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Background: Tumor-infiltrating lymphocytes (TILs) are B, T-helper, and T-cytotoxic lymphocytes migrated from the blood or lymph stream toward a tumor with the aim to infiltrate and destroy it. They can be histologically graded as brisk, nonbrisk, or absent. Malignant melanoma has been the first malignancy found to be correlated with TILs status, being brisk TILs associated with better clinical outcomes. By the terminology of "adoptive cell transfer" (ACT), the medical oncology refers to the transfer of cells in a tumor-bearing patient from the same recipient or a healthy donor., Methods: A PubMed literature search on the topic has been performed. Additional documents known to the authors and identified from the reference list of cited publications have been included., Results: In the past, autologous TILs ACT was successfully tested for the treatment of malignant melanoma and, today, it is a standardized procedure in several centers around the world. It represents the first research step toward the bioengineered chimeric antigen receptor T (CAR-T) cell therapy from autologous donor., Conclusions: Both autologous TILs ACT and CAR-T cell therapy from autologous donor exploit the anticancer power of targeted self-lymphocytes, but CAR-T cell technology also virtually allows treatment of those melanomas devoid of TILs or with so few cytotoxic TILs that are difficult to identify., (© 2020 the International Society of Dermatology.)

By definition, Richter's syndrome represents the transformation of low-grade B-cell lymphoma into high-grade B-cell lymphoma, usually refractory to treatment. Exceptional cases of transformation into very aggressive mature T-cell lymphomas have been described as an unusual manifestation of the syndrome in patients died after few months from the diagnosis, despite chemotherapy. The time is ripe to regroup these T lymphomas under a new pathological subset, through the unequivocal alternate naming of 'T rex lymphoma', by analogy with the aggressive behavior of the famous dinosaur (T. rex). In practice, it represents the transformation of low-grade B-cell lymphoma into high-grade T-cell lymphoma, burdened by a very poor prognosis, because of the underlying B-cell lymphoma, which negatively interferes with the immune response of the patient. Against this distinct lymphomatous T clone, the major therapeutic efforts should be addressed.

The pathological features of the appendix tumors fundamentally recall those of the more frequent colorectal neoplasms, although with a higher relative incidence of carcinoids, due to the abundant presence of enteroendocrine cells in the appendix wall. Moreover, different types of lymphomas, Hodgkin and non-Hodgkin, arising from the extra-nodal mucosal-associated lymphatic tissue, can be encountered. The appendix tumor microenvironment (TME) consists of a cellular component and of a noncellular component: the former includes the immunocompetent cells, while the latter represents the support stroma. Particularly in carcinoids, the immune cell reaction can be explicated by tumor-infiltrating lymphocytes, which, in some circumstances, may arrange around and inside the tumor in a brisk fashion influencing favorably the prognosis. This active reaction has to be distinguished from any preexisting inflammatory condition of the appendix and from superimposed tumor complications, such as infection or ischemia. In practice, we consider the appendix TME a complex framework with immunological, mechanic, and metabolic functions, all supported by a marked neo-lymphoangiogenesis.

Competing Interests: CONFLICTS OF INTEREST The authors declares no potential conflicts of interest

Competing Interests: CONFLICTS OF INTEREST The author declare no potential conflicts of interest.

Purpose: Dysregulation of microRNA expression has been involved in the development and progression of follicular thyroid carcinoma (FTC). The aim of this work was to study the expression of miRNA146a in FTC and the association with clinicopathological features of the disease., Methods: Thirty-eight patients affected by FTC were included in the study. Twenty patients carrying follicular thyroid adenoma (FA) were also enroled as the benign counterpart of FTC. Total RNA including miRNA146a was extracted from formalin-fixed paraffin-embedded (FFPE) pairs of affected/unaffected tissue and its expression was assessed by real-time PCR. Two selected target genes, TRAF6 (tumour necrosis factor receptor-associated factor 6) and IRAK1 (Il-1 receptor-associated kinase 1/2), were also analysed., Results: miR146a expression in FTC tissue was overall not downregulated in malignant versus unaffected tissue, but its expression was inversely correlated with clinicopathological features of FTCs at diagnosis. A decreased expression of miR146a became apparent in FTC thyroid tissue of widely compared to minimally invasive tumours. However, miR146a expression differences between contralateral unaffected tissue (extra-FTC) and FTC were not observed regardless of clinicopathological features. IRAK1, a known target for miR146a, was upregulated in FTC and the increase was mainly appreciable in Hurtle FTC variant. Unexpectedly, miR146a did not correlate with TRAF6 showing an inverse trend compared to IRAK1 although both genes regulate the activity of nuclear factor- kB (NF-kB)., Conclusion: The results of this study indicate that downregulation of miR146a, inversely correlated with clinicopathological features of FTCs at diagnosis and suggest a possible involvement of miR146a in FTC development. IRAK1 over-expression in FTC may be related to tumour development/progression. In vitro experiments are needed to support this hypothesis.

Dear Editor, Immune-checkpoint blockade is a type of passive immunotherapy aimed at enhancing preexisting anti-tumor responses of the organism, blocking self-tolerance molecular interactions between T-lymphocytes and neoplastic cells (1,2). Despite a significant increase in progression-free survival, a large proportion of patients affected by metastatic melanoma do not show durable responses even after appropriate diagnostic categorization and shared therapeutic choices (3-9). Therefore, predictive biomarkers of clinical response are urgently needed, and predictive immunohistochemistry (IHC) meets these requirements. Strong evidence suggests that DNA mismatch repair (MMR) deficiency is a frequent condition in malignant melanoma, as well as in other tumors (10). As is known, DNA MMR is a safeguard system for the detection and repair of DNA errors, which can randomly occur in the phase of DNA replication inside the cell. In humans, seven DNA MMR proteins (Mlh1, Mlh3, Msh2, Msh3, Msh6, Pms1, and Pms2) work in a coordinated and sequential manner to repair DNA mismatches. When this system is defective, the cell accumulates a series of replication errors in terms of new microsatellites; therefore, a condition of genetic hypermutability and microsatellite instability (MSI) takes place inside the cell itself (11). For this reason, my working group has started to search for MMR protein deficiency in melanoma biopsies from patients of both sexes and of all ages with metastatic spread, correlating the data with the response to pembrolizumab, the well-known anti-programmed cell death protein 1 (PD1) human monoclonal immunoglobulin G4, capable of blocking the interaction between PD1, the surface receptor of activated T-lymphocytes, and its ligand, the programmed death-ligand 1 (PD-L1), favoring melanoma cell attack by T-lymphocytes (1) rather than its depression (12). PD-L1 is highly expressed in about half of all melanomas and thus the role of PD1 in melanoma immune evasion is now well established (13). Surprisingly, the best therapeutic results to pembrolizumab, in terms of progression-free survival and overall survival, occur precisely in those patients, approximately 7% in my database, affected by deficient MMR (dMMR) melanomas. In particular, the most important benefits to pembrolizumab-based treatment have occurred in a female patient, who developed a subungual melanoma in the second finger of the left hand at the age of 41 years, together with lymph node metastases to ipsilateral axilla at the onset. The patient was promptly submitted to amputation of the first phalanx and emptying of the axillary cable. The primary tumor was a vertical growth phase melanoma with a Breslow's depth of 1.4 mm; three mitotic figures for 1 mm2 were ascertained. There was no evidence of ulceration, regression, microsatellitosis, or lymphocytic infiltration; moreover, the surgical margins tested free of disease. Further molecular analyses did not show rearrangements in B-RAF and C-KIT genes. After four years, metastases appeared in the brain and ileum; however, at present the patient is still alive and in complete pembrolizumab response with progression-free survival and overall survival of 956 days and 2546 days, respectively. The tumor was afterwards identified as a dMMR melanoma for an exclusive loss of Msh6 expression on IHC (Figure 1). This finding is in line with the fact that the U.S. Food and Drug Administration has approved the use of pembrolizumab in 2017 for unresectable or metastatic solid tumors with MMR deficiency (14). In conclusion, dMMR melanoma seems to be a particular subset of disease that can be identified with high sensibility and specificity by predictive IHC as a complete loss of one or more DNA MMR proteins and that deserves targeted therapy.

The impact of nanopathology in medicine necessarily involves also the anatomo-pathological diagnostics, because of the current large spread of nanoparticles in the environment and the wide spectrum of correlated human diseases. The main entrance gates of nanoparticles into the body are respiratory inhalation, gastro-intestinal absorption and injection of polluted drugs. In all these cases, their penetration in the lymphatic or blood streams are possible, with subsequent systemic translocation. Different diseases can be generated by nanoparticles exposure, from a direct contact irritation to the onset of granulomatous diseases. Interestingly, they can also act as endocrine disruptors on the autocrine and paracrine systems. At cellular level, nanoparticles can damage the DNA content leading to a subsequent tumorigenesis. In the forensic setting, they can be searched in case of known exposure to inorganic particulate matter or in case of diseases of unknown origin, from granulomatous reactions to foreign inclusions in neoplastic tissues. The combined physical-histopathological studies allow to relate possible environmental/industrial pollution with the pathology and offer a novel tool for forensic investigations, but, overall, they represent new technical evidences for lawyers to present in a court., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The authors declare they have no potential conflicts of interest concerning drugs, pro-ducts, or services used in the study. The Editorial Board declares that the manu-script met the ICMJE recommendation for biomedical papers. Submitted: 17. 6. 2017 Accepted: 1. 11. 2018.

Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Rare earth metals (REM) are a group of 17 chemical elements in the periodic table, namely scandium (Sc), yttrium (Y) and the lanthanides. In relation to atomic volume and geological behavior, the lanthanides are further subdivided into light, medium and heavy REM. They find many applications in the technological field; however, their impact on the human health is still conflicting and, for many aspects, unknown. During a research program carried on 113 cases of female breast cancer, immunohistochemically categorized in Her2-positive (29 cases), Her2-negative (57 cases) and triple negative (27 cases), aimed to evaluate the role of environmental particulate in carcinogenesis by elemental microanalysis, for the first time in literature we have detected a REM uptake, in detail europium (Eu), dysprosium (Dy) and praseodymium (Pr), inside the neoplastic cells belonging to a single triple negative breast cancer. Curiously, the woman affected by this form of malignancy had worked in the ceramic industry, a well-known source of REM, during her life, and she was the one and only patient of our series to be dedicated to this activity. The medical repercussions of our findings are here discussed: in fact, a REM detection in only 1 of 113 examined cases seems to exclude active roles in breast carcinogenesis and discloses new possibilities for therapeutic developments in triple negative breast cancer.

The nanopathological diagnostics (ND) is an ultra-specialized branch of pathological anatomy aimed to identify the nanoparticles of metallic, semimetallic, or nonmetallic elements in the inorganic particulate matter present inside pathological tissues, even on the nanometer scale. ND exploits an environmental scanning electron microscope, connected to an X-ray microprobe mounted on an energy-dispersive spectrometer. The searching of nanoparticles can be performed on paraffin-embedded material, omitting emissions of black overlay and plating procedures. The technique is highly sensitive and specific, reproducible and rapid, covering an entire operating cycle in few hours. Nowadays, ND finds many applications: (I) intratumor detection of heavy metals and endocrine metal disruptors; (II) identification of pathogenic nanoparticles in medical or veterinary drugs and devices, cosmetics, household products, and foodstuffs; (III) differential diagnosis of sarcoid-type granulomas (berylliosis, baritosis) and foreign body granulomas (prosthetic, iatrogenic); (IV) attestation of occupational disease correlating the datum with the occupational risk (anthracosis, asbestosis, bauxite fibrosis, byssinosis, chalicosis, siderosis, silicosis, stannosis, talcosis); and (V) forensic investigations to ascertain a causal link between disease and environmental, military, or work exposure. In addition to filling a knowledge gap, ND offers to the pathologist a current research field, with particular reference to the impact of occupational and environmental pollution on the human health and cancer.

Here, referred for the first time in literature, we present the forensic case of death, with suicidal intent, following ingestion of a conspicuous amount of quaternary ammonium compounds contained in an unguarded bottle of household detergent. The deceased person was a young female patient at a psychiatric facility; the cause of death was acute heart failure due to spotty infiltration of neutrophils, lymphocytes and plasma cells in the myocardial tissue, observable in the course of toxic myocarditis. The dominant pathogenetic factors involved are direct damage of myocardial cells and a superimposed immune response extending to the epicardial perivascular spaces. This rare form of acute myocarditis has never been previously described. Moreover, this fatal event emphasizes the need for planned clinical risk-management measures and for guidelines to prevent future adverse events of this kind in psychiatric facilities., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The latest reviews on thin melanoma (TM) continue to consider it a melanoma within 1 mm in thickness, but no consensus exists as to which patients with TM are at risk for lymph node metastases (1). Numerous studies have evaluated the impact of various predictors (Breslow thickness, Clark level, ulceration, regression, vascular invasion, mitotic activity, location, sex) for nodal disease in melanoma, but the conclusions have not been homogenous (2,3). For this reason, we read the paper by Homolak et al. with great interest, where the authors examine the sentinel lymph node biopsies (SLNB) of 184 patients affected by melanoma of thickness less than 1.5 mm, defined as thin (4). SLNB was positive in 22 patients (12%), and 30 patients (7.65%) developed metastatic disease. The group of thinnest tumors (<0.50 mm) had the highest proportion of positive nodes (33%); the group of thickest tumors (1.26-1.50 mm) had the highest proportion of patients with metastatic disease (23%). The authors divided TM into 5 groups: 1) <0.50 mm (15 patients, 5 with positive SLNB); 2) 0.50-0.75 mm (18 patients, 3 with positive SLNB); 3) 0.76-1.00 mm (67 patients, 7 with positive SLNB); 4) 1.01-1.25 mm (45 patients, 4 with positive SLNB); 5) 1.26-1.50 mm (36 patients, 3 with positive SLNB). The current staging system of the American Joint Committee on Cancer (AJCC) uses Breslow thickness as the primary attribute, and up to 1 mm thick melanoma is defined as 'thin' because it shows a good prognosis after surgical excision, with a 10-year survival rate of 85-90% in case of a tumor-free margin of at least 1 cm (5). Based on our experience, this limit should be maintained at 1 mm because TM includes four main histological subtypes, which reflect specific biological attitudes: the intra-epidermal (in situ) radial growth phase (RGP), the non-tumorigenic micro-invasive radial growth phase without regression, the micro-invasive radial growth phase with regression (>75%) of uncertain tumorigenic potential, and the tumorigenic early (≤1 mm) invasive vertical growth phase (VGP) (6-10). This proposed sub-typing fits better with the AJCC staging system, as elucidated below and in Table 1: intra-epidermal radial growth phase (pTis), micro-invasive radial growth phase without regression (pT1), micro-invasive radial growth phase with regression (pT1), early invasive vertical growth phase (pT1), invasive vertical growth phase >1 mm, ≤2 mm (pT2), invasive vertical growth phase >2 mm, ≤4 mm (pT3), invasive vertical growth phase >4 mm (pT4). The in situ RGP and micro-invasive RGP without regression are biologically indolent if completely removed, and SLNB is not necessary in these cases (6). In micro-invasive RGP with regression, performing SLNB is prudent, in particular if accompanied by high mitotic rates, while it is mandatory in early invasive VGP (7). Therefore, the prognostic predictors of nodal and distant metastases require further research in the four above-mentioned histological subtypes of thin melanoma.