Marco Mora

Follicular mucinosis: a clinicopathologic, histochemical, immunohistochemical and molecular study comparing the primary benign form and the mycosis fungoides-associated follicular mucinosis.

Objectives: To determine (i) whether primary (idiopathic) follicular mucinosis (PFM) and lymphoma‐associated follicular mucinosis (LAFM) are distinct or related entities and whether there are reliable criteria that allow the two forms to be distinguished, (ii) the histochemical properties and consequently the type of mucin that accumulates in the follicle in PFM and LAFM, and (iii) whether there is any difference between the staining properties of mucin in patients with PFM and LAFM.

Low Percentage of KRAS Mutations Revealed by Locked Nucleic Acid Polymerase Chain Reaction: Implications for Treatment of Metastatic Colorectal Cancer

Metastatic colorectal cancer (mCRC) is frequently characterized by the presence of mutations of the KRAS oncogene, which are generally associated with a poor response to treatment with anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies. With the methods currently used, a case is classified as KRAS-mutated when approximately 20% of the cells bear an activating KRAS mutation. These considerations raise the question of whether cells with a mutated KRAS can be found in mCRC cases classified as KRAS wild-type when more sensitive methods are used. In addition, the issue arises of whether these mCRC cases with low proportion of KRAS-mutated cells could account at least in part for the therapeutic failure of anti-EGFR therapies that occur in 40–60% of cases classified as KRAS wild type. In this study, we compared the classical assays with a very sensitive test, a locked nucleic acid (LNA) polymerase chain reaction (PCR), capable of detecting KRAS-mutated alleles at extremely low frequency (detection sensitivity limit 0.25% mutated DNA/wild-type DNA). By analyzing a cohort of 213 mCRC patients for KRAS mutations, we found a 20.6% discordance between the sequencing/TheraScreen methods and the LNA-PCR. Indeed, 44 mCRC patients initially considered KRAS wild type were reclassified as KRAS mutated by using the LNA-PCR test. These patients were more numerous among individuals displaying a clinical failure to anti-EGFR therapies. Failure to respond to these biological treatments occurred even in the absence of mutations in other EGFR pathway components such as BRAF.

Vulvar sebaceous hyperplasia associated with lymphedema of external genitalia

Sebaceous glands are present throughout the skin, except on palms and soles. Sebaceous glands are well developed until a few weeks after birth, probably because of maternal hormones. They almost disappear during early childhood, especially within the first few months. As a direct result of increased androgen output, sebaceous glands enlarge during puberty, and then remain stable until middle age, later tending to decrease slowly after menopause. Sebaceous gland hyperplasia (SGH) is a condition occurring most commonly on the forehead and cheeks, but occasionally affecting the areola, chest, or genital skin; sometimes it is clinically mistaken for basal cell carcinoma. Although termed hyperplasia, some authors concluded that this condition is a benign neoplasm, rather than hyperplasia, because these lesions do not undergo clinical involution. Other authors, instead, defined this lesion as a benign hamartomatous condition of epidermal appendage tumors with sebaceous differentiation, a definition that is now universally accepted. Sebaceous gland hyperplasia is reported in association with underlying mesenchymal proliferation, such as dermatofibroma, neurofibroma, melanocytic nevus, and acrochordon. Moreover, it has been described in association with benign lentiginosis and in patients treated with cyclosporine. Many factors are assumed to be involved in the pathogenesis of SGH, which, as of today, is not fully understood: prolonged ultraviolet radiation, previous surgery, and chronic inflammation have been claimed to be some pathogenic factors. Regarding chronic inflammation, after a critical review of the paper of Prayson et al., we were not able to find any strict correlation between SGH and surgery and chronic inflammation: SGH was not mentioned at all, while nodular hyperplasia of minor vestibular glands was associated with previous surgical manipulation or chronic inflammatory infiltrate. Clinically, SGH features one or, more commonly, multiple, elevated, small, soft, slightly umbilicated papules, often yellow in color. Differential diagnosis includes several tumors with sebaceous differentiation such as nevus sebaceous, sebaceous epithelioma, follicule sebaceous cystic hamartoma, sebaceous adenoma, and trichofolliculoma. Microscopically, SGH is generally characterized by a single enlarged sebaceous gland composed of numerous fully, or nearly full, mature sebaceous lobules, grouped around a centrally located and wide sebaceous duct. In focally sebaceous lobules, a peripheral row composed of 70

Downregulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal overall survival (OS) and to date no molecular markers are available to guide patient management. This study aimed to identify a prognostic miRNA signature in MPM patients who did not undergo tumor resection. Whole miRNA profiling using a microarray platform was performed using biopsies on 27 unresected MPM patients with distinct clinical outcome: 15 patients had short survival (OS<12 months) and 12 patients had long survival (OS>36 months). Three prognostic miRNAs (mir-99a, let-7c, and miR-125b) encoded at the same cluster (21q21) were selected for further validation and tested on publicly available miRNA sequencing data from 72 MPM patients with survival data. A risk model was built based on these 3 miRNAs that was validated by quantitative PCR in an independent set of 30 MPM patients. High-risk patients had shorter median OS (7.6 months) as compared with low-risk patients (median not reached). In the multivariate Cox model, a high-risk score was independently associated with shorter OS (HR=3.14; 95% CI, 1.18–8.34; P=0.022). Our study identified that the downregulation of the miR-99a/let-7/miR-125b miRNA cluster predicts poor outcome in unresected MPM.

Prognostic and Therapeutic Implications of MicroRNA in Malignant Pleural Mesothelioma

Malignant Pleural Mesothelioma (MPM) is an aggressive disease characterized by a dismal prognosis, mainly due to late diagnosis. To date, there are very few treatment options available and the refractoriness to the majority of therapeutic strategies, leading to consider MPM a relevant problem in public health. Therefore, the identification of novel prognostic markers and alternative therapeutic strategies remain a top priority. Several efforts have been made in this direction and to date a number of studies have investigated the role of microRNA as biomarkers in MPM, identifying the potential prognostic role of miR-29c* and miR-31. Very recently, the first microRNA signature able to discriminate poor or and good prognosis of MPM patients underwent surgery has been published. Very interestingly, several microRNA such as miR-1, miR-16, and miR-34b/c have been identified as potential therapeutic agents. Indeed, the forced expression of these microRNA resulted in anti-tumor effects both in vitro and in vivo. Besides, the introduction of microRNA mimic, some agents such as EphrinA1 and Onconase, seemed to exert anti-tumor effects through specific microRNA. Moreover, microRNA have also been reported to play a role in chemoresistance enhancing the sensitivity to specific drug such as pemetrexed. In this review the most relevant and updated data about the role of microRNA as prognostic markers and therapeutic agents in MPM will be presented, opening new avenues towards improved management of this aggressive disease.

Whole exome sequencing of independent lung adenocarcinoma, lung squamous cell carcinoma, and malignant peritoneal mesothelioma: A case report

AbstractThe presence of multiple primary tumors (MPT) in a single patient has been identified with an increasing frequency. A critical issue is to establish if the second tumor represents an independent primary cancer or a metastasis. Therefore, the assessment of MPT clonal origin might help understand the disease behavior and improve the management/prognosis of the patient.Herein, we report a 73-year-old male smoker who developed 2 primary lung cancers (adenocarcinoma and squamous cell carcinoma) and a malignant peritoneal mesothelioma (PM).Whole exome sequencing (WES) of the 3 tumors and of germline DNA was performed to determine the clonal origin and identify genetic cancer susceptibility.Both lung cancers were characterized by a high mutational rate with distinct mutational profiles and activation of tumor-specific pathways. Conversely, the PM harbored a relative low number of genetic variants and a novel mutation in the WT1 gene that might be involved in the carcinogenesis of nonasbestos-related mesothelioma. Finally, WES of the germinal DNA displayed several single nucleotide polymorphisms in DNA repair genes likely conferring higher cancer susceptibility.Overall, WES did not disclose any somatic genetic variant shared across the 3 tumors, suggesting their clonal independency; however, the carcinogenic effect of smoke combined with a deficiency in DNA repair genes and the patient advanced age might have been responsible for the MPT development. This case highlights the WES importance to define the clonal origin of MPT and susceptibility to cancer.