Role of Synaptophysin, Chromogranin and CD56 in adenocarcinoma and squamous cell carcinoma of the lung lacking morphological features of neuroendocrine differentiation: a retrospective large-scale study on 1170 tissue samples.

BACKGROUND: Synaptophysin, chromogranin and CD56 are recommended markers to identify pulmonary tumors with neuroendocrine differentiation. Whether the expression of these markers in pulmonary adenocarcinoma and pulmonary squamous cell carcinoma is a prognostic factor has been a matter of debate. Therefore, we investigated retrospectively a large cohort to expand the data on the role of synaptophysin, chromogranin and CD56 in non-small cell lung cancer lacking morphological features of neuroendocrine differentiation. METHODS: A cohort of 627 pulmonary adenocarcinomas (ADC) and 543 squamous cell carcinomas (SqCC) lacking morphological features of neuroendocrine differentiation was assembled and a tissue microarray was constructed. All cases were stained with synaptophysin, chromogranin and CD56. Positivity was defined as > 1% positive tumor cells. Data was correlated with clinico-pathological features including overall and disease free survival. RESULTS: 110 (18%) ADC and 80 (15%) SqCC were positive for either synaptophysin, chromogranin, CD56 or a combination. The most commonly positive single marker was synaptophysin. The least common positive marker was chromogranin. A combination of ≤2 neuroendocrine markers was positive in 2-3% of ADC and 0-1% of SqCC. There was no significant difference in overall survival in tumors with positivity for neuroendocrine markers neither in ADC (univariate: P = 0.4; hazard ratio [HR] = 0.867; multivariate: P = 0.5; HR = 0.876) nor in SqCC (univariate: P = 0.1; HR = 0.694; multivariate: P = 0.1, HR = 0.697). Likewise, there was no significant difference in disease free survival. CONCLUSIONS: We report on a cohort of 1170 cases that synaptophysin, chromogranin and CD56 are commonly expressed in ADC and SqCC and that their expression has no impact on survival, supporting the current best practice guidelines.

Single institutional experience on primary neuroendocrine neoplasms of the kidney: a rare distinct entity.

Primary pure renal neuroendocrine neoplasms (R-NENs) are a distinct and rare entity. Not much is known about the histopathology and biologic behavior of these tumors. We attempted to review the clinicopathologic aspects of these neoplasms encountered at our institution. We performed a retrospective chart review to identify primary pure (not admixed with any other tumor component) R-NENs from institutional Cancer Registry database. Pathologic review of the diagnostic archival slides was done for detailed assessment of the histologic features. R-NENs were classified according to the current WHO system for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Eight pure R-NEN cases were identified, all unifocal, and most (6/8) involved the right kidney. Three patients had poorly differentiated neuroendocrine carcinoma (NEC), and five had well-differentiated neuroendocrine tumor (NET). All tumors were located near the renal hilum, stained diffusely with synaptophysin, variably with chromogranin, and were negative for renal site-specific marker PAX8 or for markers of renal cell carcinoma. We identified two distinct patterns of growth: one of sheets with interspersed rosettes and the other of large nests with low proliferative crowded centers and peripheral cells with higher proliferation and prominent palisading. Based on Ki-67 proliferative index, the tumors were classifiable into WHO grade 1 or grade 2 (based on GEP-NEN). All three NECs characteristically showed cytologic features intermediate between classic large and small cell type. This is the first comprehensive clinicopathologic study involving the rare group of R-NEN. Classifying and grading them according to the GEP-NEN system is of prognostic significance.

Application of INSM1 in Diagnosis and Grading of Laryngeal Neuroendocrine Carcinoma.

OBJECTIVE: Chromogranin (CHG), synaptophysin (Syn), and CD56 are generally used in a panel to support diagnoses of laryngeal neuroendocrine carcinomas (NECs). However, the absence of expression of these markers does not completely exclude the diagnosis. INSM1 is a novel marker that is considered sufficiently sensitive and specific for NE differentiation. The aim of this study is not only to detect its sensitivity and specificity, but also to evaluate its application in grading for laryngeal NECs. METHODS: The clinicopathological characteristics of the 25 cases with laryngeal NECs were retrospectively analyzed. The expressions of INSM1, CHG, Syn, and CD56 were detected by immunohistochemistry. RESULTS: Of the 25 laryngeal NECs, INSM1 had higher sensitivity (92%) than Syn (84%), CHG (76%) and CD56 (76%). The average H scores of INSM1, CD56, Syn, and CHG were 160, 37.5, 300, 300 for well-differentiated neuroendocrine carcinoma (WD-NEC); 190, 149, 209, 215 for moderately differentiated neuroendocrine carcinoma (MD-NEC); 251, 208, 104, 25 for poorly differentiated neuroendocrine carcinoma with small cell (SCNEC); 109, 160, 98, 26 for large cell types (LCNEC), respectively. Of these 98 non-neuroendocrine tumors, INSM1 expression was seen in nine (9%) tumors, all were squamous cell carcinoma. And INSM1 staining was generally focal. CONCLUSION: INSM1 has high sensitivity and specificity in diagnosis of laryngeal NECs. For grading laryngeal NECs, Syn and CHG showed significant advantages in the diagnosis of WD-NEC and MD-NEC, whereas INSM1 and CD56 showed greater diagnostic value in the diagnosis of SCNEC and LCNEC, especially in SCNEC. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2662-E2668, 2021.

[Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia with tumorlet formation: A case report and review of the literature]. / Hiperplasia difusa idiopática de células neuroendocrinas pulmonares con formación de tumorlets: presentación de un caso clínico y revisión de la literatura.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is an infrequent lesion recently classified by the WHO as preinvasive. It can present with the formation of tumorlets (neuroendocrine cell groups up to 5 mm) which result in a typical histological and radiological image. We report a case of a 67-year-old women who presented with a chronic cough. The CT scan showed bilateral minute, multiple pulmonary nodules. A biopsy revealed a diffuse idiopathic pulmonary neuroendocrine cell hyperplasia with several tumorlets. After two years of follow-up, imaging studies showed no significant changes.

Neuroendocrine Cells Are Commonly Absent in the Intestinal Crypts in Autoimmune Enteropathy.

The absence of neuroendocrine (NE) cells in the intestinal mucosa in autoimmune enteropathy (AIE) has been occasionally reported. However, the status of NE cells has not been studied in detail in AIE. Small bowel and colonic biopsies were retrospectively retrieved from 18 AIE patients (26 baseline [18 small bowel and 8 colon]; and 15 follow-up [11 duodenum and 4 colon] biopsies in 11 patients). Thirty-three common variable immunodeficiency (CVID) patients (30 small bowel and 16 colon), 15 inflammatory bowel disease patients (5 duodenum and 10 colon), 13 immunoglobulinA deficiency patients (13 duodenum and 5 colon), and 10 normal controls (5 colon and 5 duodenum) were selected as control groups. Histologic features (villous atrophy, intraepithelial lymphocytosis, acute inflammation, crypt apoptosis, and absence or presence of goblet cells, Paneth cells and plasma cells) were recorded. Chromogranin immunostain was performed and chromogranin-positive NE cells were counted per 10 consecutive, well-oriented crypts. On the basis of the number of chromogranin-positive NE cells, cases were graded as being absent (≤3 NE cells), markedly decreased (≤15), and intact (>15). The NE cell status correlated with histologic features. The median age of 18 AIE patients was 38.5 years (range: 11 to 74 y) and 14 patients were male. Fourteen of 18 (78%) patients showed loss (absent or markedly decreased) of NE cells in the small bowel and/or colon in the baseline biopsies including 12 (of 18) small bowel and 6 (of 8) colon biopsies. Follow-up biopsy was available in 11 patients. Six of 7 (85%) patients who showed loss of NE cells in the baseline biopsies regained NE cells in the follow-up biopsies, and 1 patient continued to show loss of NE cells. Four patients who showed intact NE cells in the baseline remained unchanged in the follow-up. Among the control groups, 3 of 33 (9%) CVID patients showed loss of NE cells. NE cells were not lost in the biopsies of all 15 and 13 patients with inflammatory bowel disease and immunoglobulinA deficiency, respectively, or the 10 normal controls. In all 41 biopsies (26 baseline plus 15 follow-up) with AIE, NE cell loss was significantly associated with increased crypt apoptosis and loss of goblet cells (P=0.001, both) but not with other histologic findings. In conclusion, our study suggests that NE cells may also be the target cells in AIE and commonly lost in the intestinal crypts in AIE, and consequently loss of NE cells can be used as an adjunct histologic feature for diagnosis of AIE.

Expression of novel neuroendocrine marker insulinoma-associated protein 1 (INSM1) in genitourinary high-grade neuroendocrine carcinomas: An immunohistochemical study with specificity analysis and comparison to chromogranin, synaptophysin, and CD56.

Confirmation of genitourinary high-grade neuroendocrine carcinomas (GU-HGNECs) often requires immunohistochemical staining. Here we evaluated a novel neuroendocrine marker, insulinoma-associated protein 1 (INSM1), in GU-HGNECs with comparison to chromogranin, synaptophysin and CD56. Immunohistochemical expression of INSM1, chromogranin, synaptophysin, and CD56 was evaluated in 39 GU-HGNECs using full tissue sections [4 in kidney, 28 in urinary bladder, and 7 in prostate; 31 small cell carcinomas (SmCCs), 6 large cell neuroendocrine carcinomas (LCNECs), 2 mixed SmCC-LCNECs]. In 33 SmCCs/components, INSM1 showed similar sensitivity (93.9 %) to chromogranin (87.8 %), synaptophysin (93.9 %) and CD56 (87.8 %), and stained a similar percentage of tumor cells (52 %) to chromogranin (49 %) and CD56 (52 %), but lower than synaptophysin (87 %) (p < 0.0001). In 8 LCNECs/components, INSM1 is similar to chromogranin, synaptophysin or CD56 in sensitivity (62.5 %, 62.5 %, 75 %, 62.5 %, respectively) and the mean percentage of positively stained tumor cells (21 %, 44 %, 48 %, 37 %, respectively). INSM1 is more sensitive for SmCCs than LCNECs (93.9 % vs. 62.5 %, p = 0.015). INSM1 showed 97.4 % specificity upon analyzing 273 genitourinary non-neuroendocrine tumors on tissue microarrays. Our study indicates that INSM1 is a sensitive marker for genitourinary HGNECs with high specificity. For genitourinary SmCCs, INSM1 shows similar sensitivity to chromogranin, synaptophysin and CD56 but stains a lower percentage of tumor cells than synaptophysin. For genitourinary LCNECs, INSM1 showed similar sensitivity to chromogranin, synaptophysin and CD56. INSM1 is more sensitive for genitourinary SmCCs than LCNECs. Our result and literature review indicate that whether INSM1 is more sensitive than conventional neuroendocrine markers for HGNECs depends on the tumor primary sites.

Prognostic Factors Associated With Progression for Advanced-Stage/G1 and G2 Small-Bowel Neuroendocrine Tumors After Multimodal Therapy: Experience From a Tertiary Referral Center.

OBJECTIVES: Neuroendocrine tumors represent approximately 40% of primary small bowel malignancies. However, factors predictive of progression after multimodal surgical therapy have not been well described. We evaluated the characteristics of small bowel neuroendocrine tumor patients associated with progression after multimodal surgical resection. METHODS: A retrospective chart review identified 99 stage III and stage IV small bowel neuroendocrine tumor patients at Mount Sinai diagnosed and treated with surgery between 2005 and 2019. Progression-free survival (PFS) was defined as time from surgery until progression in surveillance radiologic imaging. Kaplan-Meier method was used to calculate PFS. Cox proportional hazard models were used to study the prognostic factors for PFS. RESULTS: Of 99 patients, 48 had tumor progression during the follow-up period. Median PFS was 5.7 years (95% confidence interval [CI], 3.73-8.66) for the entire cohort. Prognostic factors for PFS were age at diagnosis (hazard ratio [HR], 1.04; 95% CI, 1.01-1.07), perineural invasion (HR, 2.19; 95% CI, 1.13-4.23), and elevated preoperative chromogranin level (HR, 2.31; 95% CI, 1.01-5.27). CONCLUSIONS: Age at diagnosis, perineural invasion, and elevated preoperative chromogranin level may play a prognostic role in PFS.

Evidence of increased fecal granins in children with irritable bowel syndrome and correlates with symptoms.

BACKGROUND: Granins have been implicated in the pathophysiology of irritable bowel syndrome (IBS) in adults. We sought to determine whether fecal granins are altered in children with IBS and associated with symptoms. METHODS: Children (7-12 years of age) with IBS and healthy controls (HC) kept daily pain and stool diaries for 2 weeks. Stool samples were analyzed for chromogranins A and B (CgA, CgB) and secretogranins II and III (SgII, SgIII). Children also completed psychological measures to assess anxiety, depression, somatization, and internalizing symptoms. KEY RESULTS: Fecal CgB and SgIII concentrations were higher in all the boys (IBS plus HC, n = 48) than in all the girls (IBS plus HC, n = 75) (P = 0.02 and P = 0.046, respectively). CgA and SgIII were greater in children with IBS (n = 52) vs HC (n = 69) (P = 0.01, P = 0.017, respectively). CgB and SgII did not differ between groups. In children with IBS, the number of pain episodes per week and mean daily pain rating correlated positively with all four granins. The number of stools per day correlated positively with CgB and SgII, and the percent of diarrheal stools (6 or 7 on the Bristol Scale) correlated inversely with all four granins in boys but not in girls. Fecal granins did not correlate with psychological measures. CONCLUSIONS AND INFERENCES: As measured by fecal granins, there is evidence of neuroimmune activation in children with IBS. Granins are related to abdominal pain symptoms, stooling frequency, and stool form in children with IBS. Sex influences the fecal concentration of CgB and SgIII.

Fecal chromogranins and secretogranins are linked to the fecal and mucosal intestinal bacterial composition of IBS patients and healthy subjects.

Altered fecal levels of chromogranins (Cg) and secretogranins (Sg) are demonstrated in irritable bowel syndrome (IBS), but their role in IBS pathophysiology remains unknown. This study aimed to determine if granins are associated with bacterial composition, immune activation and IBS symptoms. Protein levels of fecal granins (CgA, CgB, SgII and SgIII) were analysed with immunoassays. Mucosal mRNA expression of granins, TPH1 and immune markers were evaluated with RT-qPCR. 16S rRNA gene sequencing was performed on fecal and mucosal bacteria. The intestinal granin profile, based on fecal protein levels and mucosal mRNA expression, could not discriminate between IBS patients (n = 88) and healthy subjects (HS, n = 33). IBS patients dominated by high fecal or mucosal granin levels, respectively, did not differ in symptom or immune profiles. Fecal-dominated and mucosal-dominated granin clusters of IBS patients and HS, demonstrated separate fecal and mucosal bacterial profiles and high fecal abundance of granins were associated with a less diverse bacterial composition and the Bacteroides enterotype. The intestinal granin profiles of IBS patients and HS are linked to the intestinal bacterial composition, diversity and enterotypes. These findings suggest that granins may be one of several host-produced factors regulating the microbiota composition of the intestine.

C-cell hyperplasia in sporadic and familial medullary thyroid carcinoma.

CONTEXT: C-cell hyperplasia (CCH) is characterized by increased mass of C-cells and has been identified as a precursor condition for medullary thyroid carcinoma (MTC). Varying proportion of MTCs is associated with CCH in different studies. This could be due to the lack of uniformity of the definitions and techniques used to identify CCH in these studies. AIMS: This study aims to study the occurrence, clinicopathological, and immunohistochemical features of CCH in MTC diagnosed during a 22-year period at a tertiary care center in North India and to review the available literature on CCH. MATERIALS AND METHODS: Eighty-seven consecutive cases of MTC were included in the study. Histological evaluation for the presence of CCH and neoplastic CCH was performed. Confirmation of CCH was done by immunohistochemistry for calcitonin and chromogranin. The presence of neoplastic CCH was correlated with clinical factors and prognostic factors. RESULTS: Of 87 cases of MTC included in the study, 71 (82%) patients were sporadic and 16 (18%) had familial MTC. Neoplastic CCH was seen in 12 (75%) familial and in 9 (13%) sporadic MTC. Patients with familial MTC were more frequently associated with neoplastic CCH than sporadic MTC (P < 0.001), were younger (P < 0.001), and had more often bilateral and multifocal tumors (P < 0.001). However, there was no significant difference in mean survival time and progression-free survival in patients with and without CCH. CONCLUSION: CCH, though more common in familial MTC, can also be seen in sporadic tumors. CCH is not associated with patient survival and disease progression.

Immunohistochemical profiles of different subsets of Merkel cell carcinoma.

The literature records many examples of Merkel cell carcinoma (MCC) exhibiting aberrant immunohistochemical profiles. These can lead to diagnostic difficulty. The objectives of the current study were (1) to examine the immunohistochemical profile of different subsets of MCC to determine whether predictable subset-specific patterns exist and (2) to establish whether shared immunophenotypic patterns might reveal links between individual subsets, as demonstrated previously at a genetic level. In 52 cases of MCC, stratified by viral status and morphology, we studied 5 markers commonly used in the diagnostic evaluation of these tumors (CK20, CK7, chromogranin, neurofilament and TTF-1). Expression of these proteins was recorded as quantitative (H-scores) and absolute (positive vs negative) variables. In general, our data indicate that the "classical" or expected panel (CK20+, NF+, Chromo+, TTF-1, CK7-) is observed significantly more often in pure Merkel cell polyomavirus (MCPyV)-positive than in MCPyV-negative cases (78% vs 25%; P = .002). Neurofilament was less frequently encountered in MCPyV-negative than in MCPyV-positive tumors (66.7% vs 100%; P = .001) and expression of TTF-1 (37.5% vs 3.6%; P = .003) and CK7 (45.8 vs 14.3; P = .02) was more frequent. No significant immonophenotypic differences were observed between pure and combined MCPyV-negative tumors. Recognition of the more aberrant immunohistochemical profile of MCPyV-negative MCC should inform the diagnostic approach to this tumor. Moreover, the shared aberrant immunophenotype in pure and combined MCPyV-negative tumors supports a link between these entities and serves to separate them from MCPyV-positive tumors.

Metastatic breast cancer simulating well-differentiated neuroendocrine neoplasms of visceral organs.

A series of metastatic breast carcinoma (MBC) mimicking visceral well-differentiated neuroendocrine neoplasms has not previously been reported. We identified 5 consultation cases originally submitted as neuroendocrine neoplasms in women but that were found to be MBC on subsequent review. All 5 neoplasms demonstrated nested architecture and relatively uniform nuclei. Four patients had a known history of breast cancer (remote in 3 and concurrent in 1), but the metastases (3 liver, 1 lung) labeled for chromogranin and/or synaptophysin, prompting misdiagnosis as neuroendocrine neoplasm. In a fifth case, a liver metastasis in a patient with a known pancreatic endocrine neoplasm was originally thought to be of pancreatic origin; an occult concurrent primary breast cancer (PBC) was subsequently identified as the source. On further immunohistochemistry (IHC), all metastases evaluated were diffusely, strongly positive for estrogen receptor (5/5 cases) and GATA3 (4/4 cases). Three patients had previously received ineffective treatment for neuroendocrine carcinoma. Based on the consultation diagnosis, all 4 patients with follow-up received hormone therapy, which was effective in 3. In a separate tissue microarray cohort of paired PBCs and hematogenous MBCs, chromogranin and/or synaptophysin IHC labeling was typically negative and increased from the PBC to the MBC in only 5% of cases. In conclusion, although neuroendocrine differentiation is uncommon in breast cancer and does not commonly increase in metastases, MBC with neuroendocrine differentiation should be considered in patients with visceral neuroendocrine neoplasms of unknown primary site. Diffuse IHC labeling for estrogen receptor and GATA3 helps establish the correct diagnosis.

Diagnostic Utility of SATB2 in Metastatic Krukenberg Tumors of the Ovary: An Immunohistochemical Study of 70 Cases With Comparison to CDX2, CK7, CK20, Chromogranin, and Synaptophysin.

SATB2 is a sensitive marker for colorectal adenocarcinomas. No study has investigated its diagnostic utility in metastatic Krukenberg tumors (MKTs) of the ovary. Here we performed immunohistochemical staining SATB2 in 70 MKTs of various origins (stomach 27, colorectum 13, appendix 20 including 19 metastatic adenocarcinomas ex goblet cell carcinoids [AdexGCC] and 1 conventional poorly differentiated carcinoma with signet ring cells, breast 5, bladder 3, lung 2) to assess its diagnostic utility. We also compared SATB2 with CDX2, CK7, CK20, chromogranin, and synaptophysin in MKTs of gastric origin (MKTs-stomach), those of colorectal origin (MKTs-colorectum) and those due to appendiceal AdexGCCs (MKT-AdexGCCs) for their sensitivity and specificity to distinguish these tumors. SATB2 staining was seen in 1/27 (4%) MKTs-stomach (40% cells), 7/13 (54%) MKTs-colorectum (mean: 17% cells, median: 7%, range: 2% to 60%), and 19/19 (100%) of MKT-AdexGCCs (mean: 97% cells, median: 100%, range: 80% to 100%) (P<0.01 between any two). SATB2 staining was seen in 1/1 metastatic appendiceal poorly differentiated carcinoma with signet ring cells (5% cells), 1/3 MKTs of bladder origin (60% cells), 0/2 MKTs of pulmonary origin, and 1/5 MKTs of breast origin (10% cells). SATB2 staining was diffuse strong in MKT-AdexGCCs whereas in other MKTs it was focal and weak in the signet ring and nonsignet ring nonglandular cells and from focal weak to diffuse strong in well-formed glands. MKTs-stomach, MKTs-colorectum, and MKT-AdexGCCs showed no significant staining difference in CDX2 (100%, 100%, 100% cases, respectively; P=1.0), CK20 (96%, 100%, 100%, respectively; P=1.0), chromogranin (59%, 31%, 63%, respectively; P>0.05) or synaptophysin (59%, 63%, 84%, respectively; P>0.05) but they had significant difference in CK7 staining (93%, 8%, 42%, respectively; P<0.05). Among these 6 markers, SATB2 is the best one to distinguish MKT-AdexGCCs from MKTs-stomach (100% sensitivity, 96% specificity) and MKTs-colorectum (100% sensitivity and 100% specificity if staining more than 75% tumor cells as the cutoff). In distinguishing MKTs-stomach from MKTs-colorectum, SATB2 is not as good as CK7 which is the best marker. Our results indicate that SATB2 is a highly sensitive marker (100% sensitivity) for metastatic MKT-AdexGCCs with high specificity (100% specificity when showing strong staining in at least 75% cells) among MKTs. SATB2 is a useful marker for determining the primary sites of MKTs of the ovary.

A case of multifocal medulloblastoma in an adult patient.

Only five cases of multifocal medulloblastoma in the adult have been reported to date. We present a case in a male patient in his 50th decade of life who presented with three extra-axial lesions associated with a parenchymatous lesion of the right middle cerebellar peduncle. Sputum sample examination revealed larvae compatible with strongyloides stercoralis, which was our main differential diagnosis. Histological and immunohistochemical studies revealed the existence of a desmoplastic medulloblastoma.

INSM1 Demonstrates Superior Performance to the Individual and Combined Use of Synaptophysin, Chromogranin and CD56 for Diagnosing Neuroendocrine Tumors of the Thoracic Cavity.

Despite the importance of recognizing neuroendocrine differentiation when diagnosing tumors of the thoracic cavity, the sensitivity of traditional neuroendocrine markers is suboptimal, particularly for high-grade neuroendocrine carcinomas such as small cell lung carcinoma and large cell neuroendocrine carcinoma. To increase sensitivity, neuroendocrine markers are routinely ordered as panels of multiple immunostains where any single positive marker is regarded as sufficient evidence of neuroendocrine differentiation. Insulinoma-associated protein 1 (INSM1) is a well-validated transcription factor of neuroendocrine differentiation that has only recently been evaluated for diagnostic use. We performed INSM1 immunohistochemistry on a large series of thoracic neuroendocrine and non-neuroendocrine tumors and compared its performance to synaptophysin, chromogranin, and CD56. INSM1 was positive in 94.9% of small cell lung carcinomas and 91.3% of large cell neuroendocrine carcinomas, compared with 74.4% and 78.3% with the combined panel of traditional markers. INSM1 also stained all (100%) of the atypical carcinoids, typical carcinoids and mediastinal paragangliomas, but only 3.3% of adenocarcinomas and 4.2% of squamous cell carcinomas. Overall, INSM1 demonstrated a sensitivity of 96.4% across all grades of thoracic neuroendocrine tumors, significantly more than the 87.4% using the panel of traditional markers (P=0.02). INSM1 is sufficiently sensitive and specific to serve as a standalone first-line marker of neuroendocrine differentiation. A more restrained approach to immunohistochemical analysis of small thoracic biopsies is appropriate given the expanding demand on this limited material for therapeutic biomarker analysis.

A study of FoxA1 expression in thyroid tumors.

FoxA1 regulates a variety of tissues during embryogenesis and early life. In thyroid, FoxA1 expression has recently been shown in C cells and medullary thyroid carcinomas but not in follicular cells. FoxA1 has also been proposed as a potential oncogene in anaplastic thyroid carcinomas. However, FoxA1 expression has not been extensively investigated in a spectrum of thyroid nonneoplastic lesions and tumors. A variety of thyroid tumors and lesions and their morphologic mimics were stained with monoclonal anti-FoxA1 antibody. For the medullary carcinomas, its expression pattern was compared with those of other conventional markers. All 67 medullary thyroid carcinomas (100%), including 1 calcitonin-negative medullary carcinoma, showed diffuse and strong FoxA1 nuclear expression. The expression pattern was homogeneous throughout the tumor. Expressions of other markers in medullary thyroid carcinomas were as follows: calcitonin, 94.7%; CEA, 91.2%; and chromogranin, 100%, generally in variable intensity. FoxA1 was completely negative in follicular neoplasms, papillary thyroid carcinomas, and poorly differentiated carcinomas, whereas it was expressed in 55% of anaplastic thyroid carcinomas (33/60) in variable intensity. FoxA1 was also strongly expressed in C-cell hyperplasia as well as solid cell nests. No FoxA1 expression was seen in thyroid gland affected by nodular hyperplasia, Hashimoto thyroiditis, and Graves disease, or in paragangliomas or parathyroid lesions. FoxA1 discriminates between medullary thyroid carcinoma and tumors of follicular derivation with sensitivity and specificity greater than calcitonin and CEA; therefore, it may serve as a reliable ancillary marker for the diagnosis of medullary thyroid carcinoma because of its reliably uniform quality of staining.