Blood Chromogranin A Is Not Effective as a Biomarker for Diagnosis or Management of Bronchopulmonary Neuroendocrine Tumors/Neoplasms.

BACKGROUND: Identification of circulating tumor markers for clinical management in bronchopulmonary (BP) neuroendocrine tumors/neoplasms (NET/NEN) is of considerable clinical interest. Chromogranin A (CgA), a "universal" NET biomarker, is considered controversial as a circulating biomarker of BPNEN. AIM: Assess utility of CgA in the diagnosis and management of BPNEN in a multicentric study. MATERIAL AND METHODS: CgA diagnostic metrics were assessed in lung NET/NENs (n = 200) and controls (n = 140), randomly assigned to a Training and Test set (100 BPC and 70 controls in each). Assay specificity was evaluated in neoplastic lung disease (n = 137) and nonneoplastic lung disease (n = 77). CgA efficacy in predicting clinical status was evaluated in the combined set of 200 NET/NENs. CgA levels in bronchopulmonary neuroendocrine tumor (BPNET) subtypes (atypical [AC] vs. typical [TC]) and grade was examined. The clinical utility of an alteration of CgA levels (±25%) was evaluated in a subset of 49 BPNET over 12 months. CgA measurement was by NEOLISATM kit (EuroDiagnostica). RESULTS: Sensitivity and specificity in the training set were 41/98%, respectively. Test set data were 42/87%. Training set area under receiver operator characteristic analysis differentiated BPC from control area under the curve (AUC) 0.61 ± 0.05 p = 0.015. Test set the data were AUC 0.58 ± 0.05, p = 0.076. In the combined set (n = 200), 67% BPNET/NEN (n = 134) had normal CgA levels. CgA levels did not distinguish histological subtypes (TC vs. AC, AUC 0.56 ± 0.04, p = 0.21), grade (p = 0.45-0.72), or progressive from stable disease (AUC 0.53 ± 0.05 p = 0.47). There was no correlation of CgA with Ki-67 index (Pearson r = 0.143, p = 0.14). For nonneoplastic diseases (chronic obstructive pulmonary disorder and idiopathic pulmonary fibrosis), CgA was elevated in 26-37%. For neoplastic disease (NSCLC, squamous cell carcinoma), CgA was elevated in 11-16%. The neuroendocrine SCLC also exhibited elevated CgA (50%). Elevated CgA was not useful for differentiating BPNET/NEN from these other pathologies. Monitoring BPNET/NEN over a 12-month period identified neither CgA levels per se nor changes in CgA were reflective of somatostatin analog treatment outcome/efficacy or the natural history of the disease (progression). CONCLUSIONS: Blood CgA levels are not clinically useful as a biomarker for lung BPNET/NEN. The low specificity and elevations in both nonneoplastic as well as other common neoplastic lung diseases identified limited clinical utility for this biomarker.

Serotonin levels and 1-year mortality in patients with neuroendocrine tumors: a systematic review and meta-analysis.

Aim: Elevated serotonin in patients with neuroendocrine tumors (NETs) may impact heart failure incidence but a quantitative relationship has not been established. Materials & methods: Systematic review and meta-analysis of studies assessing 24-h urinary 5-hydroxyindoleacetic acid (u5-HIAA) and mortality in patients with NETs (2007-2017) with a primary outcome of 1-year mortality risk and 24-h u5-HIAA. Results: We identified 1715 records of which 12 studies including 755 patients (3442 person-years with 376 deaths) were eligible for meta-analysis. Mean u5-HIAA was 149.2 mg/24 h (standard deviation: 96.6) and mortality was 13.0%. The meta-regression equation showed an 11.8% (95% CI: 8.9-17.0%; I2  = 93.0%) increase in 1-year mortality for every ten-unit increase in u5-HIAA. Conclusion: Serotonin measured by its metabolite u5-HIAA is predictive of 1-year all-cause mortality in patients with NETs.

A case of ectopic ACTH syndrome due to DDAVP-sensitive but V1b receptor-negative bronchial typical carcinoid with lymphatic metastasis and plasma ProGRP elevation.

Ectopic ACTH syndrome (EAS) is a potentially fatal endocrine disease that results from a variety of neuroendocrine tumors (NETs), such as small cell lung cancer (SCLC) and bronchial typical carcinoid. Typical carcinoid is usually slow growing, not associated with plasma progastrin releasing peptide (ProGRP) elevation. Here, we report a 47-year-old female smoker with progressive typical carcinoid and plasma ProGRP elevation. Several types of Cushingoid features were found on physical examination. In addition, laboratory examination showed elevated plasma ACTH and serum cortisol levels. These findings indicated ACTH-dependent Cushing's syndrome. Moreover, the serum cortisol level was not suppressed by overnight high-dose dexamethasone treatment, suggesting the presence of an extra-pituitary tumor. Contrast-enhanced brain MRI revealed no pituitary adenoma, which also supported the idea that EAS occurred in the present case. Strikingly, chest computed tomographic (CT) scan showed a single 18-mm peripheral nodule in the right middle lobe of the lung. Tumor marker analysis revealed an elevation in plasma ProGRP. These data suggested a possibility that SCLC secreted ACTH and caused EAS in this patient. Of note, the plasma ACTH level was increased (1.7 fold) in l-desamino-8-D-arginine vasopressin (DDAVP) test, also suggesting the specific clinical feature in this case. After additional imaging examinations, we performed surgical resection with the suspicion of limited SCLC. As a result, pathological examination revealed a vasopressin receptor Ib (V1b) receptor-negative bronchial typical carcinoid with ACTH production and mediastinal lymphatic metastasis. In summary, we present a case of EAS caused by progressive bronchial typical carcinoid with plasma ProGRP elevation. We propose a novel subtype of lung typical carcinoid.

[Typical Carcinoid of the Lung with Abnormal Elevation of Serum Pro-gastrin-releasing Peptide (ProGRP)].

A 40-year-old male was referred to our hospital because of a nodular shadow detected in the left lower lobe with the tendency to increase gently. Because fluoro-2-deoxy-D-glucose (FDG) uptake was extremely low on a FDG positron emission tomography (PET-CT), the tumor was highly suspected of the benign tumor. Five years later, a follow-up computed tomography (CT) showed the shadow to be enlarged. FDG uptake was changed to be high, and serum level of pro-gastrin-releasing peptide (Pro-GRP) was extremely elevated. Surgical treatment was chosen under suspicious diagnosis of neuroendocrine tumor, such as small cell carcinoma, large cell neuroendocrine carcinoma, and carcinoid. By the intraoperative aspiration cytology, a small cell carcinoma or a carcinoid was suspected and left lower lobectomy with systemic lymph node dissection was performed. The final histological diagnosis was a typical carcinoid. The elevated serum ProGRP immediately decreased to normal postoperatively.

Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours.

BACKGROUND: Sunitinib is approved worldwide for treatment of advanced pancreatic neuroendocrine tumours (pNET), but no validated markers exist to predict response. This analysis explored biomarkers associated with sunitinib activity and clinical benefit in patients with pNET and carcinoid tumours in a phase II study. METHODS: Plasma was assessed for vascular endothelial growth factor (VEGF)-A, soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, interleukin (IL)-8 (n=105), and stromal cell-derived factor (SDF)-1α (n=28). Pre-treatment levels were compared between tumour types and correlated with response, progression-free (PFS), and overall survival (OS). Changes in circulating myelomonocytic and endothelial cells were also analysed. RESULTS: Stromal cell-derived factor-1α and sVEGFR-2 levels were higher in pNET than in carcinoid (P=0.003 and 0.041, respectively). High (above-median) baseline SDF-1α was associated with worse PFS, OS, and response in pNET, and high sVEGFR-2 with longer OS (P⩽0.05). For carcinoid, high IL-8, sVEGFR-3, and SDF-1α were associated with shorter PFS and OS, and high IL-8 and SDF-1α with worse response (P⩽0.05). Among circulating cell types, monocytes showed the largest on-treatment decrease, particularly CD14+ monocytes co-expressing VEGFR-1 or CXCR4. CONCLUSIONS: Interleukin-8, sVEGFR-3, and SDF-1α were identified as predictors of sunitinib clinical outcome. Putative pro-tumorigenic CXCR4+ and VEGFR-1+ monocytes represent novel candidate markers and biologically relevant targets explaining the activity of sunitinib.

Risk factors of lymph node metastasis in patients with gastric neuroendocrine tumor with normal serum gastrin level.

BACKGROUND/AIMS: Locoregional gastric carcinoids with normal serum gastrin level have been recommended radical resection regardless of tumor size or depth of invasion. However, there have been some reports which showed small sporadic gastric carcinoids could be treated with local resection. The aim of this study was to elucidate risk factors of lymph node metastasis in patients with gastric carcinoids with normal serum gastrin level and determine the indications for limited resection such as endoscopic treatment. METHODOLOGY: We performed clinicopathologic reviews of thirty gastric carcinoids with normal serum gastrin level from January 1996 to December 2010. RESULTS: One case show distant metastasis and two cases showed lymph node metastasis at the time of diagnosis. For twenty seven cases which showed no regional lymph node or distant metastasis initially no additional lymph node or distant metastasis were diagnosed throughout the follow up period. Large tumor size (>10 mm), proper muscle infiltration, WHO classification grade 2 and lymphovascular invasion was noted risk factor of lymph node metastasis by univariate logistic regression analysis. CONCLUSIONS: Small (≤10 mm) gastric carcinoids with normal serum gastrin level confined to submucosa can be treated with endoscopic or local resection unless lymphovascular invasion.

Prostate cancer collaborative stage data items--their definitions, quality, usage, and clinical implications: a review of SEER data for 2004-2010.

BACKGROUND: Version 2 of the Collaborative Stage Data Collection System (CSv2) became effective with cases diagnosed in 2010. This report focuses on the CSv2 components required to derive the American Joint Committee on Cancer (AJCC) stage for prostate cancer and on the site-specific factors for prostate cancer captured in CSv2. The report also highlights differences between the AJCC 6th and 7th editions for classifying prostate cancer stage. METHODS: Data from 18 Surveillance, Epidemiology, and End Results (SEER) Program population-based registries (SEER-18) were analyzed for the years 2004-2010, which included 400,591 prostate cancer cases. RESULTS: CSv2 provides specificity with regard to the Gleason grading system by distinguishing between clinical and pathologic patterns and scores. The AJCC 7th edition incorporates prostate-specific antigen values into staging, subdivides stage II into IIA and IIB, and reclassifies extraprostatic invasion with microscopic bladder neck invasion from T4 in the 6th edition to T3a; this latter change affected the AJCC stage of 283 cases in 2010. Of the 44,578 prostate cancer cases diagnosed in 2010 that would have been classified as stage II in the AJCC 6th edition, 32.7%, 27.5%, and 39.8% are classified as stages I, IIA, and IIB, respectively, in the 7th edition. CONCLUSIONS: CSv2 provides more information than was previously available to researchers using SEER prostate data. The absence of a clearly defined clinical stage for each prostate case is the overriding limitation that researchers face in relying on Collaborative Stage information to analyze prostate cancer data.

Blood transcript analysis and metastatic recurrent small bowel carcinoid management.

BACKGROUND: Detection of neuroendocrine tumor (NET) disease progression is a key issue in determining management. Currently, assessment is by imaging (MRI/CT and Octreoscan®) and plasma Chromogranin A (CgA) measurement. CASE PRESENTATION: We report use of a NET-specific multigene PCR-derived blood transcript signature (NET Index) to assess disease and correlated CgA and gene transcripts with MRI, CT, Octreoscan®, 11C-5HTP-PET/CT and (68)Ga-DOTA-PET/CT in a patient with NET. CONCLUSIONS: Our results identify limitations in evaluating disease status by CgA and identify that a PCR-based test is more sensitive. Alteration in NET blood gene transcript levels prior to image-based tumor confirmation suggests this parameter may also have utility as an index of therapeutic efficacy.

Goblet cell carcinoids of the appendix.

Goblet cell carcinoid (GCC) tumors are a rare subgroup of neuroendocrine tumors almost exclusively originating in the appendix. The tumor most often presents in the fifth or sixth decade with a clinical picture of appendicitis or in advanced cases an abdominal mass associated with abdominal pain. Histologically tumors are most often positive for chromogranin A and synaptophysin, however, less homogenous than for classic appendix carcinoids. The malignant potential is higher than that for the classic appendix carcinoids due to local spread and distant metastases at diagnosis and the proliferation markers (Ki67 index) may determine prognosis. Octreotide receptor scintigraphy is usually negative while CT/MRI scans may be useful. Chromogranin A is usually negative and other biomarkers related to the mucinous component or the tumor (CEA, CA-19-9, and CA-125) may be used. Surgery is the main treatment with appendectomy and right hemicolectomy while patients with disseminated disease should be treated with chemotherapy. Overall 5-year survival is approximately 75%. The diagnosis and treatment of GCC tumors should be restricted to high volume NET centers in order to accumulate knowledge and improve survival in GCC NET patients. The aim of this paper is to update on epidemiology, clinical presentation, and diagnostic markers including Ki67 index, treatment, and survival.

Five-year follow-up of patients treated for 1 year with octreotide long-acting release for enterochromaffin-like cell carcinoids.

BACKGROUND: Gastric carcinoids type 1 (GC1) are neuroendocrine tumors (NETs) arising from the enterochromaffin-like (ECL) cells in patients with chronic atrophic gastritis (CAG). The treatment of GC1 has been endoscopic polypectomy or surgical tumor excision and antrectomy. One year treatment with somatostatin analogs (SSAs) diminished tumor load and ECL cell density. The effect persisted 1 year after treatment was discontinued. However, the optimal SSA dose and treatment duration are unknown. OBJECTIVES: The aim of the present work was to study macroscopic and histopathological changes in the stomach and serum markers gastrin and chromogranin A (CgA) in GC1 patients 5 years after 1 year of octreotide long-acting release (LAR) treatment. MATERIAL AND METHODS: Five patients with GC1 were included 5 years after the initial year of octreotide LAR treatment. All patients underwent upper gastrointestinal endoscopy including tumor and mucosal biopsies from oxyntic mucosa, chest and abdominal computer tomography and octreotide scintigraphy. Fasting serum gastrin and CgA were also measured. RESULTS: At 5 years, one patient had a highly malignant gastric tumor, one patient had an increased number of GCs, regional and distant metastases and three patients had an increased number of GCs. Serum gastrin and CgA increased to pre-treatment levels after 1 year of follow-up and were unchanged at the 5-year follow-up. CONCLUSIONS: The disease had progressed in all five GCs patients treated with octreotide for 12 months at 5 years of follow-up. This suggests that, if started, octreotide treatment should not be discontinued in these patients.

Acromegaly caused by ectopic growth hormone-releasing hormone production from a bronchial carcinoid tumor.

Acromegaly is usually caused by a growth hormone (GH)-secreting pituitary adenoma. In rare cases, however, it is caused by the ectopic production of growth hormone-releasing hormone (GHRH). We report a case of acromegaly due to ectopic production of GHRH from a bronchial carcinoid in a 42-year-old female. The carcinoid tumor was successfully treated with bilobectomy.

Case Report: A Challenging Localization of a Pulmonary Ectopic ACTH-Secreting Tumor in a Patient With Severe Cushing's Syndrome.

Background: Ectopic adrenocorticotropic syndrome (EAS) is a rare cause of endogenous ACTH-dependent Cushing's syndrome, usually associated with severe hypercortisolism as well as comorbidities. Tumor detection is still a challenge and often requires several imaging procedures. In this report, we describe a case of an ectopic ACTH secretion with a misleading localization of the responsible tumor due to a concomitant rectal carcinoma. Case presentation: A 49-year-old man was referred to our Endocrinology Unit due to suspicion of Cushing's syndrome. His medical history included metastatic rectal adenocarcinoma, diagnosed 5 years ago and treated with adjuvant chemotherapy, radiotherapy and surgical resection. During follow-up, a thoracic computed tomography scan revealed two pulmonary nodules located in the superior and middle lobes of the right lung with a diameter of 5 and 10 mm, respectively. However, these nodules remained radiologically stable thereafter and were not considered relevant. All biochemical tests were suggestive of EAS (basal ACTH levels: 88.2 ng/L, nv 0-46; basal cortisol levels: 44.2 µg/dl, nv 4.8-19.5; negative response to CRH test and high dose dexamethasone suppression test) and radiological localization of the ectopic ACTH-secreting tumor was scheduled. The CT scan revealed a dimensional increase of the right superior lung nodule (from 5 to 12 mm). [68Ga]-DOTA-TOC PET/CT scan was negative, while [18F]-FDG-PET/CT showed a tracer accumulation in the superior nodule. After a multidisciplinary consultation, the patient underwent thoracic surgery that started with two atypical wedge resections of nodules. Frozen section analyses showed a neuroendocrine tumor on the right middle lobe nodule and a metastatic colorectal adenocarcinoma on the superior lesion. Then, a right superior nodulectomy and a right middle lobectomy with mediastinal lymphadenectomy were performed. The final histopathological examination confirmed a typical carcinoid tumor, strongly positive for ACTH. A post-surgical follow-up showed a persistent remission of Cushing's syndrome. Conclusions: The present report describes a case of severe hypercortisolism due to EAS not detected by functional imaging methods, in which the localization of ACTH ectopic origin was puzzled by a concomitant metastatic rectal carcinoma. The multidisciplinary approach was crucial for the management of this rare disease.

A meal test improves the specificity of chromogranin A as a marker of neuroendocrine neoplasia.

Chromogranin A (CgA) is a neuroendocrine tumor (NET) marker. Modest CgA elevation is found in subjects with enterochromaffin-like (ECL) cell hyperplasia due to hypergastrinemia. Somatostatin analogs reduce CgA levels in patients with NET. Meals may affect serum CgA levels. The aims of the study were to investigate meal-induced CgA release and the short-term effect of octreotide on serum CgA levels. Four groups were studied: group A, seven patients with ECL cell hyperplasia secondary to use of proton pump inhibitors (PPIs); group B, six patients with gastric carcinoid type 1/ECL hyperplasia due to chronic atrophic gastritis (CAG); group C, six patients with nongastric NETs; group D, seven controls. The subjects were studied on three separate days with the use of three exposures: a test meal, pentagastrin subcutaneously (not group C), and octreotide intravenously. Serum CgA and gastrin were analyzed. A test meal induced a significant CgA increase in long-term PPI users and in healthy controls. The meal did not affect CgA levels in patients with gastric carcinoid type 1 or patients with NETs. The test meal increased gastrin levels in all groups except in those with CAG. Pentagastrin increased CgA levels in all groups tested except in those with CAG, while octreotide, reduced CgA and gastrin levels in all groups. Serum CgA should be determined in fasting individuals. A test meal may distinguish between increased CgA levels in PPI users from nongastric NET patients. Concomitant gastrin determination may help to discriminate between nongastric NETs and CAG. Intravenous octreotide rapidly reduces serum CgA.

Laparoscopic antrectomy for the treatment of type I gastric carcinoid tumors.

BACKGROUND: While the optimal treatment for type I gastric carcinoid tumors remains controversial, there is evidence to suggest that in multifocal disease, antrectomy may not only control local disease but also may lead to enterochromaffin-like cell (ECL) hyperplasia regression compared to medical and endoscopic treatments. MATERIALS AND METHODS: A single institution retrospective review of eight consecutive patients with multifocal type I gastric carcinoid tumor patients with no evidence of metastatic disease was performed from 2005 to 2006. All of these patients underwent laparoscopic antrectomy with Billroth II reconstruction. Patients' preoperative gastrin, chromogranin A levels, and biopsy and surgical specimen slides were compared with postoperative laboratory and biopsy slides. Pathology slides were reanalyzed by a blinded pathologist from our institution for evidence of tumor and ECL hyperplasia regression. RESULTS: All patients tolerated the procedure well with no reoperations or mortalities. Six of eight patient complained of mild reflux which was treated medically. One of eight had a mild wound infection which resolved with a course of cephalexin. Gastrin levels significantly decreased (98.9%) in all patients (P = 0.001). Furthermore, chromogranin A levels also significantly decreased (81.4%). Eight of eight patients showed no evidence of carcinoid tumor after surgery at mean biopsy follow-up of 17 mo (range 2-35 mo), however there was ECL hyperplasia after resection. Four of eight patients (50%) showed regression of ECL hyperplasia on postop biopsy, while the remaining four of eight showed no evidence of regression. CONCLUSIONS: This is the largest case series to investigate the surgical, clinical, and histologic outcomes of laparoscopic antrectomy in type I gastric carcinoid. Our data suggest that laparoscopic antrectomy is a safe and minimally invasive approach to treat nonmetastatic type I gastric carcinoid. All patients had no evidence of gross or microscopic disease at follow-up biopsy and almost half had regression of ECL hyperplasia at follow-up suggesting that antrectomy may be sufficient to prevent tumor recurrence. However, continued regular endoscopic surveillance and medical follow-up of patients with ECL hyperplasia are recommended.

Treatment of type I gastric neuroendocrine tumors with somatostatin analogs.

BACKGROUND AND AIM: There are limited data on response and long-term follow-up of octreotide therapy in type-I gastric neuroendocrine tumors. The objective of the present study was to assess the response of type-I gastric neuroendocrine tumors to octreotide-long acting, repeatable (LAR) therapy and evaluate long-term follow up of such patients after therapy. METHODS: Three patients with documented type-I gastric neuroendocrine tumors from a tertiary gastroenterology centre were studied. Octreotide-LAR therapy 20 mg intramuscularly every 28 days was administered for one year. Serum gastrin and chromogranin levels, gastroscopies and biopsies from tumor nodules at 6 months and one year on therapy and every 6 months after completion of drug therapy were taken. Follow-up after completion of therapy extended for 3 years in two and 2.5 years in one patient. RESULTS: During octreotide therapy there was normalization of serum gastrin levels and serum chromogranin levels. Tumors in all three patients had regressed at 6 months of treatment. Following cessation of therapy, there was progressive rise of serum gastrin to pre-treatment levels. Serum chromogranin levels remained within normal limits. Gastroscopic and histologic examination of gastric biopsies did not reveal recurrence of tumors in any patients. All patients tolerated therapy well and became asymptomatic soon after drug therapy. CONCLUSIONS: Octreotide-LAR therapy causes regression of type-I gastric neuroendocrine tumors. After completion of drug therapy there was no recurrence of tumors even with continued hypergastrinemia. Octreotide therapy should be considered as one of the treatment options in such patients.

Successful localization of ectopic ACTH-secreting bronchial carcinoid by selective pulmonary arterial sampling.

Among patient with ACTH-dependent Cushing's syndrome, about 10-20% of those with ectopic ACTH syndromes (EAS) have occult or unknown tumors. Despite the intensive search for the culprit tumors by dynamic endocrine tests and imaging tests, it is often difficult to localize and confirm the source of occult ectopic ACTH secretion. We report a patient with EAS caused by a small bronchial carcinoid tumor, which was successfully localized by a selective pulmonary arterial sampling for the first time. A 69-year-old woman presented with typical Cushingoid features and elevated plasma ACTH and cortisol levels, which showed lack of circadian rhythm, no suppression by high-dose dexamethasone, and no response to CRH stimulation. No mass lesion was detected by pituitary MRI, and inferior petrosal sinus sampling showed no central to peripheral ACTH gradient. Although CT scan of the chest revealed a very small nodule in the right lung, it could not be confirmed by either somatostatin receptor scintigraphy or fluorodeoxyglucose positron emission tomography. Selective pulmonary arterial sampling of the wedged blood from a pulmonary artery branch affecting the nodule showed a marked ACTH gradient, and the lobectomy of the right middle lung resulted in dramatic decreases in plasma ACTH and cortisol levels. The resected tumor was diagnosed as a bronchial carcinoid tumor with positive immunostaining for ACTH. Thus, selective pulmonary arterial sampling, because of its more site-selective measurement of hormonal secretion, could be one of the useful tools to localize and confirm the ectopic ACTH production by a small pulmonary tumor.

[Recurrent carcinoid tumor and 18F-DOPA PET]. / Récidive d'une tumeur carcinoïde et TEP à la (18)F-DOPA.

We report the case of a carcinoid tumor with suspicion of recurrence on biology. Scintigraphic explorations of the whole body had a major role in diagnostic of this recurrence. OctreoScan((R)) showed an abdominal uptake corresponding to a mesenteric lymph node. PET with (18)F-DOPA also showed a liver uptake corresponding to liver metastases.

[Atypical carcinoid of the lung with abnormal elevation of serum ProGRP level; report of a case].

We report a rare case of an atypical carcinoid of the lung with the elevation of serum ProGRP. A 79-year-old female was referred to our hospital presenting with an abnormal shadow by a chest X-ray film. Chest computed tomography (CT) scan revealed a well-defined solitary nodule in the left lower lobe. The serum level of ProGRP was elevated to 2.267 pg/ml (normal range: <46 pg/ml). Pulmonary carcinoid was pathologically suggested by a transbronchial lung biopsy. Considering the patient's general condition, a partial wide resection was performed. Pathological diagnosis was atypical carcinoid. After the operation, further increase of the serum ProGRP level was noted, and multiple liver metastases developed.

Incidental finding of MEN-1 syndrome during staging and follow-up of breast carcinoma.

Type 1 multiple endocrine neoplasia (MEN-1) syndrome is an autosomal dominant disease, associated with germline mutations in the MEN-1 tumour suppressor gene (encoding the menin protein). Recent studies, through a better characterisation of the functions of the menin protein, have started to demonstrate how changes in this protein may be related to breast cancer. We present the case of a patient whose diagnosis of MEN-1 syndrome was made during treatment for a breast tumour-this diagnosis was obtained after finding multiple neoplastic lesions that fitted the MEN-1 syndrome spectrum, during the initial staging and subsequent follow-up of a breast tumour. In line with the growing evidence that links MEN-1 syndrome to breast cancer tumorigenesis, this case report highlights the following question: should we start screening this subset of patients earlier for breast cancer?