Metastatic appendiceal goblet cell carcinoid masquerading as mucinous adenocarcinoma in effusion cytology: A diagnostic pitfall.

Goblet cell carcinoids are rare tumors of appendix having a mixed phenotype, with partial neuroendocrine differentiation and intestinal type goblet cell morphology. The reported incidence of this tumor is still limited. Till now, only two cases of metastatic goblet cell appendiceal carcinoid on effusion cytology have been reported in literature. We describe the clinico-pathological details and lay stress on fluid cytology of metastatic goblet cell carcinoid to ascitic fluid.

Introduction

Goblet cell carcinoid (GCC), first reported by Gagne in 1969, is a rare tumor of appendix having a mixed phenotype, with partial neuroendocrine differentiation and intestinal type goblet cell morphology.[12] It comprises approximately 6% of appendiceal carcinoids and usually occurs in the pure form.[3] Four types of carcinoid tumors that contain goblet cells are now recognized in the appendix: (1) Pure form composed entirely of goblet cells, (2) GCC with adenocarcinoma (adenocarcinoma ex GCC), (3) GCC with mucinous cystadenoma, and (4) the combined classical carcinoid with GCC tumor.[4] They are believed to behave in a more aggressive manner than usual appendiceal carcinoids. About 20% cases have been reported to present with metastases.[5] To the best of our knowledge, only two cases of metastatic goblet cell appendiceal carcinoid (GCAC) on effusion cytology have been reported in literature.[67] Here, we report the cytological findings of another rare case of a metastatic GCAC to ascitic fluid.

Case Report

A 45-year-old female presented with one-month history of gradual distension of abdomen and vomiting. Clinically, gross ascites was present. Past history of patient revealed that three years back, the patient was operated for bilateral ovarian tumor in a private hospital. She was asymptomatic for the next three years. The slides of ovarian tumor were reviewed, and a diagnosis of bilateral mucinous cystadenoma was made. There was no component of invasive tumor or carcinoid component in the ovarian tumor. Computed tomography (CT) scan of abdomen was done, which revealed ascites and diffuse omental thickening. Ascitic fluid was tapped. Slides were prepared on Shandon cytocentrifuge. Smears were made on glass slides, which were fixed immediately in 95% alcohol and stained by Papanicolaou method. Air-dried smears were stained by May-Grünwald-Geimsa (MGG) method. Smears of ascitic fluid were moderately cellular and composed of numerous cells disposed in acini, clusters as well as lying singly in a background of mucin. There were gland-like formations, some with central lumina. Predominant cell type was the signet ring cell with abundant vacuolated cytoplasm and nucleus pushed to periphery. A second population of cells was identified, which were smaller in size with folded nuclei, fine chromatin and scant to moderate amount of eosinophilic cytoplasm [Figure 1]. Our cytological diagnosis was compatible with that of metastatic mucinous adenocarcinoma. In view of a primary ovarian tumor and fluid cytology findings of metastatic mucinous adenocarcinoma, patient was given six cycles of chemotherapy. Repeat computed tomography (CT) scan after six months did not show any significant change in size of omental thickening. Infracolic omentectomy along with appendicectomy was performed. Gross examination of the specimen of appendix revealed a small diffuse shiny thickened area (less than 1 cm) at the tip of appendix. Hematoxylin and eosin-stained sections were obtained from formalin-fixed, paraffin–embedded tissue blocks, which revealed a submucosal infiltrate of dual population of cells, majority of which comprised of classical carcinoid tumor cells and a minor component of GCC lying in a pool of mucin. Mitosis was occasional. Necrosis was not seen. Tumor infiltrated upto peri-appendiceal fat. Sections from the omental thickening revealed infiltration by goblet cells (signet cells) only. Histopathological diagnosis of combined classical carcinoid and GCC with metastases to omentum was made. Immunohistochemical studies were performed on a Ventana Benchmark automated stainer on formalin-fixed, paraffin-embedded tissue block from both the sites. Appropriate positive and negative controls were obtained. The antibodies tested were cytokeratin (CK) 20, and the neuroendocrine markers chromogranin, synaptophysin, and neuron-specific enolase. Immunohistochemistry (IHC) in both the classical carcinoid and goblet cell component revealed positivity for neuroendocrine markers. The ascitic fluid smears were re-examined in light of histopathology findings. On carefully reviewing the slides, the second population of cells, which were fewer in number, was identified as classical carcinoid cells [Figure 1]. These were admixed with goblet cells. We could not make a diagnosis of metastatic GCAC to ascitic fluid because of our lack of experience with such a finding on cytological smears coupled with the fact that there was a frank predominance of signet ring cells in the smear. Identification of the classical carcinoid cells in ascitic fluid earlier would have prevented us from misdiagnosing this case.

Figure 1

Metastatic goblet cell carcinoid in ascitic fluid. Goblet cells (black arrow) and carcinoid cells (white arrow) are present in clusters. (a and c, Pap stain, × 400; b and d, Pap stain, × 1000)

Discussion

GCC are unusual neoplasms with dual mucinous and neuroendocrine differentiation and a distinct predilection for the appendix. Other rare sites are colon, ampulla of Vater and duodenum.[8] They commonly present as acute appendicitis often with intra-abdominal mass as opposed to appendiceal carcinoid tumors, which are commonly incidental finding. The tumor is thought to arise from pleuripotent, intestinal crypt–base stem cells that are able to differentiate along neuroendocrine and mucinous cell lines.[13] GCC behave more aggressively than classical carcinoid tumors.[478] However, they have relatively better prognosis when compared with traditional adenocarcinoma. Cytological findings of primary appendiceal GCC have not been described yet. Pathologists are seldom approached for FNAC as the patients usually present with acute appendicitis. Wojcik et al.[6] and Zafar et al.[7] described the cytological features of the two cases of metastatic GCAC in effusion cytology. They emphasized the presence of carcinoid component and signet ring cells in effusion cytology as was evident in our case. Other entities that contain signet ring cells including metastatic signet ring cell carcinomas from gastrointestinal tract, lung and also metastatic lobular carcinoma from breast may be considered in the differential diagnosis. Metastatic lobular carcinoma in effusion fluids are typically manifested as small uniform cells in an Indian file pattern. Presence of signet ring cells in these cases may show drop-like mucin in an intra-cytoplasmic vacuole. These features in combination reflect its origin from breast. Cytological picture in metastatic signet ring carcinoma from stomach is more likely to be one of single population of virtually all isolated cells rather than one of clusters of cells.[9]

Cytological misdiagnosis in present case was due to the fact that that there was a frank predominance of goblet cells in the smears, which masked the presence of minor population of classical carcinoid cells. Though the histopathological features of this tumor are classical, it is difficult to diagnose the tumor on cytology smears, especially when one cell type far exceeds the other. However, a careful search will lead to a correct diagnosis.

Present case highlights the importance of effusion cytology in diagnosing this rare tumor. The practicing pathologists need to keep this entity in mind to arrive at a correct diagnosis so that appropriate therapy can be instituted. One must not overlook even if few cells with different nuclear features are visualized on fluid cytological smears.