Publications by authors named "Giovanni Tuccari"

102 Publications

BRAFV600E mutation is associated with increased prevalence of contralateral lymph-node metastases in low and low-to-intermediate risk papillary thyroid cancer.

Nucl Med Commun 2021 Feb 19. Epub 2021 Feb 19.

Unit of Nuclear Medicine, Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Messina Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Unit of Pathological Anatomy, University of Messina Unit of Statistical and Mathematical Sciences, Department of Economics, University of Messina Department of Clinical an Experimental Medicine, University of Messina Accademia Peloritana dei Pericolanti at the University of Messina, Messina, Italy.

Objective: Papillary thyroid cancer (PTC) is the most common endocrine malignancy. Despite good prognosis being generally associated with PTC, persistent/recurrent disease can be observed in a not negligible number of patients. Accurate postoperative management can lead to a significant improvement of risk stratification/staging of PTC patients identifying those at higher risk of a more aggressive clinical course. Molecular tests were introduced at the beginning of the 2000s to improve PTC risk stratification.

Methods: We reviewed the records of 354/1185 patients affected by low or low-to-intermediate risk unilateral-PTC. In these patients, BRAFV600E mutation was looked for and 131-radioiodine therapy was performed 3 months after thyroid surgery. A radioiodine post-therapeutic imaging was obtained in all patients.

Results: BRAFV600E mutation was found in 170/354 PTC patients (female = 126). Forty-two out of 170 BRAFV600E mutation +ve patients (female = 27) had ipsilateral (n = 24) or contralateral (n = 18) loco-regional metastases at post-therapeutic imaging. Significant differences in terms of 2015 American Thyroid Association risk stratification, Hashimoto thyroiditis prevalence, tumor size, multifocality, disease staging and aggressive variant were observed between BRAFV600E mutation +ve and BRAFV600E mutation -ve patients (P ≤ 0.001;P = 0.001; P ≤ 0.001; P = 0.026; P ≤ 0.001; P ≤ 0.001). Interestingly, the prevalence of contralateral lymph-node metastases was significantly higher in BRAFV600E mutation +ve than BRAFV600E mutation -ve patients (18/42 vs. 2/22, respectively; P = 0.013).

Conclusion: This study suggests that BRAFV600E mutation represents a significant risk factor for developing contralateral lymph-node metastases and confirms that BRAFV600E mutation is associated with more aggressive PTC features and a higher prevalence of metastatic disease also in low or low-to-intermediate-risk PTC patients.
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http://dx.doi.org/10.1097/MNM.0000000000001386DOI Listing
February 2021

The COVID-19 pandemic: Pathologists support the clinical infectious diseases team.

Int J Infect Dis 2020 Dec 28;104:479-481. Epub 2020 Dec 28.

Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Pathology, University of Messina, Messina, Italy. Electronic address:

The pathologist is involved in many diagnostic steps together with the clinical infectious disease team in the management of COVID-19-affected patients. In particular, cytological and histopathological procedures as well as autoptic findings may represent useful tools to better understand the pathobiology of the disease as well as to correctly define causes of death. Moreover, pathologists have been forced to reconsider the usual laboratory workflow and introduce adequate guidelines against virus diffusion in the COVID-19 pandemic, requiring high biosafety levels.
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http://dx.doi.org/10.1016/j.ijid.2020.12.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836675PMC
December 2020

The Macro-Autophagy-Related Protein Beclin-1 Immunohistochemical Expression Correlates With Tumor Cell Type and Clinical Behavior of Uveal Melanoma.

Front Oncol 2020 20;10:589849. Epub 2020 Nov 20.

Section of Anatomic Pathology, Department Gian Filippo Ingrassia, University of Catania, Catania, Italy.

Uveal melanoma, in spite of its rarity, represents the most common primitive intraocular malignant neoplasm of the adults; it affects choroid, ciliary bodied and iris and remains clinically silent for a long time, being accidentally discovered by routine ophthalmic exams. Prognosis of uveal melanoma is poor and frequently characterized by liver metastases, within 10-15 years from diagnosis. Autophagy is a multi-step catabolic process by which cells remove damaged organelles and proteins and recycle nutrients. It has been hypothesized that in early stages of tumorigenesis autophagy has a tumor suppressor role while, in more advanced stages, it may represent a survival mechanism of neoplastic cells in response to stress. Several proteins related to autophagy cascade have been investigated in numerous subtypes of human cancer, with overall controversal results. In this paper we studied the immunohistochemical expression of 3 autophagy related proteins (Beclin-1, p62 and ATG7) in a cohort of 85 primary uveal melanoma treated by primary enucleation (39 with metastasis and 46 non metastatic) and correlated their expression with clinico-pathological parameters and blood vascular microvessel density, in order to investigate the potential prognostic role of autophagy in this rare neoplasm. We found that high immunohistochemical levels of Beclin-1 correlated with a lower risk of metastasis and higher disease-free survival times, indicating a positive prognostic role for Beclin-1 in uveal melanoma. No statistically significative differences regarding the expression of ATG7 and p62 between metastatic and non metastatic patients was detected.
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http://dx.doi.org/10.3389/fonc.2020.589849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714947PMC
November 2020

Global impact of the COVID-19 pandemic on cytopathology practice: Results from an international survey of laboratories in 23 countries.

Cancer Cytopathol 2020 Dec 27;128(12):885-894. Epub 2020 Oct 27.

Department of Public Health, University of Naples Federico II, Naples, Italy.

Background: To the authors' knowledge, the impact of the coronavirus disease 2019 (COVID-19) pandemic on cytopathology practices worldwide has not been investigated formally. In the current study, data from 41 respondents from 23 countries were reported.

Methods: Data regarding the activity of each cytopathology laboratory during 4 weeks of COVID-19 lockdown were collected and compared with those obtained during the corresponding period in 2019. The overall number and percentage of exfoliative and fine-needle aspiration cytology samples from each anatomic site were recorded. Differences in the malignancy and suspicious rates between the 2 periods were analyzed using a meta-analytical approach.

Results: Overall, the sample volume was lower compared with 2019 (104,319 samples vs 190,225 samples), with an average volume reduction of 45.3% (range, 0.1%-98.0%). The percentage of samples from the cervicovaginal tract, thyroid, and anorectal region was significantly reduced (P < .05). Conversely, the percentage of samples from the urinary tract, serous cavities, breast, lymph nodes, respiratory tract, salivary glands, central nervous system, gastrointestinal tract, pancreas, liver, and biliary tract increased (P < .05). An overall increase of 5.56% (95% CI, 3.77%-7.35%) in the malignancy rate in nongynecological samples during the COVID-19 pandemic was observed. When the suspicious category was included, the overall increase was 6.95% (95% CI, 4.63%-9.27%).

Conclusions: The COVID-19 pandemic resulted in a drastic reduction in the total number of cytology specimens regardless of anatomic site or specimen type. The rate of malignancy increased, reflecting the prioritization of patients with cancer who were considered to be at high risk. Prospective monitoring of the effect of delays in access to health services during the lockdown period is warranted.
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http://dx.doi.org/10.1002/cncy.22373DOI Listing
December 2020

Rates of lymphocytic thyroiditis and ultrasound features of citologically-interrogated thyroid nodules based on the area of residence in a Sicily province.

Endocrine 2020 Oct 15. Epub 2020 Oct 15.

Department of Clinical and Experimental Medicine, University of Messina, Viale Gazzi, 98125, Messina, Italy.

Purpose: To verify the prevalence of autoimmune thyroiditis (AIT) and the ultrasound characteristics (composition and volume) of thyroid nodules with respect to the area of residence in the province of Messina, some areas having environmental issues.

Methods: Fine-needle aspiration-interrogated nodules (n = 902) of 809 patients were evaluated upon stratification into 8 areas of residence.

Results: Overall, women were younger than men (55.3 ± 14.0 vs. 58.6 ± 12.6 years, P = 0.0083). Patients residing in three areas (one hosting two garbage dumps, one hosting a petrochemical complex and a thermoelectrical power plant, and one hosting several ceramic factories [CFA]) were younger than those residing in the city of Messina (MEA) (52.9 ± 13.4 vs. 57.7 ± 13.6 years, P < 0.0001). Also, patients residing in those three areas had a greater rate of AIT, diagnosed either ultrasonographically/serologically (22.2% of patients) or cytologically (26.3% of nodules), compared with MEA (11.7% of patients, P = 0.0007 or 20.2% of nodules, P = 0.0815). Rates of AIT ranged 12.5-28.6% in the remaining four areas. Overall, nodules in women were smaller than in men (3.6 ± 5.7 vs. 6.1 ± 9.4 ml, P = 0.0006). Compared with the other seven areas, patients living in CFA had the largest nodules (6.8 ± 6.8 ml, P = 0.0040-0.0291), with the nodule volume being inversely correlated to patient's age (r = -0.4955, P = 0.0431).

Conclusion: Rates of AIT and associated ultrasound features of thyroid nodules vary in different areas of our province. Further studies correlating these rates and features with exposure to specific toxicants are warranted.
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http://dx.doi.org/10.1007/s12020-020-02521-zDOI Listing
October 2020

MacroH2A1 Immunoexpression in Breast Cancer.

Front Oncol 2020 21;10:1519. Epub 2020 Aug 21.

Human Anatomy and Histology, Department of Biomedical and Biotechnology Sciences, University of Catania, Catania, Italy.

MacroH2A1 has two splice isoforms, macroH2A1.1 and macroH2A1.2, that have been studied in several form of cancer. In the literature there are not many scientific papers dealing with the role of macroH2A1 in breast cancer. Breast cancer is the most frequent form of malignancy in females. It tend to metastasize to the bone in ~70% of patients. Despite treatment, new bone metastases will still occur in 30-50% of cases with advanced disease. Overall 5-year survival after the diagnosis of bone metastasis is ~20%. Osteoclasts and osteoblasts of the bone microenvironment are engaged by soluble factors released by neoplastic cells, resulting in bone matrix breakdown. This malfunction enhances the proliferation of the cancer cells, creating a vicious cycle. We investigated immunohistochemical expression of macroH2A1 in primitive breast cancer, focusing on the comparison of metastatic and non-metastatic cases. Furthermore, the immunohistochemical expression of macroH2A1 has been evaluated both in all cases of nodal metastases and in distant metastases. Our data demonstrated that macroH2A1 expression was higher expressed in metastatic breast cancer (77%) vs. non-metastatic breast cancer (32%). Also in analyzed metastases cases, a high macroH2A1 expression was detected: 85 and 80% in nodal and distant metastases cases, respectively. These results supported the fact that macroH2A1 is more highly expressed in breast cancer with worst prognosis.
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http://dx.doi.org/10.3389/fonc.2020.01519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471871PMC
August 2020

Re: Assessment of preoperative pancreatic biopsy, cytological/histological review of cell-block-specimens obtained by endoscopic ultrasound-guided fine-needle aspiration: Laboratory based study.

Diagn Cytopathol 2020 Nov 27;48(11):1153-1154. Epub 2020 Jul 27.

Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Pathology, University of Messina, Messina, Italy.

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http://dx.doi.org/10.1002/dc.24555DOI Listing
November 2020

Hurthle cell carcinoma in childhood: A retrospective analysis of five cases and review of pediatric literature.

Pediatr Blood Cancer 2020 09 2;67(9):e28300. Epub 2020 Jul 2.

Division of Pediatrics, Department of Human Pathology in Adulthood and Childhood, University of Messina, Messina, Italy.

Background: the available studies on Hurthle cell carcinoma (HCC) in pediatric age are scarce and based on isolated case reports. Aims of the present study were to review the available pediatric literature on HCC (2000-2019), to describe the cohort of children with this cancer histotype, and to estimate its relative prevalence in pediatric age.

Procedure: We retrospectively reconstructed an HCC course in five patients < 19 years who were identified in our departments during the period 2000-2019, and we reviewed the available pediatric studies on this differentiated thyroid cancer (DTC) variant.

Results: HCC occurred with a relative prevalence of 5.8% at a median chronological age of 12.5 years. None of HCC patients exhibited, at diagnosis, thyroid dysfunction, extensive lateral neck disease, or distant metastases, and all showed a persistent remission over time. Three patients showed, at diagnosis, antecedents of other diseases (Hashimoto's thyroiditis, neurofibromatosis type 1, and osteosarcoma).

Conclusions: (1) In childhood, the relative prevalence of HCC among different thyroid cancer histotypes is 5.8%, that is close to the one previously reported both in the general population and in other less numerous children's cohorts; (2) HCC may develop even early, at the age of 7; (3) in childhood, HCC does not seem to have a more aggressive behavior when compared with other DTC histotypes; (4) antecedents of other diseases are not infrequent in the history of children with HCC.
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http://dx.doi.org/10.1002/pbc.28300DOI Listing
September 2020

Unusual case of pleural effusion in a young woman.

Cytopathology 2020 11 27;31(6):613-615. Epub 2020 Jul 27.

Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Messina, Italy.

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http://dx.doi.org/10.1111/cyt.12881DOI Listing
November 2020

Role of the mucins in pathogenesis of COPD: implications for therapy.

Expert Rev Respir Med 2020 05 19;14(5):465-483. Epub 2020 Mar 19.

Pneumologia, Dipartimento di Scienze Biomediche, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università di Messina, Messina, Italy.

: Evidence accumulated in the last decade has started to reveal the enormous complexity in the expression, interactions and functions of the large number of different mucins present in the different compartments of the human lower airways. This occurs both in normal subjects and in COPD patients in different clinical phases and stages of severity.: We review the known physiological mechanisms that regulate mucin production in human lower airways of normal subjects, the changes in mucin synthesis/secretion in COPD patients and the clinical efficacy of drugs that modulate mucin synthesis/secretion.: It is evident that the old simplistic concept that mucus hypersecretion in COPD patients is associated with negative clinical outcomes is not valid and that the therapeutic potential of 'mucolytic drugs' is under-appreciated due to the complexity of the associated molecular network(s). Likewise, our current knowledge of the effects of the drugs already available on the market that target mucin synthesis/secretion/structure in the lower airways is extremely limited and often indirect and more well-controlled clinical trials are needed in this area.
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http://dx.doi.org/10.1080/17476348.2020.1739525DOI Listing
May 2020

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

J Pers Med 2020 Feb 21;10(1). Epub 2020 Feb 21.

Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Pathology, University of Messina, 98125 Messina, Italy.

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.
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http://dx.doi.org/10.3390/jpm10010010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151629PMC
February 2020

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

Curr Mol Med 2019 ;19(9):665-672

Department of Human Pathology "Gaetano Barresi" - Section of Pathological Anatomy, A.O.U. Polyclinic G.Martino, 98125 Messina, Italy.

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.
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http://dx.doi.org/10.2174/1566524019666190717161359DOI Listing
August 2020

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

Biomolecules 2019 05 25;9(5). Epub 2019 May 25.

School and Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98123 Messina, Italy.

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.
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http://dx.doi.org/10.3390/biom9050203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572046PMC
May 2019

Molecular links between COPD and lung cancer: new targets for drug discovery?

Expert Opin Ther Targets 2019 06 11;23(6):539-553. Epub 2019 May 11.

b Airway Disease Section, National Heart and Lung Institute , Imperial College , London , UK.

Introduction: COPD and lung cancer are leading causes of morbidity and mortality worldwide, and they share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by their incidence in only a fraction of smokers. This reflects the ability of cigarette smoke to induce an inflammatory response in the airways of susceptible smokers. Moreover, COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage and repression of the DNA repair mechanisms, chronic exposure to pro-inflammatory cytokines, repression of innate immunity and increased cellular proliferation. Areas covered: We have focused our review on the potential pathogenic molecular links between tobacco smoking-related COPD and lung cancer and the potential molecular targets for new drug development by understanding the common signaling pathways involved in COPD and lung cancer. Expert commentary: Research in this field is mostly limited to animal models or small clinical trials. Large clinical trials are needed but mostly combined models of COPD and lung cancer are necessary to investigate the processes caused by chronic inflammation, including genetic and epigenetic alteration, and the expression of inflammatory mediators that link COPD and lung cancer, to identify new molecular therapeutic targets.
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http://dx.doi.org/10.1080/14728222.2019.1615884DOI Listing
June 2019

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Cancers (Basel) 2019 Mar 19;11(3). Epub 2019 Mar 19.

Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Pathology, University of Messina, 98123 Messina, Italy.

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 -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.
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http://dx.doi.org/10.3390/cancers11030389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468613PMC
March 2019

Correction: The prognostic significance of combined androgen receptor, E-Cadherin, Ki67 and CK5/6 expression in patients with triple negative breast cancer.

Oncotarget 2019 01 25;10(8):917. Epub 2019 Jan 25.

Medical Oncology Unit A.O. Papardo & Department of Human Pathology University of Messina, Messina, Italy.

[This corrects the article DOI: 10.18632/oncotarget.20293.].
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http://dx.doi.org/10.18632/oncotarget.26650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368234PMC
January 2019

Hepatomegaly and type 1 diabetes: a clinical case of Mauriac's syndrome.

Ital J Pediatr 2019 Jan 7;45(1). Epub 2019 Jan 7.

Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Via Consolare Valeria 1, 98125, Messina, Italy.

Background: Hepatic glycogenosis is characterized by excessive glycogen accumulation in hepatocytes and represents a complication of poor controlled type 1 diabetes. It can be caused by excessive insulin doses or recurrent ketoacidosis episodes. Mauriac's syndrome is a rare disease, which includes short stature, growth maturation delay, dyslipidemia, moon facies, protuberant abdomen, hepatomegaly with transaminase elevation. It has become even less common after the emergence of advances on diabetes treatment, but still exists. Recent reports described glycogenosis without the full spectrum of Mauriac's syndrome in both adults and children with brittle diabetes. Clinical, laboratory and histological abnormalities are reversible with appropriate glycemic control.

Case Presentation: We hereby report a case of 11-year-old male who presented with hepatic glycogenosis mimicking Mauriac's syndrome. The patient was admitted at our Pediatric Diabetes Clinic for marked hepatomegaly, short stature and for the poor metabolic control. Blood investigations and liver tests excluded most of major causes of hepatopathy. A liver biopsy allowed us to make diagnosis of hepatic glycogenosis. To control hyperglycaemia, initially we titrated daily insulin dosage, and then intravenous insulin treatment was practiced with the consequent normalization of liver enzymes.

Conclusion: Mauriac's syndrome should be considered in subjects with brittle type 1 diabetes and hepatomegaly.
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http://dx.doi.org/10.1186/s13052-018-0598-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322227PMC
January 2019

Intratumoral HER2 heterogeneity in early gastric carcinomas: potential bias in therapeutic management.

Virchows Arch 2019 03 30;474(3):401-402. Epub 2018 Nov 30.

Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Unit of Pathological Anatomy, University of Messina, A.O.U. Polyclinic G.Martino, 98125, Messina, Italy.

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http://dx.doi.org/10.1007/s00428-018-2502-2DOI Listing
March 2019

The increasing prevalence of chronic lymphocytic thyroiditis in papillary microcarcinoma.

Rev Endocr Metab Disord 2018 12;19(4):301-309

Department of Clinical and Experimental Medicine, University of Messina, Viale Gazzi, 98125, Messina, Italy.

Although the incidence of some malignancy has decreased over the recent years, this is not the case of papillary thyroid microcarcinoma (PTMC), whose incidence has increased worldwide. Most PTMC are found incidentally after histological examination of specimens from surgery for benign thyroid disease. Hashimoto's thyroiditis, whose incidence has also increased, coexists in about one in three PTMC patients. Three different mechanisms have been proposed to clarify the association between chronic lymphocytic thyroiditis and PTMC, namely tumor development/growth by: (i) TSH stimulation, (ii) expression of certain proto-oncogenes, (iii) chemokines and other molecules produced by the lymphocytic infiltrate. Whether Hashimoto's thyroiditis protects against lymph node metastasis is debated. Overall, autommune thyroiditis seems to contribute to the favorable prognosis of PTMC. Major limitations of the studies so far performed include: (i) retrospective design, (ii) limited statistical power, (iii) high risk of selection bias, (iv) and predominant Asian ethnicity of patients. Full genetic profiling of both diseases and identification of environmental factors capable to trigger them, as well as well-powered prospective studies on different ethnical groups, may help understand their causal association and why their frequencies are continuing raising.
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http://dx.doi.org/10.1007/s11154-018-9474-zDOI Listing
December 2018

Case report on pathogenetic link between gluten and IgA nephropathy.

BMC Gastroenterol 2018 May 16;18(1):64. Epub 2018 May 16.

Department of Clinical and Experimental Medicine, Unit of Nephrology and Dialysis, University of Messina, Messina, Italy.

Background: A relationship between IgA nephropathy (IgAN) and celiac disease (CD) has been reported. We show the pathogenetic link for the first time.

Case Presentation: A 39-year-old man with cystic fibrosis (CF) and CF-related diabetes started to present gross hematuria, back pain and headache. At admission, laboratory analysis showed increase in serum creatinine of 1.5 mg/dl, together with hematuria and mild proteinuria (1 g/24 h). He underwent a renal biopsy to investigate the cause of hematuria and renal failure. Biopsy was consistent with IgAN. In view of patient reported dyspepsia, an upper gastrointestinal endoscopy with duodenal biopsies was undertaken and was normal. We looked for mucosal deposits of tTG-2 in the duodenum and the renal mesangium. tTG-2 deposits were found both in the duodenum and in renal biopsies, where they topographically replicated mesangial IgA deposits. After one year on a continued gluten containing diet, the patient developed a Marsh 2 type duodenal pathology.

Conclusions: Our findings suggest a connection between CD and IgAN in terms of an immune-mediated gluten-induced pathogenesis even in the absence of villous atrophy and serum celiac autoantibodies.
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http://dx.doi.org/10.1186/s12876-018-0792-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956757PMC
May 2018

Human Epidermal Growth Factor Receptor 2 Status in Gastric Carcinomas with Distinctive Prevalent Cribriform Component.

Dis Markers 2018 18;2018:1505428. Epub 2018 Feb 18.

Section of Anatomic Pathology, Azienda Ospedaliera Universitaria "Gaetano Martino" and Department of Human Pathology "Gaetano Barresi", University of Messina, 98123 Messina, Italy.

Objectives: A cribriform architectural pattern has been reported in 9% of one unselected consecutively collected series of gastric carcinomas (GC) with unfavourable prognostic outcome. Taking into consideration the biological relevance of the human epidermal growth factor receptor 2 (HER2) status, we have analyzed a cohort of GC with a cribriform component more than 40% (CGC) to evaluate the HER2 amplification rate as a potential target for therapy with trastuzumab.

Results: HER2 overexpression was encountered in 21 of 100 (21%) GC; a progressive increase in HER2 amplification was appreciated moving from non-CGC (20.6%) towards CGC cases (21.6%), although this difference does not reach a statistical significance. Nevertheless, either in univariate or in multivariate analyses, stage and HER2 status showed a significant value (<0.001) in CGC patients.

Conclusions: Our data confirmed a worse prognosis in all CGC patients with HER2 amplification, resulting in a shorter survival time. We invite all pathologists in their daily practice to specify the occurrence of cribriform neoplastic component in GC, either in surgical or in bioptical samples, taking into practical assessment the high HER2 overexpression rate in order to correctly treat these patients with worse behavior.
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http://dx.doi.org/10.1155/2018/1505428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835249PMC
September 2018

Immunohistochemical Expression of Aquaporin-1 in Fluoro-Edenite-Induced Malignant Mesothelioma: A Preliminary Report.

Int J Mol Sci 2018 Feb 28;19(3). Epub 2018 Feb 28.

Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy.

Background: The immunohistochemical expression of aquaporin-1 (AQP1) in asbestos-related malignant pleural mesothelioma (MPM) is emerging as a useful prognostic indicator of improved survival. A significantly increased incidence of MPM in a small town in southern Italy was ascribed to exposure to fluoro-edenite (FE), a naturally occurring asbestos fiber. We investigated the immunohistochemical expression of AQP1 in patients affected by FE-related MPM; taking into consideration its suggested independent prognostic role, its possible correlation with clinicopathological parameters and patient outcome was also evaluated.

Methods: Ten patients were selected for this study, as neoplastic tissue blocks, clinical and follow-up data were available. The immunohistochemical overexpression of AQP1 was defined as ≥50% of tumor cells showing membranous staining.

Results: Six cases showed AQP1 expression in ≥50% of tumor cells; in this group, a significant association of AQP1 overexpression with an increased median overall survival (OS) of 26.3 months was observed. By contrast, four patients exhibited an AQP1 score of <50% of stained cells, with a shorter median OS of 8.9 months.

Conclusions: The present study represents further confirmation of the hypothesized prognostic role of AQP1, which seems a reliable prognostic indicator.
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http://dx.doi.org/10.3390/ijms19030685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877546PMC
February 2018

One-third of an Archivial Series of Papillary Thyroid Cancer (Years 2007-2015) Has Coexistent Chronic Lymphocytic Thyroiditis, Which Is Associated with a More Favorable Tumor-Node-Metastasis Staging.

Front Endocrinol (Lausanne) 2017 1;8:337. Epub 2017 Dec 1.

Department of Human Pathology of Adult and Evolutive Age "Gaetano Barresi"-Section of Pathological Anatomy, University of Messina, Messina, Italy.

The significance and impact of the coexistence of chronic lymphocytic thyroiditis (CLT) with thyroid cancer is still debated. To verify the influence of CLT on papillary thyroid cancer (PTC), we retrospectively collected 505 PTC cases and analyzed age at diagnosis, sex, size, lymph node status, and staging. We found that CLT was present in 168 PTC (33.3%). Compared with the 337 patients without CLT (non-CLT), CLT patients were younger (44.42 ± 13.72 vs. 47.21 ± 13.76 years,  = 0.03), had smaller tumors (9.39 ± 6.10 vs. 12 ± 9.71 mm,  = 0.002), and lower rate of lymph node metastases (12.5 vs. 21.96%,  = 0.01, OR = 0.508). Tumor-node-metastasis (TNM) staging (T1a through T4) was more favorable for the CLT group compared to the non-CLT group (for instance, T1a = 65.5 vs. 49.8%, T3 = 4.8 vs. 23.4%). This study shows that one in three patients with PTC harbors CLT, which is associated with a more favorable TNM staging, consistently with a favorable outlook of PTC.
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http://dx.doi.org/10.3389/fendo.2017.00337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716977PMC
December 2017

Autophagy in advanced low- and high-grade tubular adenocarcinomas of the stomach: An ultrastructural investigation.

Ultrastruct Pathol 2018 Jan-Feb;42(1):10-17. Epub 2017 Dec 1.

a Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Anatomic Pathology , University of Messina , Messina , Italy.

Autophagy represents a catabolic process in which cellular protein and organelles are engulfed into autophagosomes, digested in lysosomes and reutilized for the cellular metabolism. In neoplastic conditions, autophagy may act either as a tumour suppressor avoiding the accumulation of damaged proteins and organelles or as a mechanism of cell survival promoting the tumour growth. Although enhanced autophagy has been reported in hypoxic areas of solid tumors, there are only few ultrastructural reports concerning the relationships between autophagy and tumor grade. In the present study, we have performed an ultrastructural investigation aimed to document autophagy in a cohort of advanced gastric carcinomas of tubular type, correlating the observed findings with low and high tumor grade. Among 71 surgically resected cases of advanced gastric carcinomas, we have selected twelve low-grade and thirteen high-grade tubular adenocarcinomas. Autophagic vacuoles (AV) were only occasionally found in low-grade tubular carcinomas, while they constituted a frequent finding in high-grade ones (p < 0.01). Moreover, in high-grade tubular adenocarcinomas, our data revealed a morphologic association between autophagy and nuclear changes, such as multinucleation, micronucleation and nuclear buds, largely considered as ultrastructural aspects of mitotic instability. However, an increased autophagy was associated with organelle-poor cytoplasm or a senescent phenotype, characterized by lipofuscin granules and cytoplasmic vacuoles. In the light of our observations, it may be suggested that autophagy should be considered a phenomenon mainly related to the cellular differentiation and tumor progression.
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http://dx.doi.org/10.1080/01913123.2017.1388322DOI Listing
August 2018

The prognostic significance of combined androgen receptor, E-Cadherin, Ki67 and CK5/6 expression in patients with triple negative breast cancer.

Oncotarget 2017 09 16;8(44):76974-76986. Epub 2017 Aug 16.

Medical Oncology Unit A.O. Papardo & Department of Human Pathology University of Messina, Messina, Italy.

Background: Triple Negative Breast Cancer (TNBC) represents a heterogeneous group of tumors with poor prognosis owing to aggressive tumor biology and lack of targeted therapies. No clear prognostic biomarkers have been identified to date for this subgroup.

Materials And Methods: In this retrospective study we evaluated the prognostic role of 4 different molecular determinants, including androgen receptor (AR), E-cadherin (CDH1), Ki67 index, and basal cytokeratins (CKs) 5/6, in a cohort of 99 patients with TNBC. All patients received neo/adjuvant chemotherapy (mostly anthracycline/taxane-based). Immunohistochemistry (IHC) was performed in formalin-fixed paraffin-embedded primary tumor samples. CDH1 expression was considered positive as ≥ 30% of the membrane cells staining. AR positivity was defined as > 10% of positive tumor cells. High Ki67 was defined as ≥20% positive tumor cells. CK5/6 expression was judged positive if the score was ≥1.

Results: The absence of AR expression was significantly associated with highly undifferentiated tumors. Univariate analyses showed that lack of expression of CDH1, tumor size and nodal status were significantly correlated with worse RFS and OS (p< 0.05). AR expression and low Ki67 showed a trend towards better RFS and OS. Patients with absent CK5/6 expression in univariate and multivariate analyses had poorer RFS (p=0.02 and p=0.002, respectively) and OS (p=0.05 and p=0.02, respectively). Multivariate analysis showed an independent association between CDH1 expression and better RFS and OS (p< 0.05) beyond tumor size, nodal status, and grade. The Kaplan-Meier curves showed that patients with AR and CDH1 negative expression and high Ki-67 levels have a significant correlation with poor outcome.

Conclusions: Our study supports the use of IHC expression of AR, CDH1, Ki67, and CK5/6 as prognostic markers in TNBCs and suggests a link between their expression and prognosis and may help to stratify TNBC patients in different prognostic classes.
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http://dx.doi.org/10.18632/oncotarget.20293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652756PMC
September 2017

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

Oncol Lett 2017 May 14;13(5):3205-3209. Epub 2017 Mar 14.

Department of Human Pathology of Adult and Evolutive Age 'Gaetano Barresi', Polyclinic 'G. Martino', University of Messina, I-98125 Messina, Italy.

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.
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http://dx.doi.org/10.3892/ol.2017.5859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431335PMC
May 2017

An Updated Review of Cribriform Carcinomas with Emphasis on Histopathological Diagnosis and Prognostic Significance.

Oncol Rev 2017 Mar 10;11(1):317. Epub 2017 Mar 10.

Department of Human Pathology G. Barresi, University of Messina , Italy.

Cribriform is a histopathological term used to describe a neoplastic epithelial proliferation in the form of large nests perforated by many quite rounded different-sized spaces. This growth pattern may be seen in carcinomas arising in different organs, and shows important prognostic implications. Therefore, recent data in literature suggest that cribriform carcinoma is a histologically and clinically distinctive type of tumour that should be separated from other similar tumour types. In this article, the pathology of cribriform adenocarcinoma of the prostate, lung, breast, stomach, colon, thyroid, and skin is discussed with particular reference to morphologic and immunohistochemical features, differential diagnosis, and clinical behaviour.
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http://dx.doi.org/10.4081/oncol.2017.317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364999PMC
March 2017

HER2 Analysis in Sporadic Thyroid Cancer of Follicular Cell Origin.

Int J Mol Sci 2016 Dec 6;17(12). Epub 2016 Dec 6.

Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Unit of Pathological Anatomy, University of Messina, AOU Policlinico G. Martino, 98125 Messina, Italy.

The Epidermal Growth Factor Receoptor (EGFR) family member human epidermal growth factor receptor 2 (HER2) is overexpressed in many human epithelial malignancies, representing a molecular target for specific anti-neoplastic drugs. Few data are available on HER2 status in differentiated thyroid cancer (DTC). The present study was aimed to investigate HER2 status in sporadic cancers of follicular cell origin to better clarify the role of this receptor in the stratification of thyroid cancer. By immunohistochemistry and fluorescence in-situ hybridization, HER2 expression was investigated in formalin-fixed paraffin-embedded surgical specimens from 90 DTC patients, 45 follicular (FTC) and 45 papillary (PTC) histotypes. No HER2 immunostaining was recorded in background thyroid tissue. By contrast, overall HER2 overexpression was found in 20/45 (44%) FTC and 8/45 (18%) PTC, with a significant difference between the two histotypes ( = 0.046). Five of the six patients who developed metastatic disease during a median nine-year follow-up had a HER2-positive tumor. Therefore, we suggest that HER2 expression may represent an additional aid to identify a subset of patients who are characterized by a worse prognosis and are potentially eligible for targeted therapy.
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http://dx.doi.org/10.3390/ijms17122040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187840PMC
December 2016

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.

Rev Endocr Metab Disord 2016 12;17(4):521-527

Department of Human Pathology "Gaetano Barresi" - Section of Pathological Anatomy, A.O.U. Polyclinic G.Martino, 98125, Messina, Italy.

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.
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http://dx.doi.org/10.1007/s11154-016-9398-4DOI Listing
December 2016

Mast Cell Interaction with Neutrophils in Human Gastric Carcinomas: Ultrastructural Observations.

Anal Cell Pathol (Amst) 2016 2;2016:6891971. Epub 2016 Nov 2.

Department of Human Pathology "Gaetano Barresi", University of Messina and Azienda Ospedaliera Universitaria "Policlinico Gaetano Martino", 98125 Messina, Italy.

The role of mast cells in cell-cell immune interactions has received increasing attention, although their functional interaction with neutrophils still remains to be clarified in tumors. The aim of the present study was to investigate the association between mast cells and neutrophils in a series of gastric carcinomas (GC). 52 surgically resected GC specimens were routinely processed for both light and electron microscopy. Only cases showing both mast cells and neutrophils in the tumor stroma were considered in the analysis. Only 9 GC (M : F = 5 : 4; age range: 50-82 years) showed both mast cells and neutrophils in the tumor stroma. At ultrathin sections, we identified heterotypic aggregation and intermingling of mast cells and neutrophils. Mast cells had mature phenotype and showed full complement of granules with homogeneous, scroll, particle, and mixed pattern. In addition, we found normal-appearing or early apoptosis showing neutrophils. Our histological findings showed the likely interaction between mast cells and neutrophils in GC. We hypothesize that the granular content of mast cells may be released in small quantity through a mechanism called "kiss-and-run fusion," which is alternative to well-known massive anaphylactic or piecemeal degranulation.
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http://dx.doi.org/10.1155/2016/6891971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110872PMC
January 2017