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Melanoma in giant congenital nevus (M-GCN) is a rare and potentially lethal neoplasm. In children, M-GCN appears as a dermal/deep-seated melanoma (DDM-GCN) with histopathologic features difficult to distinguish from proliferative nodules (PNs-GCN). DDM-GCN in adults is an anecdotal entity and only 8 cases have been described and genetically characterized. We report the first case of DDM-GCN in a 34-year-old man characterized with a large-panel next-generation sequence (NGS) highlighting a TP53 mutation with a UV-signature (C>T substitution) in DDM but not in PNs-GCN and GCN. Curiously, DDM showed an aberrant p16 overexpression without detection of CDKN2A mutation at NGS. In line with previous studies, it supports a different pathway in children and adults: UV-induced mutations may be involved in the latter not only by CDKN2A but also by TP53 mutations, with a potentially confusing overexpression of p16 protein. While these data need to be confirmed in larger cases series, our results show that NGS could be an additional genetic diagnostic tool in DDM-GCN.

Objective and design A clinicopathological score has been proposed by Trouillas et al. to predict the evolution of pituitary adenomas. Aim of our study was to perform an independent external validation of this score and identify other potential predictor of post-surgical outcome. Methods The study sample included 566 patients with pituitary adenomas, specifically 253 FSH/LH-secreting, 147 GH-secreting, 85 PRL-secreting, 72 ACTH-secreting and 9 TSH-secreting tumours with at least 3-year post-surgical follow-up. Results In 437 cases, pituitary adenomas were non-invasive, with low (grade 1a: 378 cases) or high (grade 1b: 59 cases) proliferative activity. In 129 cases, tumours were invasive, with low (grade 2a: 87 cases) or high (grade 2b: 42 cases) proliferative activity. During the follow-up (mean: 5.8 years), 60 patients developed disease recurrence or progression, with a total of 130 patients with pituitary disease at last follow-up. Univariate analysis demonstrated a significantly higher risk of disease persistence and recurrence/progression in patients with PRL-, ACTH- and FSH/LH-secreting tumours as compared to those with somatotroph tumours, and in those with high proliferative activity (grade 1b and 2b) or >1 cm diameter. Multivariate analysis confirmed tumour type and grade to be independent predictors of disease-free-survival. Tumour invasion, Ki-67 and tumour type were the only independent prognostic factors of disease-free survival. Conclusions Our data confirmed the validity of Trouillas’ score, being tumour type and grade independent predictors of disease evolution. Therefore, we recommend to always consider both features, together with tumour histological subtype, in the clinical setting to early identify patients at higher risk of recurrence.

Introduction: Serrated lesions are a heterogeneous group of lesions routinely evaluated with different morphologic subtypes, and colorectal carcinogenesis has been related to the understanding of the serrated pathway in these lesions. In this setting, BRAF V600E mutation has been demonstrated as a marker for the serrated carcinogenic evolution, while the mismatch repair protein (MMR) was recognized in a small subset of hyperplastic polyps. Design: This study aimed to evaluate the interobserver agreement among 6 pathologists in the morphological diagnosis of the serrated lesion according to WHO Classification; furthermore, the additional MMR (MLH1, PMS2, MSH2, MSH6) and BRAF V600E (VE1) mutation status were studied by immunohistochemistry and NGS analysis. Results: We evaluated 52 serrated lesions of the colon retrieved from our pathology archives in 2019. The cohort included 48 patients: 21 males and 27 females, with a mean age of 67 years (range 50-89), of which 77.1% were identified according to regional screening protocol. All hematoxylin and eosin slides were independently reviewed by each pathologist, who classified all samples according to the WHO Classification of Digestive System Tumor (Fleiss Kappa: 0.75). The immunohistochemical expression of MMR and BRAF was evaluated in 42 samples. Loss of MLH1 and PMS2 was recorded in one serrated sessile lesion (LSS) with dysplasia, but NGS analysis resulted negative. In contrast, BRAF V600E IHC resulted positive in 22 samples (52.4%), specifically in 5 hyperplastic polyps (71.4%), 10 LSS (66.6%), 5 LSS with dysplasia (45.5%) and 2 adenomatous polyps (100%), 1 TSA negative. All BRAF V600E IHC positive cases were confirmed by NGS analysis. Conclusion: To conclude, the interobserver agreement for morphological classification of serrated lesions resulted substantial; however, behind the morphological appearance, BRAF V600E resulted in predominant mutation in LSS and hyperplastic polyps, these observations confirmed the possibility to improve the classification with IHC BRAF V600E; especially for hyperplastic polyps, it may be crucial to identify precancerous lesions and different clinical management. Citation Format: Francesca Ambrosi, Costantino Ricci, Federico Chiarucci, Stefano Chilotti, Doriana Donatella Di Nanni, Angelo Gianluca Corradini, Maria Antonietta Cumiento, Dario De Biase, Michelangelo Fiorentino. What9s more in serrated lesions: interobserver agreement and molecular features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2603.

Background: Giant cell tumor of bone is a locally aggressive, rarely metastasizing tumor that accounts for about 5% of bone tumors and generally occurs in patients between 20 and 45 years old. A driver mutation in the histone 3.3 (H3.3) gene H3F3A has been identified in as many as 96% of giant cell tumors of bone. The immunohistochemical expression of H3F3A H3.3 G34 expression was found in 97.8% of cases. In the present study, we describe our series of cases of giant cell tumor of bone in pediatric patients &lt, 16 years old. Methods: All cases of giant cell tumor of bone in pediatric patients &lt, 16 years old treated in our institute between 1982 and 2018 were reviewed. Immunohistochemistry and/or molecular analysis for H3F3A gene mutations was performed to confirm the diagnosis. A group of aneurysmal bone cysts in patients &lt, 16 years old was used as a control group. Results: Fifteen cases were retrieved. A pronounced female predominance (93%) was observed. A pure metaphyseal central location occurs in 2 skeletally immature patients. Conclusions: Giant cell tumor of bone should be distinguished from its mimickers due to differences in prognosis and treatment. Immunohistochemical and molecular detection of H3F3A gene mutation represents a reliable diagnostic tool.

Introduction Few data are available regarding the trend of IgA anti-transglutaminase antibodies (TGA-IgA) in children with celiac disease (CD) on a gluten-free diet (GFD). Our aim is to examine the normalization time of CD serology in a large pediatric population, and its predictors. Material and methods We retrospectively evaluated the normalization time of TGA-IgA and its predictive factors (age, sex, ethnicity, symptoms, associated diabetes/thyroiditis, Marsh stage, TGA-IgA and endomysial antibody levels at diagnosis, diet adherence), in 1024 children diagnosed from 2000 to 2019 in three pediatric Italian centers, on a GFD. Results TGA-IgA remission was reached in 67,3%, 80,7%, 89,8% and 94,9% after 12, 18, 24 and 36 months from starting a GFD, respectively (median time = 9 months). TGA-IgA >10´upper limit of normal at diagnosis (HR = 0.56), age 7–12 years old (HR = 0.83), poor compliance to diet (HR = 0.69), female sex (HR = 0.82), non-Caucasian ethnicity (HR = 0.75), and comorbidities (HR = 0.72) were independent factors significantly associated with longer time to normalization. Conclusions Our population is the largest in the literature, with the majority of patients normalizing CD serology within 24 months from starting a GFD. We suggest a special attention to patients with comorbidities, language barriers or age 7–12 years for a proper management and follow-up.

The presence of melanin pigment and melanocytic markers expression have been rarely reported in salivary gland tumors. Herein, two cases of carcinoma arising in pleomorphic adenoma of the parotid gland and showing diffuse expression of myoepithelial and melanocytic markers are described. The clinical-pathological clues useful in the differential diagnosis with melanoma are discussed. In addition, a review of the pertinent literature is also proposed, discussing the pathologic mechanisms potentially involved in this phenomenon. Supplementary Information The online version of this article (10.1007/s12105-021-01299-4) contains supplementary material, which is available to authorized users.

Merkel cell carcinoma (MCC) is an aggressive skin tumor with neuroendocrine differentiation, mainly affecting elderly population or immunocompromised individuals. As methylation of the human telomerase reverse transcriptase (mhTERT) has been shown to be a prognostic factor in different tumors, we investigated its role in MCC, in particular in intron 4–5 where rs10069690 has been mapped and recognized as a cancer susceptibility locus. DNA methylation analysis of hTERT gene was assessed retrospectively in a cohort of 69 MCC patients from the University of Bologna, University of Turin and University of Insubria. Overall mortality was evaluated with Kaplan-Meier curves and multivariable Royston-Parmar models. High levels of mhTERT (mhTERThigh) (HR = 2.500, p = 0.015) and p63 (HR = 2.659, p = 0.016) were the only two clinico-pathological features significantly associated with a higher overall mortality at the multivariate analysis. We did not find different levels of mhTERT between MCPyV (+) and (−) cases (21 vs 14, p = 0.554); furthermore, mhTERThigh was strongly associated with older age (80.5 vs 72 years, p = 0.026), no angioinvasion (40.7% vs 71.0%, p = 0.015), lower Ki67 (50 vs 70%, p = 0.005), and PD-L1 expressions in both tumor (0 vs 3%, p = 0.021) and immune cells (0 vs 10%, p = 0.002). mhTERT is a frequently involved epigenetic mechanism and a relevant prognostic factor in MCC. In addition, it belongs to the shared oncogenic pathways of MCC (MCPyV and UV-radiations) and it could be crucial, together with other epigenetic and genetic mechanisms as gene amplification, in determining the final levels of hTERT mRNA and telomerase activity in these patients.

Background: In the absence of a histological diagnosis, persistent albuminuria is globally accepted as the main diagnostic criteria for diabetic kidney disease (DKD). Methods: In the present retrospective study, we evaluated data from an Italian cohort of 42 deceased diabetic donors (mainly with type 2 diabetes). Using the kidney biopsies obtained at the time of donation to evaluate single or double allocation based on Karpinski score, we determined the prevalence of histological lesions attributable to diabetes. Results: All 42 donors presented with proteinuria in the normal range and an estimated glomerular filtration rate (eGFR) (chronic kidney disease [CKD]-EPI) >60 mL/min/1.73 m2. A kidney biopsy was available for 36 patients; of these, one was not interpretable and 32 showed histopathological lesions consistent with DKD and encompassing all histological classes. Thus, we found a relatively high proportion of histologically proven DKD that had been clinically undiagnosed, as none of the patient had significant proteinuria and eGFR 2. Conclusions: The data we present here support the need to implement routine kidney biopsies in normoalbuminuric diabetic subjects in the early stages of CKD. Such strategy may help to improve risk stratification in diabetic patients and guide therapeutic decisions during the early stages of the disease.

Introduction: Persistent Mullerian duct syndrome is a rare disorder of male organ development characterized by internal male pseudohermaphroditism. Persistent Mullerian duct syndrome is usually an incidental finding in patients presenting cryptorchidism, inguinal hernia, or a previous story of undescended testes. Case description: We report on two cases of persistent Mullerian duct syndrome: an adult fertile male with uterus and ectopic prostate occurring as pelvic mass and a 75-year-old organ donor with uterus and two fallopian tubes, discovered in course of organ recruitment. We performed routine histological analysis and immunohistochemical profiling of the different tissue components. Examined tissues were all benign, and the living patient is well after surgery. Conclusion: In order to prevent further complications such as infertility and potential malignant change, surgeons and surgical pathologists must be aware of this condition and should consider excision of the Mullerian remnant where possible.

Background : We report the findings of a single Italian center in the evaluation of renal lesions in deceased donors from 2001 to 2017. In risk evaluation, we applied the current Italian guidelines, which include donors with small (< 4 cm, stage pT1a) renal carcinomas in the category of non-standard donors with a negligible risk of cancer transmission. Methods : From the revision of our registries, 2,406 donors were considered in the Emilia Romagna region of Italy; organs were accepted from 1,321 individuals for a total of 3,406 organs. Results : The evaluation of donor safety required frozen section analysis for 51 donors, in which a renal suspicious lesion was detected by ultrasound. Thirty-two primary renal tumors were finally diagnosed: 26 identified by frozen sections and 6 in discarded kidneys. The 32 tumors included 13 clear cell renal cell carcinomas (RCCs), 6 papillary RCCs, 6 angiomyolipomas, 5 oncocytomas, 1 chromophobe RCC, and 1 papillary adenoma. No cases of tumor transmission were recorded in follow-up of the recipients. Conclusion : Donors with small RCCs can be accepted to increase the donor pool. Collaboration in a multidisciplinary setting is fundamental to accurately evaluate donor candidate risk assessment and to improve standardized protocols for surgeons and pathologists.

The thorax, and the lung in particular, is a frequent site of primary malignancy from different cell lines and the most common target of metastatic spread due to the high density of the vascular bed. The histopathologic diagnosis of thoracic findings is straightforward in the vast majority of cases and supported by clinical history of a known primary tumor elsewhere and imaging findings. However, the type of neoplastic dissemination may arise some doubts in the differential diagnosis between primary and secondary malignancies. Indeed, the histopathologic appearance of some metastatic tumors mimics primary malignancy (e.g., lepidic growth pattern), while primary lesions may disseminate as metastatic disease (e.g., lung adenocarcinoma with miliary pattern). More recently, the old concept of aerogenous spread of tumor cell in primary lung cancer has regained attention under the alternative robe of “spread through airspaces (STAS)” and emerged as a phenomenon associated with prognostic value in all adenocarcinoma histology, squamous cell carcinoma, and neuroendocrine carcinomas. Finally, several benign/low-grade neoplasms may lead to pulmonary metastatic dissemination.

Background In the last years, few reports have shown the feasibility of the endoscopic endonasal approach (EEA) for craniopharyngiomas in pediatric patients. For these tumors, recent studies have suggested less aggressive surgery, favoring the preservation of the patient's quality of life. Objective The aim of this study was to assess the outcome of the EEA in a large series with specific attention on the long-term functional sequelae. Materials All consecutive pediatric craniopharyngiomas operated on through this approach since 2000 were included in the study. Preoperative and postoperative operative clinical, radiologic, and pathologic features were retrieved from patient records (mean follow-up, 72 ± 67 months). Results The series included 25 patients (12 female; mean age, 8.9 ± 4.1 years). Most of the tumors presented with a supradiaphragmatic extension (88%). Removal was radical in 23 patients (92%). Complications consisted of 6 cerebrospinal fluid leaks (24%). One patient (4%) died of postoperative respiratory complications. Most patients (92%) developed panhypopituitarism and visual disturbances normalized or improved in 6 patients (43%). At follow-up, 9 patients (36%) were overweight/obese (6 were already overweight before surgery). The tumor recurrence rate was 19%. Conclusions EEA can be an effective approach for midline craniopharyngiomas in children older than 3 years. It gives a satisfactory exposure of the suprasellar region and an adequate assessment of the brain–tumor interface. Its main limitations are age-related anatomic features of nasal/paranasal sinuses and the risk of cerebrospinal fluid leak.

Epitheliosis (or usual duct hyperplasia) is a proliferation of epithelial and myoepithelial cells located within enlarged acini and small ducts, which is characterized by irregular and peripheral fenestration. Infiltrating epitheliosis (IE) is a specific lesion, characterized by classical epitheliosis flowing out into the adjacent stroma. The stroma is desmoplastic and shows keloid appearance with irregular elastosis. IE can mimic malignancy both on radiological and histological grounds. The aim of the present study is to describe the fine needle aspiration cytological features of 6 consecutive cases of IE, with histological correlation. IE cases presenting as screen detected lesions and preoperatively diagnosed on fine needle aspiration cytology (FNAC) were reviewed. All patients had radiologically breast lesions suspicious for malignancy that underwent FNAC followed by surgical resection. The FNAC smears presented some features that could lead to a misdiagnosis of malignancy, such as bloody background, high cellularity, and stromal fragments containing epithelial cells. Nevertheless, malignancy was excluded, due to the absence of atypia and the presence of myoepithelial cells in the cell clusters. IE presents a special FNAC pattern that can be misinterpreted as malignancy. Therefore, knowledge is necessary to avoid patient overtreatment.

Merkel cell carcinoma is an aggressive neuroendocrine skin tumor, for which several non-conclusive prognostic factors of adverse clinical behavior have been reported. As promoter methylation of the immune checkpoint receptor CD279/PD-1/PDCD1(mPDCD1) has been shown to be a prognostic factor in different cancers, we investigated its role in Merkel cell carcinoma. mPDCD1was assessed retrospectively in a cohort of 69 Merkel cell carcinoma patients from the University of Bologna, University of Turin and University of Insubria. Kaplan-Meier curves and log-rank tests were calculated for all variables. To assess the influence of mPDCD1, the Cox proportional hazards model and different Royston-Parmar models were evaluated. High PDCD1 methylation (mPDCD1 high ) was associated with a higher overall mortality at both the univariate analysis (log rank test: χ 2 = 5.17, p = 0.023; permutation test: p = 0.023) and the multivariate analysis (HR = 2.111, p = 0.042). The other variables associated with a higher overall mortality at the multivariate analysis were clinical stage III-IV (HR = 2.357, p = 0.008), size > 2 cm (HR = 2.248, p = 0.031) and Merkel cell polyomavirus (HR = 0.397, p = 0.015). Further, mPDCD1 high was strongly associated with older age (81 vs 76 years, p = 0.042), absence of immune cells (92.6%, p < 0.001), no expression of PD-L1 by immune cells (70.4%, p = 0.041) and by both immune and tumor cells (70.4%, p = 0.001). mPDCD1 is a valid prognostic parameter in patients affected by Merkel cell carcinoma. In addition, it could provide an estimate of the global PD-1/PD-L1 expression with potentially relevant implications from a therapeutic point of view.

In the absence of a histhological diagnosis, persistent albuminuria is globally accepted as the main diagnostic criteria for diabetic kidney disease. In the present retrospective study, we evaluated data from an Italian cohort of 42 diabetic deceased donors (mainly type 2 diabetes). Using kidney biopsies obtained at time of donation to evaluate single or double allocation based on Karpinski score, we determined the prevalence of histological lesions attributable to diabetes. All 42 donors presented with normoalbuminuria and an estimated Glomerular Filtration Rate (CKD-EPI) > 60 ml/min/1.73m2. Of the 36 patients with available kidney biopsy, one was non interpretable and 32 had histopathological lesions consistent with diabetic kidney disease and encompassing all histological classes. Thus, we found a relatively high proportion of histologically proven diabetic kidney disease that was clinically undiagnosed as none of the patient had significant albuminuria and eGFR

Papillary thyroid carcinoma is the most common thyroid malignancy and it is usually associated with a good prognosis. However, recurrence, metastases, and cancer death may occur in 10 to 15% of patients with more aggressive types of papillary thyroid carcinoma, such as tall cell, columnar cell, solid variant, or the more recently described hobnail variant of papillary thyroid carcinoma. Papillary thyroid carcinoma with a prominent hobnail pattern is a moderately differentiated papillary thyroid carcinoma variant with aggressive clinical behavior and significant mortality. The hobnail variant of papillary thyroid carcinoma shows prominent hobnail features, which have also been referred to as micropapillary. The typical hobnail/micropapillary morphological features show loss of cellular polarity/cohesiveness and support an epithelial-mesenchymal transition as a possible mechanism of metastasis. BRAF p.V600E is the most common mutation in papillary thyroid carcinoma, including the hobnail variant; recent and continuing studies are focused on defining other molecular anomalies that may be useful for prognostic stratification and may provide therapeutic targets.

Background ST2 (suppression of tumorigenity) has been described as a receptor for the interleukin-33, a member of the IL-1 family of cytokines. It is associated to coronary artery disease, all-causes mortality and cardiovascular mortality. Aims The present study was designed to assess the immunohistochemical expression of the ST2 receptor (ST2L/Il-1R) in atherosclerotic plaques of formalin fixed paraffin-embedded internal carotid arteries of patients with and without cerebro-vascular symptoms. Methods and Results The study involved 41 cases (23 asymptomatic and 18 symptomatic). All the clinical and morphological parameters examined were uniformly distributed between the two groups, with a mild predominance of degree of calcification in asymptomatic cases (p = 0.01). ST2L expression was found to be more evident as a membrane pattern in macrophages when observing carotid atherosclerotic plaques of symptomatic patients, rather than in asymptomatic patients’ plaques (77.7% vs 39.1%; p = 0.015), and its expression was particularly remarkable in VI type plaque (AHA). Significantly, ST2L was marked by the endothelium of neoangiogenetic vessels on the shoulder region of the plaque, but not (apart from a few cases) in the endothelium covering the residual lumen of the vessel. Conclusions The ST2L immunohistochemical expression was for the first time investigated in a large number of human carotid atherosclerotic plaques, as for its pattern of distribution in the different plaque cell populations. Furthermore, ST2L was particularly remarkable on macrophages, as a membrane pattern, of symptomatic patients’ plaque. Considering our data, we hypothesize that ST2L/IL33 axis could drive the mechanism of plaque development and eventually rupture.