Case Report
Management Challenges of Colorectal Mixed Adeno-Neuroendocrine Carcinoma (MANEC): Case Report and Literature Review
Meara Dean1*, Justin Du Plessis2, Charlene Chua1, Ronny Kuang1 and James Lim1
1Department of Surgery, Monash Health, Melbourne, Australia
2Department of Pathology, Austin Health, Melbourne, Australia
*Corresponding author: Meara Dean, Department of Surgery, Monash Health, Melbourne, Australia
Published: 17 Aug, 2017
Cite this article as: Dean M, Plessis JD, Chua C, Kuang R, Lim J. Management Challenges of Colorectal Mixed Adeno-Neuroendocrine Carcinoma (MANEC): Case Report and Literature Review. Ann Med Case Rep. 2017; 1: 1015.
Case Blog
We report a case of a 49-year-old man who presented acutely with abdominal pain due to
caecal MANEC with liver metastasis. His father died aged 52 from metastatic colon cancer. On
examination he had right lower abdominal tenderness and guarding. CT showed a fluid filled
appendix with surrounding fat stranding, an irregular hyperdense mass in the caecal pole and
localized lymphadenopathy (Figure 1). Laparotomy revealed a bulky caecal tumor adhered to the
peritoneum and terminal ileum, an inflamed, enlarged retrocaecal appendix and bilobed liver
metastases. A right hemi colectomy was performed with En bloc resection of the involved terminal
ileum.
Histological sections from the caecal tumor confirmed malignant epithelial cells diffusely
permeating ileocaecal and appendiceal submucosae and muscularis propriae, with tumor extension
through pericolic soft tissues onto serosal surface. The neoplasm predominately revealed small cell
morphology (A), with high grade pleomorphic cells possessing minimal cytoplasm and displaying
abundant mitotic and apoptotic figures (Figure 2) with frequent tumor cell necrosis. The tumor
also had areas of glandular differentiation (B) and unusual foci of squamous differentiation (C).
Widespread lymphovascular invasion was evident, with 6/10 lymph nodes involved by metastatic
disease.
Postoperative recovery was complicated by ileus and persistent fevers and lethargy thought due
to tumor burden as no septic source or carcinoid syndrome was detected. Palliative chemotherapy
(oral etoposide and IV carboplatin) was commenced on D27. The patient deteriorated and treatment
was withdrawn on D40, the patient died on D42.The clinical course of this patient highlights the
aggressive nature of these tumors. Although rare, clinicians and pathologists should be aware of this
entity so that patients can be identified and managed appropriately.
Classification: Although first described in 1924 the classification of these rare tumors has
remained controversial. They have previously been named composite carcinoid, mucin producing
carcinoid, small cell undifferentiated and mixed exocrine-neuroendocrine tumor. In 2010 they
were renamed MANEC and defined by the WHO as gland forming epithelial and neuroendocrine
neoplasms, where each component represents 30% of the tumor, and both components are
malignant.
Characteristics: Colonic neuroendocrine tumor is known to be
a high grade, poor prognosis tumor. La Rosa et al. [1] found a mean
survival of 16.6 months for MANEC, with no difference in prognosis
compared to colonic NEC.
The clinicopathological behavior of these tumors remains
uncertain. Yunru et al. [4] reported a mean age at diagnosis of 61.9
years. In this series 78% of patients presented with metastases to
lymph nodes and 38% to the liver. The authors concluded the poorly
differentiated component was more likely to metastasize.
Aetiology: The aetiology of divergent differentiation remains
elusive. Vortmeyer et al. [3] performed genetic analysis on 6 cases,
and found that when heterozygosity was lost in the adenocarcinoma
component it was also lost in the NEC component, suggesting a
common progenitor cell. Kawaski et al. [1] reported a similar case
to ours, where an adeno-neuroendocrine tumor also contained foci
of squamous cell carcinoma. The authors concluded this occurrence
supports the theory that neoplastic cells are capable of multidirectional
differentiation regardless of their cell or origin. La Rosa et al. found
greater than 90% of MANEC tumors exhibited hypermethylation of
GATA5, a gene that displays hypermethylation in exocrine colorectal
carcinomas.
Management: A multidisciplinary consensus regarding diagnosis
and selection of appropriate systemic therapy is essential to the management of these patients. Choice of adjuvant therapies should
target the poorly differentiated component of the tumor. Sadly in
this case and in many others reported in the literature the prognosis
remained unaltered. Further studies into the molecular, epigenetic
and the immunehistochemical profiles of these rare tumors are
required and will require collaboration between specialist centres.
Figure 1
Figure 2
References
- La Rosa S, Marando A, Furlan D, Sahnane N, Capella C. Colorectal Poorly Differentiated Neuroendocrine Carcinomas and Mixed Adenoneuroendocrine Carcinomas; Insights into the Diagnostic Immunophenotype, Assessment of Methylation Profile and Search for Prognostic Markers. Am J Surg Pathol. 2012;36(4):601-11.
- Li Y, Yau A, Schaeffer D, Magliocco A, Gui X, Urbanski S, et al. Colorectal Glandular-Neuroendocrine Mixed Tumour; Pathological Spectrum and Clinical Implications. AmJ Surg Pathol. 2011;35(3):413-25.
- Vortmeyer AO, Lubensky IA, Merino MJ, Wang CY, Pham T, Furth EE, et al. Concondance of genetic alterations in poorly differentiated colorectal neuroendocrine carcinomas and associated adenocarcinomas. J Natl Cancer Inst. 1997;89(19):1448-53.
- Hiroshi K, Junji O, Tetsuhisa Y, Keitaro T, Keisaku K, Yutaro E, et al. Colonic neuroendocrine carcinoma with adenocarcinoma and squamous cell carcinoma: Report of a case. Bulletin of the Osaka Medical College. 2007;53(2):79-83.