Prognostic Immunohistochemistry for Ki-67 and OTP on Small Biopsies of Pulmonary Carcinoid Tumors: Ki-67 Index Predicts Progression-free Survival and Atypical Histology.

Prognostic stratification of pulmonary carcinoids into "typical" and "atypical" categories requires examination of large tissue volume. However, there is a need for tools that provide similar prognostic information on small biopsy samples. Ki-67 and OTP immunohistochemistry have shown promising prognostic value in studies of resected pulmonary carcinoids, but prognostic value when using biopsy/cytology specimens is unclear. Ki-67 immunohistochemistry was performed on small biopsy/cytology specimens from pulmonary carcinoid tumors (n=139), and labeling index was scored via automated image analysis of at least 500 cells. OTP immunohistochemistry was performed on 70 cases with sufficient tissue and scored as positive or negative (<20% tumor nuclei staining). Higher Ki-67 index was associated with worse disease-specific progression-free survival (ds-PFS), with 3% and 4% thresholds having similarly strong associations with ds-PFS ( P <0.001, hazard ratio ≥11). Three-year ds-PFS was 98% for patients with Ki-67 <3% and 89% for patients with Ki-67≥3% ( P =0.0006). The optimal Ki-67 threshold for prediction of typical versus atypical carcinoid histology on subsequent resection was 3.21 (AUC 0.68). Negative OTP staining approached significance with atypical carcinoid histology ( P =0.06) but not with ds-PFS ( P =0.24, hazard ratio=3.45), although sample size was limited. We propose that Ki-67 immunohistochemistry may contribute to risk stratification for carcinoid tumor patients based on small biopsy samples. Identification of a 3% hot-spot Ki-67 threshold as optimal for prediction of ds-PFS is notable as a 3% Ki-67 threshold is currently used for gastrointestinal neuroendocrine tumor stratification, allowing consideration of a unified classification system across organ systems.

Pulmonary gangliocytic paraganglioma: An under-recognized mimic of carcinoid tumor.

Gangliocytic paragangliomas are rare neoplasms occurring almost exclusively in the ampullary region of the gastrointestinal tract. Although these tumors are not typically considered in the differential diagnosis of primary pulmonary neoplasia, 5 cases of primary pulmonary gangliocytic paragangliomas have been previously reported. Herein we report our experience with 3 additional examples, all referred to our Anatomic Pathology Consultation service. The patients (a 32-year-old man, a 69-year-old woman and a 55-year-old man) each presented with an endobronchial (2 cases) or upper lobe lung mass, ranging from 1.5 to 2.5 cm in maximum dimension. Biopsy and endobronchial debulking specimens demonstrated the classic triphasic morphology of gangliocytic paraganglioma, with epithelial, spindled and ganglion-like cells. By immunohistochemistry, the tumors were positive for keratin, synaptophysin and chromogranin A in the epithelial component, S100 protein and glial fibrillary acidic protein (GFAP) in the Schwannian spindled cells, and synaptophysin in ganglion cells. TTF1 expression was seen in the epithelial components of 2 cases. The Ki-67 labelling index was low (<2%). Primary pulmonary gangliocytic paragangliomas should be distinguished from carcinoid tumors, given the different natural histories and risk stratification approaches for these morphologically similar tumors. Awareness that gangliocytic paraganglioma may occur in the lung and appropriate immunohistochemical studies are key to correct diagnosis.

Primary Pituitary Carcinoids Do Not Exist: A Reappraisal in the Era of Pituitary Neuroendocrine Tumours.

The World Health Organization classification of pituitary tumours, published in 2022, supported a change in the terminology from "pituitary adenoma" to "pituitary neuroendocrine tumour" (PitNET). The neuroendocrine cells represent an integral part of the diffuse neuroendocrine system, including, among others, thyroid C cells, the parathyroid chief cells, and the anterior pituitary. Normal and neoplastic adenohypophyseal neuroendocrine cells have light microscopic, ultrastructural features and an immunoprofile compatible with the neuroendocrine cells and neuroendocrine tumours from other organs. Moreover, neuroendocrine cells of pituitary origin express transcription factors which indicate their cell-lineage origin. Thus, pituitary tumours are now considered as a continuum with other neuroendocrine tumours. PitNETs may occasionally be aggressive. In this context, the term "pituitary carcinoid" has no specific meaning: it either represents a PitNET, or a metastasis to the pituitary gland of a neuroendocrine tumour (NET). An accurate pathological evaluation, combined where necessary with functional radionuclide imaging, can define the origin of the tumour. We recommend that clinicians liaise with patient groups to understand the terminology to define primary tumours of adenohypophyseal cells. It is incumbent upon the responsible clinician to explain the use of the word "tumour" in a given clinical context.

Dual-Functional Metal-Organic Framework for Luminescent Detection of Carcinoid Biomarkers and High Proton Conduction.

It remains a challenge to exploit dual-functional metal-organic frameworks (MOFs) for applications, including luminescence detection and proton conduction. With the deliberate selection of the bifunctional organic ligand 5-sulfoisophthalic acid monosodium salt (NaH2bts), and the phosphonic acid ligand N,N'-piperazine (bismethylenephosphonic acid; H4L), a robust three-dimensional (3D) noninterpenetrating dual-functional MOF, [Tb(H2L)(H2bts)(H2O)]·H2O (1), has been synthesized hydrothermally. On the basis of the excellent thermal and chemical as well as superior luminescence stabilities in water and solutions with different pHs, 1 can serve as the simple, rapid, and highly selective and sensitive luminescence detection of the carcinoid biomarkers 5-hydroxytryptamine (HT) and its metabolite 5-hydroxyindole-3-acetic acid (HIAA) with detection limits of nanomolar magnitude in water and in simulated blood plasma and urine systems. Due to the change in the signals that could be readily differentiated by the naked eye under a UV lamp, a portable test paper has been developed. The probable quenching mechanisms are discussed in detail. In addition, a great number of hydrogen-bonding networks are formed among the uncoordinated carboxylic oxygen atoms, sulfonate oxygen atoms, protonated nitrogen atoms, and water molecules, which provide potential proton-hopping sites for proton conduction, leading to a maximum proton conductivity of 2.3 × 10-4 S cm-1 at 368 K and 95% relative humidity. The above results suggest that rationally designed dual-functional MOFs can open an avenue for the development of occupational diagnostic tools and alternative energy technology.

[Retrospective study of lung carcinoid: experience in a third level Spanish hospital]. / Estudio retrospectivo descriptivo sobre el tumor carcinoide pulmonar: experiencia de un centro español de tercer nivel.

INTRODUCTION: Pulmonary carcinoids are relatively rare neuroendocrine neoplasms, accounting for only 1-2% of malignant thoracic tumours. We describe our experience in the management and follow-up of such an infrequent tumour, with special emphasis on possible problems that might arise. PATIENTS AND METHODS: We present a descriptive retrospective study of all patients diagnosed with carcinoid tumour between January 2013 and January 2018. Demographic, histological and clinical data were collected and analyzed. Survival was recorded. SPSS version 21 was used for the statistical analysis. RESULTS: 42 patients with an average age of 66.26 years were included. The mean period of follow-up was 60 months and the average survival 59.12 months. The only statistically significant factor related to an improved survival time was tumour stage at diagnosis. CONCLUSION: Carcinoid tumours are infrequent, which makes the objective collecting of data difficult. For this reason, we hope that the present study will contribute to a better understanding of their evolution.

Phospho-histone-H3 immunostaining for pulmonary carcinoids: impact on clinical appraisal, interobserver correlation, and diagnostic processing efficiency.

Lung carcinoid tumors are classified as either typical or atypical based on the presence of necrosis and the maximum mitotic count per 2 mm2 area. Determining the mitotic count, which is manually conducted on slides stained with hematoxylin and eosin (HE), is time-consuming and subject to high interobserver variability. The objective of this study was to test the sensitivity and specificity of a surrogate mitosis marker, phospho-histone-H3 (PHH3) immunostaining, in the processing of pulmonary carcinoids as compared with the standard HE evaluation. Carcinoid tissue blocks that were available from lung resection specimens were analyzed using HE and PHH3 stains. Two thoracic pathologists and two residents determined the mitotic count on HE and PHH3 stains in accordance with the 2015 WHO guidelines and recorded the time required to complete this task. For both methods, the interobserver agreement among raters for the mitotic count/2 mm2 was assessed by conducting intraclass correlation analyses. We found that for both pathologists and residents, the time required to determine the mitotic count using the PHH3 method was reduced compared with the traditional HE method. Furthermore, residents detected more mitoses/2 mm2 using the PHH3 stain compared with the HE method. More importantly, the PHH3 method yielded better interobserver agreement than the HE method in terms of mitoses/mm2 detection. Overall, our data confirmed that histologic assessments of carcinoid tumors using PHH3 staining provides practical benefits in terms of scoring times, mitosis detection, and reproducibility of mitotic counts. In addition, we found that the benefit was even greater for less experienced pathologists.

Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study.

BACKGROUND: Despite a protracted disease course and multiple available therapies, patients with well-differentiated neuroendocrine tumors (NETs) inevitably experience disease progression. Programmed death-ligand 1 (PD-L1) has been associated with NET progression and prognosis. The multicohort, phase 1 KEYNOTE-028 study (ClinicalTrials.gov identifier NCT02054806) evaluated the activity and safety of the anti-programmed cell death protein 1 immunotherapy pembrolizumab in patients with well-differentiated or moderately-differentiated NETs. METHODS: Patients with PD-L1-positive, locally advanced or metastatic carcinoid or well-differentiated or moderately-differentiated pancreatic NETs (pNETs) were enrolled into separate cohorts and received pembrolizumab at a dose of 10 mg/kg every 2 weeks for up to 2 years. The objective response rate was the primary endpoint (as per Response Evaluation Criteria in Solid Tumors version 1.1, by investigator review). Safety was a secondary endpoint. RESULTS: Of 170 and 106 patients, respectively, who had evaluable samples among those screened for the carcinoid and pNET cohorts, 21% and 25%, respectively, had PD-L1-positive tumors; of these, 25 and 16 patients, respectively, were eligible and treated. The median follow-up was 20 months (range, 2-35 months) and 21 months (range, 5-32 months), respectively. The objective response rate was 12.0% (95% CI, 2.5%-31.2%) and 6.3% (95% CI, 0.2%-30.2%), respectively; 3 partial responses occurred among the carcinoid cohort and 1 among the pNET cohort. The median duration of response in the carcinoid cohort was 9.2 months (range, 6.9-11.1 months), and was not reached in the pNET cohort. No complete responses occurred. Treatment-related adverse events occurred in 68% and 69% of patients, respectively, most often diarrhea (7 patients in the carcinoid cohort and 4 patients in the pNET cohort) and fatigue (6 patients in each cohort). Hypothyroidism was the most common immune-mediated adverse event (5 patients in the carcinoid cohort and 2 patients in the pNET cohort). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity in a subset of patients with NETs and was well-tolerated.

Stage IV lung carcinoids: spectrum and evolution of proliferation rate, focusing on variants with elevated proliferation indices.

The spectrum and evolution of proliferation rates in stage IV lung carcinoids is poorly defined. In particular, there are limited data on the prevalence and characteristics of tumors exceeding the standard upper proliferative criteria-as defined largely based on early-stage carcinoids-in metastatic setting. Sixty-six patients with stage IV lung carcinoids were identified, and all evaluable samples (n = 132; mean 2 samples per patient) were analyzed for mitotic counts and Ki-67 rate. Clinicopathologic and genomic features associated with elevated proliferation rates (>10 mitoses per 2 mm2 and/or >20% hot-spot Ki-67), and evolution of proliferation rates in serial specimens were analyzed. We found that mitoses and/or Ki-67 exceeded the standard criteria in 35 of 132 (27%) samples, primarily (31/35 cases) at  metastatic sites. Although neuroendocrine neoplasms with >10 mitoses per 2 mm2 are currently regarded as de facto neuroendocrine carcinomas, the notion that these cases are part of the spectrum of carcinoids was supported by (1) well-differentiated morphology, (2) conventional proliferation rates in other samples from same patient, (3) genetic characteristics, including the lack of RB1/TP53 alterations in all tested samples (n = 19), and (4) median overall survival of 2.7 years, compared to <1 year survival of stage IV neuroendocrine carcinomas in the historic cohorts. In patients with matched primary/metastatic specimens (48 pairs), escalation of mitoses or Ki-67 by ≥10 points was observed in 35% of metastatic samples; clonal relationship in one pair with marked proliferative progression was confirmed by next-generation sequencing. Notably, escalation of proliferation rate was documented in a subset of metastases arising from resected typical carcinoids, emphasizing that the diagnosis of typical carcinoid in primary tumor does not assure low proliferation rate at metastatic sites. In conclusion, stage IV lung carcinoids frequently exceed the standard proliferative criteria established for primary tumors, and commonly exhibit proliferative escalation at metastatic sites. Despite the overlap of proliferation rates, these tumors show fundamental morphologic, genomic and clinical differences from neuroendocrine carcinomas, and should be classified separately from those tumors. Awareness of the increased proliferative spectrum in metastatic carcinoids is critical for their accurate diagnosis. Further studies are warranted to explore the impact of proliferation indices on prognosis and therapeutic responses of patients with metastatic carcinoids.

Goblet Cell Carcinoid/Carcinoma: An Update.

Goblet cell carcinoid (GCC) or goblet cell carcinoma is a unique mixed endocrine-exocrine neoplasm that is almost exclusively seen in the appendix. The hallmark of GCC is the concentric infiltration of the appendiceal wall by small tight clusters, nests or cords of tumor cells that exhibit a goblet cell morphology with a small compressed nucleus and conspicuous intracytoplasmic mucin. The coexistence of high-grade adenocarcinoma with GCC has been increasingly recognized as a common finding, which has been called adenocarcinoma ex GCC or mixed GCC-adenocarcinoma. A number of studies have shown that it is the high-grade adenocarcinomatous component that dictates the prognosis. Several histologic classification/grading systems have been proposed, which correlate with overall patient survival. Treatment options are primarily based on tumor stage and the presence or absence of a high-grade adenocarcinomatous component.

Proliferation Marker (Ki67) in Sub-Categorization of Neuroendocrine Tumours of the Lung.

OBJECTIVE: The 2015 WHO classification classifies neuroendocrine tumours (NET) of the lung into typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma based on morphology alone. Mitosis is the major parameter for this classification, and thus several studies have focused on the role of Ki67 in these tumours but without conclusive results. The aim of the study was to categorize neuroendocrine tumours of the lung based on morphology and to assess the utility of Ki67 in diagnosis. MATERIAL AND METHOD: The study included 42 cases (23 biopsies and 19 lobectomy specimens) of neuroendocrine tumours (excluding small cell carcinoma). Haematoxylin & eosin stained sections, immunohistochemistry for neuroendocrine markers and Ki67 were studied. RESULTS: Based on WHO criteria, cases were classified as typical carcinoids (83.3%), atypical carcinoids (12%) and large cell neuroendocrine carcinomas (4.7%). The Ki67 index ranged between 1%-10% (mean 2.6%), 10%-30% (mean 19%), 35%-50% (mean 42.5%) in typical carcinoid, atypical carcinoid and large cell neuroendocrine carcinoma respectively. Using the ROC curve, the cut off value of Ki67 for typical and atypical carcinoids was 7.5% (P value < 0.001), and for atypical carcinoid/large cell neuroendocrine carcinoma was 32.5% (P value=0.051). On comparing the size and infiltration pattern (both local and lymphovascular invasion) of tumours in resected specimens, there was no association with the proliferation index (P value > 0.05). CONCLUSION: Morphological features are the gold standard for subtyping of neuroendocrine tumours. Ki-67 is a potentially meaningful marker for sub-categorization of lung NETs, especially in small biopsies. However, the size and infiltrative pattern of the tumours are independent of the proliferation index.

Atypical carcinoid of the uterine cervix accompanying adenocarcinoma in situ.

CLINICAL QUESTION: A 45-year-old woman presented with painless vaginal bleeding for 2 months. A biopsy was taken from the uterine cervix, and poorly differentiated adenocarcinoma was suspected. After three cycles of neoadjuvant chemotherapy treatment, the patient underwent radical hysterectomy with bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy.Review the high quality, interactive digital Aperio slide at http://virtualacp.com/JCPCases/jclinpath-2018-205081-1/ and consider your diagnosis. WHAT IS YOUR DIAGNOSIS?: Typical carcinoid.Poorly differentiated adenocarcinoma.Atypical carcinoid.Small cell neuroendocrine carcinoma.Sex cord-stromal tumours of the uterine cervix.-The correct answer is after the discussion. DISCUSSION: Neuroendocrine tumours of the uterine cervix are a rare cancer of the female reproductive system, accounting for approximately 1% of all female cervical malignancies.1 2 In 1997, a consensus workshop suggested four types of neuroendocrine tumours of the uterine cervix: typical and atypical carcinoid tumours, small cell neuroendocrine carcinomas, and large cell carcinomas.1 Among all the categories, small cell neuroendocrine carcinomas are of the highest incidence. A PubMed search revealed that only 15 cases of atypical carcinoid tumours of the uterine cervix have been reported.3 4 Because of infrequency, the clinical and pathological features of atypical carcinoid tumours of the uterine cervix remain unknown.Atypical carcinoids are characterised by great cytological atypia, which means abundant or scanty cytoplasm and visible nucleoli with granular chromatin. Tumour cells lined up in insular, trabecular, columnar and nested organoid patterns; they are epithelioid in appearance, but can be spindled (figure 1A). Necrosis could be observed in some areas and mitotic activity is up to 10 mitotic figures/10 high-power field (figure 1B). On immunohistochemistry, atypical carcinoids are diffuse and positive for Syn, CgA and CD56 (figure 2). An electron microscopic test was done, and several neuroendocrine granules were distributed in the tumour cell plasma (figure 3).jclinpath;71/11/1030/F1F1F1Figure 1(A) Insular, trabecular and columnar patterns of tumour cells were focally observed in the deep stroma of the cervix (H&E ×200). (B) Tumour cells showed small-sized, scanty cytoplasm, enlarged and deeply stained nuclei with condensed chromatin, obvious atypia, and increased mitotic activity (H&E ×400). (C) The cervical gland has shown atypical hyperplasia and adenocarcinoma in situ (H&E ×200).jclinpath;71/11/1030/F2F2F2Figure 2Immunohistochemical study findings: (A-C) The neuroendocrine markers Syn, CgA and CD56 were diffuse with strong expression in the tumour cell plasma. (D-E) P63 and CK5/6 for the squamous cell carcinomas showed no expression. (F-G) P16 for atypical carcinoid and adenocarcinoma in situ, respectively, had strong diffuse expression. (H-I) Ki67 had low expression in both atypical carcinoid and adenocarcinoma in situ (×200).jclinpath;71/11/1030/F3F3F3Figure 3Several neuroendocrine granules were distributed in the tumour cell plasma.Neuroendocrine tumours of the uterine cervix are sometimes combined with adenocarcinoma (figure 1C); their cytological and immunohistochemical features showed the neuroendocrine and adenomatous components shared the same origin.

Histomorphometric evaluation of the Ki-67 proliferation rate and CD34 microvascular and D2-40 lymphovascular densities drives the pulmonary typical carcinoid outcome.

Ki-67 has shown promise as a prognostic factor in pulmonary carcinoids. In this study, we sought to validate the importance of Ki-67 and study the relationships between Ki-67 and other stromal biomarkers of vascular density. We examined Ki-67, CD34, and D2-40 in tumor tissues from 128 patients with surgically excised typical carcinoid of the lung. We used immunohistochemistry and morphometry to evaluate the amount of tumor staining for cellular proliferation (Ki-67), microvascular density (CD34-MVD), and D2-40 lymphovascular density. The main outcome was overall survival, considered as life expectancy until death from metastasis. Specimens from patients with central tumors showed high CD34-MVD (P = .01), which was also significantly associated with a compromised surgical margin, lymph node metastasis, and clinical stage Ib. Equally significant was high D2-40 lymphovascular density in central specimens with a compromised surgical margin and lymph node metastasis. A high Ki-67 proliferation rate was significantly associated with tumors from patients with clinical stage IIb, IIIa, and IV disease. Multivariate Cox model analysis demonstrated that tumor location and stage, surgical margin, tumor size, and N stage were significantly related to survival time (P < .05). Quantitative staining of the tumor for Ki-67 and CD34-MVD served as prognostic factors (P < .05), which were more relevant than the surgical and pathological stage. Ki-67 greater than 5% and CD34-MVD greater than 7% staining comprise a subset of patients with higher death hazard; this outcome may harbor evidence for further prospective studies of target therapy after surgical resection.

[Clinicopathologic analysis of primary carcinoid of the ovary].

Objective: To describe the clinicopathologic features, diagnosis and differential diagnosis of ovarian carcinoid tumors. Methods: A retrospective chart review was performed of all patients diagnosed with primary ovarian carcinoid tumors at Fudan University Shanghai Cancer Centre from 2007 to 2017. Results: The histologic analysis of these carcinoid tumors revealed 3 were insular, 1 was trabecular, 1 was mucinous, and 10 were strumal. Histologic features of insular and trabecular carcinoid were similar to other parts of the neuroendocrine tumor. Strumal carcinoid was composed of thyroid tissue intimately admixed with carcinoid tumor, showing trabecular pattern. Mucinous carcinoid was resembles Krukenberg tumor. Most ovarian carcinoid tomours were diffusely positive with at least one neuroendocrine marker, especially synaptophysin (14/14) and CD56(9/10). The median follow-up time was 53 months, 1 patient with squamous-cell carcinoma of cervixrecur rence in vaginal after 37 months, and only 1 patient died of disease. The remaining patients were disease-free survival. Conclusions: Primary carcinoid of the ovary is a very rare low grade malignant monodermal teratomas and somatic-type tumours arising from a dermoid. The diagnosis and differential diagnosis mainly relies on the histopathologic characteristics and the immuno-phenotype. Primary ovarian carcinoid almost always exhibit a benign clinical behavious except mucinous carcinoid.

[Atypical Pulmonary Carcinoid Tumor with Elevated Serum ProGRP;Report of a Case].

We report a case of an atypical pulmonary carcinoid with high serum ProGRP. A 78-year-old man was found to have an abnormal shadow by a chest X-ray. Chest computed tomography (CT) revealed a solitary pulmonary nodule in the right middle lobe, which was homogeneous, well demarcated, and round. The level of serum ProGRP was elevated to 104.6 pg/ml (normal<81 pg/ml). The nodule was suspected to be a pulmonary carcinoid tumor, and a right middle lobectomy with mediastinal lymph node dissection was performed. Histopathological diagnosis was an atypical pulmonary carcinoid. Pro-GRP decreased to be normal level 5 month after operation.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) Syndrome and Carcinoid Tumors With/Without NECH: A Clinicopathologic, Radiologic, and Immunomolecular Comparison Study.

The diagnostic criteria of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) are not well defined, and DIPNECH can be mistaken for carcinoids associated with neuroendocrine cell hyperplasia (NECH). In this study, we compared clinical, radiologic, histologic, immunohistochemical, and molecular features of DIPNECH and isolated carcinoids with/without NECH. The study population included 151 cases (77 female patients and 74 male patients), 19 with DIPNECH and 132 with carcinoids with/without NECH. None of the cases displayed molecular alterations or anaplastic lymphoma kinase expression. Compared with individuals with carcinoids with/without NECH, patients with DIPNECH were more likely to be female individuals (P<0.0001), nonsmokers (P=0.021), and symptomatic, and to have an obstructive/mixed respiratory defect, peripheral location of the lesions, and air trapping (P<0.0001) on chest computed tomography, and constrictive bronchiolitis on histology (P<0.0001). Among immunohistochemical markers, DIPNECH was associated with higher expression of thyroid transcription factor-1, CD10, and gastrin-releasing peptide/bombesin-like peptide (P<0.0001). Yet, when a purely histopathologic definition of DIPNECH was applied, 40% of isolated carcinoids also met the diagnostic criteria for DIPNECH, even in the absence of symptoms and/or radiologic abnormalities. Therefore, as DIPNECH represents a distinct clinical syndrome, we suggest the term DIPNECH be limited to cases presenting with respiratory symptoms, functional and/or radiologic abnormalities, and constrictive bronchiolitis on histology.

Appendiceal goblet cell carcinoid: common errors in staging and clinical interpretation with a proposal for an improved terminology.

Goblet cell carcinoid (GCC) is staged and treated as adenocarcinoma (AC) and not as neuroendocrine tumor (NET) or neuroendocrine carcinoma. The term carcinoid may lead to incorrect interpretation as NET. The aim of the study was to explore pitfalls in staging and clinical interpretation of GCC and mixed GCC-AC, and propose strategies to avoid common errors. Diagnostic terminology, staging, and clinical interpretation were evaluated in 58 cases (27 GCCs, 31 mixed GCC-ACs). Opinions were collected from 23 pathologists using a survey. Clinical notes were reviewed to assess the interpretation of pathology diagnoses by oncologists. NET staging was incorrectly used for 25% of GCCs and 5% of mixed GCC-ACs. In the survey, 43% of pathologists incorrectly indicated that NET staging is applicable to GCCs, and 43% incorrectly responded that Ki-67 proliferation index is necessary for GCC grading. Two cases each of GCC and mixed GCC-AC were incorrectly interpreted as neuroendocrine neoplasms by oncologists, and platinum-based therapy was considered for 2 GCC-AC cases because of the mistaken impression of neuroendocrine carcinoma created by use of the World Health Organization 2010 term mixed adenoneuroendocrine carcinoma. The term carcinoid in GCC and use of mixed adenoneuroendocrine carcinoma for mixed GCC-AC lead to errors in staging and treatment. We propose that goblet cell carcinoid should be changed to goblet cell carcinoma, whereas GCC with AC should be referred to as mixed GCC-AC with a comment about the proportion of each component and the histologic subtype of AC. This terminology will facilitate appropriate staging and clinical management, and avoid errors in interpretation.

Pharmacology of Octreotide: Clinical Implications for Anesthesiologists and Associated Risks.

Many patients presenting with a history of foregut, midgut neuroendocrine tumors (NETs) or carcinoid syndrome can experience life-threatening carcinoid crises during anesthesia or surgery. Clinicians should understand the pharmacology of octreotide and appreciate the use of continuous infusions of high-dose octreotide, which can minimize intraoperative carcinoid crises. We administer a prophylactic 500-µg bolus of octreotide intravenously (IV) and begin a continuous infusion of 500 µg/h for all NET patients. Advantages include low cost and excellent safety profile. High-dose octreotide for midgut and foregut NETs requires an appreciation of the pathophysiology involved in the disease, pharmacology, drug-drug interactions, and side effects.

Microcarcinoid arising in patients with long-standing ulcerative colitis: histological analysis.

Some case reports of neuroendocrine tumors and neuroendocrine carcinoma associated with ulcerative colitis (UC) have been published. Most neuroendocrine tumor cases are small lesions corresponding to microcarcinoids (MCs). However, published case reports have presented findings of MCs as single-case reports. Thus, the frequency of MCs is still unclear. In this study, we described the clinical and morphological features of 14 cases of UC-associated MCs and estimated the frequency of MCs. Consecutive patients with UC who underwent complete removal of the large intestine were assessed, and 135 patients were selected. Of the 135 cases, 14 cases (10.4%) in which MC lesions were observed histologically were classified as the MC group, and the remaining 121 cases were classified as the control group. Seven cases in the MC group (50%) exhibited colitic cancer. No cases in either group had distinct carcinoid tumors. All MC lesions were located in the rectum, and the sizes ranged from 0.1 to 5.5 mm. Eight cases (57%) had multiple MC lesions. The frequency of MCs in UC was estimated to be 10.4%. Most cases of MC were quite unlikely to develop into clinically distinct carcinoid tumors. Thus, when MC lesions remain microscopic, they may not represent true neoplasms, which require immediate surgical resection. Because MC often arose in cases with UC complicated by dysplasia or cancer, patients with UC whose rectal biopsies reveal MC may be at high risk of colitic cancer.

Carcinoid-Like/Labyrinthine Pattern in Sebaceous Neoplasms Represents a Sebaceous Mantle Phenotype: Immunohistochemical Analysis of Aberrant Vimentin Expression and Cytokeratin 20-Positive Merkel Cell Distribution.

This study investigated the nature of carcinoid-like, labyrinthine, rippled, and conventional cell arrangements in sebaceous neoplasms, focusing on vimentin expression and Merkel cell distribution in sebaceous neoplasms relative to these findings in normal sebaceous units and other sebaceous conditions. Immunohistochemistry for vimentin and cytokeratin 20 (CK20) was evaluated in carcinoid-like (n = 2), labyrinthine (n = 4), rippled (n = 3), and conventional (n = 6) sebaceomas; sebaceous mantle hyperplasia (n = 1); steatocystomas (n = 5); fibrofolliculomas (n = 4); sebaceous mantleoma (n = 1); sebaceous gland hyperplasias (n = 4); sebaceous adenomas (n = 4); and sebaceous carcinomas (n = 4) as well as normal skin tissue. The sebaceous mantle and its hamartoma (fibrofolliculoma) showed weak positivity for vimentin in the basal layer of the epithelial component and contained a few CK20-positive Merkel cells within the epithelial component, whereas mature sebaceous lobules were negative for vimentin and did not contain any Merkel cells. All sebaceomas with carcinoid-like or labyrinthine pattern highly expressed vimentin. CK20-positive Merkel cells were distributed with varying numbers in carcinoid-like pattern (2/2) and labyrinthine pattern (3/4) sebaceomas, sebaceous mantle hyperplasia (1/1), steatocystomas (3/5), fibrofolliculomas (3/4), and sebaceous mantleoma (1/1). Vimentin expression and Merkel cell distribution were observed in normal sebaceous mantles and sebaceous mantle-associated lesions, which could be evidence of a sebaceous mantle nature in the limited setting of sebaceous lesions. Furthermore, carcinoid-like/labyrinthine pattern sebaceomas also showed vimentin immunoreactivity and contained Merkel cells. Therefore, carcinoid-like/labyrinthine pattern of cell arrangement in sebaceous neoplasms may represent a morphological phenotype of sebaceous mantles.