The micropapillary/hobnail variant of papillary thyroid carcinoma: A review of series described in the literature compared to a series from one southern Italy pathology institution.

Papillary thyroid carcinoma (PTC) has a good prognosis with a 10-yr survival greater than 90%. Recently, a micro-papillary pattern with hobnail appearance (MPHC) in PTC has been indicated as associated with poor prognosis, but this suggestion is based only on a few cases from geographical areas different from ours. Two-hundred ninety-nine consecutive PTC cases were collected between the years of 1992 and 2014 at our institution. The corresponding histologic sections (at least 6 for each case) were stained with hematoxylin and eosin and reviewed independently by two pathologists to reach a consensus on the identification and quantification of the MPHC. As done in other cohorts, parallel serial sections were stained with antisera for thyroglobulin, epithelial membrane antigen, thyroid-transcription-factor-1 and Ki 67. BRAF gene mutation at codon 600 and RET/PTC1 gene rearrangements were searched. A comparative statistical analysis was done between the present series and previously published series. Of the 295 PTC, 124 (42.5%) were follicular, 104 (35%) classic, 34 (11.5%) sclerosing, 15 (5%) tall cells, 10 (3.4%) Warthin-like, and 8 (2.7%) MPHC. Four MHPC cases (50%) harbored the BRAF V600E variant, while one was positive for RET/PTC1 rearrangement. Our rate of MPHC-PTC (2.7%) is 2X to 8X greater than those reported previously for cohorts from North America + North Italy, Korea and Mexico. MPHC prognosis appears to be better compared to other cohorts, probably due to not only to the lower rate of the vascular invasion, but also to the smaller size of the MPHC-PTC nodule.

Beyond the skin involvement in Darier disease: A complicated neuropsychiatric phenotype.

Psichiatric illness such as depression, schizophrenia and cognitive deficiency are frequently associated with the Darier Disease. Physicians should be aware of such association to allow prompt diagnosis and early interventions of potentially life-threatening psychiatric disorders.

NGS-Based Analysis of Atypical Deep Penetrating Nevi.

Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or epithelioid melanocytes with a distinctive wedge-shaped configuration showing activation of the WNT pathway, with unusual cyto-architectural features. It is unclear whether they show a distinct genomic profile associated with a diverse metastatic potential. We describe herein a cohort of 21 atypical DPNs analyzed by next-generation sequencing using the Ion AmpliSeq™ Comprehensive Cancer Panel. We found that ß-catenin exon 3 was mutated in 95% and MAP kinase pathway genes in 71% of the cases. Less frequent mutations were observed in HRAS (19%) and MAP2K1 (24%). Isocitrate dehydrogenases 1 (IDH1) mutations, including R132C, V178I, and S278L, were identified in 38% of cases and co-existed with BRAF/HRAS mutations. The only case with progressive nodal disease carried alterations in the ß-catenin pathway and mutations in IDH1 and NRAS (codon 61). By a comprehensive mutation analysis, we found low genetic heterogeneity and a lack of significant associations between specific gene mutations and histopathological features, despite atypical features. Whether the acquisition of an NRAS or IDH1 mutation in an atypical DPN may represent a molecular evolution implying a pathway to melanoma progression should be confirmed in a larger series.

Nodular fasciitis of the anterior chest wall mimicking myxofibrosarcoma: A case report and literature review.

Nodular fasciitis is a benign tumor of soft tissues originating from the proliferation of fibroblasts and myofibroblasts, generally developing between the subcutaneous tissue and the underlying muscular layer. Nodular fasciitis predominantly localizes in the upper extremities, trunk, head and neck. Biomolecular and immunohistochemical analyses result essential to demonstrate the benign origin of the process, also confirmed by very low recurrence rate after complete excision, which represents the gold standard for treatment. We report the case of a 36 years-old man who developed a nodular protuberance clinically evident in the upper-left side of the thorax. We further, highlight the main characteristics of this rare neoplasm trough a thorough review of the literature.

HER2 Heterogeneity in Personalized Therapy of Gastro-Oesophageal Malignancies: An Overview by Different Methodologies.

Human epidermal growth factor receptor-2 (HER2)-expression gastro-oesophageal adenocarcinomas (GEA) gained interest as an important target for therapy with trastuzumab. In the current review, we focused the current knowledge on HER2 status in dysplastic and neoplastic gastric conditions, analyzing the methodological procedures to identify HER2 expression/amplification, as well as the proposed scoring recommendations. One of the most relevant questions to evaluate the useful impact of HER2 status on therapeutic choice in GEAs is represented by the significant heterogeneity of HER2 protein and gene expression that may affect the targeted treatment selection. Future development of biotechnology will continue to evolve in order to offer more powerful detection systems for the assessment of HER2 status. Finally, liquid biopsy as well as mutation/amplification of several additional genes may furnish an early detection of secondary HER2 resistance mechanisms in GEAs with a better monitoring of the treatment response.

Pilomatrixoma of the right thigh: Sonographic-pathologic correlation in a young man.

Pilomatrixoma, also known as calcifying epithelioma of Malherbe, is a histological type of benign subcutaneous tumor arising from the cutaneous adnexa. We present our experience and the characteristic findings of a pilomatrixoma of the right thigh in a young healthy man. The lesion had grown slowly in size over the past year and this was the reason for referral to the Department of Plastic Surgery. Ultrasound imaging was performed and, through the use of B-mode, color-Doppler, and elastosonography, the lesion was depicted. The patient was therefore scheduled for surgery. Pilomatrixomas at times can pose a diagnostic challenge, especially when the location is unusual. Ultrasound and its tools, that is, color-Doppler and elastography, can assist the clinician arising the suspicion of pilomatrixoma.

BRAF Status in Papillary Microcarcinomas of the Thyroid Gland: a Brief Review.

Papillary thyroid microcarcinoma (PTMC) is defined by the World Health Organization as papillary cancer measuring 10 mm or less in diameter. Generally, PTMC shows an indolent clinical behavior with a good prognosis, although a minority of PTMC is characterized by an aggressive course. However, efforts to identify this aggressive subset of PTMC after surgery remain inconclusive. Several oncogenic pathways have been identified in thyroid cancer and have been applied translationally to improve prognosis and clinical management. In particular, the BRAFV600E mutation was found more frequently in large, aggressive, recurrent and advanced tumors. We aimed at reviewing studies on BRAFV600E mutation as a prognostic factor in PTMC.

Immunohistochemical Expression of Autophagy-Related Proteins in Advanced Tubular Gastric Adenocarcinomas and Its Implications.

In neoplastic conditions, autophagy may act as a tumor suppressor avoiding the accumulation of damaged proteins and organelles or as a mechanism of cell survival promoting the tumor growth. Although ultrastructural analysis has been considered the traditional method to identify autophagy, some proteins such as microtubule-associated protein 1 light chain 3 (LC3A/B), Beclin-1 and activating molecule in Beclin-1-regulated autophagy protein-1 (AMBRA-1) may be considered as markers of autophagy-assisted cancerogenesis. Herein, we analyzed a cohort of advanced tubular gastric adenocarcinomas by the abovementioned immunohistochemical antisera; through immunohistochemistry, autophagy (A-IHC) is diagnosed when at least two out of the three proteins are positive in the samples. Immunostaining for LC3A/B, Beclin-1, and AMBRA-1 was exclusively found in neoplastic elements, but not in surrounding stromal cells. In detail, LC3A/B and Beclin 1 were expressed both in the cytoplasm and in the nucleus of the cancer cells, while AMBRA-1 was preferentially localized in the nucleus, mainly in high grade cases. LC3A/B, Beclin 1, and AMBRA-1 expression were positive in 18 (56.2%), 17 (53.1%), and 12 (37.5%) cases, respectively. The sensibility and specificity of LC3A/B and Beclin-1 ranged from 81.25% to 93.75%, with high efficiency (90.63%) for Beclin-1. Moreover, the ultrastructural autophagic index (AI) was also available in all cases. All high-grade cases documented a Ki-67 labelling index (LI) ≥ 30%, even if three low-grade cases revealed a high Ki-67 value; p53 positivity was encountered in 21/32 (65.62%) of cases, independently of the tumor grade. A statistically significant correlation among A-IHC and clinicopathological parameters such as grade, stage, clinical course, Ki-67 LI and AI was revealed. Univariate analysis documented a significant p-value for the same autophagic variables. Additionally, multivariate survival analysis identified the grade, AI and A-IHC as independent significant variables. Finally, the overall survival curves of all cases of gastric tubular adenocarcinoma were greatly dependent on A-IHC. Therefore, we suggest that autophagic-related proteins might be considered promising predictive prognostic factors of advanced gastric cancer. Further investigations may be required to determine whether new targeted therapies should be addressed to autophagy-related proteins.

A Large Extraskeletal Chondroma: An Unusual Location in the Lower Extremity, Huge Extraskeletal Chondroma: An Unusual Localization in the Leg.

INTRODUCTION: Extraskeletal chondroma (EC) is a rare benign neoplasm predominantly composed of mature hyaline cartilage; it develops in the soft tissues without any connection to bone cortex, intra-articular synovium, or periosteum. To date, only few cases have been reported in the leg, mainly in the knee, thigh, and popliteal region. CASE REPORT: We describe herein the case of a 42-year-old woman with a 4-year history of a slow-growing, painful swelling on the posteromedial region of her left leg. Magnetic resonance imaging showed the presence of a huge mass occupying soleus muscle, compressing, and displacing anteriorly gastrocnemius muscle. After an incisional diagnostic biopsy, a complete surgical excision of the tumor was performed. On the basis of clinicoradiological and morphological findings, a diagnosis of EC was made. CONCLUSION: This report represents a clinicoradiological and morphological analysis about a very rare huge EC arising in the posteromedial region of the leg.

Interleukin-33 Involvement in Nonsmall Cell Lung Carcinomas: An Update.

Lung carcinogenesis is a multistep process involving genetic mutations and epigenetic changes, with the acquisition of a malignant phenotype characterized by apoptosis resistance, unregulated proliferation and differentiation, invasion, and metastatic abilities. However, neoplastic development and progression seem to be aided by non-neoplastic cells; the molecules they produced can either promote the immune response or, alternatively, support tumor pathogenesis. Consequently, the relative contribution of tumor-associated inflammatory pathways to cancer development has become crucial information. Interleukin-33 (IL-33) is an IL-1-like alarmin, and it is a ligand for the suppressor of tumorigenicity 2 (ST2) receptor. IL-33 functions as a dual role cytokine with the ability to induce T-helper-type 2 (Th2) immune cells and translocate into the nucleus, suppressing gene transcription. Although its function in immunity- and immune-related disorders is well known, its role in tumorigenesis is still debated. The IL-33/ST2 axis is emerging as a powerful modulator of the tumor microenvironment (TME) by recruiting immune cells, able to modify the TME, supporting malignant proliferation or improving antitumor immunity. In the present review, we discuss IL-33's potential role in lung carcinogenesis and its possible application as a therapeutic target.

Immunoexpression of lactoferrin in triple-negative breast cancer patients: A proposal to select a less aggressive subgroup.

Triple-negative breast cancer (TNBC) indicates a subset of breast carcinomas that does not express estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). According to the literature, TNBCs are aggressive tumors, characterized by a high incidence of recurrence and a high risk of disease progression. Lactoferrin (LF) is a single-chain, iron-binding glycoprotein of ~700 amino acids, which is involved in a wide range of biological activities, including iron-trafficking and carcinogenesis. The present study aimed to assess LF expression in human TNBC samples and the possible correlation with clinico-pathological parameters associated with biological aggressiveness. LF immunohistochemical expression was investigated in formalin-fixed, paraffin-embedded samples of human TNBC. Cases were analyzed according to an intensity distribution (ID) score, and only those showing an ID score of >2 were considered as positive for LF. LF immunostaining was encountered in 26.15% cases. A significant correlation was found between LF expression and a low Ki-67 labeling index (P=0.040), the absence of recurrence (P=0.010) and alive status (P=0.020). LF may assist in identifying a subset of TNBC with less aggressive biological behavior. The meaning of LF expression in TNBC remains unclear and is controversial. The present findings indicated that LF expression is correlated with a low growth fraction in these tumors. Thus, it is possible that the inhibition of the LF axis may be a valid therapeutic target for TNBC, and this should be confirmed by future studies.

HOXB13 as an immunohistochemical marker of prostatic origin in metastatic tumors.

HOBX13 is a transcription factor expressed in the normal prostatic glands and overexpressed in prostate cancer. Recent studies suggested that HOXB13 represents a prostate-specific marker in the differential diagnosis between prostatic and urothelial carcinoma. The aim of this study was to analyze and compare the diagnostic value of HOXB13 and prostate-specific antigen (PSA) immunoexpression for the detection of prostatic origin in metastatic tumours. PSA and HOXB13 immunohistochemical expression was assessed in 50 metastatic tumors, including 15 metastases from prostatic adenocarcinoma, 11 from lung adenocarcinoma, 12 from urinary bladder urothelial carcinoma, 11 from colorectal carcinoma, and in 1 from hepatocellular carcinoma. Strong staining for HOXB13 was observed in >75% of neoplastic cells in 15/15 (100%) metastases from prostate cancer. Weak staining in <25% of cells was found in 2/12 (17%) metastases from urothelial carcinoma. PSA immunostaining was detected only in 8 (53%) cases of prostatic origin. The sensitivity and specificity for metastatic prostate cancer were 100% and 94% for HOXB13 and 53% and 100% for PSA. Due to its high sensitivity and specificity, HOXB13 may be included in the pool of prostate-specific markers in metastases showing absent or weak staining for PSA before excluding prostatic derivation.

Androgen Receptor (AR), E-Cadherin, and Ki-67 as Emerging Targets and Novel Prognostic Markers in Triple-Negative Breast Cancer (TNBC) Patients.

BACKGROUND: TNBC is an aggressive subset of breast cancer (BC) without specific target therapy. METHODS: This observational, retrospective study included 45 cases of TNBC. The aim of this study was to evaluate the expression of the AR, E-cadherin and Ki-67 in relation to histological type, time to relapse and overall survival (OS). Immunohistochemistry (IHC) was carried out on formalin-fixed paraffin-embedded tumor samples obtained from patients defined TNBC. RESULTS: The AR was positive (IHC >10%) in 26.6%. E-cadherin (CDH1) expression was considered positive if the score was ≥ 2. This expression was negative in 53.3% cases. The Ki-67 index was ≥ 20% in 37.7%. Univariate analyses showed that AR, CDH1 and Ki-67 are significantly associated with OS. Multivariate analysis showed that AR and Ki-67 expression are independent variables associated with OS. The statistical analysis showed that patients with AR negative and Ki-67 positive expression have a significant correlation with poor outcome. CONCLUSIONS: Our data suggest that the combination of AR and E-cadherin expression as well as Ki-67 status might be useful prognostic markers in TNBC. Hence, these molecular determinants could play an interesting role to classify subgroups of TNBC.