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CASE REPORT
Year : 2019  |  Volume : 6  |  Issue : 1  |  Page : 31-35

Mixed adenoneuroendocrine carcinoma: A report of four cases from South India


1 Assistant Professor, Department of Pathology, Sri Venkateshwaraa Medical, College Hospital and Research Centre, Puducherry, India
2 Department of Pathology, JIPMER, Puducherry, India

Date of Submission17-Aug-2018
Date of Acceptance29-Jan-2019
Date of Web Publication30-Apr-2019

Correspondence Address:
Dr. Saravanakumari Vijayakumar
Assistant Professor, Department of Pathology, Sri Venkateshwaraa Medical, College Hospital and Research Centre, Puducherry - 605 006
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jhrr.jhrr_39_18

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  Abstract 


Neuroendocrine tumors (NET) are rare. Common sites of NETs are the gastrointestinal tract and pancreas. In 2010, the World Health Organization classified NETs into mixed adenoneuroendocrine carcinoma, neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma (MANEC), tumors that have both exocrine and endocrine components of at least 30% each. Since it is relatively a new entity, only case reports and case series are available. In the past 7 years, there were only eight reports from India. We report a further four cases of this nascent disorder from a single institution, obtained retrospectively. The first includes an elderly man with upper gastrointestinal symptoms and underwent subtotal gastrectomy for antropyloric growth, which was a low-grade MANEC. The second was a female patient with chronic pancreatitis and presented with obstructive jaundice due to an ampullary growth. Whipple's specimen showed an intermediate-grade MANEC. The third case was a 40-year-old female with caecal growth and ovarian mass and was found to have a low-grade MANEC. The fourth, also in a female, was a case of abdominal wall abscess with an intraabdominal connection to the intestine and she had omental deposits and high-grade MANEC. The pathological findings are discussed and compared other reports from the country.

Keywords: India, mixed adenoneuroendocrine carcinoma, neuroendocrine carcinoma, neuroendocrine tumors


How to cite this article:
Vijayakumar S, Jacob SE, Badhe BA, Srinivas BH. Mixed adenoneuroendocrine carcinoma: A report of four cases from South India. J Health Res Rev 2019;6:31-5

How to cite this URL:
Vijayakumar S, Jacob SE, Badhe BA, Srinivas BH. Mixed adenoneuroendocrine carcinoma: A report of four cases from South India. J Health Res Rev [serial online] 2019 [cited 2019 Jul 19];6:31-5. Available from: http://www.jhrr.org/text.asp?2019/6/1/31/257479




  Introduction Top


Neuroendocrine tumors (NET) of the gastrointestinal tract (GIT) were originally termed as Karzinoide (carcinoid tumor) by Siegfried Oberndorfer in 1907.[1] These tumors arise from either enterochromaffin or Kulchitsky cells in the crypt of Lieberkühn, which have the property of amine precursor uptake and decarboxylation.[2] Cordier first reported a gastrointestinal tumor with carcinoma and neuroendocrine components. Lewin et al. classified NET into three subtypes, namely, collision, combined, and amphicrine tumors.[3] A collision tumor (composite tumor) has both endocrine and exocrine components confined to different areas of the same neoplasm; a combined tumor has both components distributed intimately and diffusely. In 1938, the coexistence of endocrine and exocrine secretory products in single cells were described by Feyrter.[4] Ratzenhofer et al. used “amphicrine” to label the coexistence of mucin vacuoles and neuroendocrine granules in the same cell.[4]

NETs are rare, with an incidence of 2–3 among 100,000/year. The most common sites of their origin are the GIT and pancreas. The thyroid and testes can rarely produce NETs. These tumors arise from pluripotent progenitor cells and develop a neuroendocrine phenotype.[5] The World Health Organization (WHO) in 2010 classified them, based on Ki67 into (i) NET G1 and G2, (ii) Neuroendocrine carcinoma (NEC) G3, (iii) Mixed adenoneuroendocrine carcinoma (MANEC), and (iv) Hyperplastic and preneoplastic lesions.[5],[6] MANECs are defined as tumors with mixed exocrine and endocrine components, with each contributing ≥30% of the lesion.[3] In addition, two of three neuroendocrine markers such as chromogranin, synaptophysin, and CD56 must be present for the diagnosis of MANEC.[7] There are only eight instances of MANEC reported from India.[8],[9],[10],[11],[12],[13],[14]

NETs are usually seen in the elderly and are more common in males. The involvement of the GIT occurs in the form of annular or polypoidal lesions leading to obstructive symptoms.[3] Abdominal pain and jaundice are the common presenting symptoms of biliary NETs. Occasionally, carcinoid syndrome, Zollinger–Ellison syndrome and other hormone-secreting syndromes may be seen. Tumors are often asymptomatic due to their non-functional status and may be detected incidentally as during appendicectomy. Nonfunctioning tumors present late and may have metastases at presentation.[5] Investigations include the assay of the biochemical substances secreted, imaging (Computed Tomography – [CT], magnetic resonance imaging, and Scintigraphy), and procedures such as endoscopies and biopsies.[5] Diagnosis is confirmed by use of immunohistochemical (IHC) techniques to stain for substances such as synaptophysin and chromogranin. Curative surgical resection, chemotherapy, radiotherapy, somatostatin analogs, embolization of liver secondaries, and targeted radionuclide therapy are some of the therapeutic modalities in MANEC, with surgery being the most commonly used.[5] The optimal strategy for such patients is still not clear.[15]

Grossly, tumors are polypoidal masses or ulcero-stenotic lesions, ranging from 0.5 to 14 cm.[3] Microscopically, both exocrine and endocrine components contribute at least 30% each. Exocrine components are either adenomatous (villous/tubulovillous) or carcinomatous (squamous/adenocarcinoma). The endocrine component is composed of small, intermediate, and large cell types. Small to intermediate cell types do exhibit scant cytoplasm, round nuclei, granular chromatin, and inconspicuous nucleoli in diffuse or nested pattern with areas of diffuse geographic necrosis and mitosis of 20–30/10 hpf. In large cell types, abundant cytoplasm, vesicular nuclei with prominent nucleoli, arranged in an organoid, trabecular, and palisading pattern are seen. IHC markers for MANECs include chromogranin (60%–70%), synaptophysin (75%–90%), CD56 (50%), NSE, CK7, CDX2, CK 20, and carcinoembryonic antigen (CEA).[3] Colorectal MANEC shows CDX2 positivity in large cell types. Synaptophysin is most specific while chromogranin is more sensitive for neuroendocrine differentiation; neuron-specific enolase (NSE) negativity is seen in 20%. In a study of 39 cases, peritumoral lymphoid invasion and large cell-subtype were reported to be favorable prognostic markers.[3]

MANEC is a rare disease, and most reports are as case series from institutions worldwide. As per our knowledge, such reports from India have been presented only as case reports, with only eight instances. The present case series will add a further four to the growing repository of MANEC.


  Case Reports Top


Case 1

A 70-year-old male came with complaints of weight loss, anorexia, abdominal discomfort, vomiting for 1 month and had one episode of coffee-ground hematemesis for which he underwent an esophagogastroscopy. Examination revealed pallor and emaciation without other significant examination findings. His investigation revealed microcytic hypochromic anemia of 6.2 g%, and he was transfused 2 units of RBCs before surgery. An antropyloric growth was found for which he underwent subtotal gastrectomy. Gross specimen showed loss of rugosity, with focal thickening measuring 5 cm × 2.5 cm × 1 cm; rest of the mucosa appeared normal. The resected margins were tumor free. Four nodes were isolated from the lesser omentum. Microscopically, the thickened area showed adenocarcinoma and neuroendocrine components in glandular and nest/cord patterns respectively [Figure 1]. Adenocarcinoma component was epithelial membrane antigen (EMA) positive; neuroendocrine component revealed positivity for NSE and synaptophysin; the Ki index was 2%, and the diagnosis was MANEC G1 (combined tumor).
Figure 1: (a) Stomach growth-tumour cells arranged in glands, cords, and nest with moderate amount of cytoplasm, pleomorphic nuclei and prominent nucleoli (H and E, ×4). (b) Tumour cells show synaptophysin positivity (IHC, ×10). (c) Tumour cells shows weak epithelial membrane antigen membrane positivity (IHC, ×10). (d) Tumour cells shows strong Chromogranin positivity (IHC, ×10)

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Case 2

A 35-year-old female with chronic pancreatitis (of unknown etiology) for the past 3 years and a biliary stricture came with right upper quadrant pain, fever, and cholestatic jaundice of 10 days' duration. Examination showed icterus without any systemic findings. Liver function tests revealed elevated alkaline phosphatase 924 U/L, total bilirubin 17.6 mg/dL, direct bilirubin 13.9 mg/dL with elevated counts of 16,800/cumm. She underwent endoscopic retrograde cholangiopancreatography that revealed an ampullary growth [Figure 2]a and b]. Whipple's procedure was performed. Cut-section of Whipple's specimen showed a grey-white solid homogeneous mass, 1.8 cm × 1.5 cm × 1 cm in the ampulla. The bile duct distal to the tumor appeared dilated. Microscopically, the tumor section revealed 40% and 60% of adenocarcinoma and neuroendocrine components, respectively. This tumor infiltrated the duodenal submucosa, and extended into the muscularis propria; the serosa was tumour-free [Figure 3]. Adenocarcinoma tumor cells were positive for CK7 and CK19. Neuroendocrine cells were NSE and synaptophysin positive, with a Ki of 3%, leading to a diagnosis of MANEC T3N0Mx.
Figure 2: (a) Computed tomography abdomen of Case 2 shows a periampullary growth. (b) Computed tomography abdomen of Case 2 shows pneumobilia. (c) Computed tomography pelvis of Case 3 shows a large multiloculated multi-septated ovarian cystic lesion

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Figure 3: (a) Ampullary region-tumour cells of both adenocarcinoma and neuroendocrine components infiltrating muscularis layer (H and E, ×10). (b) CK19 positivity (adenocarcinoma) and negativity (neuroendocrine component) (IHC, ×10). (c) Synaptophysin positivity (neuroendocrine component). (d) Ki index – 2% (IHC, ×40)

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Case 3

This 40-year-old female came with right lower quadrant abdominal pain, constipation, loss of appetite, and loss of weight for the past month. Examination revealed emaciation, dry oral mucosa, bald tongue, pallor with right iliac fossa tenderness. Investigations showed anemia of 8.6 g/dL, normal liver and renal function tests, normal stool examination and negative viral serologies. Colonoscopy showed a caecal growth. Ultrasonogram and CT abdomen revealed a right-ovarian multiloculated cyst [Figure 2]c. She underwent right hemicolectomy and ovariectomy. The outer intestinal surface of the hemicolectomy specimen was unremarkable. Cut-section of the caecum showed a circumferential ulceroproliferative growth measuring 6 cm × 5 cm × 3 cm with both solid and mucinous areas. The right ovary measured 7 cm × 5 cm × 3 cm without a capsular breach, and the cut-surface showed a multiloculated cyst filled with mucinous material. Microscopically, the caecal mass showed tumor cells arranged in glandular and insular patterns, with pools of extracellular mucin. These were positive for EMA, synaptophysin, and NSE, with Ki of 2%. Chromogranin was inconclusive [Figure 4]. The ovarian section showed a mucin-filled cyst with entangled tumor cells, positive for CK20 and CEA, and negativity for CA125 thus confirming a diagnosis of MANEC G1 amphicrine tumor with ovarian metastasis.
Figure 4: (a) Caecal growth-tumour cells arranged in glands, nest and cords pattern, admixed with pools of mucin (H and E, ×10). (b) Epithelial membrane antigen positivity (both glandular and neuroendocrine tumour cells) (IHC, ×4). (c) Synaptophysin positivity (both exocrine and endocrine tumour cells) (IHC, ×10)

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Case 4

A 51 year-old female presented with left-sided anterior abdominal wall swelling and fever of 10 days' duration. A supraumbilical 3 cm × 3 cm swelling with pus-pointing was noticed. She did not have diabetes or a history of trauma. Hematological and biochemical investigations were non-contributory. Contrast CT of the abdomen revealed an abscess communicating intra-abdominally with the small intestine. Resection anastomoses of the small intestine and appendicectomy were performed. Grossly, the small intestine was congested without any perforation. Cut-section of the intestine revealed a circumferential ulceroproliferative gray-white solid mass, 5 cm × 4 cm × 2.5 cm infiltrating the serosa. The resected ends were tumor free. An omental deposit of 2 cm × 1 cm × 0.5 cm, solid gray-white, with friable areas, was also received. The appendix had a fecalith. Microscopically, the tumor section showed cells arranged in gland, nests, and sheets with high N/C ratio, moderate atypia, a mitotic rate of 20/10 hpf infiltrating the serosa, admixed with dense lymphoplasmocytic infiltrate. The cells were positive for panCK and synaptophysin (>30% cells) and showed weak chromogranin positivity. Ki was 60%. Omental section showed similar features [Figure 5]. The appendix was histologically unremarkable. The diagnosis was MANEC G3 (amphicrine variant).
Figure 5: (a) Tumour cell arranged in glands, nest, and sheets with high N/C ratio admixed with dense lymphocytic infiltrate; mitosis of 20/10 hpf (H and E, ×10). (b and c) Tumour cells are both chromogranin and cytokeratin positive respectively (IHC, ×40). (d) Ki index-60%

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  Discussion Top


The sites of gastroenteropancreatic NETs NETs are the gastric fundus/corpus, proximal duodenum, ampulla of Vater, terminal ileum, appendix, lower rectum, and pancreas.[9] The first rectal MANECs have been reported only in 2018.[16] Biliary NETs constitute <1% of all NETs. We had one biliary NET among the four cases. The most common sites of primary, based on the American and European databases are the pancreas and cecum. We do not have such Indian data. Neuroendocrine malignancies at the time of diagnosis, are either localized or have regional/distant metastasis.[17] Genetic features of NECs have not been fully elucidated. Hypotheses postulated include an adenocarcinoma cell dedifferentiating into a NET cell during progression, and a monoclonal pluripotent epithelial stem cell differentiating into an exocrine and neuroendocrine component. Potential genetic mechanisms include DNA damage, RAS signaling, and involvement of p27 tumor suppressor gene.[1]

MANEC is graded into G1 (low grade, mitotic rate <2/10HPF or Ki <3%), G2 (intermediate, 2–10/10HPF or Ki 3%–20%), and G3 (high grade, >20/10HPF or Ki >20%). 1HPF = 2 mm2; Ki index 500–200 cells.[2] We had two low-grade tumors and one each of intermediate and high grades. The clinical presentation depends on the neuroendocrine cell secretion, and these tumors are further classified into functioning and non-functioning tumors.[5] Functioning NET of the midgut is called carcinoid tumors because of the substances secreted. Nonfunctioning tumors may be found incidentally, or they may be discovered due to the local effects of the tumors as in all our cases which were from the midgut.[5] Rarely, they can present as an acute abdomen.[18] Occasionally, they can be associated with other tumors such as lymphoma.[19] MANEC tumors usually present in the sixth and seventh decades, but the mean age of our patients was 49 years.[20],[21] Among the eight previously reported cases from India, three were biliary, four were from the stomach and one from the caecum in comparison to our study, where one each was from the stomach, ampulla, jejunum, and caecum. Among the biliary MANECs, one was from the hepatic duct, and two were from the gallbladder.[10],[11],[12] Due to the retrospective nature, clinical images at the time of presentation to the hospital were unavailable.

Distant metastasis depends on tumor size, proliferation index, and invasion of muscularis propria, lymphovascular, and perineural structures. The cases with stomach MANEC had nodal metastasis similar to Case 1.[8],[9],[14] The reported case of caecal MANEC was an elderly female unlike ours (Case 3) who was younger but with ovarian metastasis.[13] There were no ampullary MANECs reported from India. Three stomach MANECs had received chemotherapy following surgery, with follow-up details being available.[9],[14] Chemotherapy was also given to one gall bladder MANEC.[11] No adjuvant therapy was given to the hepatic duct MANEC because of good recovery following surgery.[12] Chemotherapy details were unavailable regarding MANEC of the other gall bladder, caecum, and stomach.[8],[10],[13] Since we collected data retrospectively, we did not have data on chemotherapy or follow-up of any of our patients, and hence the morbidity/mortality is unknown.


  Conclusion Top


MANEC is a rare condition, partly due to the WHO having classified only in 2010. Only case series and case reports are available, with even referral centers reporting only 30–70 cases each due to the rarity of the condition. More Indian literature is necessary since epidemiological data are scarce partly due to unawareness of the condition. The optimal treatment, especially regarding chemotherapy, radiotherapy, and other adjuvant measures, is unknown since the number of patients is small. We have added a further four cases to the growing Indian repository of this nascent disease.

Informed consent

Written informed consent for patient information and histological images published was obtained by the patients or a legally authorized representative.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

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