The diagnostic accuracy of pleomorphic adenoma in fine needle aspiration: Features leading to false positive and false negative diagnoses and the utility of cell blocks.

OBJECTIVE: Fine needle aspiration (FNA) is a well-established tool in preoperative diagnosis of salivary gland lesions with diagnostic accuracy of 90%. Pleomorphic adenoma (PA) is the most common salivary gland tumor comprising 45%-74% of all salivary gland tumors with FNA diagnostic accuracy of 89.5%-96.2%. The aim of the present study was to determine and analyze potential cytomorphological pitfalls and evaluate the diagnostic accuracy in FNA diagnosis of PA. METHODS: Salivary gland specimens with both cytological and histological diagnoses were searched over a 10-year-period (2009-2018) from a laboratory information system of Pathology Department, Fimlab Laboratories, Tampere and matched to determine concordant and discordant PA cases. Sufficient material in histological and cytological sample was found in 401 cases. In 218 cases (54.4%) diagnosis was true-negative PA, in 169 cases (42.1%) diagnosis was true-positive PA and there were 14 discordant cases: 4 false-positive cases and 10 false-negative cases. False-negative cases were reclassified and subgrouped according to The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC). RESULTS: Cytomorphologically, cell type predominance was more often myoepithelial in true-positive cases (65%) and epithelial both in false-negative (70%, p = .007) and false-positive cases (75%, p = .027). Well-formed ducts were present in cytology in all true-positive cases (p < .001). Only 10% of true-positive cases did not show any matrix in cytology (p < .001). Nuclear changes were common in false-negative cases (80%, p = .002) and false-positive cases (75%, p = .003). Beneficial cell block (CB) was more common in true-positive cases (85%) than in false-negative cases (50%, p = .041) or in false-positive cases (50%, p = .116) and a lack of beneficial CB led more often to a false diagnosis (70% false diagnosis without beneficial CB versus 29% false diagnosis with beneficial CB). CONCLUSION: The present study showed diagnostic accuracy of 96.5% for FNA in PA diagnosis. Sensitivity, specificity, positive predictive value and negative predictive value were 94.4%, 98.2%, 97.7%, and 95.6%, respectively. The benefit of CBs was more evident in true-positive cases (85%).

Secretory carcinoma of the salivary gland, a rare entity: An international multi-institutional study.

BACKGROUND: Secretory carcinoma (SC) of the salivary gland is a rare entity with limited published literature on cytomorphology. The authors present the largest cohort to date of SC fine-needle aspiration (FNA) cases. METHODS: FNA cases of histologically confirmed SC were retrospectively retrieved from 12 academic institutions in the United States, Italy, Finland, and Brazil. The collated data included patient demographics, imaging findings, cytopathologic diagnoses according to the Milan System for Reporting Salivary Gland Cytopathology, cytomorphologic characteristics, and immunohistochemical/molecular profiles. RESULTS: In total, 40 SCs were identified (male-to-female ratio, 14:26) in patients with a mean age of 52 years (age range, 13-80 years). Ultrasound imagining revealed a hypoechoic, ovoid, poorly defined, or lobulated mass. The most common primary site was the parotid gland (30 of 40 tumors). Regional lymph node metastasis (9 patients) and distant metastasis (4 patients; brain, liver, lungs, and mediastinum) were noted. Two patients died of disease. FNA smears were cellular and demonstrated mainly large, round cells with intracytoplasmic vacuoles or granules and round-to-oval nuclei with smooth nuclear contour, minimal irregularities, and prominent nucleoli arranged predominantly in clusters, papillary formations, and single cells. The background was variable and contained inflammatory cells, mucin, or proteinaceous material. The diagnoses were malignant (19 of 38 tumors; 50%), suspicious for malignancy (10 of 38 tumors; 26%), salivary gland neoplasm of uncertain malignant potential (7 of 38 tumors; 18%), and atypia of undetermined significance (2 of 38 tumors; 6%) according to the Milan System for Reporting Salivary Gland Cytopathology. Two malignant cases (2 of 40 tumors; 5%) were metastases. The neoplastic cells were immunoreactive for S100 (23 of 24 tumors), mammaglobin (18 of 18 tumors), GATA-3 (13 of 13 tumors), AE1/AE3 (7 of 7 tumors), and vimentin (6 of 6 tumors). ETV6-NTRK3 fusion was detected in 32 of 33 tumors by fluorescence in situ hybridization (n = 32) and next-generation sequencing (n = 1). CONCLUSIONS: Familiarity with cytomorphologic features and the immunohistochemical/molecular profile of SC can enhance diagnostic accuracy.

FNA diagnostics of secondary malignancies in the salivary gland: Bi-institutional experience of 36 cases.

OBJECTIVE: Fine-needle aspiration (FNA) is a key diagnostic method in the evaluation of salivary gland lesions. Secondary tumors of salivary glands represent only 5% of all malignancies of major salivary glands. The goal of our study was to examine the cytological and clinical features of secondary tumors sampled by FNA. MATERIALS AND METHODS: A series of 36 secondary tumors from the pathology departments of two university hospitals are presented. Clinical referrals to FNA, cytological features, immunohistochemical results, and histopathological diagnoses were reviewed in all cases. RESULTS: The study population consisted of 36 cases (19 males and 17 females) with mean age 70.9 ± 13.0 years (range 41-96 years). The most common site of the metastasis was parotid gland (n = 26). The primary malignancy was known in 17 cases at the time of FNA diagnosis. The most common primary site was skin of head and neck area (11 cases) followed by lungs (n = 5) and tonsils (n = 5), kidney (n = 2) and breast (n = 2) and thyroid gland, gastrointestinal tract and soft tissue, 1 case of each. In 8 cases, the primary site remained unknown. The diagnostic or confirmatory immunocytochemistry was performed on cell blocks in 21 cases. CONCLUSIONS: FNA is a reliable technique in the diagnosis of salivary gland secondary malignancies. The knowledge of the personal history of malignancy is essential for the successful immunocytochemical targeted diagnosis without any delay.

The expression and prognostic relevance of programmed cell death protein 1 in tongue squamous cell carcinoma.

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor which plays an important role in a patient's immune responses to microbial and cancer antigens. It is expressed in tumor-infiltrating lymphocytes (TILs) with many different malignancies. The aim of the study was to evaluate PD-1 expression and its prognostic value in tongue cancer. The data of tongue squamous cell carcinoma (TSCC) patients (N = 81) treated in Tampere University Hospital between 1999 and 2013 were used. Control data consisted of patients with non-malignant tongue mucous membrane lesions (N = 48). The formalin-fixed paraffin-embedded samples were stained immunohistochemically and scanned via digital microscope. The staining of PD-1 was examined semi-quantitatively. The density and intensity of PD-1 + cells were significantly higher in TSCC than in control samples. The expression of PD-1 correlated with better survival. The expression of PD-1 could be a potential prognostic marker in TSCC. Further research using larger sample size is needed.

Salivary Gland FNA Diagnostics in a Real-Life Setting: One-Year-Experiences of the Implementation of the Milan System in a Tertiary Care Center.

The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was introduced in 2018 following other organ specific cytopathological reporting systems and it aimed at bringing a practical, evidence-based, user-friendly classification system with characterization and management algorithms. At the Department of Pathology, Fimlab Laboratories, Tampere, Finland all salivary fine needle aspirations (FNAs) have been given cytopathological diagnoses according to the MSRSGC since January 2018. Analyses of a one-year-period (January 2018-December 2018) consisted of 183 salivary FNA samples from 138 patients with correlation to histopathology in 90 cases with surgical follow-up. The MSRSGC performance in patient based analysis was as follows: accuracy was 90.9%, sensitivity was 61.5%, specificity was 100%, positive predictive value was 100%, and negative predictive value was 89.4%, respectively. Risks of malignancy (ROMs) in MSRSGC categories were: 0.0% (0/15) in non-diagnostic category, 100.0% (1/1) in non-neoplastic category biased by only one falsely-negative lymphoma case, 14.3% (1/7) in atypia of undetermined significance category, 0.0% (0/28) in benign neoplasm category, 27.3% (3/11) in neoplasm of uncertain malignant potential category, and 100% for both suspicious for malignancy (4/4) and malignancy (4/4) categories, respectively. The MSRSGC has been proven as a reliable classification system in salivary gland FNA routine diagnostics in a tertiary care center.

Cytopathological features of secretory carcinoma of salivary glands and ancillary techniques in its diagnostics: impact of new Milan system for reporting salivary gland cytopathology.

Secretory carcinoma (SC) of salivary glands is a newly described low-grade malignancy characterized by the presence of ETV6 rearrangement. Only a few cases and very small series with cytomorphology were reported so far. Six cases of fine-needle aspirations (FNAs) from afterward histologically, immunohistochemically and genetically confirmed SCs were retrieved from the archives of the authors. Ancillary immunocytochemistry (ICC) and translocation detection were performed on cell blocks (CBs). All aspirates were sufficiently cellular and cells were arranged in more or less cohesive groups with only mild nuclear polymorphism. The cytoplasm was eosinophilic, granulated and vacuolated, especially in CBs. Secretory material within the microcystic spaces was periodic acid-Schiff (PAS) positive. Triple positivity of immunomarkers S-100 protein, mammaglobin and vimentin was present. The proliferation index was low. Ancillary techniques suggested the possibility of SC in a few cytology cases; nevertheless, the final diagnosis was based on histomorphology, immunohistochemistry and genetics. The SC of salivary glands is detectable pre-operatively using ICC and genetics. The presence of the diagnostic ETV6 rearrangement increases the accuracy of FNA to the maximum. According to the Milan system, cases genetically not confirmed should be categorized as Suspicious for Malignancy or Salivary Gland Neoplasm of Uncertain Malignant Potential (SUMP), both requiring surgery.

Tumor-infiltrating lymphocytes associate with outcome in nonendemic nasopharyngeal carcinoma: a multicenter study.

The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been studied recently in many cancers. For the first time in a nonendemic region, we have evaluated the prognostic value of TILs in a whole population-based nationwide cohort of nasopharyngeal carcinoma (NPC) in Finland. A total of 115 cases from Finnish hospitals were included. TILs were analyzed using hematoxylin and eosin-stained slides according to the criteria of the International Immuno-Oncology Biomarker Working Group. TILs were evaluated separately in stromal and tumor compartments. The log-rank test and univariable and multivariable analyses were used to compare survival in patients with tumors with low and high TILs. A significant positive correlation was observed between the occurrence of intratumoral and stromal TILs (P < .001). In multivariable analysis, NPC cases with low intratumoral TILs had poor overall survival with a hazard ratio (HR) of 2.55 and 95% confidence interval (95% CI) of 1.60 to 4.05 (P < .001). Cases with low intratumoral TILs also had poor disease-specific survival (HR, 2.02; 95% CI, 1.16-3.52; P = .015). Keratinized tumors with low intratumoral TILs were associated with an even poorer overall survival (HR, 3.94; 95% CI, 2.17-7.15; P < .001) and a poor disease-specific survival (HR, 2.97; 95% CI, 1.46-6.05; P = .009). Our study demonstrates that the evaluation of TILs is simple and can be assessed routinely in NPC.

The expression of cancerous inhibitor protein phosphatase 2A in chronic rhinosinusitis with nasal polyps.

CONCLUSION: The study suggests that cancerous inhibitor of protein phosphatase 2A (CIP2A) expression and eosinophilia associate with chronic rhinosinusitis with nasal polyps with aspirin exacerbated respiratory disease (CRSwNP + AERD). Further studies with a larger sample size are needed to evaluate further the role of CIP2A and related pathways in CRSwNP + AERD. OBJECTIVES: Low prostaglandin E2 levels putatively associate with CRSwNP + AERD and decreased c-Myc levels. The aim of this study was to evaluate the expression and revision-predictive role of oncoprotein CIP2A, another c-Myc modulator, in CRSwNP with/without AERD, and in antrochoanal polyps. METHOD: Ninety retrospective archival objective glasses of nasal polyp tissue from CRSwNP or ACP patients were used for assessing mucosal eosinophilia. Of this population, 90 archival nasal polyp specimens were available for immunohistochemical staining with a polyclonal anti-CIP2A antibody, together with 19 control nasal mucosa specimens. CIP2A staining intensity and tissue eosinophilia were assessed by two blinded observers with a light microscope. Subject characteristics from 90 patients and 19 controls were obtained from patient records and additionally by a questionnaire from controls. The follow-up data was available from patient records of 84 patients and 16 controls. RESULTS: The expression of epithelial CIP2A was detected both in control inferior turbinate mucosa and nasal polyps. The expression was significantly lower in the CRSwNP + AERD group compared to controls and CRSwNP without AERD (p < 0.01). High mucosal eosinophilia associated with CRSwNP (p < 0.01). Neither CIP2A nor eosinophilia predicted the need for revision surgery (p > 0.05), whereas previous surgery, allergic rhinitis, and use of corticosteroids did predict the need for revision surgery (p < 0.05).

Tumoral Expression of CD44 and HIF1α Predict Stage I Oral Cavity Squamous Cell Carcinoma Outcome.

OBJECTIVES/HYPOTHESIS: No biomarkers are used to estimate the prognosis in oral cavity squamous cell carcinoma (OSCC). In our previously published work, we have reported the prognostic value of CD44 and hypoxia inducible factor (HIF)-1α in patients with stage I disease. STUDY DESIGN: In this study, we tested our previous observations in a larger cohort. We also studied the predictive value of common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 in this material. METHODS: CD44, HIF1α, and CLEVER-1 were immunohistochemically analyzed in paraffin-embedded tissue material of stage I OSCC patients treated at three Finnish university hospitals. Microscopy results were correlated with OSCC outcome. RESULTS: As in our pilot study, the CD44lowHIF1αhigh signature was associated with poorer disease-free survival. Clear correlations between CLEVER-1 expression and clinical outcome were not evident. CONCLUSION: Our results suggest that immunohistochemistry of CD44 and HIF1α may be useful in identification of patients with poor prognoses. These parameters could be used to select the optimal treatment modalities for stage I OSCC patients. LEVEL OF EVIDENCE: 2b.

Depth of invasion, tumor budding, and worst pattern of invasion: prognostic indicators in early-stage oral tongue cancer.

BACKGROUND: Oral (mobile) tongue squamous cell carcinoma (SCC) is characterized by a highly variable prognosis in early-stage disease (T1/T2 N0M0). The ability to classify early oral tongue SCCs into low-risk and high-risk categories would represent a major advancement in their management. METHODS: Depth of invasion, tumor budding, histologic risk-assessment score (HRS), and cancer-associated fibroblast (CAF) density were studied in 233 cases of T1/T2 N0M0 oral tongue SCC managed in 5 university hospitals in Finland. RESULTS: Tumor budding (≥5 clusters at the invasive front of the tumor) and depth of invasion (≥4 mm) were associated with poor prognosis in patients with early oral tongue SCC (hazard ratio [HR], 2.04; 95% confidence interval [CI], 1.17-3.55; HR, 2.55; 95% CI, 1.25-5.20, respectively) after multivariate analysis. The HRS and CAF density did not predict survival. However, high-risk worst pattern of invasion (WPOI), a component of HRS, was also an independent prognostic factor (HR, 4.47; 95% CI, 1.59-12.51). CONCLUSION: Analyzing the depth of invasion, tumor budding, and/or WPOI in prognostication and treatment planning of T1/T2 N0M0 oral tongue SCC is recommended.

[Recurrent pneumonia in a teenage boy]. / Teini-ikäisen pojan toistuvat keuhkokuumeet.

Pneumonia is a common paediatric and juvenile infection, which upon proper treatment will almost always heal completely. Sometimes pneumonia will become prolonged or recur, causing the need to consider additional investigations. Refractory or recurrent pneumonia in children may be caused by a structural, functional or immunological factor. Diseases of the lung tissue are rare. We describe a teenage boy, whose recurrent pneumonia revealed an underlying malignant disease, mucoepidermioid carcinoma.

Bax and Bcl-2 are focally overexpressed in the normal epithelium of cancerous prostates.

OBJECTIVE: Development of prostate cancer is connected with a disturbance of apoptosis. Prostate cancer is multifocal, suggesting that the control of apoptosis is impaired at multiple foci. We wanted to know whether apoptosis is generally disturbed in cancerous prostates and if changes in apoptotic control could be detected even in the absence of any morphologically visible changes. Therefore, we compared expression of two common apoptotic markers, Bax and Bcl-2, in normal epithelium of cancerous prostates and controls. We also evaluated the expression of these proteins in hyperplasia, prostatic intraepithelial neoplasia (PIN), carcinomas of different Gleason grades and capsular perineural invasion. MATERIAL AND METHODS: The tissue material was obtained from radical prostatectomies, transurethral resection chips and autopsies. Individual tissue arrays were done for each patient. The intensity of Bax and Bcl-2 immunostaining was estimated semiquantitatively. The data were analyzed using a linear mixed-models analysis as well as dichotomized staining indices. RESULTS: Normal epithelium of cancerous prostates contained foci with high expression of Bax and Bcl-2. The expression of Bax in Gleason grades 3-5 carcinoma was significantly higher than that in Gleason grade 2, and was highest in foci with perineural invasion. The expression of Bcl-2 was strongest in PIN foci. CONCLUSIONS: Expression of Bax and Bcl-2 in normal epithelium of cancerous prostates suggests that increases in these indirect markers may reflect altered apoptotic control in these foci. Further studies are needed to show whether these changes represent the earliest step of the multifocal carcinogenetic process. Control of apoptosis seems to be involved and modulated during local progression of prostate cancer.