Amphicrine Carcinoma Research Articles

Integrated multi-omics assessment of lineage plasticity in a prostate cancer patient with brain and dural metastases

Metastases to the brain are rare in prostate cancer. Here, we describe a patient with two treatment-emergent metastatic lesions, one to the brain with neuroendocrine prostate cancer (NEPC) histology and one to the dural membrane of adenocarcinoma histology. We performed genomic, transcriptomic, and proteomic characterization of these lesions and the primary tumor to investigate molecular features promoting these metastases. The two metastatic lesions had high genomic similarity, including TP53 mutation and PTEN deletion, with the most striking difference being the additional loss of RB1 in the NEPC lesion. Interestingly, the dural lesion expressed both androgen receptor and neuroendocrine markers, suggesting amphicrine carcinoma (AMPC). When analyzing pioneer transcription factors, the AMPC lesion exhibited elevated FOXA1 activity while the brain NEPC lesion showed elevated HOXC10, NFYB, and OTX2 expression suggesting novel roles in NEPC formation or brain tropism. Our results highlight the utility of performing multi-omic characterization, especially in rare cancer subtypes.

Gastric amphicrine carcinoma: A histopathological diagnostic conundrum

Amphicrine carcinoma is rarely reported in literature. It is characterised by dual positivity of neuroendocrine markers and mucin stain in the same cells depicting divergent differentiation. Recently published WorldHealth Organisation (WHO) classification of neuroendocrine neoplasm of 2022 differentiates it from adenocarcinoma and mixed neuroendocrine-nonneuroendocrine neoplasms (MiNEN) it shows varied histomorphology and on rare occasions neuroendocrine features may not be evident in poorly differentiated carcinoma. Hence, diagnosis based solely on histomorphology can be misleading. This is a case of amphicrine carcinoma in an elderly female which showed poorly differentiated morphology along with signet ring cells. Same cells demonstrated immunopositivity for synaptophysin, chromogranin A and were also positive for mucin stains (PAS, PAS-D and Alcian blue). This case report, thus, emphasises the importance of neuroendocrine markers as a part of routine immunohistochemistry in poorly differentiated gastric carcinomas to aid diagnosis of amphicrine carcinoma.

Mucinous Amphicrine Carcinoma of the Pancreas: A Diagnostic Pitfall.

Mucinous Amphicrine Carcinoma of the Pancreas: A Diagnostic Pitfall.

Clinicopathological features of colorectal amphicrine carcinoma

Objective: To investigate the clinicopathological, immunophenotypic and molecular features of colorectal amphicrine carcinoma (AC). Methods: Eight cases of colorectal AC were collected at the Nanjing Drum Tower Hospital and Nanjing First Hospital, Nanjing, China from 2013 to 2020. The histopathological, immunohistochemical and molecular features were analyzed. The relevant literature was reviewed. Results: There were 6 males and 2 females, with an average age of 56 years (range 28-80 years). The tumor sites were as follows: 4 cases in sigmoid colon, 3 cases in rectum, and 1 case in transverse colon. Microscopically, there were three different patterns in the tumors, including nests with collagen hyperplasia, sheets of cells with scant stroma, and glandular or cribriform growth of goblet- or signet ring-like cells. The tumor cells generally had abundant cytoplasm with abundant mucin or eosinophilic granules. The nuclei were oval or irregular with fine chromatin and inconspicuous nucleoli. Mitotic figures were common. Neuroendocrine granules and mucin granules could be identified clearly under electron microscope. All cases showed frequent perineural and lymphovascular invasions, lymphatic metastasis, and advanced stage. Regarding immunohistochemical and specific stains, the tumor cells expressed more than two neuroendocrine markers, particularly CD56 and synaptophysin which were diffusely positive in 7 of the 8 cases. They also showed intracellular mucin in the amphicrine components which was positive for D-PAS. KRAS G12C or NRAS Q61 gene mutations were found in 2 patients. Among the six cases with complete follow-up, four of them died of the disease within three years of the diagnoses, while two were alive without known disease progression. Conclusions: Colorectal AC is a rare, distinct entity with both epithelial and neuroendocrine differentiation. It mainly occurs in the sigmoid colon and rectum. It typically has aggressive clinical courses, dismal prognosis and characteristic histological features and immunophenotype, which highlight the importance of recognizing this entity for clinicians and pathologists.

Genetic alterations in gastric amphicrine carcinomas and comparison with gastric mixed neuroendocrine-non-neuroendocrine neoplasms

AbstractGastric amphicrine carcinoma, in which endocrine and epithelial cell features are present within the same cells, is often confused with gastric mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). In this study, we performed high-resolution copy number (CN) profiling and whole exome sequencing (WES) of formalin-fixed and paraffin-embedded (FFPE) tissues from eight gastric amphicrine carcinomas and compared the molecular features with those of the adenocarcinoma and neuroendocrine carcinoma (NEC) components of eight gastric MiNENs. The most frequent high-level CN variant was a gain of 20q13.12–20q13.2, which was found in five gastric amphicrine carcinomas. Amplifications of MYT1, NTSR1, and ZBTB46 located in this region were demonstrated by qPCR and immunohistochemistry. The CN characteristics of gastric amphicrine carcinomas were different from those of MiNENs in hierarchical clustering analysis, suggesting that amphicrine carcinoma is a separate entity from MiNEN. Moreover, the CN level of C5 (complement C5) was higher in amphicrine carcinoma than in both the adenocarcinoma and the NEC component of MiNENs, suggesting that amphicrine carcinomas might benefit more from C5 inhibitors than MiNENs. WES showed frequent somatic mutations of TP53 (37.5%, 3/8) and APC (25.0%, 2/8) in amphicrine carcinoma. There were no specific mutation characteristics to distinguish amphicrine carcinoma from MiNEN. An integrated KEGG pathway analysis showed that the estrogen signaling pathway was enriched in amphicrine carcinomas, which might be associated with the high morbidity of male patients. In summary, our study revealed the unique CN and mutation characteristics of gastric amphicrine carcinoma and differentiated these characteristics from those of MiNENs. These data provide a foundation for further studies on the development and progression of amphicrine carcinoma.

Transcription Factor Expression in Sinonasal Neuroendocrine Neoplasms and Olfactory Neuroblastoma (ONB): Hyams’ Grades 1–3 ONBs Expand the Spectrum of SATB2 and GATA3-Positive Neoplasms

Sinonasal neuroendocrine neoplasms (SN-NENs) are rare and mostly include neuroendocrine carcinoma (NEC), whereas neuroendocrine tumor (NET) is exceptional in this site. Olfactory neuroblastoma (ONB) is a malignant neuroectodermal neoplasm arising in the nasal cavity. Albeit crucial for correct patients’ management, the distinction of high grade ONB from NEC is challenging and requires additional diagnostic markers. The transcription factor SATB2 has been recently introduced in routine diagnostics as an immunohistochemical marker of distal intestine differentiation. No specific data are available about SATB2 and GATA3 expression in SN-NENs. GATA3, SATB2, and, for comparison, CDX2 expression were investigated in a series of epithelial and non-epithelial SN-NENs. We collected 26 cases of ONB and 7 cases of epithelial SN-NENs diagnosed and treated in our Institution. ONBs were graded according to Hyams’ system and epithelial NENs were reclassified into 5 NECs, 1 MiNEN, and 1 amphicrine carcinoma. Immunohistochemistry was performed using standard automated protocols. Hyams’ grades 1–3 ONBs stained diffusely and intensely for SATB2, whereas grade 4 ONBs and NECs were globally negative. The non-neuroendocrine component of MiNEN and the amphicrine carcinoma were strongly positive. GATA3 was heterogeneously and unpredictably expressed in Hyams’ grades 1–3 ONBs, whereas grade 4 ONBs and NECs were completely negative. CDX2 was negative in all cases. Our study identifies, for the first time, SATB2 and GATA3 expression as features of Hyams’ grades 1–3 ONBs, expands the spectrum of SATB2 and GATA3-positive neoplasms, and suggests that Hyams’ grade 4 ONBs are not only clinically but also biologically different from low graded ONBs.

Clinicopathological analysis of amphicrine carcinoma of the stomach

目的： 探讨胃具有腺和神经内分泌双向分化的癌（AC）的临床病理学特征。 方法： 收集苏州大学附属第三医院/常州市第一人民医院2019—2020年诊断的胃AC 2例患者的临床资料，观察其组织形态学特征，通过免疫组织化学染色、特殊染色及二代测序等技术分析其免疫表型及分子特征，并复习相关文献。 结果： 2例患者均为男性。例1，54岁，病变位于胃窦，肿瘤最大径为4 cm；例2，75岁，病变位于贲门，肿瘤最大径为2 cm。镜下观察肿瘤细胞主要呈片状或条索状分布，细胞异型性大，核仁明显，核分裂象多见，肿瘤细胞主要为印戒细胞样，例1可见神经内分泌肿瘤成分，并伴淋巴结转移，例2局灶伴有细胞外黏液，还可见瘤巨细胞。2例肿瘤细胞均弥漫强阳性表达突触素、嗜铬粒素A和CD56，广谱细胞角蛋白、MUC1和MUC4也有表达，不表达MUC2、MUC5AC及MUC6。特殊染色结果：阿辛蓝-过碘酸雪夫（AB-PAS）染色阳性。二代测序结果：例1 RAD51D p.Arg266Cys错义突变，例2 TSC1、SMAD4、PALB2、VEGFA、FGFR3错义突变，TP53无义突变，PTEN剪接位点变异，MYC拷贝数扩增。 结论： 胃AC是一种同时具有神经内分泌和腺上皮分化特征的罕见肿瘤，结合组织学形态、免疫表型、AB-PAS染色结果及基因变异特点有助于诊断。.

Primary hepatic neoplasms arising in cirrhotic livers can have a variable spectrum of neuroendocrine differentiation

Primary hepatic neoplasms with neuroendocrine differentiation are extremely rare. Their clinicopathological features and molecular genetic basis are largely unknown. We identified four cases of primary hepatic neoplasms with neuroendocrine differentiation. Electronic medical records were reviewed for clinical history, imaging findings, laboratory results, and follow-up. Pathology slides, immunohistochemistry, and ancillary studies were reviewed. There were two females and two males with age ranging from 52 to 74 years. There was one amphicrine carcinoma with tumor cells simultaneously demonstrating both hepatocellular and neuroendocrine differentiation, one mixed hepatocellular-neuroendocrine carcinoma (NEC) with hepatocellular component intermingled with neuroendocrine component, one small cell NEC, and one well-differentiated neuroendocrine tumor. Next- generation sequencing of the mixed hepatocellular-NEC and small cell NEC showed molecular/genetic alterations commonly seen in hepatocellular carcinoma (HCC). All four cases arose in a background of cirrhosis. Primary hepatic neoplasms arising in cirrhotic livers can have a spectrum of neuroendocrine differentiation. Presence of a NEC component may be an indicator of aggressiveness. In addition, primary hepatic carcinomas with neuroendocrine differentiation likely share the same molecular pathways as HCC.

Neuroendocrine Neoplasms of the Gallbladder: A Clinicopathological Analysis of 13 Patients and a Review of the Literature.

Objectives Mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) are rare gallbladder neuroendocrine neoplasms (GB-NENs). This study is aimed at investigating the clinicopathological features of GB-NENs and identifying prognostic factors related to overall survival (OS) of GB-MiNENs. Methods The clinical data and pathological features of 13 patients with GB-NENs in our hospital were retrospectively reviewed. Additionally, 41 GB-MiNENs cases reported in English literature were reviewed and survival analysis was performed. Results The mean age of thirteen patients (6 males and 7 females) with GB-NENs was 57.2 years (range: 35-75 years). Two patients were diagnosed with NET grade 1 (G1), two patients with NEC (large cell/small cell = 1/1), and nine patients with MiNENs. Of these 9 patients with MiNENs, 8 had composite tumors and 1 had amphicrine carcinoma. Microscopically, the adenocarcinoma component was located in the surface mucosa, and the neuroendocrine component was in the area of deep invasion, liver infiltration, and lymph node metastasis. Total analysis of 41 GB-MiNENs showed that patients were mainly elderly women (female/male ratio, 2.4 : 1.0; median age, 60 years). Kaplan-Meier's analysis demonstrated that liver metastasis and TNM stage III-IV were associated with decreased OS (P < 0.05), whereas age, sex, tumor size, grade of the neuroendocrine component, lymph node metastasis, and adjuvant chemotherapy were not significantly prognostic indicators of OS. Multivariate analysis identified liver metastasis (hazard ratio = 4.262, 95%confidence interval = 1.066‐17.044, P = 0.040) as an independent unfavorable prognostic factor. Conclusions GB-MiNENs were the most common type of GB-NENs in our case series, and neuroendocrine components exhibited more aggressive lymph node metastasis and local invasion than adenocarcinoma. Liver metastasis was a poor prognostic indicator in GB-MiNENs patients.

Amphicrine carcinoma of the stomach and intestine: a clinicopathologic and pan-cancer transcriptome analysis of a distinct entity

Background and aimAmphicrine carcinoma, in which endocrine and epithelial cell constituents are present within the same cell, is very rare. This study characterized the clinicopathologic and survival analysis of this tumor, further compared the genetic diversities among amphicrine carcinoma and other tumors.Materials and methodsThe clinicopathologic characteristics and survival outcomes of amphicrine carcinoma in this study were analyzed. The pan-cancer transcriptome assay was utilized to compare the genetic expression profile of this entity with that of conventional adenocarcinoma or neuroendocrine tumors.ResultsTen cases (all in male patients) were identified in the stomach or intestine, with a median patient age of 62 years. There were characteristic patterns in the tumors: tubular, fusion or single-file growth of goblet- or signet ring-like cells. Four tumors were classified as low-grade and 6 as high-grade according to the histologic architecture. All cases were positive for neuroendocrine markers (synaptophysin and chromogranin A) and showed intracellular mucin in the amphicrine components. Four cases exhibited mRNA expression patterns showing transcriptional homogeneity with conventional adenocarcinomas and genetic diversity from neuroendocrine tumors. During the follow-up period, 3 patients died of disease, all of whom had high-grade tumors. Patients with high-grade amphicrine carcinoma had worse outcomes than those with low-grade tumors.ConclusionsThis study confirms the morphological, immunostaining and transcriptome alterations in amphicrine carcinoma distinct from those in conventional adenocarcinomas and neuroendocrine tumors, but additional studies are warranted to determine the biological behavior and therapeutic response.

Evolving concepts in prostatic neuroendocrine manifestations: from focal divergent differentiation to amphicrine carcinoma

Prostatic neuroendocrine manifestations encompass a heterogeneous spectrum of morphologic entities. In the era of evidence-based and precision-led treatment, distinction of biologically relevant clinical manifestations expanded the evolving clinical role of pathologists. Recent observations on the occurrence of hormone therapy-induced aggressive prostatic cancers with neuroendocrine features have triggered the need to refine the spectrum and nomenclature of prostatic neuroendocrine manifestations. Although the morphologic assessment still remains the basis of the diagnostic workup of prostatic neoplasms, the application of ancillary biomarkers is crucial in the accurate classification of such presentations. This review provides a diagnostic roadmap for the practicing pathologist by reviewing the characteristic morphologic, immunohistochemical, and molecular correlates of various faces of prostatic neuroendocrine manifestations.

Pulmonary Carcinomas With Mucinous and Neuroendocrine Differentiation: Expanding the Spectrum of Amphicrine Carcinomas.

Amphicrine carcinoma is a distinct type of carcinoma characterized by synchronous exocrine and endocrine differentiation within the same tumor cell. Such tumors are exceedingly rare and most commonly recognized in the gastrointestinal tract. In the lung, sporadic descriptions of such lesions exist. This report presents 3 more such tumors, expanding the spectrum of amphicrine carcinomas in this organ. The patients were 3 men, 53 to 78 years of age (mean: 63 y) and all were current or former smokers. In one patient the tumor was an incidental finding, the others presented with lower respiratory symptoms. Microscopically, the lesions had an organoid pattern, consisting of nests of large tumor cells with peripheral palisading, vesicular nuclei and prominent nucleoli reminiscent of large cell neuroendocrine carcinoma. In addition, the tumor nests also showed glandular features, characterized by gland-like lumina filled with mucin and intracytoplasmic mucin droplets. Immunohistochemical studies showed diffuse reactivity of the tumor cells with synaptophysin and chromogranin and variable reactivity with TTF-1. Mucin stains highlighted extracellular and intracellular mucin deposition. Clinical follow-up demonstrated that one patient had died of his disease 12 months after surgery while another was alive and free of disease 21 months after surgery. The third patient was alive with widespread metastatic disease 8 months after diagnosis. This series highlights a rare variant of pulmonary carcinoma showing synchronous exocrine and endocrine differentiation. Recognition of this type of tumor is important in terms of tumor classification and to identify an entity with potential aggressive behavior.

Periampullary neuroendocrine tumor with large intracellular mucin globules, an amphicrine tumor?

Amphicrine carcinoma is a rare type of mixed adenoneuroendocrine carcinoma in which both exocrine and endocrine components are co-expressed in the same tumor cells. We report a case of a 57 year old man with a complex cystic and solid periampullary mass which shows a misleading poorly differentiated morphology. The tumor cells are positive for neuroendocrine markers with some cells showing large intracytoplasmic mucin. Additionally, CEA immunostain is weakly, but diffusely positive in the same tumor cells. The tumor may represent an amphicrine carcinoma, however, it has been reported that neuroendocrine cells may show aberrant mucin production. To what extent of mucin production should the tumor have to be considered as amphicrine is the question without answer, and currently the diagnostic criteria for amphicrine carcinoma have not been well established.

Hepatic perihilar amphicrine cholangiocarcinoma: A case report

Mixed neuroendocrine nonneuroendocrine neoplasms (MiNEN) are tumors composed of adenocarcinoma and neuroendocrine neoplasm and include collision, combined, and amphicrine. Within the hepatobiliary tree, tumors of this histologic type are extremely rare, particularly the amphicrine type. In this case study, we describe a 63-year-old man with a hepatic hilar amphicrine tumor. An initial diagnosis of neuroendocrine tumor was made based on biopsy (chromogranin and synaptophysin positivity). On resection, the tumor contained histologic features of both adenocarcinoma and neuroendocrine carcinoma. Immunohistochemically, all tumor cells expressed both chromogranin and synaptophysin, keratin 7, and Cam5.2. Mucin production was evident in both components demonstrated by mucicarmine stain. Albumin RNA in situ hybridization (ISH) was positive, supporting hepatic source. The tumor is classified as an amphicrine carcinoma given the dual expression of both adenocarcinoma and neuroendocrine markers in both components. This is the first amphicrine carcinoma of the hepatic hilum reported in the literature.

Prostate carcinoma with amphicrine features: further refining the spectrum of neuroendocrine differentiation in tumours of primary prostatic origin?

The current World Health Organization classification categorises high-grade neuroendocrine (NE) carcinomas of the prostate into small-cell and large-cell types. A distinct form of carcinoma showing synchronous dual exocrine and NE differentiation, termed amphicrine carcinoma, has been described at various other sites, primarily within the gastrointestinal tract. The aim of this study was to investigate the clinicopathological features of a series of metastatic prostate carcinoma (PCa) cases with amphicrine features. Five cases of high-grade PCa showing an amphicrine immunohistochemical phenotype were prospectively collected. The serum prostate-specific antigen (PSA) level at diagnosis ranged from 38 ng/ml to 992 ng/ml (median 200 ng/ml). All five patients had metastatic disease, four at initial presentation. Microscopically, the tumours showed a solid/nested growth pattern composed of cells with amphophilic cytoplasm, vesicular nuclei, and macronucleoli. Morphological features of small-cell or large-cell NE carcinoma were absent. As compared with conventional high-grade PCa, the tumour cells showed a higher level of nuclear pleomorphism, brisk mitotic activity, and a high Ki67 proliferation index (median 50%). All cases showed immunohistochemical positivity for PSA, androgen receptor, and prostate-specific acid phosphatase, combined with diffuse or confluent/non-focal positivity for chromogranin-A and synaptophysin. Two hormone-naive cases showed a clinical response to androgen deprivation therapy. This series highlights a previously undefined, clinically aggressive variant of PCa showing dual exocrine and NE differentiation, for which we are proposing the term PCa with amphicrine features. Increased recognition of these tumours may lead to a better understanding of their biology, and ultimately improve their clinical management.

Amphicrine Carcinoma of the Ampullary Region

Amphicrine carcinoma is a peculiar tumor in which the cells have both exocrine and neuroendocrine differentiation, with mucus and neuroendocrine granules within the cytoplasm. In the 2010 WHO classification of tumors of the digestive tract, they have been included in the intermediate-grade malignant category of mixed adenoneuroendocrine carcinomas (MANECs). These tumors are extremely rare in the gastrointestinal tract. Four cases have been reported in the stomach, three in the pancreas, and one in the liver. To the best of our knowledge, this report describes the first case of amphicrine carcinoma in the ampullary region.

Amphicrine carcinoma of caecum: a case report and literature review

Background Amphicrine carcinomas are a rare subgroup of mixed adenoneuroendocrine carcinomas (MANECs) in which tumour cells show evidence of both glandular and endocrine differentiation. Methods We present a case of caecal amphicrine carcinoma in a 76-year-old woman. She developed metastatic peritoneal disease 2 months after her right hemicolectomy. Light microscopy and immunohistochemical findings with regard to diagnostic and prognostic factors are described and the literature is reviewed. Conclusion Mixed exocrine-neuroendocrine neoplasms, now renamed as mixed adenoneuroendocrine carcinomas (MANECs) are, by definition, neoplasms in which each component represents at least 30% of the lesion. In apmhicrine tumours, first described by Feyrter (1938), exocrine and neuroendocrine features are co-expressed by same neoplastic cells. There has not been a consistent classification system of these tumours for many decades. Following the recent WHO classification of neuroendocrine tumours of digestive system (2010), Rosa et al . divided MANECs into two groups: high and intermediate grade malignant neoplasms. They classified amphicrine carcinomas as intermediate grade malignancies. The optimal strategy of management of MANECs is largely unknown, due to rarity of these neoplasms. The adaptation of a consistent classification system is the first step in gathering more accurate prognostic data and evaluating treatment options.

Hepatic Metastasis of Composite Adenocarcinoma and Neuroendocrine Carcinoma

Composite glandular neuroendocrine tumors of the gastrointestinal tract are rare tumors. These dual-nature tumors can be divided into three subtypes: composite, collision, and amphicrine tumors. The term composite tumor applies to those neoplasms that contain intimately mixed glandular and neuroendocrine components. In collision tumors, the glandular and neuroendocrine components are closely juxtaposed but the individual cells are not mixed. Amphicrine carcinoma is applied when dual differentiation is present within the same cell [1]. Review of the English literature demonstrated sporadic case reports of composite tumors in the stomach, gallbladder, bile duct, pancreas, colon, and rectum [2–7]. In addition to the rarity of this lesion in the colon and rectum, to our knowledge, this is the first report of such colonic tumor to be diagnosed in the literature from the liver metastasis. The histogenesis of tumors containing both glandular and neuroendocrine components has generated much interest. Although it was not fully elucidated, recent molecular studies supported an origin from a multipotential stem cell for these tumors. The sequence of malignant progression is through adenoma to carcinoma with both glandular and neuroendocrine components sharing a common mechanism of carcinogenesis [1, 8]. Case Report

Amphicrine carcinoma of the liver

Amphicrine tumors are defined by evidence of both glandular and neuroendocrine differentiation in the same cell. These are extremely rare tumors, with only scattered case reports in the pancreas and stomach. We here report a case of amphicrine carcinoma occurring in apparent isolation in the liver. The tumor was characterized by signet ring cell morphology, mucicarmine, and periodic acid Schiff with diastase (PASD) positivity, and expression of chromogranin, synaptophysin, villin, and CDX2. No other tumor was identified by radiological or endoscopic examination of the gastrointestinal tract. The patient is disease-free 22 months after the resection. We speculate that this represents the first reported occurrence of primary amphicrine carcinoma of the liver.

Cytokeratins 7 and 20 Immunoexpression Profile in Goblet Cell and Classical Carcinoids of Appendix

Goblet cell carcinoid (GCC) of the vermiform appendix is an uncommon neoplasm and its histogenesis is controversial. Whether GCC represents a morphological variant of classical appendiceal carcinoid or a mucin-producing adenocarcinoma is still conjectural. Little is known about the immunohistochemical expression of cytokeratins 7 (CK7) and 20 (CK20) in appendiceal neuroendocrine tumors. In this study, we compared the expression of CK7 and CK20 in 17 cases of appendiceal GCC and 25 cases of classical carcinoid. The tumors were also evaluated for Ki-67 proliferation index, mitotic activity, tumor necrosis, extracellular pools of mucin, obvious intestinal type adenocarcinomatous foci, angiolymphatic permeation, perineural/neural infiltration, and the depth of invasion of the appendix wall. Mesoappendiceal extension was present in 14 of 17 (82.3%) cases of GCC, whereas angiolymphatic and perineural/intraaneural involvement were found in 10 of 17 (58.8%) and 14 of 17 (82.3%) cases, respectively. The mitotic count ranged from 0 per 10 high power fields to 6 per 10 high power fields, with an average of 1.4 per 10 high power fields. Necrosis was not seen in any case and pools of extravasated mucin were present in 5 of 17 (29.4%) cases. Immunohistochemically, all 17 (100%) of GCC exhibited strong and diffuse immunopositivity for CK20, whereas expression of CK7 was present in 12 cases (70.5%), ranging from 5 to 50% of tumor cells being labeled. The Ki-67 labeling index ranged from 0 to 75% and showed no correlation to mitotic activity, angiolymphatic invasion or perineural/intraneural permeation. On the other hand, 25 cases of classical carcinoid tumors were consistently negative for CK7; however, 4 cases (16%) showed immunolabeling for CK20 in 25-50% of the tumor cells. The Ki-67 labeling index in classical carcinoids ranged from 0 to 5%. This study shows that in addition to the morphological differences, GCC (CK7/CK20-positive) and classical carcinoid (CK7/CK20-negative) differ in their expression of CK7 and CK20. In addition, GCC shows the same CK7/CK20 immunoexpression as colorectal adenocarcinoma. Goblet cell carcinoid should be regarded as a crypt cell or an amphicrine carcinoma rather than a variant of carcinoid tumor, a lesion that has benign connotations.