Among thyroid papillary carcinomas (PTCs), the follicular variant is the most common and includes encapsulated forms (EFVPTCs). Noninvasive EFVPTCs have very low risk of recurrence or other adverse events and have been recently proposed to be designated as noninvasive follicular thyroid neoplasm with papillary-like nuclear features or NIFTP, thus eliminating the term carcinoma. This proposal is expected to significantly impact the risk of malignancy associated with the currently used diagnostic categories of thyroid cytology. In this study, we analyzed the fine needle aspiration biopsy (FNAB) cytology features of 96 histologically proven NIFTPs and determined how the main nuclear features of NIFTP correlate between cytological and histological samples. Blind review of FNAB cytology from NIFTP nodules yielded the diagnosis of "follicular neoplasm" (Bethesda category IV) in 56% of cases, "suspicious for malignancy" (category V) in 27%, "atypia of undetermined significance/follicular lesion of undetermined significance" (category III) in 15%, and "malignant" (category VI) in 2%. We found good correlation (κ=0.62) of nuclear features between histological and cytological specimens. NIFTP nuclear features (size, irregularities of contours, and chromatin clearing) were significantly different from those of benign nodules but not from those of invasive EFVPTC. Our data indicate that most of the NIFTP nodules yield an indeterminate cytological diagnosis in FNAB cytology and nuclear features found in cytology samples are reproducibly identified in corresponding histology samples. Because of the overlapping nuclear features with invasive EFVPTC, NIFTP cannot be reliably diagnosed preoperatively but should be listed in differential diagnosis of all indeterminate categories of thyroid cytology.

Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Myxoid changes have been rarely reported both in adrenocortical adenomas and carcinomas. The recent observation by our group of an adrenal myxoid tumor with morphologically borderline features but aggressive clinical behavior prompted us to review a series of 196 adrenocortical lesions, comprising 122 carcinomas and 74 adenomas, to define the morphological, phenotypical and clinical characteristics of adrenocortical tumors with myxoid features. Fourteen cases, including 12 carcinomas and 2 borderline tumors, formed the basis of this report, and were characterized by a variably abundant myxoid component (from 5% to 90% of tumor) and two distinct cellular growth patterns: the first (10 cases), mostly associated with a predominant myxoid stromal component, was made of small cells with mild atypia arranged in cords and microcysts; the second (4 cases) was characterized by focal myxoid changes in tumors otherwise similar to conventional adrenocortical carcinoma, with large atypical cells having an eosinophilic cytoplasm and a diffuse or nodular architecture. The above mentioned patters were absent in all adenomas reviewed. A peculiar reactivity to neurofilaments was seen, mostly associated to the presence of predominant rather that focal myxoid stromal changes, as well as in 40% of conventional adrenocortical carcinomas, thus representing an undescribed potential pitfall in the differential diagnosis of adrenal lesions. Myxoid adrenocortical tumors probably represent a rare but histologically and phenotipically distinct entity and, although rare cases of benign lesions are on record, they seem to be generally associated to morphological and clinical features of malignancy.

The pathological diagnosis of adrenocortical carcinoma (ACC) is still challenging for its rarity and the presence of special variants (pediatric, oncocytic, myxoid, and sarcomatoid). It is based on the recognition at light microscopy of at least three among nine morphological parameters, according to the Weiss scoring system, which has been introduced 27 years ago and nowadays is the most widely employed. Nevertheless, the diagnostic performance of this system is very high but does not reach a sensitivity and specificity of 100%, its diagnostic applicability is potentially low among non-expert pathologists, and a group of borderline cases with only one or two criteria exist of uncertain behavior. Moreover, it is scarcely reproducible in the ACC morphological variants. In fact, specifically for the pure oncocytic neoplasms that seem to have a better prognosis in comparison to the conventional ACCs, a modified system (the Lin-Weiss-Bisceglia) has been proposed. With the aim to simplify the ACC diagnosis, 2 years ago, the "reticulin" diagnostic algorithm has been proposed, based on the observation that the tumoral reticulin framework (highlighted by reticulin silver-based histochemical staining) is consistently disrupted in malignant cases but only in a small subset of benign cases. Following this algorithm, in the presence of reticulin alterations, malignancy is further defined through the identification of at least one of the following parameters: necrosis, high mitotic rate, and venous invasion. As a complement to the morphological approach, some immunohistochemical markers (such as steroidogenic factor 1) have been proposed as diagnostic and prognostic adjuncts but still lack wide clinical validation.