Diffuse C-Cells Hyperplasia Is the Source of False Positive Calcitonin Measurement in FNA Washout Fluids of Thyroid Nodules: A Rational Clinical Approach to Avoiding Unnecessary Surgery.

PURPOSE: The FNA-CT is useful for the diagnosis of MTC. The aim of this study was to evaluate the performance of FNA-CT in TNs coexisting with CCH. METHODS: This study retrospectively reviewed the records of 11 patients with TNs submitted to thyroidectomy on the basis of elevated basal and/or stimulated serum CT values, which at histology were not confirmed to be MTC. The results obtained in this group were compared with those of a previously reported group of histologically proven MTC patients submitted to an identical presurgical evaluation. All patients, negative for known mutations in the RET proto-oncogene, were preoperatively submitted to neck ultrasound, FNA-cytology, and FNA-CT. RESULTS: Approximately 6 of 11 patients showed increased (>36 ng/mL, as established in previous studies not involving patients with CCH) FNA-CT. All these patients showed diffuse CCH at histology in the thyroid lobe submitted to FNA; 5 of them were benign at histology, while only one was malignant (papillary thyroid carcinoma, PTC). The remaining 5 of 11 patients had low FNA-CT (<36 ng/mL), and all of them showed only focal CCH in the lobe submitted to FNA; three of them were malignant (2 PTC, 1 follicular carcinoma), while two were benign. CONCLUSIONS: Employing the currently proposed cut-off values, false-positive FNA-CT results may be observed in benign/malignant TNs with coexisting diffuse CCH. FNA-CT must therefore be cautiously used in the diagnostic approach for patients with TNs and a slightly increased basal or stimulated serum CT concentration in order to avoid unnecessary surgery.

Association between hashimoto thyroiditis and differentiated thyroid cancer: A single-center experience.

Hashimoto's thyroiditis is the most common cause of hypothyroidism in the iodine-sufficient areas of the world. Differentiated thyroid cancer is the most common thyroid cancer subtype, accounting for more than 95% of cases, and it is considered a tumor with a good prognosis, although a certain number of patients experience a poor clinical outcome. Hashimoto's thyroiditis has been found to coexist with differentiated thyroid cancer in surgical specimens, but the relationship between these two entities has not yet been clarified. Our study aims to analyze the relationship between these two diseases, highlighting the incidence of histological diagnosis of Hashimoto thyroiditis in differentiated thyroid cancer patients, and assess how this autoimmune disorder influences the risk of structural disease recurrence and recurrence rate.

Parathyroid Carcinoma in the Setting of Tertiary Hyperparathyroidism: Case Report and Review of the Literature.

INTRODUCTION: Parathyroid carcinoma is one of the rarest cancers in normal population, and it is extremely uncommon in the setting of tertiary hyperparathyroidism. Indeed, only 24 cases have been reported in the literature. Presentation of the Case. We report the case of parathyroid carcinoma in a 51-year-old man, with a history of end-stage renal disease due to a horseshoe kidney treated with haemodialysis since 2013. He came to our attention due to an increase in calcium and parathyroid hormone serum levels. Neck ultrasound (US) showed a solid hypodense mass, probably the right inferior parathyroid gland, with an estimated size of 25 × 15 × 13 mm; the 99mTc-sestamibi SPECT/CT scan revealed a large radiotracer activity area in the right cervical region, compatible with a hyperfunctioning right inferior parathyroid gland. So, a tertiary hyperparathyroidism diagnosis was made. In April 2018, resection of three parathyroid glands was performed. Histopathological examination demonstrated the right inferior parathyroid gland specimen to be a parathyroid carcinoma, due to the presence of multiple, full-thickness, capsular infiltration foci, and a venous vascular invasion focus. Discussion. Diagnosis of parathyroid carcinoma in tertiary hyperparathyroidism is remarkably complex because of the lack of clinical diagnostic criteria and, in many cases, is made postoperatively at histopathological examination. CONCLUSION: To date, radical surgery represents the mainstay of treatment, with a five- and ten-year survival rates overall acceptable.

Predictive Factors of Lymph Node Metastasis in Patients With Papillary Microcarcinoma of the Thyroid: Retrospective Analysis on 293 Cases.

Introduction: Papillary thyroid microcarcinoma (PTMC) is defined as a tumor with a larger diameter ≤ 1 cm and is considered having an indolent course and an excellent prognosis. Nevertheless, the incidence of lymph node metastasis in PTMC is not negligible, reaching up to 65% in some series. The aim of this study was to assess the incidence of lymph node metastasis in patients with PTMC and to evaluate predictive factors for lymph node metastasis. Methods: We included in this retrospective observational study patients who underwent thyroidectomy with pathological diagnosis of PTMC at our department from January 2003 to June 2019. Results: Two hundred ninety-three patients were included in the study. The incidence of lymph node metastasis was 13.7%. Multivariate analysis revealed as independent risk factors for lymph node metastasis age <45 years, nodule size ≥6 mm, tall cell variant of PTC, extrathyroidal extension, and angioinvasion. Conversely, autoimmune thyroiditis was found as a protective factor for lymph node metastasis. A subgroup of patients, with nodule size ≤ 5 mm, presented non-aggressive features. Conclusion: The incidence of lymph node metastasis in PTMC is considerable; the size of the tumor appears to be the most significant predictive factor for lymph node metastasis. The traditional cut-off value used for definition of microcarcinoma could be reconsidered to identify patients with an indolent course of the tumor, where active surveillance could be the appropriate treatment, and on the other hand, patients with potentially aggressive tumors requiring an adequate surgical intervention. Clinical Trial Registration: The trial was registered at ClinicalTrials.gov (ID: NCT04274829).

Predictive Factors of Recurrence in Patients with Differentiated Thyroid Carcinoma: A Retrospective Analysis on 579 Patients.

Differentiated thyroid carcinoma (DTC) is usually associated with a favorable prognosis. Nevertheless, up to 30% of patients present a local or distant recurrence. The aim of this study was to assess the incidence of recurrence after surgery for DTC and to identify predictive factors of recurrence. We included in this retrospective study 579 consecutive patients who underwent thyroidectomy for DTC from 2011 to 2016 at our institution. We observed biochemical or structural recurrent disease in 36 (6.2%) patients; five-year disease-free survival was 94.1%. On univariate analysis, male sex, histotype, lymph node yield, lymph node metastasis, extrathyroidal invasion and multicentricity were associated with significantly higher risk of recurrence, while microcarcinoma was correlated with significantly lower risk of recurrence. On multivariate analysis, only lymph node metastases (OR 4.724, p = 0.012) and microcarcinoma (OR 0.328, p = 0.034) were detected as independent predictive factors of recurrence. Postoperative management should be individualized and commensurate with the risk of recurrence: Patients with high-risk carcinoma should undergo strict follow-up and aggressive treatment. Furthermore, assessment of the risk should be repeated over time, considering individual response to therapy.

Tall cell carcinoma arising in a thyroglossal duct cyst: A case report.

INTRODUCTION: Thyroglossal duct cyst carcinomas are extremely rare and their clinical presentation is similar to that of benign cysts. The diagnosis is based on physical examination, laboratory tests, and most importantly multiple imaging techniques (ultrasonography, computed tomography and magnetic resonance imaging), and fine needle aspiration cytology. PRESENTATION OF CASE: We report a very unusual case of a tall cell variant of papillary carcinoma arising in a thyroglossal duct cyst in association with a follicular variant of papillary microcarcinoma and a tall cell variant of papillary carcinoma arising from the thyroid gland. DISCUSSION: Although rarely described in the medical literature, ectopic thyroid tissue present in the thyroglossal duct cyst could be involved in the development of a poorly differentiated carcinoma. The frequent observation of an associated primitive thyroid carcinoma makes surgical management of thyroid gland controversial. CONCLUSION: For the optimal management of this rare pathological condition, a comprehensive preoperative evaluation and meticulous intra-operative appraisal are fundamental.

Renal cell carcinoma metastasis to thyroid tumor: a case report and review of the literature.

INTRODUCTION: Metastatic neoplasms to the thyroid gland are rare in clinical practice. Clear cell renal carcinoma is the most frequent site of origin of thyroid metastases and represents 12 to 34% of all secondary thyroid tumors. Tumor-to-tumor metastases, in which a thyroid neoplasm is the recipient of a metastasis, are exceedingly rare. We report a case of clear cell renal carcinoma metastatic to a follicular adenoma. This is the tenth case of renal cell carcinoma metastasis to thyroid tumor reported in the literature. CASE PRESENTATION: A 62-year-old Caucasian woman with a history of clear cell renal carcinoma was admitted to our institution for multinodular goiter. A histological examination after total thyroidectomy revealed clear cell renal carcinoma metastasis to a thyroid follicular adenoma. CONCLUSIONS: Preoperative diagnosis of secondary thyroid neoplasm is difficult to achieve. The diagnosis of metastatic disease should be taken into account if patients have a history of clear cell renal carcinoma or if there is a multifocal growth pattern and clear cell appearance of the cytoplasm.

Thyroid diseases cause mismatch between MIBI scan and neck ultrasound in the diagnosis of hyperfunctioning parathyroids: usefulness of FNA-PTH assay.

DESIGN: To evaluate the efficacy of the main tools in the diagnostic localization of hyperfunctioning parathyroids (HP) in primary hyperparathyroidism (pHPT) with concomitant thyroid diseases. METHODS: Forty-three patients with pHPT associated with nodular goiter (NG, n=32) and/or autoimmune thyroid diseases (AITDs, n=11) for a total of 63 neck lesions were considered. Sixteen patients displaying HP (16 lesions), unequivocally localized by sestaMIBI scintigraphy (MIBI) and neck ultrasound (US) (group I), were compared with 27 patients (47 neck lesions) displaying equivocal parathyroid localization (group II). In all cases, neck US, MIBI scan, cytology, and parathyroid hormone assay in fine-needle aspiration washout fluid (FNA-PTH) were performed. All patients finally underwent surgery. RESULTS: According to histological examination, high FNA-PTH values (>103 pg/ml) correctly identified all HP in both groups of patients (100% of sensitivity and specificity). Both MIBI and US correctly identified all HP only in group I patients; in contrast, four patterns of mismatch between these techniques were observed in group II patients, leading to low diagnostic performances of neck US (71.4% sensitivity and 78.9% specificity) and of MIBI scan (35.7% sensitivity and 42.1% specificity). The latter was due to both false-negative (mainly in AITD) and false-positive (mainly in NG) scan images. CONCLUSIONS: Coexistent thyroid diseases are responsible for mismatch between MIBI and US images resulting in equivocal HP localization. In these cases, FNA-PTH resulted in the most accurate tool to identify HP. However, although safe, it should be advised only to patients with uncertain HP localization.

Association between carotid plaque enhancement shown by multidetector CT angiography and histologically validated microvessel density.

PURPOSE: Carotid plaques analysed by MDCTA can show contrast enhancement. The purpose of this study was to explore the association between carotid plaque enhancement (CPE) and microvessel density. MATERIALS AND METHODS: We obtained IRB approval. Twenty-nine consecutive (male, 20; median age, 63) symptomatic patients studied with 16-detector CT were prospectively analysed. Examinations were performed before and after intravenous contrast medium administration, and analysis of plaque enhancement was performed. Patients underwent "en bloc" carotid endarterectomy; histological sections were prepared and the presence of microvessels quantified. Logistic regression analysis as well as ROC curve and area under the curve was calculated. RESULTS: A statistically significant association between the degree of CPE and microvessel density (P = 0.009; rho = 0.553) was observed. The ROC curve analysis confirmed this association with an area under the curve of 0.906, 0.735, 0.644 and 0.546 for CPE of 10 HU, 15 HU, 20 HU and 25 HU respectively. There was a statistically significant difference between the CPE and the degree of neovascularisation (P = 0.0003). CONCLUSION: Results of this preliminary study suggest that CPE might be associated with the microvessel density. Histological analysis seems to demonstrate that the degree of intra-plaque neo-vascularisation is statistically associated with CPE. KEY POINTS: Carotid artery plaque enhancement at CT is associated with microvessel density. The degree of intra-plaque neo-vascularisation is statistically associated with carotid plaque enhancement. Plaque enhancement at CT should be considered when assessing vulnerable plaques.

Tissue distribution of Ret, GFRalpha-1, GFRalpha-2 and GFRalpha-3 receptors in the human brainstem at fetal, neonatal and adult age.

Occurrence and localization of receptor components of the glial cell line-derived neurotrophic factor (GDNF) family ligands, the Ret receptor tyrosine kinase and the GDNF family receptor (GFR) alpha-1 to -3, were examined by immunohistochemistry in the normal human brainstem at fetal, neonatal, and adult age. Immunoreactive elements were detectable at all examined ages with uneven distribution and consistent pattern for each receptor. As a rule, the GFRalpha-1 and GFRalpha-2 antisera produced the most abundant and diffuse tissue labelling. Immunoreactive perikarya were observed within sensory and motor nuclei of cranial nerves, dorsal column nuclei, olivary nuclear complex, reticular formation, pontine nuclei, locus caeruleus, raphe nuclei, substantia nigra, and quadrigeminal plate. Nerve fibers occurred within gracile and cuneate fasciculi, trigeminal spinal tract and nucleus, facial, trigeminal, vestibular and oculomotor nerves, solitary tract, medial longitudinal fasciculus, medial lemniscus, and inferior and superior cerebellar peduncles. Occasionally, glial cells were stained. Age changes were appreciable in the distribution pattern of each receptor. On the whole, in the grey matter, labelled perikarya were more frequently observed in pre- and perinatal than in adult specimens; on the other hand, in discrete regions, nerve fibers and terminals were abundant and showed a plexiform arrangement only in adult tissue; finally, distinct fiber systems in the white matter were immunolabelled only at pre- and perinatal ages. The results obtained suggest the involvement of Ret and GFRalpha receptors signalling in processes subserving both the organization of discrete brainstem neuronal systems during development and their functional activity and maintenance in adult life.

Calcitonin measurement in wash-out fluid from fine needle aspiration of neck masses in patients with primary and metastatic medullary thyroid carcinoma.

OBJECTIVE: The aim of the study was to evaluate the usefulness of calcitonin (CT) assay in fine-needle aspiration biopsy (FNAB) wash-out fluid alone or combined with cytology in the presurgical study of medullary thyroid carcinoma (MTC) patients with thyroid nodules (TNs) and of suspicious neck MTC recurrences/metastases. SUBJECTS AND METHODS: A total of 36 ultrasound-guided FNABs were performed in neck masses from 23 patients with borderline or high basal and pentagastrin-stimulated serum CT. Cytology and CT-FNAB were performed on a total of 18 TNs and three neck lymph nodes (LNs) from 12 patients examined before thyroidectomy, and on six suspicious local recurrences (LRs) and nine LNs from nine totally thyroidectomized MTC patients. On the basis of CT-FNAB values found in 15 non-MTC lesions, CT-FNAB more than 36 pg/ml was considered as indicative of MTC. RESULTS: All 21 positive CT-FNAB lesions (10 TNs, six LNs, and five LRs), 13 with positive cytology, were confirmed as MTC at histology. Of the 15 negative CT-FNAB suspicious masses (eight TNs, six LNs, and one LR), five displayed a benign lesion at histology. The remaining 10 cases, all with benign cytology, were not operated on, and no evidence of MTC was detected at follow-up. CT-FNAB reached 100% sensitivity and specificity for MTC, while cytology displayed 61.9% sensitivity and 80% specificity. CONCLUSIONS: Ultrasound-guided CT-FNAB was the best tool to identify primary MTC and LRs/node metastases in MTC operated subjects. This may have important implications in the management of MTC.

RET proto-oncogene in Sardinia: V804M is the most frequent mutation and may be associated with FMTC/MEN-2A phenotype.

OBJECTIVE: Genetic screening of RET proto-oncogene is a powerful tool for the early identification of familial cases of medullary thyroid carcinoma (MTC), comprising isolated familial thyroid medullary carcinoma (FMTC) and multiple endocrine neoplasia syndromes 2A (MEN-2A) and 2B (MEN-2B). We report the results obtained by RET mutation analysis of subjects living in Sardinia, an Italian island whose inhabitants display a peculiar genetic background due to geographic isolation and low immigration rate for several centuries. DESIGN: Retrospective study reporting data on 67 patients referred during the last 5 years for RET analysis because affected by MTC or first degree relatives of MTC patients. MAIN OUTCOME: Only three mutations were identified affecting codons 620 (exon 10), 634 (exon 11), and 804 (exon 14); surprisingly, the most prevalent mutation found was V804M (overall prevalence: 59%). This finding is quite different from previous studies carried out in other Caucasian and non-Caucasian populations, in which the frequency of the V804M mutation is consistently reported less than 5%. The phenotype associated to V804M mutation was mostly FMTC (16/17 cases = 94.1%), but in one case (5.9%) primary hyperparathyroidism was found, suggesting a MEN-2A. CONCLUSIONS: These results underline the importance of the genetic background in the distribution of RET mutations and should be taken into consideration when performing genetic evaluation of MTC patients.

Tissue distribution of neurturin, persephin and artemin in the human brainstem at fetal, neonatal and adult age.

The occurrence of the glial cell line-derived neurotrophic factor (GDNF) family ligands neurturin (NTN), persephin (PSP), and artemin (ART) was examined by immunohistochemistry in the normal human brainstem at pre-, perinatal and adult age. Immunolabelled neurons were unevenly distributed and each trophin had a consistent distribution pattern. As a rule, the NTN antiserum produced the most abundant and diffuse tissue labelling, whereas the lowest density of positive elements was observed after ART immunostaining. Labelling for NTN, PSP, and ART occurred at all examined ages. For each trophin, neuronal perikarya were observed within sensory and motor nuclei of cranial nerves, dorsal column nuclei, olivary nuclear complex, reticular formation, pontine nuclei, locus caeruleus, raphe nuclei, substantia nigra, and quadrigeminal plate. Nerve fibers occurred within gracile and cuneate fasciculi, trigeminal spinal tract and nucleus, oculomotor and facial nerves, solitary tract, vestibular nerve, medial longitudinal fasciculus, medial and lateral lemnisci, and inferior and superior cerebellar peduncles. Age changes were detected in the distribution pattern for each trophin. On the whole, in the grey matter, labelled perikarya were more frequently observed in pre- and perinatal than in adult specimens; on the other hand, in discrete regions, nerve fibers and terminals were abundant and showed a definite arrangement only in adult tissue; finally, distinct fiber systems in the white matter were immunolabelled only at pre- and perinatal ages. The results support the concept of a trophic involvement of NTN, PSP, and ART in the development, functional activity and maintenance of a variety of human brainstem neuronal systems.

GDNF family ligand receptor components Ret and GFRalpha-1 in the human trigeminal ganglion and sensory nuclei.

The occurrence of Ret and GFRalpha-1 receptors is shown by immunohistochemistry in the human trigeminal sensory system at pre-, postnatal and adult age. Receptor-labeled neurons occur in both trigeminal ganglion and mesencephalic nucleus. In adult trigeminal ganglion, about 75% of Ret- and 65% of GFRalpha-1-labeled neurons are small- and medium-sized. The proportion of Ret+ and GFRalpha-1+ trigeminal ganglion neurons in the adult is about 25 and 60%, respectively. The majority of Ret+ are double labeled for GFRalpha-1 and glial cell line-derived neurotrophic factor (GDNF). Most of the GFRalpha-1+ cells contain GDNF and about 50% of them contain Ret. Triple labeling shows many Ret+/GDNF+/GFRalpha-1+ neurons, but also a number of Ret-/GDNF+/GFRalpha-1+ and Ret+/GDNF-/GFRalpha-1+ cells. Both Ret+ and GFRalpha-1+ neuronal subpopulations overlap with that containing calcitonin gene-related peptide. Ret+ pericellular basket-like nerve fibers occur in the adult trigeminal ganglion. Centrally, immunoreactivity is restricted to the spinal nucleus pars caudalis and pars interpolaris and to the mesencephalic nucleus. In adult specimens, Ret+ nerve fibers and puncta gather in the inner substantia gelatinosa. Ret+ neurons occur in the spinal nucleus and are more frequent in newborn than in adult subjects. Central GFRalpha-1+-labeled neurons and punctate elements are sparse. These findings support the involvement of GDNF and possibly other cognate ligands in the trophism of human trigeminal primary sensory neurons from prenatal life to adulthood, indicating a selective commitment to cells devoted to protopathic and proprioceptive sensory transmission. They also support the possibility that receptor molecules other than Ret could be active in transducing the ligand signal.

Ret, GFRalpha-1, GFRalpha-2 and GFRalpha-3 receptors in the human hippocampus and fascia dentata.

The immunohistochemical occurrence and localization of the receptor components of the glial cell line-derived neurotrophic factor (GDNF) family ligands, the Ret receptor tyrosine kinase and GDNF family receptor (GFR) alpha-1 to -3, is described in the human post-mortem hippocampal formation at pre- and full-term newborn, and adult age. Two different antibodies for each of the four-receptor molecules were used. Western blot analysis indicates that the availability of GFRalpha receptor proteins may vary with age and post-mortem delay. The immunohistochemical detectability of GFRalpha-1, GFRalpha-2, GFRalpha-3 and Ret receptor molecules is shown in the rat up to 72 h post-mortem. In the human specimens, labelled neuronal perikarya were detectable for each receptor protein at all examined ages, with prevalent localization in the pyramidal layer of the Ammon's horn and hilus and granular layer of the fascia dentata. In the adult subjects, abundant punctate-like structures were also present. Labelled glial elements were identifiable. Comparison of the pattern of immunoreactive elements among young and adult subjects suggests that the intracellular distribution of the GDNF family ligands may vary between pre- and perinatal life and adult age. The results obtained suggest the involvement of the Ret and GFRalpha receptors signalling in processes subserving both the organization of this cortical region during development and the functional activity and maintenance of the mature hippocampal neurons.

Rhabdoid tumor of the thyroid gland: a variant of anaplastic carcinoma.

Rhabdoid tumor of the thyroid gland is a very rare neoplasm, characterized by significant metastatic potential. All of the 6 cases reported in the recent literature had poor outcomes. We report an additional case involving, to our knowledge, the oldest patient reported so far. A 67-year-old woman had a nodular goiter for all of her adult life and presented with a rapidly growing mass in the right lobe. Histologic examination showed a highly cellular neoplasm with a solid infiltrative growth pattern. Extracapsular invasion was evident. Rhabdoid cells were large, with abundant cytoplasm, eosinophilic inclusions, and eccentric nuclei containing distinct nucleoli. Immunohistochemistry identified vimentin, sarcomeric actin, myoglobin, and cytokeratin expression in the tumor cells; they were negative for desmin, thyroglobulin, and calcitonin. Scattered follicles with nuclear features of papillary thyroid carcinoma were detected; these cells were immunoreactive for thyroglobulin and TTF-1. Reverse transcriptase polymerase chain reaction using specific primers for RET/PTC1 and RET/PTC3 fusion genes identified a RET/PTC3 gene rearrangement in the rhabdoid tumor. Despite radiotherapy, the neoplasm rapidly progressed, with massive local and mediastinal metastasis leading to death 5 months after presentation. The hypothesis that rhabdoid tumor is a variant of anaplastic thyroid carcinoma is supported by the identification of a RET/PTC gene rearrangement, a feature of carcinomas of follicular cell derivation.

[Cervico-mediastinal hematoma secondary to extracapsular hemorrhage of parathyroid carcinoma. Clinical case and review of the literature]. / Ematoma cervico-mediastinico secondario ad emorragia extracapsulare di carcinoma paratiroideo. Caso clinico e revisione della letteratura.

Extracapsular parathyroid haemorrhage is a rare but ominous occurrence, which may cause cervico-mediastinal haematoma and a severe calcaemia imbalance. We identified only 23 cases reported in the literature and these were always secondary to adenoma, hyperplasia or cysts, and never to carcinoma. We describe a case of a 56-year-old man who was admitted to our Institute because of the sudden development of an anterior neck swelling, together with dysphagia, dyspnoea and hoarseness. Physical examination revealed a large ecchymosis extending from the anterior neck to the upper chest, while the early symptoms had disappeared. Laboratory studies, ultrasonography and 99mtTC-Sestamibi scintiscan demonstrated the presence of primary parathyroidism due to a right inferior parathyroid neoplasm. At operation, the parathyroid was excised en bloc with the right thyroid lobe because they were joined together by an extensive fibrous reaction. Histological examination showed a well-differentiated parathyroid carcinoma with evidence of recent haemorrhage. To the best of our knowledge this is the first case of extracapsular haemorrhage due to a parathyroid carcinoma. In summary, although parathyroid haemorrhage is a rare condition, it should always be suspected when a painful mass or diffuse swelling suddenly occurs in the anterior neck, with or without ecchymosis, especially when serum calcium and phosphorus are abnormal.

Neurotrophin-like immunoreactivity in the human pre-term newborn, infant, and adult cerebellum.

The immunohistochemical occurrence of the neurotrophin (NT) proteins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), and neurotrophin-3 (NT-3) is shown in the pre-term newborn, infant, and adult human post-mortem cerebellum. The NT-like immunoreactive structures were unevenly distributed and showed regional differences among cerebellar lobules and folia. NGF-, NT-4-, and NT-3-positive neuronal perikarya were observed in all specimens examined. At variance with the other neurotrophins, the BDNF antiserum labelled neuronal cell bodies only in newborn life and infancy, as well as extensive nerve fibre systems, whose density increased with age. The NT-antibodies, tested by Western blot on human cerebellum homogenates, revealed immunoreactive bands corresponding to proteins of heterogenous molecular weight. The results obtained provide a first demonstration of the tissue localization of the NTs in the human cerebellum from perinatal to adult age, thus suggesting their involvement in the development, differentiation and maintenance of the cerebellar connectivity. Codistribution of the four NTs or sets of them was observed in cortical and deep nuclei neurons. Multiple trophic roles for NTs, encompassing the classic target-derived and local mechanisms of support, are envisaged as significant in development, differentiation, and maintenance of the human cerebellar connectivity.