Carcinoma ex-pleomorphic adenoma (CPA) is subclassified based on the extent of penetration of the malignant component beyond the fibrous capsule of the pre-existing pleomorphic adenoma (PA). These subclasses are considered to be prognostically significant since the non-invasive/minimally invasive groups have an excellent outcome. Nevertheless, there is no consensus as to the cutoff value to distinguish between minimal and wide invasion, even though the 2005 WHO classification defines 1.5 mm as cutoff. The objective of this study is to evaluate a consecutive series of CPA, in order to establish what the effect is of the extent of extra-capsular invasion on prognosis. Fifty-eight cases of CPA were reviewed to obtain demographic and pathological information. Extent of invasion was measured. Eleven cases were non-invasive, 9 had ≤1.5 mm invasion, and for the remainder, the depth of invasion ranged between 2.5 and >10 mm. Distant metastases or death did not occur in the first two groups. In the group with ≥2.5 mm invasion, 15 patients had progressive disease and 9 of them died. The minimum extent of invasion associated with tumor progression and death was 2.5 mm. Two histologically non-invasive carcinomas had regional lymph node metastasis. CPA with ≤1.5 mm depth of invasion has good prognosis. Nevertheless, the lymph node metastases found in two cases of this group question the concept that intracapsular/minimally invasive CPA has a prognosis similar to that of PA. The minimum extent of invasion associated with death was 2.5 mm, which is at variance with findings in other recent series. Thirteen cases with depth of invasion exceeding 2.5 mm did well, confirming that additional factors should be considered in the clinical management of these patients.

According to our results, distinct mutations on EIF1AX may be related to different phenotypes/behaviours. Despite being a small series, which reflects the difficulty in retrieving PDTC and ATC surgical samples with well-differentiated and/or benign areas, our study may provide new insights into thyroid cancer tumourigenesis and dedifferentiation.

Salivary gland tumor classification encompasses a vast list of benign and malignant neoplasms. Their morphological diversity is recognized not only between different entities but also within individual tumors. Tumor categories as described by the World Health Organization reflect, in part, a true genetic heterogeneity (e.g., translocations involving CRTC1 and CRTC3-MAML2 genes in mucoepidermoid carcinoma and MYB-NFIB fusion in adenoid cystic carcinoma). Carcinoma ex pleomorphic adenoma shows diversity in its histological appearance, but recurrent rearrangements on PLAG1 and HMGA2 are common to its benign precursor. More recently, new categories have been defined, like secretory carcinoma with the t(12;15) (p13;q25) ETV6-NTRK3 translocation and clear-cell carcinoma with EWSR1-ATF1 fusion. Recent studies on cribriform adenocarcinoma of minor salivary gland origin and epithelial-myoepithelial carcinoma point to a correlation with their morphological features. All of these advances show that the search of a histogenetic and genetic basis for salivary gland tumors is helping to clarify morphological categories and unraveling new ones. Nevertheless, currently morphology is still the hallmark of tumor classification and the gold standard. The therapeutic options for advanced tumors remain very limited but the discovery of translocation-generated gene fusions and increased knowledge of the genomic information of salivary gland tumors is creating opportunities for the development of specific targeted therapies.

Fibromatosis-like metaplastic carcinoma (FLMCa) of the breast is a rare low-grade spindle cell carcinoma, of which the biological characteristics have not been well studied. This study aims to assess, in FLMCa, immunohistochemical expression of claudins (CLDN) and features connected with the claudin-low subtype, such as the presence of tumor initiating cells (TIC), epithelial-mesenchymal transition (EMT) phenotype, as well as EGFR activating mutations. Three cases of FLMCa were retrieved from our hospital archives. Histological and immunohistochemical characteristics were reviewed. Expression of CLDN-1, CLDN-3, CLDN-4 and CLDN-7, CD44 and CD24 (TIC phenotype), and vimentin and E-cadherin (EMT features) were studied. EGFR mutations on exons 18, 19, 20, and 21 were investigated by real-time PCR. In all cases, the low-grade spindle cell component was predominant, with two cases presenting <5 % of epithelioid and squamous areas. The tumors expressed basal cytokeratins and vimentin and were hormone receptor and ERBB2 negative. CLDN membrane expression was negative in the spindle cell component. The epithelioid areas were CLDN-1 positive. Nuclear/cytoplasmatic expression of CLDN-4 was observed in all components, except in one case in which it was strongly expressed in the non-spindle areas. All three cases were CD44+/CD24-. E-cadherin was focally expressed in epithelioid cells, only in the squamous areas. Activating EGFR mutations were not found. One patient developed local recurrences, metastases and died. FLMCa have the immunohistochemical profile of claudin-low breast tumors, with low expression of adhesion molecules, presence of TIC and EMT phenotype. No EGFR activating mutations were found.

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