Given the high incidence and excellent prognosis of many papillary thyroid microcarcinomas, the Porto proposal uses the designation papillary microtumor (PMT) for papillary microcarcinomas (PMCs) without risk factors to minimize overtreatment and patients’ stress. To validate Porto proposal criteria, we examined a series of 190 PMC series, also studying sex hormone receptors and BRAF ^V600E mutation. Our updated Porto proposal (uPp) reclassifies as PMT incidental PMCs found at thyroidectomy lacking the following criteria: (a) detected under the age of 19 years; (b) with multiple tumors measuring >1 cm adding up all diameters; and (c) with aggressive morphologic features (extrathyroidal extension, angioinvasion, tall, and/or hobnail cells). PMCs not fulfilling uPp criteria were considered “true” PMCs. A total of 102 PMCs were subclassified as PMT, 88 as PMC, with no age or sex differences between subgroups. Total thyroidectomy and iodine-131 therapy were significantly more common in PMC. After a median follow-up of 9.6 years, lymph node metastases, distant metastases, and mortality were only found in the PMC subgroup. No subgroup differences were found in calcifications or desmoplasia. Expression of estrogen receptor-α and estrogen receptor-β, progesterone receptor, and androgen receptor was higher in PMC than in nontumorous thyroid tissue. BRAF mutations were detected in 44.7% of PMC, with no differences between subgroups. In surgical specimens, the uPp is a safe pathology tool to identify those PMC with extremely low malignant potential. This terminology could reduce psychological stress associated with cancer diagnosis, avoid overtreatment, and be incorporated into daily pathologic practice.

Cribriform morular thyroid carcinoma (CMTC) is a rare malignant thyroid tumor with a peculiar growth pattern secondary to permanent activation of the WNT/β-catenin pathway. CMTC may be associated with familial adenomatous polyposis or sporadic; it shares morphological features with papillary thyroid carcinoma (PTC) and was considered a variant of PTC in the 2017 WHO classification of tumors of endocrine organs. The new 5th edition of the WHO classification of endocrine and neuroendocrine tumors considered CMTC an independent thyroid neoplasm of uncertain histogenesis. A thymic/ultimobranchial pouch-related differentiation in CMTC has been recently postulated. We, however, have used the pathological and immunohistochemical features of this case of CMTC with 2 novel oncogenic somatic variants (c.3428_3429insA, p.(Tyr1143Ter) and c.3565del, p. (Ser1189Hisfs*76) of the APC gene to propose an origin from follicular cells (or their endodermal precursors). As usual in CMTC, the morular component of this tumor was positive for CDX2. Given the fact that WNT/β-catenin signaling, through CDX2, activates large intestine and small intestine gene expression, we postulate that in CMTC, the tumor cells have their terminal differentiation blocked, thus showing a peculiar primitive endodermal (intestinal-like) phenotype negative for sodium-iodide symporter, thyroperoxidase, and thyroglobulin. Establishing the histogenesis of CMTC is very relevant for the development of appropriate therapies of redifferentiation, particularly in patients where the tumor cannot be controlled by surgery.

The validation of several predictive biomarkers has improved the clinical outcomes of non-small cell lung carcinoma (NSCLC) patients. Single tests do not cover the mutational co-occurrences, so they do not detect other alterations, which in many cases are responsible for disease progression. We describe the development and implementation of a customized next generation sequencing (NGS) panel. We analyzed 236 formalin-fixed paraffin-embedded (FFPE) NSCLC samples from the Clinical University Hospital of Santiago de Compostela (Galicia, Northwest Spain) in 2020. Detection of EGFR, KRAS, NRAS, BRAF mutations and ALK, ROS1 rearrangements were determined by real-time polymerase chain reaction (RT-PCR), immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). These results were compared with those obtained by the NGS panel to evaluate the performance of the NGS method and to identify potential novel mutations. Ten discrepancies between NGS and the orthogonal methods were found: 2 cases in the EGFR gene, 1 in the KRAS gene, 5 in the BRAF gene and 2 in the ALK gene. The most prevalent pathogenic alterations detected by NGS were: TP53 (48.7%), KRAS (23.7%), STK11 (9.7%), EGFR (8.5%), PIK3CA (5.5%), CDKN2A (4.7%), BRAF (3.4%) and MET exon skipping 14 (3%); rearrangements were found in ALK and RET (3.5% and 1.7%, respectively). 41.5% of NSCLC patients are harbored co-occurring mutations. Our findings confirmed the robustness, sensitivity and specificity of NGS compared to conventional approaches. NGS has a role not only in the detection of actionable alterations (including concurrent mutations), but also in stratifying patients for therapy.