Application of the Milan system for reporting salivary gland cytopathology to core needle biopsies of the parotid gland.

AIMS: The Milan system for reporting salivary gland cytopathology was developed by an international group of experts and first published in 2018 with the goal to standardise reporting of salivary gland aspirates. Seven categories with distinct risks of malignancy were proposed. Core needle biopsies (CNB) of salivary glands are also common, but reporting lacks standardisation. Here we explore the feasibility of a Milan-like reporting system on CNB of the parotid gland. METHODS AND RESULTS: Our laboratory information system was searched for parotid gland CNBs from 2010 to 2021. Reports were translated into a Milan-like reporting system. When available, CNB findings were correlated with cytology and resection specimens. In order to compare the performance of CNB with fine-needle aspirations (FNA), we established a second cohort of cases consisting of parotid FNA with surgical follow-up. The risk of neoplasia (RON) and risk of malignancy (ROM) was calculated for FNA and CNB Milan categories using cases with follow-up resection. We analysed 100 cases of parotid gland CNB. Of these cases, 32 underwent subsequent resection, while 52 had concurrent FNA. A total of 20 cases had concurrent FNA and underwent follow-up resection. In 63 (63%) cases, a specific diagnosis was provided on CNB, with 18 cases undergoing follow-up resection having an accuracy rate of 94%. CONCLUSIONS: This study confirms the feasible of using a Milan-like system in the setting of parotid gland CNB with differentiation in RON and ROM. CNB allows assessment of architectural features that may allow more specific diagnoses in some cases.

Challenging differential diagnoses in small biopsies from the sinonasal tract.

Sinonasal biopsy specimens are a challenging area in anatomic pathology. The small, often fragmented or crushed nature of these biopsies can hinder morphologic assessment. Additionally, many of the tumors in this area are rare and share morphologic, and sometime immunophenotypic similarities. In many cases, immunohistochemistry is helpful if not necessary to reach a specific diagnosis. In other cases, a specific diagnosis is not possible and a differential diagnosis must be given on a biopsy specimen despite access to a well-equipped immunohistochemistry laboratory. This review article groups some of the more challenging entities in the sinonasal region based on morphologic patterns. These include low grade squamoid lesions such as sinonasal (Schneiderian) papilloma and DEK::AFF2 rearranged carcinoma, glandular neoplasms such as intestinal and non-intestinal type sinonasal adenocarcinoma, high-grade carcinomas such as HPV-related multiphenotypic sinonasal carcinoma, NUT carcinoma and SWI/SNF deficient carcinomas, small round blue cell tumors such as teratocarcinosarcoma, neuroendocrine carcinoma and olfactory neuroblastoma, and finally, low grade spindle cell neoplasms such as glomangiopericytoma, biphenotypic sinonasal sarcoma and solitary fibrous tumor.

The Increasing Problem of Syphilis Manifesting as Head and Neck Cancer: A Case Series.

Syphilis is an infectious disease caused by the spirochete Treponema pallidum. Rates have been rising in the US and globally. Known as the "Great Imitator," syphilis can involve head and neck subsites, and often can masquerade as possible carcinoma of the head and neck. Here, we present three distinct cases of syphilis presenting as suspected head and neck malignancy involving the oropharynx, larynx and oral cavity. All cases were diagnosed on surgical pathologic examination of diseased tissues and treated. It is important for practicing otolaryngologists to understand head and neck manifestations of syphilis to facilitate proper diagnosis and treatment. Laryngoscope, 134:236-239, 2024.

Fine needle aspiration biopsy of epithelioid-mesenchymal neoplasm with PTCH1-GLI1 fusion: A case report.

Mesenchymal tumors harboring GLI1 gene fusions are a rare new entity that typically occur in the head and neck region of young to middle aged adults, with a particular predilection for the tongue. We report herein a case of epithelioid mesenchymal tumor with PTCH1-GLI1 gene fusion of the right submental region in an 82-year-old male never smoker. Ultrasound-guided fine needle aspiration (FNA) with concomitant core needle biopsy was performed. Cytology smears revealed a hypercellular, monotonous aspirate comprised of epithelioid to plasmacytoid cells with round regular nuclei and moderate amounts of cytoplasm. There were admixed granulomata. The patient underwent surgical resection with limited neck dissection and subsequent pathologic examination with performed next generation sequencing confirmed the presence of epithelioid mesenchymal tumor with PTCH1-GLI1 gene fusion. To our knowledge, this is the first reported example of a mesenchymal tumor harboring GLI1 gene fusion initially evaluated by FNA.

Histology segmentation using active learning on regions of interest in oral cavity squamous cell carcinoma.

In digital pathology, deep learning has been shown to have a wide range of applications, from cancer grading to segmenting structures like glomeruli. One of the main hurdles for digital pathology to be truly effective is the size of the dataset needed for generalization to address the spectrum of possible morphologies. Small datasets limit classifiers' ability to generalize. Yet, when we move to larger datasets of whole slide images (WSIs) of tissue, these datasets may cause network bottlenecks as each WSI at its original magnification can be upwards of 100 000 by 100 000 pixels, and over a gigabyte in file size. Compounding this problem, high quality pathologist annotations are difficult to obtain, as the volume of necessary annotations to create a classifier that can generalize would be extremely costly in terms of pathologist-hours. In this work, we use Active Learning (AL), a process for iterative interactive training, to create a modified U-net classifier on the region of interest (ROI) scale. We then compare this to Random Learning (RL), where images for addition to the dataset for retraining are randomly selected. Our hypothesis is that AL shows benefits for generating segmentation results versus randomly selecting images to annotate. We show that after 3 iterations, that AL, with an average Dice coefficient of 0.461, outperforms RL, with an average Dice Coefficient of 0.375, by 0.086.

Thyroid sclerosing mucoepidermoid carcinoma with eosinophilia in conjunction with parotid basal cell adenoma: Cytologic, histologic, and molecular features.

Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a rare malignancy in the thyroid: only 56 cases with histologic descriptions are reported in the literature and fewer reports describe the cytomorphology. Given the rarity of SMECE, data on the cytomorphologic and molecular features are limited. We report a case of a 53-year-old woman with a 5 cm left thyroid mass. Fine-needle aspiration (FNA) revealed atypia of undetermined significance and pathology of left thyroid lobectomy specimen showed SMECE. Additionally, a left pre-auricular lump was noted and FNA followed by left superficial parotidectomy showed basal cell adenoma. Next-generation sequencing showed point mutations in NTRK3 and NF1. Unlike salivary gland mucoepidermoid carcinoma, MAML2 translocations are not present in SMECE. Even though it is a rare entity, awareness of SMECE of the thyroid is important. In this case report we review the cytomorphologic, histologic, and molecular features.

The utility of high-risk human papillomavirus E6/E7 mRNA in situ hybridization in assessing HPV status on cell block.

INTRODUCTION: Assessment of human papillomavirus (HPV) status is critical to the treatment and prognosis of patients with oropharyngeal squamous cell carcinoma. Patients often present with enlarged cervical lymph nodes which are amenable to fine needle aspiration (FNA) and cell block creation. The most widely used method for assessing HPV status is the surrogate marker p16. Other HPV specific methods such as high-risk HPV E6/E7 mRNA in situ hybridization (ISH) have been shown to perform as well as p16 and are easier to interpret. Our study evaluates the utility of high-risk HPV mRNA ISH in cell block specimens. METHODS: Thirty-six cases of metastatic squamous cell carcinoma in cervical neck lymph node FNAs were identified over a 3-year period. All cases had p16 immunohistochemistry (IHC) performed on cell block. HR HPV mRNA ISH was performed on the cell block and compared to the p16 results. Additionally, p16 and HR HPV mRNA ISH status was assessed in those cases with corresponding surgical resections. RESULTS: HR HPV mRNA ISH confirmed the p16 IHC (either positive or negative) in 24 of the 36 cases (66.7%). Six false negative cases were p16 negative/HR HPV mRNA ISH positive. HR HPV mRNA ISH was positive in 75% of the four p16 equivocal cases. Two cases were p16 positive/HR HPV mRNA ISH negative. CONCLUSIONS: HR HPV mRNA ISH is no more difficult to perform in the IHC lab and is easier to interpret than p16 IHC. HR HPV mRNA ISH is a useful alternative to p16 in cell block specimens.

ROC analysis of p16 expression in cell blocks of metastatic head and neck squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous cell carcinoma is associated with human papillomavirus (HPV) and often presents with early metastasis to cervical neck lymph nodes that are amenable to fine-needle aspiration (FNA). The most common method of HPV status determination is p16 immunohistochemistry (IHC). The literature suggests that a lower threshold is needed for p16 positivity on cell block. We examined and quantified p16 IHC staining on cell block and used receiver operating characteristics (ROC) curve analysis to determine an optimal cutoff value with high sensitivity and specificity. METHODS: Thirty-six FNAs of metastatic squamous cell carcinoma from cervical lymph nodes with p16 IHC were evaluated. The p16 stain was quantified in 5% increments and high-risk HPV mRNA in situ hybridization was performed as a gold standard test. Statistical analysis was performed. RESULTS: Interobserver variability was evaluated and was shown to be low with an intraclass correlation coefficient of 0.857. ROC analysis was performed and showed that a cell block p16 IHC cutoff of 15% yielded the highest sensitivity (80%) and specificity (81.8%). CONCLUSION: Our data show that a threshold of 15% p16 staining in cell block maximizes sensitivity and specificity.

Long-Term Maintenance of Acinar Cells in Human Submandibular Glands After Radiation Therapy.

PURPOSE: In a combined retrospective and prospective study, human salivary glands were investigated after radiation treatment for head and neck cancers. The aim was to assess acinar cell loss and morphologic changes after radiation therapy and to determine whether irradiated salivary glands have regenerative potential. METHODS AND MATERIALS: Irradiated human submandibular and parotid salivary glands were collected from 16 patients at a range of time intervals after completion of radiation therapy (RT). Control samples were collected from 14 patients who had not received radiation treatments. Tissue sections were analyzed using immunohistochemistry to stain for molecular markers. RESULTS: Human submandibular and parotid glands isolated less than 1 year after RT showed a near complete loss of acinar cells. However, acinar units expressing functional secretory markers were observed in all samples isolated at later intervals after RT. Significantly lower acinar cell numbers and increased fibrosis were found in glands treated with combined radiation and chemotherapy, in comparison to glands treated with RT alone. Irradiated samples showed increased staining for duct cell keratin markers, as well as many cells coexpressing acinar- and duct cell-specific markers, in comparison to nonirradiated control samples. CONCLUSIONS: After RT, acinar cell clusters are maintained in human submandibular glands for years. The surviving acinar cells retain proliferative potential, although significant regeneration does not occur. Persistent DNA damage, increased fibrosis, and altered cell identity suggest mechanisms that may impair regeneration.

The Utility of Thromboelastography to Guide Blood Product Transfusion.

OBJECTIVES: To provide an overview of the clot viscoelastic testing technology and to describe its utility in guiding blood product transfusions. METHODS: A case scenario will be discussed as well as interpretation of thromboelastography (TEG) tracings. In addition, literature examining the utility of viscoelastic testing in guiding patient management and blood product transfusions will be reviewed. RESULTS: TEG/rotational thromboelastometry (ROTEM) is useful in evaluating clot kinetics in trauma and acutely bleeding patients. TEG/ROTEM parameters are reflective of values measured using standard coagulation assays; however, TEG/ROTEM parameters are more rapidly available and more costly. TEG and ROTEM are used in three main settings: cardiac surgery, liver transplantation, and trauma to assess global hemostasis and administration of blood products. CONCLUSIONS: TEG/ROTEM can be helpful in guiding resuscitation and blood product transfusion. Several studies have demonstrated a reduction in transfusion of blood components with TEG/ROTEM; however, other studies have suggested that TEG/ROTEM is not clinically effective in guiding transfusion.

Primary Dedifferentiated Amelanotic Anorectal Melanoma: Report of a Rare Case.

Anorectal melanoma (ARM) is an uncommon aggressive malignancy that comprises 0.5% to 1.6% of all melanoma manifestations. Dedifferentiated melanoma is very rare with loss of all melanocytic differentiation markers and is usually seen in metastatic melanoma of cutaneous origin. In this article, we report the first case of primary dedifferentiated amelanotic ARM in a 68-year-old male who presented with anal discomfort that was initially treated as inflamed hemorrhoids. Physical examination revealed a large protruding anal mass, biopsy of which showed biphasic malignant tumor cells with distinct immunoprofiles: a superficial spindled/sarcomatoid component positive for SOX10 and S100, and a deeper epithelioid/rhabdoid component positive for desmin, AE1/AE3, and EMA. Both components were negative for HMB-45, Melan-A/MART-1, c-Kit, and other lineage markers. Molecular analysis by polymerase chain reaction demonstrated wild-type BRAF and KRAS genes. A diagnosis of dedifferentiated ARM was made based on the coexistence of a differentiated component (spindled: S100 and SOX10 positive) and a dedifferentiated component (epithelioid: all melanoma markers including S100 and SOX10 negative). Shortly afterwards, the patient developed extensive pulmonary and liver metastases and expired 20 days after the diagnosis was rendered, reinforcing the highly aggressive nature of this disease entity.

Enhanced spectral analysis of blood flow during post-occlusive reactive hyperaemia test in different tissue depths.

The objective of this study was to investigate the impairment of microcirculation in schizophrenic patients by means of spectral analysis of blood flow signals and to determine if microcirculation is unequally altered in different tissue depths. Furthermore, the impact of gender and age on the spectral parameters of the Laser Doppler Flowmetry (LDF) signal in healthy and diseased microcirculation are to be analysed. The segmented spectral analysis (SSA) algorithm was applied to LDF signals of a provoked post-ischemic stage and compared to the traditional total spectral analysis, hypothesizing that SSA reveals more detailed information on the dynamic behaviour of the blood flow. 15 healthy subjects (CON, mean age 32.4 years) and 15 patients (PAT, mean age 33.0 years) were enrolled. Spectral analysis was performed on two LDF signals at a depth of 2mm and 6-8mm. Features in five frequency subintervals were determined. Our results indicate that microcirculation is strongly impaired in patients. SSA of blood flow revealed differences between CON and PAT in all three frequency intervals referring to local vasomotion (endothelial p=0.03; sympathetic p=0.02, myogenic p=0.03) as well as the respiratory (p=0.02) and cardiac (p=0.006) bands in the deeper tissue. In contrast, in the near-surface tissue only the endothelial (p=0.006) and cardiac (p=0.006) components were altered. Furthermore, SSA determined a gender- and age dependency regarding blood flow. In conclusion, we could demonstrate that microcirculation in schizophrenic patients is significantly impaired, depending on its location in the near-surface skin or in the superficial muscle tissue. These alterations of microcirculation are more pronounced in the deeper tissue depth of about 6-8mm and are influenced by gender and age.

Dynamic microvascular blood flow analysis during post-occlusive reactive hyperemia test in patients with schizophrenia.

Patients suffering from schizophrenia have an increased mortality risk due to cardiovascular events. Recently the analysis of peripheral circulation has revealed interesting results in the study of vascular pathological conditions assuming that the state of microcirculation of the skin is at least partly representative for the constitution of other vascular beds including those of the cardiac muscle and arteries. The objective of this study was to investigate the microcirculation in patients with acute schizophrenia (PAT, n = 15, mean age 33.0 years, 7 male, 8 female) to identify whether spectral features from blood flow signals derived through laser Doppler spectrometry are significantly altered compared to healthy subjects (CON, n = 15, mean age 32.4 years, 7 male, 8 female) by means of the post-occlusive reactive hyperemia test. It was also explored if a segmentation of the post-ischemic stage can disclose more detailed and additional information about the dynamic behavior of the blood flow during hyperemic response. For this reason, time-frequency analyses were performed to observe the course of the blood flow frequency components over time. Our results indicate significant differences in the patients group, already detectable under baseline conditions but also in the hyperemic phase. The main modifications affect the respiratory (p = 0.006) as well as the cardiac (p = 0.001) activity. It was further shown that the application of a segmented analysis of the post-ischemic state considerably improves the differentiation between both groups. Only with the introduced segmentation algorithm using a window length of 2048 samples and a shift of 128 and 256 samples we could demonstrate influences of the disease on the endothelial (p = 0.029), the sympathetic (p = 0.019) and the myogenic (p = 0.029) mechanisms. These information provide further insights into the appearance of schizophrenia and could lead to an improvement of the patients' treatment to avoid the occurrence of cardiovascular events.

Peripheral endothelial dysfunction in patients suffering from acute schizophrenia: a potential marker for cardiovascular morbidity?

Patients suffering from schizophrenia have an increased standardized ratio for cardiovascular mortality compared to the general population. Endothelial function was identified as a prominent parameter for cardiac risk stratification in patients with heart disease. Here, we aimed to analyze the reactivity of the microcirculation applying the post-occlusive reactive hyperemia (PORH) test and spectral analysis of skin vasomotion as markers of endothelial function. We investigated 21 unmedicated patients suffering from paranoid schizophrenia as well as 21 matched controls. The capillary blood flow was assessed on the right forearm after compression of the brachial artery. Parameters of PORH such as time to peak (TP) or PORH index were calculated. In addition, spectral analysis of skin vasomotion was performed and five frequency bands (endothelial, sympathetic, vascular myogenic, respiratory and heart beat activity) were studied. Psychotic symptoms were quantified using the Positive and Negative Syndrome Scale (PANSS) and correlated to the parameters obtained. We report a blunted hyperemic response in patients after occlusion of the brachial artery indicated by significantly increased TP and decreased PORH indices. In contrast, vasomotion as investigated by spectral analysis of skin flow was rather sparsely altered showing differences at rest for the sympathetic and cardiac components only. Our results are suggestive of peripheral endothelial dysfunction in unmedicated patients suffering from schizophrenia. Future, prospective studies should address the relation of endothelial dysfunction to cardiac morbidity in patients with schizophrenia.

Increased sensitivity to heat pain after sad mood induction in female patients with major depression.

Patients suffering from major depressive disorder (MDD) have been shown to exhibit increased thresholds towards experimentally induced thermal pain applied to the skin. In contrast, the induction of sad mood can increase pain perception in healthy controls. Here, we aimed to test the hypothesis that heat pain thresholds are further increased after sad mood induction in depressed patients. Thermal pain thresholds were obtained from 25 female depressed patients and 25 controls before and after sad mood induction applying a modified Velten Mood Induction procedure (MIP). Valence and arousal ratings were obtained using the self-assessment manikin. The Montgomery Depression Rating Scale and the Beck Depression Inventory (BDI) were obtained at baseline from all participants. Pain thresholds at baseline did not significantly differ between groups. Pain thresholds and valence of mood significantly decreased both in patients and controls, while arousal showed an inverse time course between groups. Therefore, our hypothesis could not be confirmed. From these data, we propose that the depressed mood as seen in MDD patients influences pain experience differently as compared to the shorter-lasting mood change after MIP. A differential interaction of both affective states with brain areas of the pain matrix might be assumed. Eventually, the induction of sad mood might mirror the increased number of pain complaints in depressed patients and thus adds to the current concept of adjuvant antidepressant treatment both in depressed patients with pain complaints and in chronic pain patients.