate management can be instituted.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.  Back to cited text no. 1
Parkin DM, Ferlay J, Curado MP, Bray F, Edwards B, Shin HR, et al. Fifty years of cancer incidence: CI5 I-IX. Int J Cancer 2010;127:2918-27.  Back to cited text no. 2
Huang Q, Wu H, Nie L, Shi J, Lebenthal A, Chen J, et al. Primary high-grade neuroendocrine carcinoma of the esophagus: A clinicopathologic and immunohistochemical study of 42 resection cases. Am J Surg Pathol 2013;37:467-83.  Back to cited text no. 3
La Rosa S, Sessa F, Uccella S. Mixed Neuroendocrine-nonneuroendocrine neoplasms (MiNENs): Unifying the concept of a heterogeneous group of neoplasms. Endocr Pathol 2016;27:284-311.  Back to cited text no. 4
WHO Classification of Tumours Editorial Board. WHO Classification of Tumours. Digestive System Tumours. 5th ed. Lyon, France: International Agency for Research on Cancer (IARC); 2019.  Back to cited text no. 5
de Mestier L, Cros J, Neuzillet C, Hentic O, Egal A, Muller N, et al. Digestive system mixed neuroendocrine-non-neuroendocrine neoplasms. Neuroendocrinology 2017;105:412-25.  Back to cited text no. 6
Scarpa A, Chang DK, Nones K, Corbo V, Patch AM, Bailey P, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 2017;543:65-71.  Back to cited text no. 7
Chou A, Itchins M, de Reuver PR, Arena J, Clarkson A, Sheen A, et al. ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumors. Hum Pathol 2018;82:249-57.  Back to cited text no. 8
Mawhinney MR, Glasgow RE. Current treatment options for the management of esophageal cancer. Cancer Manag Res 2012;4:367-77.  Back to cited text no. 9
Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol 2012;19:68-74.  Back to cited text no. 10

Correspondence Address:
Mohamed Sulaiman
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_143_21

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