Ki67 in endocrine neoplasms: to count or not to count, this is the question! A systematic review from the English language literature.

BACKGROUND: Endocrine neoplasms are generally slow-growing tumors that can show hormonal activity and give metastases. In most cases they are benign and clearly malignant forms are easy to diagnose. However, borderline forms may occur and be, for the pathologists, very difficult to classify. In these cases, there is a strong need to identify factors that may aid. Official classification systems for endocrine neoplasms are based on the evaluation of proliferation and, in most cases, they rely on mitotic count. In support, the study of Ki67 is carried out which, however, has not yet been included in any official classification system, except for neuroendocrine neoplasms of the gastro-entero-pancreatic tract. PURPOSE: The aim of the present study was to investigate the proven or unproven role of Ki67 in endocrine neoplasms, in different districts, in order to bring to light the substantial differences, in terms of proliferation, existing between neoplasms so similar, but at the same time, so different. METHODS: A thorough search of English language literature was performed, looking for articles concerning Ki67 in five endocrine neoplasms (pituitary adenomas, thyroid neoplasms, adrenocortical neoplasms, pheochromocytomas and paragangliomas). RESULTS: From 2170, 236 articles were selected and it was seen that the endocrine neoplasm in which Ki67 was most studied was the pituitary, where it still shows a controversial role. In other neoplasms different roles were identified. CONCLUSION: The pathologist should be aware of the contribution that this proliferative marker can give to the diagnosis and, sometimes, to the therapy selection, for the clinician.

OPTIMAL IMPROVEMENT IN FUNCTION AFTER TOTAL HIP AND KNEE REPLACEMENT: HOW DEEP DO YOU KNOW YOUR PATIENT’S MIND?

Osteoarthritis (OA) of the hip and knee causes pain and loss of joint mobility, leading to limitations in physical function. When conservative treatment fails total hip and knee replacement is a cost-effective surgical option. Patients have high expectations regarding functional outcome after these procedures. If such expectations are not met, they may still be dissatisfied with the outcome of a technically successful procedure. Recently, numerous studies reported that psychological factors can influence the outcome of total knee replacement (tkr) and total hip artrhoplasty with total hip replacement (thr). We conducted a prospective study on a consecutive sample of 280 patients affected by hip or knee OA who underwent total joint replacement. At patients’ admission, Harris Hip Score (HHS) and Knee Society Score (KSS) were used to assess pain and function. Furthermore, SF-36, Mini-Mental Status Examination (MMSE), Symptom Checklist-90-R (SCL-90-R), Coping Orientation to Problems Experienced (BRIEF-COPE) and the Amsterdam Preoperative Anxiety and Information Scale (APAIS) were administered. Patients had clinical and radio graphical follow up at 1, 3 and 6 months post-operatively. The HHS and KSS values before surgery showed a linear correlation with both SCL-90-R and MMSE. None of the investigated variables influenced post-operative HHS and KSS scores; however, the improvement of functional scores resulted conditioned by SCL-90-R values, VAS score, schooling and MMSE. Psychological factors and mental status in primary total hip and knee replacement can affect outcome and patient satisfaction. Strategies focused on identification and facing of these conditions must be considered to improve outcome of total replacement.

Action tremor in Parkinson's disease: frequency and relationship to motor and non-motor signs.

BACKGROUND AND PURPOSE: Action tremor may occur in patients with Parkinson's disease and cause misdiagnosis with other movement disorders such as essential tremor and dystonia. Data on the frequency of action tremor in Parkinson's disease and on the relationships with other motor and non-motor signs are limited. METHODS: A cross-sectional study of 237 patients with Parkinson's disease staging 1-2 on the Hoehn-Yahr scale was conducted. Data on action tremor and other motor and non-motor signs were collected using the Unified Parkinson's Disease Rating Scale part III and the Non-Motor Symptoms Scale. RESULTS: Action tremor was found in 46% of patients and was associated with both severity of rest tremor (adjusted odds ratio 3.0, P < 0.001) and severity of rigidity (adjusted odds ratio 1.5, P = 0.004). No association was found between action tremor and severity of bradykinesia (adjusted odds ratio 0.97, P = 0.4) or axial symptoms (adjusted odds ratio 0.9, P = 0.3). Moreover, patients who had action tremor reported a significant lower mean number of non-motor symptoms than those who had not (2.1 ± 1.3 vs. 2.4 ± 1.3; P = 0.04). CONCLUSIONS: Action tremor is a relatively frequent motor sign in patients with Parkinson's disease staging 1-2 on the Hoehn-Yahr scale. Action tremor correlates with rest tremor and rigidity and may be associated with a lower burden of non-motor symptoms. These findings suggest a contribution of non-dopaminergic mechanisms to action tremor pathophysiology.

Paravertebral high cervical chordoma. A case report.

Spinal chordomas are more often located on the midline and are associated with marked destruction of the vertebral bodies. We report a rare case of large cervical (C2-C3) right lateral paravertebral chordoma extending into the spinal canal through a very enlarged intervertebral foramen. The tumor was initially diagnosed as a mucous adenocarcinoma on a percutaneous needle biopsy. However, the neuroradiological features, including the well-defined tumor margins, the regular and sclerosing lytic bone changes with regular enlargement of the intervertebral C2-C3 foramen, were in favor of a more slowly growing lesion, such as schwannoma or neurofibroma. At surgery a well-demarcated capsulated tumor involving the nerve root was partially resected. Histology was in favor of a low-grade chordoma (Ki-67/MIB-1<1%). Postoperative proton beam therapy was also performed. The differential neuroradiological diagnosis is discussed.

Advances in trans-sphenoidal pituitary surgery.

Pituitary surgery is a continuous evolving speciality of the neurosurgeons' armamentarium, requiring precise anatomical knowledge, technical skills and integrated appreciation of the pituitary pathophysiology. Actually, it could be considered the result of a close cooperation between different specialists, i.e. the ophthalmologist, the neuroradiologist, the endocrinologist, the neurosurgeon, the pathologist, etc. In this teamwork environment each member plays his own role, offering his contribute to the final result; every effort is performed to provide patients with the best possible procedure, individually measured. The endoscopic pituitary surgery performed by means of a transsphenoidal approach perfectly fits this scenario, being though advocated as the result of an evolutionary process rather than a revolutionary one. The "pure" endoscopic transsphenoidal surgery - consisting of a whole procedure performed with the endoscope alone and without the use of any transsphenoidal retractor - offers some advantages due to the endoscope itself: a superior close-up view of the relevant anatomy, very important at the tumor/gland interface and an enlarged working angle are provided with an increased panoramic vision inside the surgical area. Results in terms of mass removal, relief of clinical symptoms, cure of the underlying disease and complication rate are similar to those reported in the major microsurgical series but patient compliance is by far better.

Validation of the Italian version of the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E).

The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) was developed for the rapid detection of a major depressive episode in people with epilepsy. It has been proven to be a user-friendly screening instrument. This study describes the development, validation, and psychometric properties of the Italian version of the NDDI-E. A consecutive sample of 120 outpatients with epilepsy has been assessed using the M.I.N.I. Plus version 5.0.0 and the NDDI-E. All patients had no major difficulties in understanding or answering the questions of the Italian version. Cronbach's alpha coefficient was 0.851. Receiver operating characteristic analysis showed an area under the curve of 0.943 (CI95%=0.902-0.985; SE 0.021; p<0.001), a cut off score of 13, a sensitivity of 86.2%, a specificity of 89%, a positive predictive value of 71.4%, and a negative predictive value of 95.3%.

Intracranial dural metastasis from uterine leiomyosarcoma with orbital extension.

Intracranial metastases from uterine leiomyosarcoma are very rare and have been found mainly in the brain (17 cases); on the other hand, metastases to the skull, dura and orbit are really exceptional. The authors report the case of a 57-year-old woman who presented with a 6-week history of right proptosis, left hemiparesis, intracranial hypertension and torpor 8 months after surgery for uterine leiomyosarcoma. CT scan showed a very large right frontal tumor with both intracranial and intraorbital extension. At operation the tumor was found to arise from the dura of the right anterior cranial fossa; complete removal of the intracranial tumor mass and partial removal of the intraorbital component were performed. However, early tumor regrowth was observed 45 days after operation and death occurred 2 months later. Pathologic examination showed a high-grade sarcoma with smooth muscle differentiation and high mitotic activity. Immunohistochemical staining revealed positivity for actin and vimentin and negativity for S-100 protein, cytocheratin and desmin. This is the first reported case of uterine leiomyosarcoma metastatic to the dura of the anterior cranial fossa with intracranial and intraorbital extension. An aggressive surgical resection is the best treatment of intracranial metastatic leiomyosarcoma, because of the scarce response to radiotherapy and chemotherapy. However, the outcome is poor, with early recurrence.

Symptomatic spinal cord metastasis from cerebral oligodendroglioma.

Spinal subarachnoid spread is not uncommon in brain oligodendrogliomas; on the other hand, symptomatic involvement of the spinal cord and cauda is very rare, with only 16 reported cases. We report the case of a 41-year-old man who underwent resection of a low-grade frontal oligodendroglioma 4 years previously. He was again observed because of bilateral sciatic pain followed by left leg paresis. A spine MRI showed an intramedullary T12-L1 tumor with root enhancement. At operation, an intramedullary anaplastic oligodendroglioma with left exophytic component was found and partially resected. Two weeks later, a large left frontoparietal anaplastic oligodendroglioma was diagnosed and completely resected. The patient was neurologically stable for 8 months and died 1 year after the spinal surgery because of diffuse brain and spinal leptomeningeal spread. The review of the reported cases shows that spinal symptomatic metastases can occur in both low-grade and anaplastic oligodendrogliomas, even many years after surgery of the primary tumor; however, they exceptionally occur as first clinical manifestation or as anaplastic progression. The spinal seeding represents a negative event leading to a short survival.

miR-221/222 overexpession in human glioblastoma increases invasiveness by targeting the protein phosphate PTPµ.

Glioblastoma is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, survival of patients remains poor. In order to identify microRNAs (miRs) involved in glioma tumorigenesis, we evaluated, by a miRarray, differential expression of miRs in the tumorigenic glioma LN-18, LN-229 and U87MG cells compared with the non-tumorigenic T98G cells. Among different miRs we focused our attention on miR-221 and -222. We demonstrated the presence of a binding site for these two miRs in the 3' untranslated region of the protein tyrosine phosphatase µ (PTPµ). Previous studies indicated that PTPµ suppresses cell migration and is downregulated in glioblastoma. Significantly, we found that miR-221 and -222 overexpression induced a downregulation of PTPµ as analyzed by both western blot and real-time PCR. Furthermore, miR-222 and -221 induced an increase in cell migration and growth in soft agar in glioma cells. Interestingly, the re-expression of PTPµ gene was able to revert the miR-222 and -221 effects on cell migration. Furthermore, we found an inverse correlation between miR-221 and -222 and PTPµ in human glioma cancer samples. In conclusion, our results suggest that miR-221 and -222 regulate glioma tumorigenesis at least in part through the control of PTPµ protein expression.

MRI features of spinal solitary fibrous tumors. A report of two cases and literature review.

Spinal solitary fibrous tumors (SFT) are very rare neoplasms occurring in the spinal canal, with only 38 cases reported in ten years since the first description. We describe two cases of SFT of the spine and review 33 well-documented cases in the literature to define distinctive radiological and surgical features raising the suspicion of a spinal SFT before histological verification. A 67-year-old man with cervical myeloradiculopathy had a large extramedullary tumor of the cervical spinal canal extending from C4 to C7. On MRI the tumor was isointense on T1-sequences and hypointense on T2-sequences, and had marked contrast enhancement. At surgery, the tumor was intradural extramedullary, with no dural or root attachment, but it was adherent to the cord. Complete tumor removal was achieved with good outcome. A 75-year-old man with progressive thoracic myelopathy had an intramedullary tumor at C6 and C7 level, which was hypointense on T1- and T2-weighted images of MRI. At surgery, the tumor was intramedullary and strongly adherent to the cord; it was successfully removed. Both tumors were composed of elongated cells with a collagen-matrix background. Immunohistochemical staining was positive for vimentin, CD34, and bcl-2, and negative for EMA and S-100 protein. A careful analysis of our own and the other reported cases of spinal SFTs may disclose some peculiar features of this rare tumor. A spinal intramedullary or extramedullary tumor, hypointense on T2-weighted images of MRI, which intraoperatively shows hard consistency, scarce vascularization, no nerve root involvement, no or weak dural attachment, absence of arachnoidal interface, and adherence to the spinal cord may suggest the diagnosis of SFT.

Spinal meningiomas: age-related features.

OBJECTIVES: Spinal meningiomas mainly occur in old patients, with a remarkable female prevalence. This study investigates the different features between younger and older patients in an adult population (>18 years). MATERIALS AND METHODS: A surgical series of 120 adult patients operated on for spinal meningiomas at the Neurosurgical Clinic of the "Federico II" University of Naples is reviewed. In this series 117 patients with a sporadic spinal meningioma were divided in two groups: group I including 30 patients (25.6%) younger than 50 years of age, group II including 87 patients (74.4%) older than 50 years. 3 patients had a spinal meningioma and neurofibromatosis. Several parameters, including sex, predisposing factors, tumor location and growth, histology, recurrences, proliferation index Ki-67 LI, and outcome, are considered and compared in the two age groups. RESULTS: Group I showed an incidence of high cervical spine (C1-C4) meningiomas higher than group II (23.3% vs 3.4%, p=0.026) and lower rate of thoracic tumors (60% vs 82.7%, p=0.04). No significant differences of histological type and Ki-67 LI were found. Group I had 2 cases of atypical meningiomas (6.6% vs 0%, ns). Recurrences occurred in 6.6% of group I and 2.6% of group II, with no significance. In recurrent meningiomas values of Ki-67 LI were significantly higher than values in not recurrent meningiomas (p=0.0001), whereas no difference of estrogen and progesterone receptor expression was noted. CONCLUSIONS: Younger adult patients with spinal meningiomas show not rare occurrence of NF (9%) and significantly higher incidence of high cervical and lower incidence of thoracic localizations with respect to the older patients. On the other hand, there are not significant differences of histology, Ki-67 LI and recurrence rate, excepting for a slight difference for atypical meningiomas.

Type II muscle fibers atrophy associated with silent corticotroph adenoma in a dog.

The Silent Corticotroph Adenoma (SCA) is a pituitary adenoma variant characterized by the immunoreactivity for adrenocorticotropic hormone (ACTH) and related peptides, without the clinical signs of Cushing's disease. SCA has been postulated to either secrete structurally abnormal ACTH that is inactive but detectable by immunohistochemistry or radioimmunoassay, or to secrete ACTH intermittently or at low levels continuously. Excess of ACTH has been associated to type II muscle atrophy. We describe a case of type II muscle fibers atrophy associated with silent corticotroph adenoma in a dog. The dog showed moderate to severe proximal muscle wasting and weakness with normal levels of muscle-associated enzymes. In the limb muscle biopsies, type II fibers were uniformly smaller than type I fibers. In temporalis muscles, there were few atrophic fibers, and several irregular areas of loss of enzymatic activity observed in NADH, SDH and COX stains. The tumour showed a trabecular growth pattern and immunohistochemical analysis demonstrated the presence of cytoplasmic immunoreactivity for ACTH. The muscle atrophy was considered to be related to an excess of inactive ACTH. Studying spontaneous occurring rare diseases in animals could help to understand the mechanism of similar diseases in human has well.

Cognitive and psychosocial features in childhood and juvenile MS: two-year follow-up.

OBJECTIVE: To assess the evolution of cognitive and psychosocial functioning in a cohort of childhood and juvenile multiple sclerosis (MS) cases after a mean period of 2 years had elapsed since baseline evaluation. METHODS: In this cohort study, we used the same extensive neuropsychological battery with alternative versions of the tests assessing memory, attention/concentration, executive functions, and language. Fatigue and depression were also measured. An interview on school and daily living activities was obtained from the parents. The cognitive performance of the patients was compared with that of demographically matched healthy controls (HC). RESULTS: Fifty-six patients and 50 HC were assessed. At follow-up, criteria for cognitive impairment (failure on at least 3 tests) were fulfilled in 39 patients (70%) and 75% of the cases were classified as having a deteriorating cognitive performance. Changes were prominent in tests of verbal memory, complex attention, verbal fluency, and receptive language. In the regression analysis, the only significant predictor of cognitive deterioration was older age of the subject (odds ratio 1.9, 95% confidence interval 1.2-2.9, p = 0.003). Psychiatric disorders, most frequently depression, were diagnosed in 12 patients (30.5%). Fatigue was reported by 21% of the patients. MS negatively affected school and everyday activities in 30% to 40% of the subjects. CONCLUSIONS: Our findings confirm the importance of systematic assessment of cognitive and psychosocial issues in children and teens with MS. The progressive nature of the cognitive difficulties emphasizes the need for developing effective treatment strategies.

Psychosocial issue in children and adolescents with multiple sclerosis.

In adult-onset multiple sclerosis (MS) cases, major depression, fatigue and psychological distress are common, whereas there is little information on these issues in children with the disease. The aim of this study was to assess psychosocial disorders in an Italian cohort of children and adolescent with MS. We evaluated 56 patients through self-assessment scales of depression (Children Depression Inventory) and fatigue (Fatigue Severity Scale), a psychiatric interview [Kiddie-SADS-Present and Lifetime Version (K-SADS-PL)] and an interview on school and everyday activities. Significant fatigue was found in 11 patients (20%). Twelve of the 39 patients who underwent the K-SADS-PL received a formal diagnosis of an affective disorder. Moreover, MS affected school activities in 28% of cases, daily living activities in 41% and social relationships in 28%. Our study confirms the critical role of psychosocial difficulties in children and adolescents with MS and provides a few cues to clinical management.

Expression of growth factors in brain tumors: correlation with tumor grade, recurrence and survival.

OBJECTIVE: The aim of this study is to evaluate the correlation between the expression of some growth factors (GFs) and the tumor grade, recurrence and survival of brain glial and ependymal tumors. MATERIAL AND METHODS: The expression of vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), tenascine, transforming growth factor (TGFbeta), isomeres, platelet-derived growth factor (PDGF) and p53 was studied in 40 primary brain tumors, both low-grade and high-grade, including astrocytomas, oligodendrogliomas, glioblastomas and ependymomas. The same GFs were also studied in 46 specimens of recurrent tumors from the same patients. The positivity and intensity of the immunohistochemical expression were correlated with the tumor grade, the interval and type of recurrence, and the survival. RESULTS: The expression of all GFs, excepting TGFbeta1, TGFbetaRI and tenascine, was found to be correlated with the tumor grade in all tumors of both astroglial and oligodendroglial origin, whereas ependymomas showed significant differences only for EGFR. Low-grade (Grade II) tumors recurring as anaplastic (Grade III) forms showed GF expression rather similar to initially high-grade gliomas and significantly higher than that of low-grade (Grade II) tumors in both initial surgery and recurrence. Besides, low-grade (Grade II) tumors recurring as low-grade showed significantly longer median recurrence time (5.4 vs. 3.5 years) and better median survival (8.3 vs. 5.4 years) than those recurring as anaplastic forms (WHO III). CONCLUSION: The immunohistochemical study of expression of VEGF, EGFR, TGFbeta2, TGFbeta3, PDGF and p53 in all low-grade (Grade II) brain gliomas at the first operation may help to differentiate cases with slower evolution and longer survival from those with higher potential of anaplastic transformation.

Intracranial extension of salivary gland tumors.

OBJECTIVE: The aim of this report is to describe 3 cases of salivary gland tumors with intracranial extension associated to an extracerebral mass lesion, and to discuss the frequence, pathology and treatment of these very rare localizations. CLINICAL MATERIAL: The 3 patients were 1 woman and 2 men, aged 44, 53 and 74 years, respectively. The primary tumors were an adenocarcinoma and a malignant oncocytoma of the parotid gland and an adenoid cystic carcinoma of the submandibular gland. The location of the intradural extra-axial tumor was the middle fossa and temporal region in 2 cases and the cerebellopontine angle in 1. Surgical treatment consisted in the seemingly complete removal of 2 tumors with middle fossa localization and partial removal of the cerebellopontine angle lesion. Radiotherapy was administered in all 3 cases and chemotherapy in 2. RESULTS: 1 patient is alive and free of recurrence 32 months after removal of the intracranial tumor; 2 other patients died 28 months and 12 months postoperatively. CONCLUSIONS: The intracranial extension of salivary gland tumors is a very rare event. An aggressive surgical resection followed by radiotherapy is justified in cases with significant intracranial mass lesions and scarce bone and dural involvement.

Early clinical and neuroradiological worsening after radiotherapy and concomitant temozolomide in patients with glioblastoma: tumour progression or radionecrosis?

OBJECTIVES: This study investigates the diagnosis and management of patients with resected brain glioblastomas who presented early clinical and neuroradiological worsening after the completion of the Stupp protocol. Its aim is to discuss the occurrence of early radionecrosis. METHODS: Fifty patients with brain glioblastoma treated by surgical resection and Stupp protocol were reviewed; 15 among them (30%) had early clinical and neuroradiological worsening at the 6-month follow-up. The MR spectroscopy and surgical findings of these patients are reviewed. RESULTS: MR spectroscopy was in favour of tumour recurrence in 14 among 15 patients and showed radionecrosis in one. Among 10 patients who were reoperated on, 7 had histologically verified tumour recurrence or regrowth, whereas in 3 histopathology showed necrosis without evidence of tumour. The 7 patients with tumour progression had prevalence of focal neuroradiological signs (6/7) and a survival of 7.5-12 months (median survival 10 months). The 4 patients with early radionecrosis (including one patient who was not reoperated on) had clinical worsening with mental deterioration, confusion and ataxia, and MR spectroscopy positive for tumour recurrence in 3. Three were alive 24-30 months after the end of the radiotherapy, whereas one died at 40 months. CONCLUSION: Early radionecrosis after the Stupp protocol is not a rare event due to the radiosensitization effect of temozolomide. This phenomenon may predict a durable response to radiotherapy. MR spectroscopy may simulate tumour recurrence. A correct diagnosis is necessary to avoid useless reoperations and incorrect withdrawal of temozolomide.

Cognitive and psychosocial features of childhood and juvenile MS.

OBJECTIVE: To assess the impact of multiple sclerosis (MS) on cognitive and psychosocial functioning in childhood and juvenile cases. METHODS: We used an extensive neuropsychological battery assessing IQ, memory, attention/concentration, executive functions, and language. Fatigue and depression were also measured. An interview on school and daily living activities was obtained from the parents. Performance of cases was compared with that of demographically matched healthy controls. RESULTS: Sixty-three patients and 57 healthy controls were assessed. Five patients (8%) exhibited a particularly low IQ (<70). Criteria for cognitive impairment (failure on at least three tests) were fulfilled in 19 patients (31%), whereas 32 patients (53%) failed at least two tests. Beyond deficits in memory, complex attention, and executive functions, the profile of deficits was characterized by involvement of linguistic abilities. In the regression analysis, the only significant predictor of cognitive impairment was an IQ score lower than 90 (odds ratio [OR] 18.2, 95% CI 4.6-71.7, p < 0.001). Considering the IQ score as a dependent variable, the only significant predictor was represented by younger age at onset (OR 0.7, 95% CI 0.5-0.9, p = 0.009). Depressive symptoms were reported by 6% of the cases, and fatigue was reported by 73% of the cases. MS negatively affected school and everyday activities in 56% of the subjects. CONCLUSIONS: In childhood and juvenile cases, multiple sclerosis (MS) is associated with cognitive impairment and low IQ scores, the latter related to younger age at onset. These aspects are of critical importance in helping children and adolescents with MS to manage their difficulties and psychosocial challenges.

Diagnostic and prognostic implications of the World Health Organization classification of neuroendocrine tumors.

BACKGROUND: Neuroendocrine differentiation of tumors is often difficult to establish. In the same manner, the evaluation of the prognostic role of neuroendocrine differentiation may constitute a relevant clinical problem. Although different classifications are used for neuroendocrine tumors (NET) of different origin, the last World Health Organization (WHO) classification of NET, originally proposed for gastroenteropancreatic tumors, has proved to be a practical tool to allow pathologists to uniform the diagnoses and re-classify these tumors into 3 main categories. AIM: The present study was carried out in order to evaluate diagnostic and prognostic implications of NET reclassification according to the last WHO classification of NET. MATERIALS AND METHODS: Thirty-one tumors with an initial diagnosis referable to a NET achieved before 1999 were independently evaluated by 3 pathologists on the basis of the 2000 WHO classification of NET. Immunohistochemistry for panneuroendocrine markers and Ki-67 was also performed in all cases. RESULTS: Twelve, 14, and 4 tumors were respectively reclassified as well-differentiated NET, well-differentiated neuroendocrine carcinoma and poorly differentiated neuroendocrine carcinoma; 1 tumor was reclassified as mixed endocrine-exocrine tumor. Two or more neuroendocrine markers were expressed in all NET regardless of histotype, differentiation degree, and site of primary tumor. After revision, 10 of the 31 tumors under study (32%) changed histo-prognostic category when compared to the initial diagnosis. Ki-67 score was the best predictor of survival at the multivariate analysis. CONCLUSION: The WHO classification is suitable to accurately reclassify tumors with an initial diagnosis referable to a NET and to separate these tumors in 3 well-distinct histo-prognostic categories with relevant clinical implications. Ki-67 score seems to be a better predictor of survival than the degree of differentiation.