The phenotypic landscape of primary biliary cholangitis and autoimmune hepatitis variants.

Autoimmune Hepatitis (AIH) and Primary Biliary Cholangitis (PBC) stand as distinct diseases, yet occasionally intertwine with overlapping features, posing diagnostic and management challenges. This recognition traces back to the 1970s, with initial case reports highlighing this complexity. Diagnostic scoring systems like IAIHG and simplified criteria for AIH were introduced but are inherently limited in diagnosing variant syndromes. The so-called Paris Criteria offer a diagnostic framework with high sensitivity and specificity for variant syndromes, although disagreements among international guidelines persist. Histological findings in AIH and PBC may exhibit overlapping features, rendering histology alone inadequate for a definitive diagnosis. Autoantibody profiles could be helpful, but similarly cannot be considered alone to reach a solid and consistent evaluation. Treatment strategies vary based on the predominant features observed. Individuals with overlapping characteristics favoring AIH ideally benefit from corticosteroids, while patients primarily manifesting PBC features should initially receive treatment with choleretic drugs like ursodeoxycholic acid (UDCA).

The impact of the non-invasive follicular thyroid neoplasm with papillary-like nuclear feature terminology in the routine diagnosis of thyroid tumours.

BACKGROUND: Due to the recent proposal of the non-invasive follicular thyroid neoplasm with papillary-like nuclear feature (NIFTP) category, the authors analyse the state of the art in the challenging diagnosis of follicular thyroid neoplasms in routine practice. METHODS AND RESULTS: A consecutive series of 200 histological diagnoses, with complete cytological correlation, was analysed following the introduction of the NIFTP definition. The study was conducted in a general hospital with a high prevalence of thyroid benign nodules that accounted for approximately 60% of surgically-treated nodules. The significant incidence of the new NIFTP category was 7%. Concurrently, a gradual decrease of the follicular variant of papillary thyroid carcinoma (fvPTC) was observed (3.5%). When evaluating the FNA biopsies within the NIFTP group, despite the systematic evaluation of nuclear crowding, enlargement, irregularities and clearing, the final cytological class was often indeterminate for malignancy (Thy3/III-IV, 71%). At histology, the application of the semiquantitative NIFTP score for the evaluation of the PTC-like nuclear features was able to discriminate benign lesions (score 0/1) from fvPTC (score 2/3). A certain degree of overlapping still persisted between NIFTP and fvPTC (score 2) or between NIFTP and benign lesions (score 1). CONCLUSIONS: In the routine evaluation of FNA biopsies, the presence of subtle and questionable PTC-like nuclear features still remains a controversial aspect of the diagnostic workflow. Given that the NIFTP category was introduced to stratify the low-risk group of thyroid tumours more precisely, pathologists should force themselves to apply the nuclear score rigorously and to classify cases assigned a score of 1 as benign proliferations.

Proteomics for the diagnosis of thyroid lesions: preliminary report.

OBJECTIVE: Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a unique proteomic technology that explores the spatial distribution of biomolecules directly in situ, thus integrating molecular and morphological information. The possibility of correlating distribution maps of multiple analyses with cytological features makes it an ideal research tool for discovering new diagnostic markers. A previous study showed that MALDI-IMS could help discrimination between different types of thyroid lesions, especially papillary thyroid carcinoma (PTC); the present feasibility study on ex vivo fine needle aspiration (FNA) smears describes its potential in detecting new proteomic targets of other thyroid lesions (follicular lesions, medullary carcinoma). METHODS: MALDI-IMS was conducted on ex vivo FNAs obtained from surgical specimens and corresponding in vivo samples. Differences between proteomic profiles of different thyroid lesions were compared. RESULTS: Comparing the protein profiles of hyperplastic nodules obtained from three different patients with each other, and with a new PTC, showed a high degree of concordance, indicating good reproducibility of the IMS technology on cytological samples, suggesting its potential as a tool for biomarker discovery. Furthermore, comparison of the average proteomic profiles of hyperplastic nodules with a Hürthle cell adenoma revealed significant differences, underlying the capability of MALDI-IMS to distinguish between different thyroid lesions. Finally, the proteomic profile of medullary thyroid carcinoma was also characterized. CONCLUSIONS: Our results confirmed the possible role of MALDI-IMS in the search for diagnostic targets of PTC and follicular lesions, which could be applied in larger trials aimed at the identification of proteins, convertible to cost-effective diagnostic tools such as immunohistochemistry. These tests could be used to analyse in vivo cytological smears, improving the preoperative diagnosis of indeterminate thyroid nodules.

Acid sphingomyelinase determines melanoma progression and metastatic behaviour via the microphtalmia-associated transcription factor signalling pathway.

Melanoma is a rapidly growing and highly metastatic cancer with high mortality rates, for which a resolutive treatment is lacking. Identification of novel therapeutic strategies and biomarkers of tumour stage is thus of particular relevance. We report here on a novel biomarker and possible candidate therapeutic target, the sphingolipid metabolising enzyme acid sphingomyelinase (A-SMase). A-SMase expression correlates inversely with tumour stage in human melanoma biopsies. Studies in a mouse model of melanoma and on cell lines derived from mouse and human melanomas demonstrated that A-SMase levels of expression actually determine the malignant phenotype of melanoma cells in terms of pigmentation, tumour progression, invasiveness and metastatic ability. The action of A-SMase is mediated by the activation of the extracellular signal-regulated kinase, the subsequent proteasomal degradation of the Microphtalmia-associated transcription factor (Mitf) and inhibition of cyclin-dependent kinase 2, Bcl-2 and c-Met, downstream targets of Mitf involved in tumour cell proliferation, survival and metastatisation.

Histochemistry: historical development and current use in pathology.

We describe the history of the histochemical stains that contributed most to the development of modern pathology during the last two centuries. Histochemical stains are presented in a list, which provides the essential information about year, country and main use of each to enable the reader to follow the chronological and geographical history of histochemistry. In addition to the historical evaluation of histochemistry development, we investigate how many classical histochemical stains survive in a modern laboratory of pathology and how often they are used for diagnostic practice compared to immunohistochemical (IHC) techniques. A ratio of about one histochemical reaction to 13 IHC reactions was tabulated. Finally, our data make it possible to define different cultural approaches to the terminology of histochemical and IHC stains: the former were based on eponyms, which link the stain with the name of its inventor, while the latter use a more impersonal biological terminology.

'Indeterminate for malignancy' (Tir3/Thy3 in the Italian and British systems for classification) thyroid fine needle aspiration (FNA) cytology reporting: morphological criteria and clinical impact.

BACKGROUND: The British system (Thy1-5), the Bethesda system for reporting thyroid cytopathology (BSRTC) and the Italian Society of Anatomic Pathology and Cytology (SIAPEC) classification represent the most important international classifications for thyroid cytopathology. Irrespective of the system used, the 'indeterminate' categories are still debated among cytopathologists, particularly with regard to diagnostic criteria, clinical impact of subclassification and role of molecular techniques. AIM: We aimed to find answers to the following questions: Are there shared criteria in cytological preparations that allow the division of indeterminate follicular lesions into subcategories? What is the true clinical impact of this possible subclassification? METHODS: Among 1150 consecutive thyroid fine needle aspiration (FNA) specimens, 80 patients had nodules with a final cytological report of Tir3 (SIAPEC)/Thy3. These 80 cases were re-evaluated and subclassified according to morphological criteria into three groups: pure follicular proliferations, Hürthle cell follicular lesions and atypical proliferations. RESULTS: Sixteen (20%) cases were categorized as pure follicular proliferations, 40 (50%) as Hürthle cell follicular lesions and 24 (30%) as atypical proliferations. Surgery was performed in 57 cases (71%). Cyto-histological correlation showed that follicular adenoma was the most frequent final diagnosis in the cases treated by surgery (24/57, 42%). The overall malignancy rate in the Tir3 category was 28% (16/57). Atypical proliferations were more often malignant than either of the follicular groups (53% versus 19%, P = 0.019). CONCLUSIONS: A five-tiered classification, subdividing the 'indeterminate for malignancy' class into 'follicular proliferations' and 'atypical lesions' could be adopted. As a result of their higher risk of malignancy, surgical management of the atypical lesions would be justified. In future, the introduction of a genetic panel might contribute to their stratification, to the determination of a more accurate risk of malignancy of the atypical lesions and to the verification of follicular proliferations that are benign.

Colonoscopic findings in coeliac disease on a gluten-free diet.

BACKGROUND: to date, there are few data on colonoscopic findings in patients with celiac disease, and most of these obtained in patients with iron deficiency anaemia. AIMS: we assessed colonoscopic findings in unselected patients with coeliac disease, since there are no studies available also considering morphological aspects, and there is literature suggestion of increased prevalence of colorectal tumours. MATERIAL AND METHODS: colonoscopies with multiple biopsies were retrospectively analyzed in 42 coeliac disease patients on gluten-free diet above age 40; 16 had clinical or laboratory features of iron deficiency anaemia. Mucosal biopsies were evaluated for the presence of intraepithelial lymphocytes and of mucosal eosinophils, in addition to conventional histologic assessment, and compared with those obtained in 15 controls. RESULTS: macroscopic abnormalities (polyps, diverticula, inflammatory changes) were found in 26% of patients. Microscopic abnormalities (lymphocytic colitis, melanosis coli, rectal histiocytosis) were found in 36% of patients. None of these findings was found in controls. Coeliac disease patients had significantly higher eosinophil score than controls in the right colon, whereas this was not significantly different between groups in the left colon. CONCLUSIONS: colonoscopic findings in coeliac disease on gluten-free diet may reveal significant findings, even in patients without iron deficiency anaemia. There is the need of further studies in larger cohorts of patients to establish whether colonoscopy in these patients may be clinically useful.

Colonoscopic findings in coeliac disease on a gluten-free diet

Background: to date, there are few data on colonoscopic findings in patients with celiac disease, and most of these obtained in patients with iron deficiency anaemia. Aims: we assessed colonoscopic findings in unselected patients with coeliac disease, since there are no studies available also considering morphological aspects, and there is literature suggestion of increased prevalence of colorectal tumours. Material and methods: colonoscopies with multiple biopsies were retrospectively analyzed in 42 coeliac disease patients on gluten-free diet above age 40; 16 had clinical or laboratory features of iron deficiency anaemia. Mucosal biopsies were evaluated for the presence of intraepithelial lymphocytes and of mucosal eosinophils, in addition to conventional histologic assessment, and compared with those obtained in 15 controls. Results: macroscopic abnormalities (polyps, diverticula, inflammatory changes) were found in 26% of patients. Microscopic abnormalities (lymphocytic colitis, melanosis coli, rectal histiocytosis) were found in 36% of patients. None of these findings was found in controls. Coeliac disease patients had significantly higher eosinophil score than controls in the right colon, whereas this was not significantly different between groups in the left colon. Conclusions: colonoscopic findings in coeliac disease on gluten-free diet may reveal significant findings, even in patients without iron deficiency anaemia. There is the need of further studies in larger cohorts of patients to establish whether colonoscopy in these patients may be clinically useful(AU)

Renal hilus paraganglioma: a case report and brief review.

Paraganglioma is a rare tumour that originates from any paraganglia. Among extra-adrenal paraganglioma, renal hilus is a rare location. The authors report a case of a 43-year-old female who was admitted for evaluation of a renal mass detected incidentally by ultrasound imaging. Suspecting malignancy, the patient underwent radical nephrectomy. Upon macroscopic examination, the lesion was located into the renal hilus. Histological study revealed a neoplasm constituted of nests of monomorphic cuboidal cells with basophilic granular cytoplasm and round to oval nuclei. Necrosis was absent. The proliferative index (Mib-1) was very low (< 5%). Immunohistochemical examination revealed reactivity for neuron specific enolase (NSE), chromogranin A and synaptophysin. The final diagnosis was renal hilus paraganglioma. The paper shows the difficulty in diagnostic approaches to paraganglioma in this atypical site.

A case of ARDS associated with influenza A - H1N1 infection treated with extracorporeal respiratory support.

After the first outbreak identified in Mexico in late March 2009, influenza A sustained by a modified H1N1 virus ("swine flu") rapidly spread to all continents. This article describes the first Italian case of life-threatening ARDS associated with H1N1 infection, treated with extracorporeal respiratory assistance (venovenous extracorporeal membrane oxygenation [ECMO]). A 24-year-old, previously healthy man was admitted to the Intensive Care Unit (ICU) of the local hospital for rapidly progressive respiratory failure with refractory impairment of gas exchange unresponsive to rescue therapies (recruitment manoeuvres, pronation and nitric oxide inhalation). An extracorporeal respiratory assistance (venovenous ECMO) was performed. It allowed a correction of the respiratory acidosis and made possible the transportation of the patient to the ICU (approximately 150 km from the first hospital). A nasal swab tested positive for H1N1 infection and treatment with oseltamivir was started. The chest computed tomography scan showed bilateral massive, patchy consolidation of lung parenchyma; lab tests showed leukopenia, elevated CPK levels and renal failure. The patient required high dosages of norepinephrine for septic shock and continuous renal replacement therapy. The clinical course was complicated by Pseudomonas aeruginosa superinfection, treated with intravenous and aerosolised colistin. ECMO was withheld after 15 days, while recovery of renal and respiratory function was slower. The patient was discharged from the ICU 34 days after admission. In this case, ECMO was life-saving and made the inter-hospital transfer of the patient possible.

[Myeloid sarcoma in uterine leiomyoma]. / Sarcoma mieloide in leiomioma del miometrio.

In this case report we present a 44-year-old woman with a 2-weekhistory of vaginal bleeding. Gynaecological examination revealed the presence of a polypoid neoformation in the endometrial cavity with a maximum diameter of 4 cm. Histological analysis showed a classic leiomyoma infiltrated by a second monomorphic, highly undifferentiated neoplasia. Immunohistochemical analysis revealed a negative reaction for cytokeratin, CD10, inhibin, CD99, CD20, CD3, TdT and CD34, and positivity for CD45, MPO, CD68 and CD117. A diagnosis of myeloid sarcoma in myometrial leiomyoma was made. The following days the patient showed the onset of an acute myeloid leukaemia M5a. Forty days after diagnosis the patient died for complications related to immunodeficiency caused by therapy. Especially when a common antibody panel reveals negativity for epithelial, mesenchymal and lymphoid markers, this case underlines the importance of considering myeloid sarcoma in differential diagnosis of undifferentiated tumours arising in an extramedullary site in order to avoid errors and permit optimal therapeutic management.

[Cutaneous inflammatory pseudotumor (plasmocytoid granuloma)]. / Pseudotumore infiammatorio cutaneo (granuloma plasmocitoide).

Cutaneous inflammatory pseudotumor is a rare benign condition that should be macroscopically differentiated, from dermatofibroma and metastases of carcinoma and, histologically from cutaneous lymphomas and other more aggressive diseases. We report herein the case of a 63-year-old man with a painless nodule of the left arm skin with a rapid growth (1 month ago). The histological examination revealed a well-defined dermal nodule of plasmacytoid cells, without connection or infiltration of the epidermis. At high power the polymorphous cellular infiltrate was, constituted by medium- small elements with widespread features of lympho-plasmocytoid differentiation or clear plasmacellular features. Immunohistochemical analysis showed a polyclonal cytological pattern with expression of both immunoglobulin light chains kappa e lambda by plasmacytoid and admixed B and T lymphocytes. The final diagnosis was Plasmocytoid granuloma an entity that is recognized within the so called "Cutaneous inflammatory pseudotumor" together with the myofibroblastic tumor.

Combined transcranial and endoscopic nasal resection for esthesioneuroblastoma. Technical note.

Esthesioneuroblastoma is a rare malignant neoplasm arising in the nasal cavity. Huge esthesioneuroblastomas, extending into the ethmoid roof and the cribriform plate, or invading the anterior cranial fossa, have traditionally been treated by craniofacial resection. Because of the invasiveness and potentially disfiguring results of a transfacial approach, a new technique has been proposed, combining endoscopic nasal and anterior craniotomy resection. We describe the case of a young male presenting with a large esthesioneuroblastoma involving the nasal cavity and the anterior cranial fossa, causing a huge skull base destruction. A combined transcranial and endoscopic nasal resection resulted in a macroscopically total removal of the tumor. The operative technique is reviewed in detail, along with the method used for the reconstruction of the anterior skull base defect.