Single Institution Experience in the Management of Locally Advanced (pT4) Differentiated Thyroid Carcinomas.

BACKGROUND: Locally infiltrating (T4) differentiated thyroid carcinomas (DTC) represent a challenge. Surgical strategy and adjuvant therapy should be planned balancing morbidity and oncologic outcome. A series of patients with T4 DTC who underwent multidisciplinary evaluation and treatment is reported. The main study endpoints were the oncologic outcome, complication rates, and risk factors for tumor recurrence. PATIENTS AND METHODS: All DTC cases operated between 2009 and 2021 were reviewed and T4 DTC cases were identified. En bloc resection of inferior laryngeal nerve (ILN), tracheal, and/or internal jugular vein (IJV) was performed in cases of massive infiltration. In cases of pharyngoesophageal junction (PEJ) invasion, the shaving technique was always applied. RESULTS: Among 4775 DTC cases, 60 were T4. ILN infiltration was documented in 45 cases (en bloc resection in 9), tracheal infiltration in 14 (tracheal resection in 2), PEJ invasion in 11 (R0 resection in 7 cases and < 1 cm residual tissue in 4 cases), IJV resection in 6, and laryngeal in 2. In total, 11 postoperative ILN palsy, 23 transient hypoparathyroidisms, and 2 hematomas requiring reoperation were registered. Final histology showed 7 pN0, 22 pN1a, and 31 pN1b tumors. Aggressive variants were observed in 47 patients. All but 1 patient underwent radioiodine treatment, 12 underwent adjuvant external beam radiation therapy (EBRT), and 2 underwent chemotherapy. At a median follow-up of 58 months, no tumor-related death was registered, and seven patients required reoperation for recurrence. Tracheal invasion was the only significant factor negatively impacting recurrence (p = 0.045). CONCLUSIONS: A multidisciplinary approach is essential for the management of T4 DTC. Individualized and balanced surgical strategy and adjuvant treatments, in particular EBRT, ensure control of locally advanced disease with acceptable morbidity.

Second edition of the Milan System for Reporting Salivary Gland Cytopathology: Refining the role of salivary gland FNA.

The use of standardised reporting systems for non-gynaecologic cytopathology has made enormous gains in popularity during the past decade, including for thyroid fine-needle aspiration, urine cytology, serous effusions, pancreas, lymph nodes, lung and more. In February 2018, the first edition of the Atlas of the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was published. The MSRSGC defines six diagnostic fine-needle aspiration categories encompassing the spectrum of non-neoplastic, benign and malignant lesions of the salivary glands. The goal of the MSRSGC is to combine each diagnostic category with a defined risk of malignancy and a specific clinical and/or surgical management algorithm. Since its initial publication in 2018, more than 200 studies and commentaries have been published, confirming the role of the MSRSGC. The second edition of the MSRSGC, published in July 2023, includes refined risks of malignancy based on systematic reviews and meta-analyses, a new chapter summarising the use of salivary gland imaging, new advances in ancillary testing and updates in nomenclature.

Some uncommon cystic lesions in the anterior head and neck region: Pitfalls to be avoided on cytology.

Cystic lesions of the anterior head and neck region are a challenging and frequent finding on cytological smears. The scant amount of cellular material in cystic slides poses the greatest difficulty to interpretation, so that frequently they are diagnosed as inadequate or with minimal cellular component. Despite the majority of cystic lesions being benign, a minor portion consist of malignant cystic entities. In these latter cases, the evidence of very scant malignant cells can be misdiagnosed and/or underestimated, leading to a false negative diagnosis. Many papers have already described and detailed the range of possible benign and malignant cystic lesions in head and neck. In the current review we have focused on the less common entities that often lead to serious misinterpretation.

Metastases to the parotid glands: An institutional experience.

BACKGROUND: Metastatic lesions to the salivary gland are rare and mostly affect the parotids. Metastases represent 8% of all malignant lesions of the parotid gland. Around 80% originate from squamous cell carcinomas (SCC) of the head and neck region. Fine needle aspiration (FNA) plays a crucial role in distinguishing primary salivary gland lesions from metastases. Herein we describe our series of metastases to the parotid glands. MATERIALS AND METHODS: We analysed 630 parotid gland FNAs over a decade including conventional and liquid-based cytology specimens. Ancillary techniques such as immunocytochemistry (ICC) were conducted on cell blocks. RESULTS: Eighty (12.4%) cases were malignant lesions, of which 53 (63.75%) were metastases including 24% melanoma, 22.6% SCC, 19% renal carcinomas, 7.5% breast carcinomas, 11.3% lung, 9% intestinal and 1.8% testicular, malignant solitary fibrous tumour and Merkel cell carcinoma. The 53 cases, classified according to the Milan system for salivary cytopathology, belonged to 5 Suspicious for malignancy (SFM) and 48 malignant (M) categories. Forty had a known history of primary malignancy (75.4%), while 13 were suspicious to be a metastatic localisation (24.5%), distributed as 5SFM (2SCC and 3Melanoma) and 8 M. A combination of clinical history, cytomorphology and ICC identified 100% of them. CONCLUSIONS: Fine needle aspiration plays a central role in the diagnostic workup of patients with metastatic lesions to their parotid glands, thereby defining the correct management. Diagnostic accuracy may be enhanced by applying ICC. Although melanoma and SCC are the most common histological types, several other malignancies may also metastasize to the parotid glands and should be kept into consideration.

Atypical glandular cells and predictive features of malignancy in Pap smears: A retrospective monocentric study.

OBJECTIVE: The introduction of cytological screening with the Papanicolau smear significantly reduced cervical cancer mortality. However, Pap smear examination can be challenging, being based on the observer ability to decode different cytological and architectural features. This study aims to evaluate the malignancy rate of AGC (atypical glandular cells) category, investigating the relationships between cytological and histological diagnosis. METHODS: Eighty-nine patients, diagnosed as AGC at cytological evaluation and followed up with biopsy or surgical procedure at Policlinico Gemelli Hospital, Rome, Italy, were included in the study. The cytopathological architectural (feathering, rosette formation, overlapping, loss of polarity, papillary formation, three-dimensional formation) and nuclear (N/C ratio, nuclear enlargement and hyperchromasia, mitoses, nuclei irregularity, evident nucleoli) features of AGC were evaluated. Statistical analyses were performed to assess cyto-histological correlation and determine the relevance of architectural and nuclear features in the diagnosis of malignancy. RESULTS: Of the 89 AGC patients, 48 cases (53.93%) were diagnosed as AGC-NOS and 41 (46.07%) were diagnosed as AGC-FN, according to the Bethesda classification system. The follow-up biopsies or surgical resections revealed malignancy in 46 patients (51.69%). The rates of malignancy for AGC-NOS and AGC-FN were 35.41% and 70.73% respectively. Furthermore, analysing cytopathological features, we found that both architectural and nuclear criteria were statistically significant (p < 0.05). Only overlapping, nuclear irregularity and increased N/C ratio were not found to be statistically significant for detecting malignancy. CONCLUSIONS: Cytological diagnosis of glandular lesions remains a valid tool, when appropriate clinical correlation and expert evaluation are available.

Cystic lesions in the salivary gland. Pitfalls to be avoided on cytology.

Cystic lesions of the salivary glands are very uncommon entities. However, on occasion, some neoplasms of the salivary glands show a cystic component, which may be predominant or only partially cystic. Basal cell adenoma, canalicular adenoma, oncocytoma, sebaceous adenoma, intraductal papilloma, epithelial-myoepithelial carcinoma, intraductal carcinoma, and secretory carcinoma are such cystic entities. Cystic degeneration and necrosis, which can develop within solid tumours, represent another possibility. The ability to recognise this type of lesion is a challenge in diagnostic cytology because hypocellular fluid is frequently recovered. Furthermore, evaluating all of the differential diagnoses for cystic lesions of the salivary glands is helpful in obtaining the correct diagnosis. Herein, we evaluate the various types of cystic lesions within the salivary glands.

Delphi expert consensus for whole slide imaging in thyroid cytopathology.

OBJECTIVE: Despite an increase in thyroid fine needle aspiration (FNA) and advances in whole slide imaging (WSI) adoption, digital pathology is still considered inadequate for primary diagnosis of these cases. Herein, we aim to validate the utility of WSI in thyroid FNAs employing the Delphi method strategy. METHODS: A panel of experts from seven reference cytology centres was recruited. The study consisted of two consecutive rounds: (1) an open-ended, free-response questionnaire generating a list of survey items; and (2) a consensus analysis of 80 selected shared WSIs from 80 cases by six investigators answering six morphological questions utilising a 1 to 5 Likert scale. RESULTS: High consensus was achieved for all parameters, with an overall average score of 4.27. The broad majority of items (84%) were ranked either 4 or 5 by each physician. Two badly scanned cases were responsible for more than half of the low-ranked (≤2) values (57%). Good to excellent (≥3) diagnostic confidence was reached in more than 95.2% of cases. For most cases (78%) WSI assessment was not limited by technical issues linked to the image acquisition process. CONCLUSION: This systematic Delphi study indicates broad consensus among participating physicians on the application of DP to thyroid cytopathology, supporting expert opinion that WSI is reliable and safe for primary diagnostic purposes.

Placental diabesity: placental VEGF and CD31 expression according to pregestational BMI and gestational weight gain in women with gestational diabetes.

PURPOSE: The aim of this study is to investigate the placental expression of VEGF and CD31 in pregnancies complicated by gestational diabetes (GDM) and the influence of pregestational BMI and gestational weight gain (GWG) on this expression. METHODS: We prospectively enrolled pregnant women with diagnosis of GDM and healthy controls who delivered in our Center between December 2016 and May 2017. Patients were grouped according to the presence of GDM and we compared pregnancy characteristics, placental VEGF and CD31 expression between the cases and controls. Immunochemistry analysis was performed to assess biomarkers positivity. Positivity of biomarkers was assessed in a dichotomic fashion with positivity set at 5% for VEGF and 1% for CD31. RESULTS: 39 patients matched inclusion criteria, 29 (74.3%) women with GDM and 10 (25.7%) healthy controls. Immunochemistry analysis showed that VEGF was more expressed in placentas from women with GDM compared to controls (21/29, 72.4% vs 2/10, 20%; p = 0.007), and CD31 was more expressed in placentas from women with GDM compared to controls (6/29, 20.7% vs 0/10, 0%; risk difference 0.2). VEGF positivity was associated with the presence of GDM (aOR 22.02, 95% CI 1.13-428.08, p = 0.04), pregestational BMI (aOR 1.53, 1.00-2.34, p = 0.05) and GWG (aOR 1.47, 95% CI 1.03-2.11, p = 0.03). CD31 positivity was associated with the pregestational BMI (aOR 1.47, 95% CI 1.00-2.17, p = 0.05) and with the gestational weight gain (aOR 1.32, 95% CI 1.01-1.72, p = 0.04). CONCLUSION: Pregnancies complicated by GDM are characterized by increased placental expression of VEGF and CD31, and the expression of these markers is also independently associated to maternal increased pregestational BMI and GWG, defining the concept of "placental diabesity".

Bladder Epicheck Test: A Novel Tool to Support Urothelial Carcinoma Diagnosis in Urine Samples.

Bladder cancer and upper urothelial tract carcinoma are common diseases with a high risk of recurrence, thus necessitating follow-up after initial treatment. The management of non-muscle invasive bladder carcinoma (NMIBC) after transurethral resection involves surveillance, intravesical therapy, and cytology with cystoscopy. Urinary cytology, cystoscopy, and radiological evaluation of the upper urinary tract are recommended during follow-up in the international urological guidelines. Cystoscopy is the standard examination for the first assessment and follow-up of NMIBC, and urine cytology is a widely used urinary test with high sensitivity for high-grade urothelial carcinoma (HGUC) and carcinoma in situ (CIS). In recent years, various urinary assays, including DNA methylation markers, have been used to detect bladder tumors. Among these, the Bladder EpiCheck test is one of the most widely used and is based on analysis of the methylation profile of urothelial cells to detect bladder neoplasms. This review assesses the importance of methylation analysis and the Bladder EpiCheck test as urinary biomarkers for diagnosing urothelial carcinomas in patients in follow-up for NMIBC, helping cytology and cystoscopy in doubtful cases. A combined approach of cytology and methylation analysis is suggested not only to diagnose HGUC, but also to predict clinical and histological recurrences.

BRAF-AXL-PD-L1 Signaling Axis as a Possible Biological Marker for RAI Treatment in the Thyroid Cancer ATA Intermediate Risk Category.

The use of radioiodine therapy (RIT) is debated in intermediate-risk differentiated thyroid cancer (DTC) patients. The understanding of the molecular mechanisms involved in the pathogenesis of DTC can be useful to refine patient selection for RIT. We analyzed the mutational status of BRAF, RAS, TERT, PIK3 and RET, and the expression of PD-L1 (as a CPS score), the NIS and AXL genes and the tumor-infiltrating lymphocytes (TIL, as the CD4/CD8 ratio), in the tumor tissue in a cohort of forty-six ATA intermediate-risk patients, homogeneously treated with surgery and RIT. We found a significant correlation between BRAF mutations and a less than excellent (LER, according to 2015 ATA classification) response to RIT treatment (p = 0.001), higher expression of the AXL gene (p = 0.007), lower expression of NIS (p = 0.045) and higher expression of PD-L1 (p = 0.004). Moreover, the LER patient group had a significantly higher level of AXL (p = 0.0003), a lower level of NIS (p = 0.0004) and a higher PD-L1 level (p = 0.0001) in comparison to patients having an excellent response to RIT. We also found a significant direct correlation between the AXL level and PD-L1 expression (p < 0.0001) and a significant inverse correlation between AXL and NIS expression and TILs (p = 0.0009 and p = 0.028, respectively). These data suggest that BRAF mutations and AXL expression are involved in LER among DTC patients and in the higher expression of PD-L1 and CD8, becoming new possible biomarkers to personalize RIT in the ATA intermediate-risk group, as well as the use of higher radioiodine activity or other possible therapies.

Approach to FNA of Thyroid Gland Cysts.

Fine needle aspiration is a well-known procedure for the diagnosis and management of thyroid lesions, representing the first diagnostic tool for the definition of their nature. In clinical practice, a thyroid nodule can be classified as solid, cystic, and partially cystic based on its internal components. Different thyroid imaging reporting systems and cytologic diagnostic systems have focused their attention on solid nodules, which are more frequently linked with a malignant outcome. In fact, numerous papers demonstrated that nodules with microcalcifications, a taller-than-wide shape, hypoechogeneity, and irregular margins, are more likely to be malignant on histology. Nevertheless, according to the literature, the risk of malignancy in a partially cystic thyroid nodule ranges between 3.3 and 17-5%, including, for instance, the possible diagnosis of a cystic papillary thyroid carcinoma and other malignant entities. Therefore, in the current review article, we are going to discuss the approach to thyroid cystic lesions on fine needle aspiration cytology.

Diagnostic impact of safety protocols for processing peritoneal washing specimens during the global pandemic of coronavirus disease 2019: A comparative study from 195 cytological samples.

BACKGROUND: The global pandemic of the coronavirus disease 2019 represents a major concern for health services worldwide, and has also induced major changes in cytopathology practice. AIM: We aimed to verify the diagnostic performance of cytological evaluation under a new safety protocol during the pandemic compared to the standard pre-pandemic procedure. We also aimed to assess how cytological diagnoses and sampling were impacted during the pandemic period compared to the pandemic-free period in 2019. MATERIALS AND METHODS: Cytological samples of peritoneal washings taken during the first 10 months of the pandemic emergency in Italy (March 11, 2020 to January 11, 2021) were compared to samples from the preceding 10-month time frame (May 11, 2019 to March 10, 2020). RESULTS: One hundred ninety-five specimens were analysed in the present study. We observed no noticeable differences in cytological diagnoses during the pandemic period compared to the pre-pandemic period. The case numbers by diagnostic category for the pre-pandemic vs pandemic periods, respectively, were as follows: non-diagnostic, 0 vs 0 cases; negative for malignancy, 86 vs 52 cases; atypia of uncertain significance, 7 vs 1 cases; suspicious for malignancy, 0 vs 2 cases; malignant, 42 vs 4 cases. CONCLUSION: While a consistent reduction in the number of cytological examinations has been observed during the COVID-19 period, our institutional safety protocol for processing cytological samples did not affect the diagnostic reliability of peritoneal washing cytology.

DOG1 as an Immunohistochemical Marker of Acinic Cell Carcinoma: A Systematic Review and Meta-Analysis.

DOG1 is a transmembrane protein originally discovered on gastrointestinal stromal tumors and works as a calcium-activated chloride channel protein. There are a limited number of articles on the potential utility of this antibody in the diagnosis of salivary gland tumors in routine practice. In this study, we aimed to investigate the role of DOG1 as an immunohistochemical marker in patients with salivary acinic cell carcinoma (ACC) through meta-analysis. A literature search was performed of the PubMed, Scopus, and Web of Science databases for English-language studies published from January 2010 to September 2021. The literature search revealed 148 articles, of which 20 were included in the study. The overall rate of DOG1 expression in salivary acinic cell carcinoma was 55% (95% CI = 0.43-0.58). Although ACC is a challenging diagnosis, paying careful attention to the cytomorphological features in conjunction with DOG1 immunostaining can help to reach an accurate diagnosis.

What psammoma bodies can represent in the thyroid. What we recently learnt from a story of lack of evidence.

The detection of psammoma bodies (PBs) in the thyroid gland is commonly associated to classic papillary thyroid carcinoma (PTC) and are frequently encountered in differnt subtypes of PTCs. Nonetheless, the evidence of PBs without a PTC may represent a diagnostic challenge. The general statement is that PBs represent a metastatic finding of PTC either when encountered inside the thyroid parenchyma or in the perithyroidal lymph nodes. The majority of authors assess that in presence of PBs, a search for an occult PTC is strongly encouraged and mandatory, especially if a lobectomy had been performed. In fact, it is not uncommon that a contralateral or ipsilateral tumor, mostly PTC, is found leading to the suggestion that the best recommendation is to submit the entire thyroid tissue. Nonetheless, when a cancer has not been found, the possibility of the rare evenience that PBs are likely to be associated with benign conditions should be considered among the differential diagnosis. Herein a short commentary and review of the literature on PBs detection and its diagnosis, based on our recent experience.

Malignant phyllodes tumor of the breast: a systematic review.

Phyllodes tumors (PT) are fibroepithelial neoplasms of the breast showing a peculiar leaf-like appearance. They account for 0.3 to 1% of all primary breast tumors and 2.5% of all fibroepithelial breast tumors. PT are classified into benign, borderline and malignant based upon their stromal morphology with a distribution of 60%, 20%, and 20%, respectively. Malignant PT of the breast constitute an uncommon challenging group of fibroepithelial neoplasms. They have a relatively high tendency to recur, although distant metastasis is uncommon, and nearly exclusive to malignant PT. Adequate surgical resection remains the standard approach to achieve maximal local control. Giant malignant PT are rare and a pose a diagnostic dilemma for pathologists, especially when comprised of sarcomatous elements. This review highlights the morphological features of PT detected in cytology and histology specimens and discusses diagnostic pitfalls and differential diagnosis.

Impact of chorioamnionitis on maternal and fetal levels of proinflammatory S100A12.

Histologic chorioamnionitis (HCA) may lead to the fetal inflammatory response syndrome (FIRS). The aim of this pilot study was to evaluate S100A12, a marker of innate immune activation, in mothers with or without HCA and in their infants. Concentrations of S100A12, interleukin 6 (IL-6), and C-reactive protein (CRP) were evaluated in maternal, cord, and neonatal blood of very preterm infants. Histologic examinations of the placenta and umbilical cords were performed. The 48 mother-neonate pairs enrolled were subdivided into two groups: HCA group (N = 15) and control group without HCA (N = 33). Maternal S100A12 levels were similar between HCA and control group. Similarly, S100A12 concentrations in cord and neonatal blood did not differ between the groups. However, high S100A12 concentrations were detected in cord and neonatal blood of two out of three neonates exposed to HCA associated with advanced funisitis. Concentrations of IL-6 and CRP were higher in maternal blood of the HCA group compared with controls (p < 0.05, p < 0.001; respectively), but no differences in cord or neonatal blood was found.Conclusion:S100A12 did neither identify mothers with HCA nor very preterm infants exposed to HCA. It is currently unknown if S100A12 may identify neonates with FIRS. What is known: • Histologic chorioamnionitis (HCA) may lead to the fetal inflammatory response syndrome (FIRS). • S100A12 represents an early, sensitive, and specific diagnostic marker of inflammatory processes. What is new: • S100A12 did neither identify mothers with HCA nor very preterm infants exposed to HCA. • It is currently still unclear if S100A12 has a potential in identifying preterm infants with FIRS.

Utility of ultrasound-guided fine needle aspiration cytology in assessing malignancy in head and neck pathology.

OBJECTIVE: Fine needle aspiration cytology (FNAC) is a well-established diagnostic procedure for head and neck masses not clearly originating from mucosal or cutaneous surfaces. We analysed head and neck masses evaluated over a 2-year period, to assess the reliability of FNAC for the evaluation of malignancy. METHODS: We enrolled all patients undergoing FNAC, from April 2013 to July 2015, in a single service of a large Italian university hospital. Relevant clinical data and ultrasonographic parameters of the lesions were recorded. We performed both conventional and thin-prep smears. Clinical presentation, ultrasonographic features and final cytology diagnoses were analysed and correlated with histology. RESULTS: The series included 301 lesions in 285 patients, with a single (94.4%) or two (5.6%) lesions. Only eight samples were considered non-diagnostic/inadequate (2.6%). Among the cases, 139 FNAC (46.1%) underwent surgery. Cytological-histological correspondence was found in 89% of the cases. Concerning malignancy, we documented less than 4% false positives and less than 2.5% false negatives, with 92.7% sensitivity and 94.6% specificity. CONCLUSION: FNAC diagnosis can be highly specific. Most importantly, it is highly reliable in assessing malignancy, thus defining the priority and guiding the management procedures.

Relevance of rosette patterns in variants of papillary thyroid carcinoma.

INTRODUCTION: The detection of rosette-like clusters (RLC) of follicular cells in thyroid carcinoma has been reported mostly in the columnar cell variant of papillary thyroid carcinoma (PTC). Despite the fact that diagnosing variants of PTC is no longer encouraged by The Bethesda System for Reporting Thyroid Cytopathology, the identification of cytomorphological features such as RLC linked with these tumours might help reduce possible misinterpretation in thyroid fine needle aspiration (FNA) cytology. We accordingly investigated the potential correlation of architectural patterns including RLC with PTC variants. METHODS: We analysed 225 thyroid FNA cytology cases diagnosed as suspicious for malignancy (SFM) and positive for malignancy (M) over a 1-year time where all samples had corresponding histology. We also included 150 benign lesions from the same period. The presence of RLC vs similar appearing solid clusters, papillary structures and microfollicles were evaluated. We also performed immunocytochemistry and molecular testing for BRAFV600E. RESULTS: We included 100 (44.4%) SFM favouring PTC and 125 (55.6%) M cases with cyto-histological correlation. On histology, all SFM and M cases showed malignancy including 140 (62.2%) classic PTC and 85 (37.8%) PTC variants. The cytomorphological patterns in all FNA samples included solid (74%), papillary (89%), microfollicular (70%), and pseudo-RLC morphology (25.7%). We identified only pseudo-RLC in 33 FNA specimens from PTC variant cases that included tall cell variant (42.4%), hobnail variant (21.2%) and miscellaneous variants (36.3%) of PTC. No definitive RLC were detected in our series. Immunocytochemistry and BRAFV600E were not specifically linked with an RLC pattern. CONCLUSIONS: These findings demonstrate that in our dataset the architectural pattern of RLC was not recognised within PTC variants. However, we did identify a pseudo-RLC pattern that was observed in association with tall cell variant and hobnail variant cases of PTC.

Biosafety procedures for handling intraoperative surgical samples during COVID-19 pandemic: an Italian pathology laboratory experience.

Up to now, Italy is one of the European centers with the most active Coronavirus cases with 233,836 positive cases and 33,601 total deaths as of June 3rd. During this pandemic and dramatic emergency, Italian hospitals had also to face neoplastic pathologies, that still afflict the Italian population, requiring urgent surgical and oncological treatment. In our Cancer Center Hospital, the high volume of surgical procedures have demanded an equally high volume of intraoperative pathological examinations, but also posed an additional major challenge for the safety of the staff involved. The current commentary reports our experience in the past two months (since March 9th) for a total of 1271 frozen exams from 893 suspect COVID-19 patients (31 confirmed).