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Adenocarcinoma ex-goblet cell carcinoid of the ascending colon concurrent with conventional adenocarcinoma

2018; Elsevier BV; Volume: 50; Issue: 7 Linguagem: Inglês

10.1016/j.pathol.2018.06.005

1465-3931

Kyu Yun Jang, Ho Sung Park, Sang Jae Noh, Ho Lee, Min Ro Lee,

Appendicitis Diagnosis and Management

Goblet cell carcinoid (GCC), also known in the literature as adenocarcinoid, mucinous carcinoid, and mixed crypt cell carcinoma, is a unique type of mixed epithelial-neuroendocrine tumour that accounts for approximately 14% of all appendiceal neoplasms.1McCusker M.E. Cote T.R. Clegg L.X. Sobin L.H. Primary malignant neoplasms of the appendix: a population-based study from the surveillance, epidemiology and end-results program, 1973-1998.Cancer. 2002; 94: 3307-3312Crossref PubMed Scopus (420) Google Scholar Although GCC almost exclusively occurs in the appendix, a few cases of extra-appendiceal GCCs that present as primary lesions in the stomach, small bowel, and colorectum have been reported.2Gui X. Qin L. Gao Z.H. Falck V. Harpaz N. Goblet cell carcinoids at extraappendiceal locations of gastrointestinal tract: an underrecognized diagnostic pitfall.J Surg Oncol. 2011; 103: 790-795Crossref PubMed Scopus (21) Google Scholar Recently, the capacity of GCC to transform into high-grade adenocarcinoma has been recognised.3Tang L.H. Shia J. Soslow R.A. et al.Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix.Am J Surg Pathol. 2008; 32: 1429-1443Crossref PubMed Scopus (219) Google Scholar, 4Burke A.P. Sobin L.H. Federspiel B.H. Shekitka K.M. Helwig E.B. Goblet cell carcinoids and related tumors of the vermiform appendix.Am J Clin Pathol. 1990; 94: 27-35Crossref PubMed Scopus (132) Google Scholar Such cases were diagnosed as adenocarcinoma ex-GCC or mixed GCC-adenocarcinoma.3Tang L.H. Shia J. Soslow R.A. et al.Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix.Am J Surg Pathol. 2008; 32: 1429-1443Crossref PubMed Scopus (219) Google Scholar, 5Taggart M.W. Abraham S.C. Overman M.J. Mansfield P.F. Rashid A. Goblet cell carcinoid tumor, mixed goblet cell carcinoid-adenocarcinoma, and adenocarcinoma of the appendix: comparison of clinicopathologic features and prognosis.Arch Pathol Lab Med. 2015; 139: 782-790Crossref PubMed Scopus (59) Google Scholar Here, we present a patient with adenocarcinoma ex-GCC with no detectable appendiceal tumour that was concurrent with conventional adenocarcinomas in the ascending colon. A 79-year-old man who complained of constipation was admitted to our hospital for the evaluation of multiple polypoid masses of the ascending colon that had been detected 2 months earlier at local clinic. A physical examination of the abdomen was unremarkable, and laboratory findings were within normal ranges. An endoscopic examination revealed multiple polypoid masses that measured 4 cm in the greatest dimension, in the ascending colon. Small polyps were also detected in the sigmoid colon and rectum. A laparoscopic right hemicolectomy was performed, under the clinical impression of ascending colon cancer. Grossly, there were three separate, large, polypoid masses in the ascending colon that measured 1.7 cm (mass 1), 3.4 cm (mass 2), and 1.5 cm (mass 3) in the greatest dimension (Fig. 1A). Mass 1 revealed mucosal dimpling due to ulceration, whereas masses 2 and 3 revealed no mucosal changes. The resected specimen also included the appendix, which showed a grossly normal appearance (Fig. 1A, arrow). Microscopically, mass 1 demonstrated proliferating neoplastic cells that caused expansion of the lamina propria and invaded into the superficial portion of the muscularis propria (Fig. 1B). The adjacent colonic epithelium revealed no evidence of dysplasia. Most tumour cells were arranged in well-formed, rosette-like clusters, some of which had rigid luminal borders (Fig. 1C). Tumour cells with apparent signet ring cell features displayed a disorganised arrangement and irregularly shaped cell clusters with jagged contours (Fig. 1D), which occupied less than a quarter of the mass 1 (Fig. 1B, dotted line). The rosette-like clusters contained numerous neuroendocrine cells, few Paneth cells, and occasional goblet cells that resembled signet ring cells (Fig. 1E). The neuroendocrine cells had indistinct cell borders, eosinophilic cytoplasm, and basally located, pleomorphic nuclei with fine granular chromatin and distinct nucleoli. The goblet cells, which exhibited a loss of preserved goblet cell architecture, had voluminous, bubbly cytoplasm that contained basophilic mucin and irregular, hyperchromatic nuclei (Fig. 1F). The tumour cells showed lymphatic and perineural invasion; however, mitotic figures were not evident. The neuroendocrine cell component showed patchy staining for chromogranin A (Fig. 1G) and synaptophysin (Fig. 1H). The goblet cell component showed mucicarmine-positive mucin droplets and was immunoreactive for MUC2 (Fig. 1I), CEA, and CK20. Both masses 2 and 3 were adenocarcinomas that arose from tubular adenomas and invaded into the submucosa (Fig. 2A,C). They consisted of well-formed glands that fused with each other (Fig. 2B). Even though the appendix was grossly normal, it was entirely sectioned and submitted for histological examination to search for potential primary lesions. The microscopic findings of the appendix were unremarkable (Fig. 2D). Immunohistochemical staining for cytokeratin and chromogranin A revealed positive results only in the appendiceal epithelial cells (Fig. 2E) and the resident endocrine cells (Fig. 2F), respectively. Based on histological and immunohistochemical findings, we diagnosed the patient with combined adenocarcinoma ex-GCC of the ascending colon without detectable appendiceal tumours and conventional adenocarcinoma. The patient remains in good health, with no recurrence or metastasis at his 17-month follow-up after surgery.Fig. 2(A–C) Microscopic findings of mass 2 (A,B) and 3 (C). (A) Mass 2 is an adenocarcinoma arising in a tubular adenoma and invading into the submucosa (H&E). (C) Mass 3 is also an adenocarcinoma arising in a tubular adenoma (H&E). (B) Mass 2 consists of well-formed glands that are fused with each other (H&E). (D–F) Microscopic findings and immunostaining of the appendix. (D) The appendix reveals no specific pathological lesions (H&E). (E) The appendiceal epithelial cells are positive for cytokeratin. (F) The resident endocrine cells in the appendiceal crypt are positive for chromogranin A.View Large Image Figure ViewerDownload Hi-res image Download (PPT) GCC is a distinct tumour type that occurs almost exclusively in the appendix and consists of an admixed population of signet ring-like cells that resemble intestinal goblet cells in small, rounded nests or cords and neuroendocrine cells arranged in organoid patterns. Thus, GCC is regarded as a mixed glandular-endocrine tumour variant. GCC is predominantly characterised by submucosal growth and typically infiltrates the appendiceal wall, in a concentric manner. Many authors have considered GCC as a type of neuroendocrine tumour (NET) because of its organoid growth pattern, presence of scattered neuroendocrine cells, presence of neurosecretory granules, and lack of precursor mucosal lesion.6Toumpanakis C. Standish R.A. Baishnab E. Winslet M.C. Caplin M.E. Goblet cell carcinoid tumors (adenocarcinoid) of the appendix.Dis Colon Rectum. 2007; 50: 315-322Crossref PubMed Scopus (58) Google Scholar, 7Albores-Saavedra J. Henson D.E. Batich K. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix.Am J Surg Pathol. 2009; 33: 1259-1260Google Scholar However, some investigators insist that GCC is a separate entity, because it is morphologically and biologically distinguishable from classical NETs. NETs of the appendix reveal a neuroendocrine phenotype with the capacity for amine and peptide hormone production.8Goddard M.J. Lonsdale R.N. The histogenesis of appendiceal carcinoid tumours.Histopathology. 1992; 20: 345-349Crossref PubMed Scopus (42) Google Scholar However, GCCs of the appendix have a mixed phenotype, with neuroendocrine differentiation and intestinal type goblet cell morphology.4Burke A.P. Sobin L.H. Federspiel B.H. Shekitka K.M. Helwig E.B. Goblet cell carcinoids and related tumors of the vermiform appendix.Am J Clin Pathol. 1990; 94: 27-35Crossref PubMed Scopus (132) Google Scholar In addition, GCCs often show only scattered positive cells upon staining with neuroendocrine markers, such as chromogranin A and synaptophysin, while classical NETs show strong and diffuse immunoreactivity for these markers. Moreover, GCC occurs at a 10-year older age and reveals worse prognoses than classical NET.1McCusker M.E. Cote T.R. Clegg L.X. Sobin L.H. Primary malignant neoplasms of the appendix: a population-based study from the surveillance, epidemiology and end-results program, 1973-1998.Cancer. 2002; 94: 3307-3312Crossref PubMed Scopus (420) Google Scholar Some authors have even grouped GCC as an adenocarcinoma because of the presence of intracellular mucin and frequent transcoelomic spread and metastases.9McGory M.L. Maggard M.A. Kang H. O'Connell J.B. Ko C.Y. Malignancies of the appendix: beyond case series reports.Dis Colon Rectum. 2005; 48: 2264-2271Crossref PubMed Scopus (177) Google Scholar Only rare cases of GCC present with extra-appendiceal primary lesions in the stomach, small bowel, and colorectum.2Gui X. Qin L. Gao Z.H. Falck V. Harpaz N. Goblet cell carcinoids at extraappendiceal locations of gastrointestinal tract: an underrecognized diagnostic pitfall.J Surg Oncol. 2011; 103: 790-795Crossref PubMed Scopus (21) Google Scholar However, the characteristic histology of GCC, including small, round, uniform, and glandular units composed of goblet cells, seldom, if ever, appears in tumours that arise from any other organs. Thus, GCCs have a recognisable appendiceal origin, even at metastatic sites, although the morphological features of the metastatic GCCs often do not resemble those of the corresponding primary GCCs. In addition, seven of nine extra-appendiceal GCCs that could be evaluated in the appendix had a disclosed appendiceal primary lesion, even 1 year after the initial treatment.2Gui X. Qin L. Gao Z.H. Falck V. Harpaz N. Goblet cell carcinoids at extraappendiceal locations of gastrointestinal tract: an underrecognized diagnostic pitfall.J Surg Oncol. 2011; 103: 790-795Crossref PubMed Scopus (21) Google Scholar While it may be reasonable to exclude the appendix as a primary source for GCCs discovered in extra-appendiceal locations, no appendiceal origin of GCCs may be demonstrated, as in the present case. The complicating issue is that GCCs are indistinguishable from adenocarcinomas that display signet ring cells, solid sheets of cells, fused or cribriform glands, and single-file structures. Furthermore, GCCs can transform into high-grade, non-GCC-adenocarcinoma patterns.3Tang L.H. Shia J. Soslow R.A. et al.Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix.Am J Surg Pathol. 2008; 32: 1429-1443Crossref PubMed Scopus (219) Google Scholar, 4Burke A.P. Sobin L.H. Federspiel B.H. Shekitka K.M. Helwig E.B. Goblet cell carcinoids and related tumors of the vermiform appendix.Am J Clin Pathol. 1990; 94: 27-35Crossref PubMed Scopus (132) Google Scholar Such cases were named adenocarcinoma ex-GCC or mixed GCC-adenocarcinoma.3Tang L.H. Shia J. Soslow R.A. et al.Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix.Am J Surg Pathol. 2008; 32: 1429-1443Crossref PubMed Scopus (219) Google Scholar, 5Taggart M.W. Abraham S.C. Overman M.J. Mansfield P.F. Rashid A. Goblet cell carcinoid tumor, mixed goblet cell carcinoid-adenocarcinoma, and adenocarcinoma of the appendix: comparison of clinicopathologic features and prognosis.Arch Pathol Lab Med. 2015; 139: 782-790Crossref PubMed Scopus (59) Google Scholar Tubular patterns of non-mucinous cells may be mistaken for other tubular-type carcinomas of the gastrointestinal tract. However, the tubules of GCC are more distinctive because of their relatively round, non-complex, rosette-like architecture and rigid luminal borders. A few reports have suggested quantitative criteria for adenocarcinoma ex-GCC, based on the proportion of carcinomatous growth.4Burke A.P. Sobin L.H. Federspiel B.H. Shekitka K.M. Helwig E.B. Goblet cell carcinoids and related tumors of the vermiform appendix.Am J Clin Pathol. 1990; 94: 27-35Crossref PubMed Scopus (132) Google Scholar, 5Taggart M.W. Abraham S.C. Overman M.J. Mansfield P.F. Rashid A. Goblet cell carcinoid tumor, mixed goblet cell carcinoid-adenocarcinoma, and adenocarcinoma of the appendix: comparison of clinicopathologic features and prognosis.Arch Pathol Lab Med. 2015; 139: 782-790Crossref PubMed Scopus (59) Google Scholar Taggart et al.5Taggart M.W. Abraham S.C. Overman M.J. Mansfield P.F. Rashid A. Goblet cell carcinoid tumor, mixed goblet cell carcinoid-adenocarcinoma, and adenocarcinoma of the appendix: comparison of clinicopathologic features and prognosis.Arch Pathol Lab Med. 2015; 139: 782-790Crossref PubMed Scopus (59) Google Scholar demonstrated that patients with GCCs comprising carcinomatous components accounting for less than 25% of the tumour had no metastases or residual disease and better prognoses than those with carcinomatous components accounting for greater than 50% of the tumour. Tang et al.3Tang L.H. Shia J. Soslow R.A. et al.Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix.Am J Surg Pathol. 2008; 32: 1429-1443Crossref PubMed Scopus (219) Google Scholar suggested that patients with signet ring cell type adenocarcinoma ex-GCC had more favourable prognoses than those with poorly differentiated adenocarcinoma type.3Tang L.H. Shia J. Soslow R.A. et al.Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix.Am J Surg Pathol. 2008; 32: 1429-1443Crossref PubMed Scopus (219) Google Scholar In the colorectum, most concurrent tumours are composed of adenocarcinoma/adenoma and NET grade 1, which is almost a typical carcinoid. As far as we know, the present case is the first of concurrent adenocarcinoma ex-GCC and conventional adenocarcinomas in the literature. Similar to the present case, most concurrent tumours have been reported as incidental findings, and unfortunately, the mechanism of concurrence is not clearly understood. Reid et al.10Reid M.D. Basturk O. Shaib W.L. et al.Adenocarcinoma ex-goblet cell carcinoid (appendiceal-type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-abdominal dissemination: an analysis of 77 cases.Mod Pathol. 2016; 29: 1243-1253Crossref PubMed Scopus (39) Google Scholar described eight histological patterns for adenocarcinoma ex-GCCs that occurred in combination with at least two or more. Among the eight histological patterns, the present case can be classified into the combination of microglandular and poorly cohesive goblet cell patterns. It has also been suggested that age above 55 years and perineural invasion are statistically independent factors for good prognoses.10Reid M.D. Basturk O. Shaib W.L. et al.Adenocarcinoma ex-goblet cell carcinoid (appendiceal-type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-abdominal dissemination: an analysis of 77 cases.Mod Pathol. 2016; 29: 1243-1253Crossref PubMed Scopus (39) Google Scholar Even though adenocarcinoma ex-GCC has been considered a low-grade malignancy with a better prognosis than de novo adenocarcinoma,5Taggart M.W. Abraham S.C. Overman M.J. Mansfield P.F. Rashid A. Goblet cell carcinoid tumor, mixed goblet cell carcinoid-adenocarcinoma, and adenocarcinoma of the appendix: comparison of clinicopathologic features and prognosis.Arch Pathol Lab Med. 2015; 139: 782-790Crossref PubMed Scopus (59) Google Scholar more than half of patients with GCCs present metastasis at the time of initial diagnosis.3Tang L.H. Shia J. Soslow R.A. et al.Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix.Am J Surg Pathol. 2008; 32: 1429-1443Crossref PubMed Scopus (219) Google Scholar Both the proportion and histological type of the adenocarcinoma component in GCCs correlate with the survival of patients with adenocarcinoma ex-GCC;3Tang L.H. Shia J. Soslow R.A. et al.Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix.Am J Surg Pathol. 2008; 32: 1429-1443Crossref PubMed Scopus (219) Google Scholar, 5Taggart M.W. Abraham S.C. Overman M.J. Mansfield P.F. Rashid A. Goblet cell carcinoid tumor, mixed goblet cell carcinoid-adenocarcinoma, and adenocarcinoma of the appendix: comparison of clinicopathologic features and prognosis.Arch Pathol Lab Med. 2015; 139: 782-790Crossref PubMed Scopus (59) Google Scholar therefore, careful evaluation of the morphological features and appropriate pathological classifications of GCCs may be important for accurate diagnosis, clinical management, and outcome predictions. Because the awareness of this entity and the pathological classification according to its histological component is very important for patient prognosis, we report this case with a review of the literature. The authors thank Dr Seung-Mo Hong (Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea) for his histological review of this case. This work was supported by the research funds of Chonbuk National University in 2012, and by grants from the Medical Research Center Program (NRF-2017R1A5A2015061) through the National Research Foundation (NRF), which is funded by the Korean government (MSIP).