SARS-CoV-2 Spike Protein Activates Human Lung Macrophages.

COVID-19 is a viral disease caused by SARS-CoV-2. This disease is characterized primarily, but not exclusively, by respiratory tract inflammation. SARS-CoV-2 infection relies on the binding of spike protein to ACE2 on the host cells. The virus uses the protease TMPRSS2 as an entry activator. Human lung macrophages (HLMs) are the most abundant immune cells in the lung and fulfill a variety of specialized functions mediated by the production of cytokines and chemokines. The aim of this project was to investigate the effects of spike protein on HLM activation and the expression of ACE2 and TMPRSS2 in HLMs. Spike protein induced CXCL8, IL-6, TNF-α, and IL-1ß release from HLMs; promoted efficient phagocytosis; and induced dysfunction of intracellular Ca2+ concentration by increasing lysosomal Ca2+ content in HLMs. Microscopy experiments revealed that HLM tracking was affected by spike protein activation. Finally, HLMs constitutively expressed mRNAs for ACE2 and TMPRSS2. In conclusion, during SARS-CoV-2 infection, macrophages seem to play a key role in lung injury, resulting in immunological dysfunction and respiratory disease.

Medullary thyroid carcinoma with double negative calcitonin and CEA: a case report and update of literature review.

BACKGROUND: Medullary thyroid carcinoma is a malignant uncommon and aggressive tumour of the parafollicular C cells. In about 75% of cases it is sporadic while, in case of RET mutation, it is associated to multiple endocrine neoplasia type 2 (25% of cases). The biochemical features of medullary thyroid carcinoma include the production of calcitonin and carcinoembryogenic antigen. The above-mentioned features are useful in the diagnostic process as well as in the follow up and in the prognostication of the disease. Even if calcitonin elevation is strongly associated to MTC, it can also be found increased in many pathological different conditions as pregnancy, lactation, C-cells hyperplasia, autoimmune thyroiditis, end stage renal disease, lung and prostate cancer and several neuroendocrine tumours. Major medullary thyroid tumours are usually connected to high doses of circulating calcitonin, in fact non-secretory variants have hardly been described. CASE PRESENTATION: We herein report the case of a 59 years old male, who had undergone total thyroidectomy for multinodular goiter with negative preoperative calcitonin, showing medullary thyroid carcinoma at definitive pathology. To the best of our knowledge, this is the first case documenting a non-secretory medullary thyroid carcinoma, with double negative markers at the time of diagnosis and at the relapse. CONCLUSION: A Literature review underlining pathological hypothesis, differential diagnosis and alternative and innovative biomarkers to identify non-secretory medullary thyroid carcinoma was carried out.

HPV Virus Transcriptional Status Assessment in a Case of Sinonasal Carcinoma.

Human Papilloma Virus (HPV) can play a causative role in the development of sinonasal tract malignancies. In fact, HPV may be the most significant causative agent implicated in sinonasal tumorigenesis and is implicated in as many as 21% of sinonasal carcinomas. To date, there are no definitive, reliable and cost-effective, diagnostic tests approved by the FDA for the unequivocal determination of HPV status in head and neck cancers. We followed an exhaustive algorithm to correctly test HPV infection, including a sequential approach with p16INK4a IHC, viral DNA genotyping and in situ hybridization for E6/E7 mRNA. Here, we report a case of sinonasal carcinoma with discordant results using HPV test assays. The tumor we describe showed an irregular immunoreactivity for p16INK4a, and it tested positive for HPV DNA; nevertheless, it was negative for HR-HPV mRNA. We discuss the possible meaning of this discrepancy. It would be advisable to test HPV transcriptional status of sinonasal carcinoma on a diagnostic routine basis, not only by p16INK4a IHC assay, but also by HPV DNA genotyping and HR-HPV mRNA assessment.

Fine-needle cytology in the follow-up of breast carcinoma.

The postoperative follow-up strategies for breast carcinoma (BC) utilize different procedures; the aim of this study was to investigate the role of fine-needle cytology (FNC) in the follow-up of BC patients. Two hundred sixty-six FNC samples from 190 BC patients have been reviewed. The target anatomical sites were 190 breast including 155 ipsilateral and 145 contralateral breast lesions and 76 extra-mammary nodules. Extra-mammary lesions included lymph nodes, thyroidal nodules, soft tissue lesions, (subcutaneous and sub-scars), salivary glands and deep located masses. Diagnostic distribution of the breast lesions was as follows: 51 positive, 15 indeterminate/suspicious, 119 negative and 5 inadequate. Positive cases included 43 ipsilateral and 8 contralateral BC, 9 BC in different quadrants from those of onset of the first BC. Sensitivity, specificity and accuracy have been 90, 91 and 90&, respectively. FNC, in a correct setting, is a reliable and effective method for the follow-up management of BC patients.

Time to Recurrence of Intracranial Meningiomas from a Monoinstitutional Surgical Series.

BACKGROUND: Meningiomas show variable tendency to recur. While risk factors of recurrence have been largely investigated in literature, a paucity of data is available on the time to recurrence. Our purpose was to identify main factors affecting the time to recurrence to assist preoperative treatment decision-making strategy and to define a tailored clinical and neuroradiological follow-up. METHODS: Data of 35 patients with intracranial meningioma recurrences have been retrospectively reviewed. Demographic (patient age at initial diagnosis and sex), radiologic (meningioma location, pattern of regrowth and topography of recurrences at first reoperation), pathologic (WHO grade and Ki67-MIB1 at initial surgery and at first reoperation, progesterone receptor [PR] expression), and surgical (extent of resection at initial surgery according to Simpsons grading system, number of reoperations) factors were analyzed. RESULTS: Time to recurrence ranged from 20 to 120 months. Extent of resection at initial surgery was Simpson grade I in 7 patients (20%), grade II in 10 (28.5%), grade III in 14 (40%), and grade IV in 4 (11.5%). Longer median time to recurrence was observed for skull base localization (P < 0.01), Simpson grades I and II versus grades III (P = 0.01) and IV (P = 0.02), values of Ki67-MIB1 ≤ 4% (P = 0.001), and PR > 60% (P = 0.03); conversely, sex, age, number of reoperations, unchanged/progression of Ki67, and/or World Health Organization grade between first surgery and reoperation did not correlate in statistically significant way with time to recurrence. CONCLUSIONS: The extent of resection and the Ki67-MIB1 represent the most important factors predicting shorter recurrence time of intracranial meningiomas. Patients with incomplete (Simpson grades III and IV) resection and high Ki67-MIB1 values, especially at non-skull base localization and with low PR values, require a closer short-term clinical and radiologic follow-up in the first years after surgery.

A deep learning model to predict Ki-67 positivity in oral squamous cell carcinoma.

Anatomical pathology is undergoing its third revolution, transitioning from analogical to digital pathology and incorporating new artificial intelligence technologies into clinical practice. Aside from classification, detection, and segmentation models, predictive models are gaining traction since they can impact diagnostic processes and laboratory activity, lowering consumable usage and turnaround time. Our research aimed to create a deep-learning model to generate synthetic Ki-67 immunohistochemistry from Haematoxylin and Eosin (H&E) stained images. We used 175 oral squamous cell carcinoma (OSCC) from the University Federico II's Pathology Unit's archives to train our model to generate 4 Tissue Micro Arrays (TMAs). We sectioned one slide from each TMA, first stained with H&E and then re-stained with anti-Ki-67 immunohistochemistry (IHC). In digitised slides, cores were disarrayed, and the matching cores of the 2 stained were aligned to construct a dataset to train a Pix2Pix algorithm to convert H&E images to IHC. Pathologists could recognise the synthetic images in only half of the cases in a specially designed likelihood test. Hence, our model produced realistic synthetic images. We next used QuPath to quantify IHC positivity, achieving remarkable levels of agreement between genuine and synthetic IHC. Furthermore, a categorical analysis employing 3 Ki-67 positivity cut-offs (5%, 10%, and 15%) revealed high positive-predictive values. Our model is a promising tool for collecting Ki-67 positivity information directly on H&E slides, reducing laboratory demand and improving patient management. It is also a valuable option for smaller laboratories to easily and quickly screen bioptic samples and prioritise them in a digital pathology workflow.

Clinical and Molecular Characteristics of Gonadotroph Pituitary Tumors According to the WHO Classification.

Since 2017, hormone-negative pituitary neuroendocrine tumors expressing the steroidogenic factor SF1 have been recognized as gonadotroph tumors (GnPT) but have been poorly studied. To further characterize their bio-clinical spectrum, 54 GnPT defined by immunostaining for FSH and/or LH (group 1, n = 41) or SF1 only (group 2, n = 13) were compared and studied for SF1, ßFSH, ßLH, CCNA2, CCNB1, CCND1, caspase 3, D2R, and AIP gene expression by qRT-PCR. Immunohistochemistry for AIP and/or D2R was performed in representative cases. Overall, patients were significantly younger in group 1 (P = 0.040 vs group 2), with a similar trend excluding recurrent cases (P = 0.078), and no significant difference in gender, tumor size, invasion or Ki67. SF1 expression was similar in both groups but negatively correlated with the patient's age (P = 0.013) and positively correlated with ßLH (P < 0.001) expression. Beta-FSH and AIP were significantly higher in group 1 (P = 0.042 and P = 0.024, respectively). Ki67 was unrelated to gonadotroph markers but positively correlated with CCNB1 (P = 0.001) and negatively correlated with CCND1 (P = 0.008). D2R and AIP were strongly correlated with each other (P < 0.001), and both positively correlated with SF1, ßFSH, ßLH, and CCND1. AIP immunopositivity was frequently observed in both groups, with a similar median score, and unrelated to Ki67. D2R immunostaining was best detected with a polyclonal antibody and mostly cytoplasmic. This study indicates that hormone-negative GnPT tend to occur in older patients but do not significantly differ from other GnPT in terms of invasion or proliferation. It also points out the current limits of D2R immunostaining in such tumors.

Biphenotypic Sinonasal Sarcoma with Orbital Invasion: A Literature Review and Modular System of Surgical Approaches.

Background: Biphenotypic sinonasal sarcoma is a rare low-grade tumor arising from the sinonasal tract, featuring locally aggressive biological behavior, with a tendency to invade the orbit and skull base. There are no defined guidelines of treatment; thus, the management varies among different institutions. The aim of the present study is to provide a modular system of surgical approaches according to the lesion pattern of growth from a literature review. Materials and Methods: A comprehensive and detailed literature review on the PubMed and Embase online electronic databases on biphenotypic sinonasal sarcoma with orbital invasion was conducted. A personal case exhibiting peculiar features was also added. Demographic (patient's sex and age), clinical (presenting symptoms and time to treatment), neuroradiological (anatomical origin and pattern of growth), and treatment (type of treatment, surgical approach, extent of resection, peri- and postoperative complications, and adjuvant therapies) data, as well as clinical outcome, recurrence rates, and overall survival, were analyzed. Results: Thirty-one patients harboring biphenotypic sinonasal sarcoma with orbital invasion were identified. Tumors mainly affected female patients (66.7%) and a middle-aged population (median 55.2 years old). Simultaneous skull base involvement occurred in most cases (80.6%). Surgery was performed in all but one case (97%), as unique treatment (59%) or in association with radio-(23.5%) and/or chemotherapy (5.9%/2.9%), allowing for gross total tumor resection in most cases (66.7%). The endoscopic endonasal approach was the most adopted surgical corridor (51.7%). The local recurrence rate was 19.3%, and only two cases of tumor-related mortality occurred. Conclusions: Surgery is the only curative treatment, with the main goal to restore/improve/arrest progression of clinical manifestations. The endoscopic endonasal route represents the master approach for lesions confined to the midline. Microsurgical transcranial and endoscopic transorbital approaches have a complementary role for addressing the lesion's component with large intracranial extension or affecting the paramedian aspect of the anterior cranial fossa and superior-lateral orbital compartment, respectively. The approach selection should be made case by case according to the tumor pattern of growth.

Outcomes of Thoracoscopic Lobectomy after Recent COVID-19 Infection.

BACKGROUND: The COVID-19 outbreak had a massive impact on lung cancer patients with the rise in the incidence and mortality of lung cancer. METHODS: We evaluated whether a recent COVID-19 infection affected the outcome of patients undergoing thoracoscopic lobectomy for lung cancer using a retrospective observational mono-centric study conducted between January 2020 and August 2022. Postoperative complications and 90-day mortality were reported. We compared lung cancer patients with a recent history of COVID-19 infection prior to thoracoscopic lobectomy to those without recent COVID-19 infection. Univariable and multivariable analyses were performed. RESULTS: One hundred and fifty-three consecutive lung cancer patients were enrolled. Of these 30 (19%), had a history of recent COVID-19 infection prior to surgery. COVID-19 was not associated with a higher complication rate or 90-day mortality. Patients with recent COVID-19 infection had more frequent pleural adhesions (p = 0.006). There were no differences between groups regarding postoperative complications, conversion, drain removal time, total drainage output, and length of hospital stay. CONCLUSIONS: COVID-19 infection did not affect the outcomes of thoracoscopic lobectomy for lung cancer. The treatment of these patients should not be delayed in case of recent COVID-19 infection and should not differ from that of the general population.

Immunohistochemical expression of PRAME is a marker of poor prognosis in uveal melanoma: A clinico-pathologic and immunohistochemical study on a series of 85 cases.

PReferentially expressed Antigen in Melanoma (PRAME) is a cancer testis antigen, first isolated in tumor-reactive T-cell clones from a metastatic melanoma patient. It has been widely studied in skin pathology as an immunohistochemical marker capable of distinguishing between benign nevi and malignant melanomas. PRAME has been found to be also expressed in non-melanocytic tumors, including lung, breast, kidney and ovarian cancer. However, less is known about the diagnostic and/or prognostic role of this protein in uveal melanoma (UM); few studies have reported that PRAME expression seems to give to UM patients an additional metastatic risk beyond the other already-known prognostic parameters. In the present retrospective study, we aimed to correlate PRAME immunoreactivity to other clinico-pathologic features and follow-up data on a large series of 85 cases (45 non-metastasizing and 40 metastasizing tumors) of primary UM. A statistically significant correlation was found between PRAME expression and higher metastatic risk and lower metastasis-free survival. We propose to include PRAME in the immunohistochemical panel of UM as an easily usable marker capable of predicting higher metastatic risk and stratifying patients' outcome.

A Retrospective Multicenter Italian Analysis of Epidemiological, Clinical and Histopathological Features in a Sample of Patients with Acinic Cell Carcinoma of the Parotid Gland.

BACKGROUND: The acinic cell carcinoma (AciCC) of the parotid gland is a rare tumor with an indolent behavior; however, a subgroup of this tumor presents an aggressive behavior with a tendency to recur. The aim of this multicenter study was to identify and stratify those patients with AciCC at high risk of tumor recurrence. METHODS: A retrospective study was carried out involving 77 patients treated with surgery between January 2000 and September 2022, in different Italian referral centers. Data about tumor characteristics and its recurrence were collected. The histological specimens and slides were independently reviewed by a senior pathologist coordinator (L.C.) and the institution's local head and neck pathologist. RESULTS: The patients' age average was 53.6 years, with a female prevalence in the group. The mean follow-up was 67.4 months (1-258, SD 59.39). The five-year overall survival (OS) was 83.2%. The 5-year disease-free survival (DFS) was 60% (95% CI 58.2-61.7). A high incidence of necrosis, extraglandular spread, lymphovascular invasion (LVI), atypical mitosis, and cellular pleomorphism was observed in the high-risk tumors compared to the low-risk ones. CONCLUSION: AciCC generally had an indolent behavior, optimal OS, DFS with few cervical node metastases, and rare distant relapses. This multicenter retrospective case series provides evidence of the need for clinical-epidemiological-histological stratification for patients at risk of poor outcomes. Our results suggest that the correct definition of high-risk AciCC should include tumor size, the presence of necrosis, extraglandular spread, LVI, atypical mitosis, and cellular pleomorphism.

Immunotherapy for Aggressive and Metastatic Pituitary Neuroendocrine Tumors (PitNETs): State-of-the Art.

Background: Aggressive and metastatic PitNETs are challenging conditions. Immune checkpoint inhibitors (ICIs) are currently considered in cases resistant to temozolomide (TMZ). However, clinical experience is essentially limited to case reports, with variable outcomes. Material and Methods: The effects of ICIs on 12 aggressive/metastatic PitNETs from the literature were reviewed and analyzed according to tumor characteristics, with the additional description of a silent-Pit1 metastatic tumor responding to pembrolizumab. Results: Most cases were metastatic (10/13: 6 corticotroph, 3 lactotroph, 1 silent Pit1); 3 were aggressive (2 corticotroph, 1 lactotroph). ICIS was used either as monotherapy or in combination. At last follow-up on ICI, a complete response (CR) was present in 3 cases and a partial response (PR) in 2 cases (4/5 metastatic). One sustained stable disease (SD) was reported. Progressive disease (PD) was observed in 7 cases, 3 of them after initial SD (n = 1) or PR (n = 3), with 2 reported deaths. PDL1 expression was studied in 10 cases and was high (>95%) in 2 Pit1-derived metastatic PitNETs (1 CR and 1 remarkable PR) but absent/low (<1%) in the remaining cases (including 1 CP and 2 PR). Elevated tumor mutation burden could be informative in corticotroph PitNETs, especially in mismatch repair-deficient tumors. Conclusion: Significant benefits from ICIs were documented in about half of TMZ-resistant PitNETS. High PDL1 expression was associated with remarkable responses but may be dispensable. Based on their acceptable tolerance and awaiting recognized predictors of response, ICIs may be considered a valuable option for such patients.

Human Lung-Resident Macrophages Express and Are Targets of Thymic Stromal Lymphopoietin in the Tumor Microenvironment.

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine highly expressed by epithelial cells and several innate and adaptive immune cells. TSLP exerts its biological effects by binding to a heterodimeric complex composed of TSLP receptor (TSLPR) and IL-7Rα. In humans, there are two TSLP isoforms: the short form (sfTSLP), constitutively expressed, and the long form (lfTSLP), which is upregulated in inflammation. TSLP has been implicated in the induction and progression of several experimental and human cancers. Primary human lung macrophages (HLMs), monocyte-derived macrophages (MDMs), and peripheral blood monocytes consitutively expressed sfTSLP mRNA. Incubation of HLMs, MDMs, and monocytes with lipopolysaccharide (LPS) or IL-4, but not with IL-13, induced TSLP release from HLMs. LPS, but not IL-4 or IL-13, induced CXCL8 release from HLMs. LPS, IL-4 alone or in combination with IL-13, induced the expression of lfTSLP, but not of sfTSLP from HLMs. Preincubation of HLMs with IL-4, alone or in combination with IL-13, but not IL-13 alone, synergistically enhanced TSLP release from LPS-activated macrophages. By contrast, IL-4, alone or in combination with IL-13, inhibited LPS-induced CXCL8 release from HLMs. Immunoreactive TSLP was detected in lysates of HLMs, MDMs, and monocytes. Incubation of HLMs with TSLP induced the release of proinflammatory (TNF-α), angiogenic (VEGF-A, angiopoietin 2), and lymphangiogenic (VEGF-C) factors. TSLP, TSLPR, and IL-7Rα were expressed in intratumoral and peritumoral areas of human lung cancer. sfTSLP and lfTSLP mRNAs were differentially expressed in peritumoral and intratumoral lung cancer tissues. The TSLP system, expressed in HLMs, MDMs, and monocytes, could play a role in chronic inflammatory disorders including lung cancer.

Low-Grade Intraductal Carcinoma of the Parotid Gland: A Case Report and Literature Review.

Low-grade intraductal carcinoma is a rare neoplasia with an excellent prognosis, previously classified as low-grade cribriform cystadenocarcinoma and low-grade salivary duct carcinoma. The tumor mainly occurs in the parotid gland and presents a ductal phenotype and an intraductal/intracystic growth pattern. It resembles intraductal breast lesions such as atypical ductal hyperplasia, papillary and cribriform ductal carcinoma in situ. Despite its infrequency, discriminating low-grade intraductal carcinoma from other salivary gland tumors is crucial, especially because of its favorable prognosis. A 74-year-old woman with a history of neurofibromatosis underwent a superficial parotidectomy to remove a sharply demarcated multi-cystic mass, diagnosed as category 4 at FNAC. The histological examination revealed a demarcated but unencapsulated lesion composed of a bigger cyst surrounded by several smaller cysts, lined by a monolayer or bilayer epithelium alternated with a cribriform proliferation, characterized by "Roman-bridges", with occasional micro-papillae. A myoepithelial component, with a basal disposition, was present, confirmed by intense staining for protein p63 and SMA. Immunohistochemical stains showed intense, strong uniform positivity for pan-cytokeratin, protein S100, and SOX10. The Ki67 proliferation index was low (< 10%). A diagnosis of Low-grade Intraductal Carcinoma (LGIC) of the parotid was made. We performed a literature search in PUBMED for "Intraductal carcinoma", "Low-grade Intraductal Carcinoma", "Cribriform Cystadenocarcinoma", "Salivary Duct Carcinoma", and "Low-Grade Salivary Duct Carcinoma". We selected 17 papers published between 1983 and 2020; the most affected anatomical site was the parotid gland (77/90), followed by minor salivary glands (6/90), the intraparotid lymph nodes (3/90) and the submandibular gland (4/90). Their main histopathological features are reported in the paper. Here we present a case report and a review of scientific literature on this topic to provide some essential diagnostic tools to discriminate this rare entity.

Tissue Expression of Carbonic Anhydrase IX Correlates to More Aggressive Phenotype of Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common cancer in the white-skinned population accounting for about 15% of all neoplasms. Its incidence is increasing worldwide, at a rate of about 10% per year. BCC, although infrequently metastasizing, very often causes extensive tissue losses, due to the high propensity toward stromal infiltration, particularly in its dedifferentiated forms, with disfiguring and debilitating results. To date, there still is limited availability of therapeutic treatments alternative to surgery. We evaluated the immunohistochemical expression of the carbonic anhydrase IX (CAIX), one of the main markers of tissue hypoxia, in a set of 85 archived FFPE BCC tissues, including the main subtypes, with different clinical outcomes, to demonstrate a possible relationship between hypoxic phenotype and biological aggressiveness of these neoplasms. Our results showed that the expression level of the CAIX protein contributes to the stratification of BCC in the different risk classes for recurrence. We hypothesize for CAIX a potential therapeutic role as a target therapy in the treatment of more aggressive BCCs, thus providing an alternative to surgical and pharmacological therapy with Hedgehog inhibitors, a promising example of target therapy in BCCs.

Neuropilin-1 Expression Associates with Poor Prognosis in HNSCC and Elicits EGFR Activation upon CDDP-Induced Cytotoxic Stress.

Head and neck squamous cell carcinoma (HNSCC) includes a group of aggressive malignancies characterized by the overexpression of the epidermal growth factor receptor (EGFR) in 90% of cases. Neuropilin-1 (NRP-1) acts as an EGFR co-receptor, enhancing, upon ligand stimulation, EGFR signaling in several cellular models. However, NRP-1 remains poorly characterized in HNSCC. By utilizing in vitro cellular models of HNSCC, we report that NRP-1 is involved in the regulation of EGFR signaling. In fact, NRP-1 can lead to cisplatin-induced EGFR phosphorylation, an escape mechanism activated by cancer cells upon cytotoxic stress. Furthermore, we evaluated Neuropilin-1 staining in tissue samples of an HNSCC case series (n = 218), unraveling a prognostic value for the Neuropilin-1 tissue expression. These data suggest a potential role for NRP-1 in HNSCC cancer progression, expanding the repertoire of signaling in which NRP-1 is involved and eliciting the need for further investigations on NRP-1 as a suitable target for HNSCC novel therapeutic approaches.

[Two cases of EGFR-mutated lung adenocarcinoma treated with bronchial recanalization and first-line therapy with afatinib.] / Due casi di adenocarcinoma del polmone EGFR mutati trattati con ricanalizzazione bronchiale e terapia di prima linea con afatinib.

In 2019, we admitted two non-smoking patients with severe dyspnea from invasion of the main airway due to lung cancer. The patients were 57 and 67 years old; both presented with critical stenosis due to infiltration of the right main bronchus and in both cases, due to severe respiratory insufficiency, an indication of unclogging of the right stenotic main bronchus with rigid bronchoscope and Laser yttrium aluminum perovskite (YAP)-Nd in the operating room was given. At the end of the recanalization operation, a tracheobronchial prothesis, the GSS-Y 40x30x30 mm by Novatech, was positioned in Case 1; a nitinol self-expanding prothesis, the SILMET® 14x40 mm by Novatech, was positioned in Case 2. Once the histological diagnosis of EGFR-mutated adenocarcinoma was established, we started first-line treatment with afatinib 40 mg die tablets.

Expression of P16INK4a in Uveal Melanoma: New Perspectives.

Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite sharing the name and similar morphological features with cutaneous melanoma (CM), it is an entirely different neoplasia with a particular genetic background and clinical behavior. CDKN2A is a gene located at chromosome 9p21, encoding for P16INK4a and P14(ARF) proteins, whose role as a tumor suppressor has been clearly defined in many malignant tumors. CDKN2A frequently presents germline mutations in familial CM and epigenetic downregulation in a considerable percentage of sporadic CM. It has been hypothesized that CDKN2A alterations are early events in CM development, playing a central role in the malignant transformation of melanocytes. Alterations of the CDKN2A gene reduce the expression of P16INK4a in most CM subtypes. Immunohistochemical evaluation of P16INK4a is currently used, in association with Ki67 and HMB45, in pathology practice to discriminate between dysplastic nevi and melanoma. On the other hand, CKDN2A is rarely mutated in UM, and the immunohistochemical expression of P16INK4a has only been reported in small case series. We tested P16INK4a expression on paraffin-embedded tissue sections from 9 tissue microarrays (TMAs), built with 2 mm cores derived from 133 uveal melanoma FFPE blocks, collected from 1990 to 2018, and from selected paraffin-blocks of 3 UM liver metastases. The immunohistochemical expression of P16INK4a was assessed with a visual evaluation by light microscopy and then with a digital approach. Both approaches, with an acceptable concordance rate, revealed P16INK4a expression in a large proportion of UM cases and all liver metastases, opening new possibilities of using it in the differential diagnosis between cutaneous and uveal melanoma metastases in cases of unknown primary tumor or patients with two different primary melanomas.