Atypical Mitoses Research Articles

Deciphering Plasmodium Condensin Core Subunits of Structural Maintenance of Chromosomes 2 (SMC2) as a Putative Drug Target for Antimalarial Drug

Background: The structural maintenance of chromosomes (SMC) proteins plays a noteworthy role in chromosome dynamics. Several recent studies reported that the condensin core subunits of structural maintenance of chromosomes 2 (SMC2) play important roles in the atypical mitosis of the Plasmodium life cycle and may perform different functions during different proliferative stages. For eukaryotes, the structural maintenance of chromosomes (SMC) proteins are divided into six subunits and form three heterodimers of structural maintenance of chromosomes (SMC1/3) cohesion complex, structural maintenance of chromosomes (SMC2/4) condensin complex, and structural maintenance of chromosomes (SMC5/6) complex for chromosome cohesion, condensation, and DNA damage repair, respectively. Objective: The objective of this study was to investigate the structural maintenance of chromosomes 2 (SMC2) protein of P. falciparum as a putative drug target of malariacausing Plasmodium falciparum. Methods: In this study, we investigated the structural maintenance of chromosomes 2 (SMC2) protein of P. falciparum as a putative drug target of malaria-causing P. falciparum by using in-silico approaches like Homology modeling, in-silico evaluation of the modeled structure, molecular docking study to investigate the interaction of receptor-ligand, and molecular dynamic simulation study with MM calculation. Results: We reported the structural maintenance of chromosomes 2 (SMC2) protein of P. falciparum as a potent drug target that can pave the way for novel drug discovery to mitigate malaria. Conclusion: In-silico-based studies play a significant role in understanding any protein for potential drug development.

Artificial intelligence-based automated determination in breast and colon cancer and distinction between atypical and typical mitosis using a cloud-based platform

Artificial intelligence (AI) technology in pathology has been utilized in many areas and requires supervised machine learning. Notably, the annotations that define the ground truth for the identification of different confusing process pathologies, vary from study to study. In this study, we present our findings in the detection of invasive breast cancer for the IHC/ISH assessment system, along with the automated analysis of each tissue layer, cancer type, etc. in colorectal specimens. Additionally, models for the detection of atypical and typical mitosis in several organs were developed using existing whole-slide image (WSI) sets from other AI projects. All H&E slides were scanned by different scanners with a resolution of 0.12–0.50 μm/pixel, and then uploaded to a cloud-based AI platform. Convolutional neural networks (CNN) training sets consisted of invasive carcinoma, atypical and typical mitosis, and colonic tissue elements (mucosa-epithelium, lamina propria, muscularis mucosa, submucosa, muscularis propria, subserosa, vessels, and lymph nodes). In total, 59 WSIs from 59 breast cases, 217 WSIs from 54 colon cases, and 28 WSIs from 23 different types of tumor cases with relatively higher amounts of mitosis were annotated for the training. The harmonic average of precision and sensitivity was scored as F1 by AI. The final AI models of the Breast Project showed an F1 score of 94.49% for Invasive carcinoma. The mitosis project showed F1 scores of 80.18%, 97.40%, and 97.68% for mitosis, atypical, and typical mitosis layers, respectively. Overall F1 scores for the current results of the colon project were 90.02% for invasive carcinoma, 94.81% for the submucosa layer, and 98.02% for vessels and lymph nodes. After the training and optimization of the AI models and validation of each model, external validators evaluated the results of the AI models via blind-reader tasks. The AI models developed in this study were able to identify tumor foci, distinguish in situ areas, define colonic layers, detect vessels and lymph nodes, and catch the difference between atypical and typical mitosis. All results were exported for integration into our in-house applications for breast cancer and AI model development for both whole-block and whole-slide image-based 3D imaging assessment.

Phyllodes - like Tumor of the Anogenital Mammary - like Glands – A Rare Entity

Abstract Introduction/Objective Phyllodes tumor (PT), a biphasic fibroepithelial tumor typically found in the breast, is an exceedingly rare finding outside the mammary gland, with only about 160 cases reported to date. We describe a rare case of PT arising from anogenital mammary-like glands (AGMLG). Methods/Case Report A 68-year-old woman presented with a small perianal mass that was incidentally detected during hemorrhoidectomy procedure. It appeared as a pedunculated olive-sized mass on the perianal skin. A papillectomy was performed, and upon sectioning, a solid-cystic lesion measuring 2.0 x 1.4 x 0.9 cm was observed. Microscopic examination revealed a biphasic pattern comprising of glandular epithelium and a stromal component, with a predominance of the latter and together they formed leaf-like slits. These spaces were lined by a bilayered epithelium consisting of secretory (apocrine)-type cells and myoepithelial cells resembling mammary glandular epithelia. Focal clusters of benign glands, morphologically consistent with AGMLGs, were identified at the periphery of the tumor. Immunohistochemically, epithelial components reacted positively for GATA3, mammoglobin, CK7, estrogen receptor and progesterone receptor, while the myoepithelial cells were highlighted by calponin and p63. The AGMLGs in the periphery also stained for GATA3, estrogen receptor and progesterone receptor. The mitotic rate was low (1 to 2 per 50 high-power fields), without atypical mitoses. The lesion was diagnosed as a benign PT. Results (if a Case Study enter NA) NA Conclusion The current case highlights the importance of recognizing PT when it occurs at extra-mammary locations. The entity merits greater attention not only for its malignant potential but also due to the mystery surrounding its origin and the histogenetic link to breast tissue.

Keratin 20 positive SDH-deficient renal cell carcinoma: a case report and literature review

This study aims to broaden the morphological scope of SDH-deficient renal cell carcinoma and to assist clinicians and pathologists in better understanding this entity to prevent misdiagnosis. This study used immunohistochemistry staining and the first-generation sequencing Sanger method for gene detection. It retrospectively analysed the clinical pathology, molecular characteristics, biological behaviour, and treatment information of one case of SDH-deficient renal cell carcinoma. The patient was a 57-year-old female with right back pain for more than 20 days and had no personal or family history of kidney tumours. In addition, the tumour cells had clear boundaries in morphology, and residual normal renal tubules could be seen around them. There were also ossification and adipose tissue around the tumour centre. The tumour cells were arranged in a glandular tubular and cord-like manner. Vacuolar and eosinophilic inclusion bodies could be observed in the cytoplasm. The nucleus was regular, the chromatin distribution was fine, and there were no obvious nucleoli. They were low-grade nuclei. In addition, no atypical mitosis or necrosis could been found. Furthermore, immunohistochemistry staining showed SDHB-negative and keratin 20 -positive tumour. Meanwhile, the first-generation sequencing also pointed out the presence of SDHB gene mutations in the tumour. After 12 months of follow-up, there was no evidence of disease recurrence in the patient. SDH-deficient renal cell carcinoma is a rare tumour associated with SDH gene germline mutations, and suspected cases should undergo SDHB immunohistochemistry staining. Most SDH-deficient renal cell carcinomas have a good prognosis, but undifferentiated cases require long-term follow-up.

8774 An Uncommon Presentation Of A Large Silent Pheochromocytoma

Abstract Disclosure: M. Lozano: None. A. Pinero-Pilona: None. Background: The reported estimated incidence of pheochromocytoma is approximately 2-8 cases per 1 million people per year. Of those, silent pheochromocytomas will make up about 8%. Thus, biochemically silent and non-secreting pheochromocytomas are a very rare phenomenon. Clinical Case: A 74-year-old Caucasian female with significant past medical history of primary hypothyroidism, hypercholesterolemia, and nasal sinus carcinoma s/p surgery (in remission) presented to the clinic for endocrine evaluation of a right adrenal mass. The patient was asymptomatic and denied headaches, tachycardia, sweating, severe hypertension, diabetes, muscle weakness, easy bruising, or striae. The mass was initially diagnosed as an incidental finding after a contrast CT scan of the abdomen was performed for diverticulitis. The right adrenal enhancing mass was 2.3 x 3.9 x 4.1 cm in diameter. Subsequent MRI abdomen with and without contrast ordered by the referring physician showed that the adrenal mass had grown to 4.9 x 3.8 x 5.4 cm and was hyperenhancing in nature with central T2 hyperintense signal. Notably, multiple “parasitized and arborealized” vessels were detected within the mass. Such findings led us to suspect metastatic versus primary adrenal neoplasm such as cortical carcinoma as a working diagnosis. Other laboratory studies including plasma free metanephrines (<10 pg/mL, normal 0-88 pg/mL), plasma normetanephrines (29.2 pg/mL, normal 0-285.2 pg/mL) and 24-hour urine collections (24 hr urine epinephrine - 3 ug/24 hr [normal 0-20 ug/24 hr]; 24 hr urine norepinephrine - 75 ug/24 hr [normal 0-135 ug/24 hr]; 24 hr urine VMA - 3 mg/24 hr [normal 0-7.5 mg/24 hr]) were negative for pheochromocytoma. As her mass was greater than 4 cm in diameter, surgical referral was then recommended to the patient. Right adrenalectomy was performed. Pathology report was consistent with pheochromocytoma as supported by immunohistochemistry. Ki-67 proliferation index was 0-10% (average 3-4%, rare hotspots 10%). Atrophy and vascular ectasia were present in residual non-neoplastic adrenal cortex and medulla. Histology showed a nested growth pattern, absence of composite tumor elements, absence of necrosis, and no atypical mitoses. The incidence of non-secreting pheochromocytomas has been quoted to be 0.000064% (1). Conclusion: The case illustrates an uncommon presentation of a large, silent pheochromocytoma with negative plasma metanephrines accompanied by negative urine studies, which have a negative predictive value close to 100% in ruling out a pheochromocytoma. Our case emphasizes the importance of considering pheochromocytoma on the differential of adrenal masses with high attenuation or high enhancement even when biochemical studies suggest otherwise. Reference: (1) Radojkovic, D., et al. "CLINICALLY" SILENT GIANT PHEOCHROMOCYTOMA. CASE REPORT." Acta Endocrinologica (1841-0987) 9.1 (2013). Presentation: 6/1/2024

8769 A Case of Metastatic and Catecholamine Producing Bilateral Pheochromocytoma in a Patient with RET Gene Mutation

Abstract Disclosure: R.A. Mayers: None. A. Szafran-Swietlik: None. RET mutation, observed in multiple endocrine neoplasia type 2 syndromes, is implicated in the development of pheochromocytomas of the kinase signaling cluster. Such tumors have lower metastatic risk and adrenergic production compared to the ones from the other clusters. We present a case of a metastatic, bilateral, small and biochemically active pheochromocytoma .This is the case of a 27-year-old man diagnosed with MEN 2A. He underwent total thyroidectomy due to medullary thyroid carcinoma at 2 years old. He was deemed cured and started on levothyroxine replacement. Since then, his plasma metanephrines by liquid chromatography-mass spectrometry and urine metanephrines done in a yearly basis as screening, were always within range of normality. Over the years, he developed substance abuse disorder with use of Kratom and methamphetamines and was admitted in a rehabilitation center multiple times in the last three years. During this time, the patient was reported to be slightly tachycardiac which was initially attributed to the use of substances. On the last year, an echocardiogram done as evaluation of his tachycardia showed an ejection fraction of 35%. Later, his annual metanephrine levels were markedly elevated (free metanephrine: 137 pg/mL and free normetanephrine : 157 pg/mL, normal ranges reported as less than 57 pg/mL and less than 148 pg/mL respectively). Abdominal tomography showed a right adrenal nodule of 1.2 cm and a left adrenal nodule of 1.6 cm, both with more than 10 Hounsfield Units. A Metaiodobenzylguanidine scan revealed a left adrenal nodule of 1.8 cm with diffuse radiotracer uptake, a right adrenal nodule of 1.2 cm with radiotracer activity and 3 subtle areas of focally increased radiotracer activity in the liver, two in left hepatic lobe and other in posterior right upper lobe. He underwent bilateral adrenalectomy with cortical sparring. Pathology results evidenced a left adrenal with a unifocal mass of 1.8 cm and a right adrenal with a mass of 1.2 cm , both without lymphovascular, capsular, local invasion or necrosis, a mitotic rate of 1-2 without atypical mitosis, not encapsulated with clean margins and positive for synaptophysin , chromogranin and S100 stains. An additional mass of 0.7 cm on the right adrenal gland was described with similar characteristics to the described before except for the involvement of the surgical margins. Currently on the literature there are different opinions regarding screening approach for pheochromocytomas in the presence of RET mutations. There are not strong recommendations regarding the use of imaging as a screening tool in this group of patients. It is important to consider that there are cases, as the one described in this report, that might present metastatic disease even with the presence of small pheochromocytomas that belong to the cluster of kinase signaling. Presentation: 6/3/2024

Neural network model development for detecting atypical mitoses in histological slides

Background: Modern computer systems allow digitizing and examining images of histological preparations, which led the authors to the idea of using machine learning tools in digital pathohistology. The ability of neural networks to find sub-visual image features in digitized histological preparations provides the basis for better qualitative and quantitative image analysis. Existing machine learning methods provide good accuracy and speed in recognizing various images, which gives hope for their wide application, including in oncologic diagnostics. AIM: Use methods of mathematical modeling to identify pathological mitoses in histological preparations as the main sign of the difference between malignant and benign tumor growth. MATERIALS AND METHODS: Histological images of the N.N. Priorov National Medical Research Center of Traumatology and Orthopedics were used as a data set for the neural network model. The model was tested using 188 histologic slides from 67 patients treated at the institute. Histological preparations were scanned on a Leica Aperio CS2 microscope with a ×400 resolution and converted into JPEG format with further processing. Next, the test images were analyzed in streaming mode using the created neural network model in order to obtain the coordinates of the desired diagnostic object — pathological mitosis and the probability with which the model found the object of this category. The obtained images were analyzed by a pathologist to determine whether the detected object corresponded to pathological mitosis. RESULTS: The authors have chosen an architecture, developed a methodology for training a neural network, and created a model that can be used to detect pathologic mitoses in histologic preparations. The authors do not attempt to replace the physician, but show the possibility of an integrated approach to data analysis by a computer system and a pathologist. Conclusions: The developed mathematical model of neural network used as a part of technological solution for recognizing pathological mitoses in scanned histological preparations can be used as a tool to reduce the time of research and increase the accuracy of diagnosis by a pathologist.

Leiomyosarcoma of the esophagus, arising from lamina muscularis mucosae, in a combination with microinvasive squamous cell carcinoma-A case report.

Leiomyosarcoma of the esophagus is a very rare disease, accounting for less than 0.5% of malignant esophageal tumors. Esophageal leiomyosarcoma combined with squamous cell carcinoma is even rarer than solitary leiomyosarcoma. To our knowledge, there are less than ten cases of simultaneously diagnosed leiomyosarcoma and squamous cell carcinoma of the esophagus. A 66-year-old male was admitted to our hospital suffering from epigastric pain, asthenia, weight loss, and difficulties when feeding with solid food which had been present for 2 weeks. A computed tomography scan showed a large tumor tissue mass in the mid-to-distal part of the esophagus. The patient underwent robot-assisted surgery-an esophagectomy with esophagogastrostomy. Histologically, the tumor consisted of highly pleomorphic spindle cells with multiple atypical mitosis and necrotic areas. An immunohistochemical examination was performed to distinguish leiomyosarcoma from spindle cell squamous carcinoma or malignant GIST. Tumor cells stained diffusely positive for smooth muscle actin, but negative for p63, CD117, and CKAE1/AE3. Tumor invasion involved mucosa and submucosa, without tunica muscularis propria. Microinvasive well-differentiated squamous cell carcinoma was also noted in the mucosa at the borders between the tumor and the healthy part of the esophagus. The aim of the manuscript is to present an extremely rare case of combined polypoid leiomyosarcoma and microinvasive squamous cell carcinoma of the esophagus, cured by robot-assisted surgical intervention and to emphasize that such cases should be examined carefully, including additional diagnostic tests such as Immunohistochemistry (IHC) in order to define the correct diagnosis.

Collecting Duct Carcinoma in the Kidneys: A Rare Case Report

Background: Collecting duct carcinoma (CDC) is one of the rare pathological subtypes of renal cell carcinoma, with high malignancy and poor prognosis. Pathological examination is the gold standard in confirming the diagnosis of CDC. CDC is described as a tumor that has a tubulopapillary architecture and forms a hobnail pattern along the glandular tube. Case presentation: A 56-year-old woman with the main complaint of a lump in the right abdomen for 1.5 months before entering the hospital. The lump in the stomach is getting bigger, complaints are accompanied by intermittent pain, nausea, vomiting, body feeling weak, and decreased appetite. The patient then underwent a CT-Scan examination of the abdomen and concluded that fluid/water was found next to the right kidney, and a hypodense lesion appeared in segment 6 of the right lobe of the liver. Histopathological examination of large tissue shows pieces of kidney tissue with a connective tissue capsule on the outside containing glomeruli and tubules lined by cuboidal epithelium as well as a proliferation of tumor cells that grow infiltratively in the connective tissue stroma which is partly desmoplastic and fatty tissue between the glomeruli and tubules. Tumor cells are arranged to form tubulopapillary and tubulocystic structures. These cells with pleomorphic nuclei, some hyperchromatic, some vesicular, coarse chromatin, clear nuclei, and atypical mitoses can be found and tumor cell embolism in the blood vessels and perineural invasion can be seen. There were spots and clusters of lymphocytes and plasma cells as well as areas of bleeding and necrosis. Conclusion: The patient was diagnosed with collecting duct carcinoma (CDC).

Poorly differentiated thyroid cancer: Clinical, pathological, mutational, and outcome analysis.

Poorly differentiated thyroid cancer (PDTC) remains a challenge not only for pathologists and surgeons because of the difficulties associated with the diagnostic process and the compelling need for difficult thyroidectomy, but it is also of high clinical relevance because it is responsible for mortality in non-anaplastic follicular cell-derived thyroid cancer. Cases of PDTC within a 30-year period were reviewed by two independent pathologists. Histological features like atypical mitosis, necrosis, capsular, and vascular invasion were studied. Mutation analysis was done for BRAF, RET/PTC, RAS, and PI3KCA, and P53 was performed using immunohistochemistry. There were 39 patients with a median age of 53 years; 14 patients were more than 55 years of age. At presentation, 38.4% had compressive features and the median tumor size was 9 cm. At presentation, 67.7% had an extrathyroidal extension (ETE). R0 resection was achieved in 41%, with 12 cases resulting in a difficult thyroidectomy. Necrosis was seen in 65.7% and mitosis in 73.3% with well-differentiated components in 41%. The commonest mutation was RAS (23.1%). Survival was higher in the operable group (54.26, 95% confidence interval [CI]: 30.83-77.70 vs. 20.25, 95% CI: 0-54.07) months, respectively; however, 10-year survival was only 5% and only the tumor size and presence of mitosis were independent risk factors. PDTC presents with worrisome features like large size, ETE, and rapid growth. Aggressive surgical resection with extended/radical thyroidectomy may result in better loco-regional control and improved survival. RAS was the frequent mutation detected. It is worthwhile to identify prognostic factors that can predict the course of PDTC.

Abstract 6184: A novel approach to Barrett's esophagus risk stratification: Whole-slide image analysis for aneuploidy detection

Abstract Background Barrett’s esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC) and there is a need for biomarkers in BE for risk stratification for cancer progression. Aneuploidy has been suggested as a factor in the development, initiation or progression of EAC in patients with BE, and it has been found predictive for EAC progression (Hadjinicolaou, et al. 2020, Sikkema, et al. 2009). However, current assays for detecting aneuploidy require valuable tissue, hence validation studies are limited. We hypothesise that routine histology images can be used to detect ploidy status. We aim to develop a sensitive, accurate, and easy-to-use deep learning tool for this purpose. Methods We used a weakly supervised deep learning-based approach called clustering-constrained-attention multiple-instance learning (CLAM) (Lu et al., 2021) to detect aneuploidy on hematoxylin and eosin-stained whole slide images of endoscopical biopsies from BE, for which the ploidy status had been determined by flow cytometry. To benchmark the model’s performance, we also trained a traditional fully supervised algorithm, ResNet50 (He et al., 2016), with the same dataset. The models were trained on 388 slides (51 aneuploid) from the Seattle Barrett’s Esophagus Annotated Resource (BEAR) and then applied to an independent test cohort of BEAR patients, consisting of 279 slides (36 aneuploid). Results The multi-attention-branch CLAM model achieved AUC of 0.82 and 76.4% balanced accuracy for aneuploidy on the internal test subset (10% of the cohort). On the independent test dataset, the model achieved AUC of 0.85 and 79.3% balanced accuracy, while performance of the fully supervised model was AUC of 0.65 and 33.1 balanced accuracy. In a challenging subset for image-based diagnosis, including 253 samples (29 aneuploid) without dysplasia or atypical mitosis (a major feature of aneuploidy samples) the model achieved a 67.6% accuracy and an AUC of 0.83. Both the flow results (p=2.84e-7) and the model's predictions (p=2.18e-3) revealed a correlation between progression to EAC and ploidy status. Conclusion We developed a deep learning model for predicting aneuploidy in BE biopsies. The weakly-supervised approach can perform much better compared to the traditional fully-supervised model. Aneuploidy is correlated with cancer progression and stands as a promising candidate for the prediction of cancer progression in BE patients. Although atypical mitosis is the primary histological indicator of aneuploidy, our model can still make aneuploid predictions in the absence of atypical mitosis, as it doesn't rely solely on a single parameter. Our model is efficient, capable of processing hundreds of samples resource-effectively, and thus an ideal adjunct to standard histologic evaluation. This classifier may facilitate molecular-based improvements in identifying individuals at high risk of progression. Citation Format: Caner Ercan, Xiaoxi Pan, Thomas G. Paulson, Matthew D. Stachler, Carlo C. Maley, Yinyin Yuan. A novel approach to Barrett's esophagus risk stratification: Whole-slide image analysis for aneuploidy detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6184.

MED15::ATF1-Rearranged Tumor: A Novel Cutaneous Tumor With Melanocytic Differentiation

We recently described novel dermal tumors with melanocytic differentiation and morphologic and biological similarities to cutaneous clear cell sarcoma, including CRTC1::TRIM11 cutaneous tumor, and clear cell tumors with melanocytic differentiation and either ACTIN::MITF or MITF::CREM. Here, we describe a series of 3 patients presenting with tumors reminiscent of CRTC1::TRIM11 cutaneous tumor, found to demonstrate a novel MED15::ATF1 fusion. All 3 patients were children (5-16 years old). Primary excision of case 1 showed a circumscribed wedge-shaped silhouette with peripheral intercalation into collagen fibers and scattered lymphoid aggregates. All 3 tumors abutted the epidermis; one showed a junctional component. Tumors were highly cellular and comprised of monomorphic, oval-to-round epithelioid cells arranged in vague nests and short fascicles in variably fibrotic stroma. Mitotic rate was high (hotspot 6-12/mm2), without atypical mitoses. Necrosis was focally present in case 3. All cases showed strong, diffuse nuclear staining for SOX10 and MITF (2/2) but showed variable expression for S100 protein (1/3) and other melanocytic markers—Melan-A (focal in 2/3), HMB45 (focal in 1/3), and Pan-Melanoma (patchy in 1/1). Whole-exome RNA sequencing demonstrated a MED15::ATF1 fusion without any other notable alterations. Cases 1 and 2 were completely excised without recurrence (12 months). Case 3 developed a grossly apparent regional lymph node spread shortly after primary biopsy. The patient was treated with wide excision, radiation, cervical lymph node dissection (4/46 with >75% lymph node replacement), and neoadjuvant and adjuvant nivolumab (alive without disease at cycle 11). This series is presented to aid in future diagnosis of this novel dermal tumor with melanocytic differentiation and emphasize the potential for aggressive biologic behavior, which should be considered in patient management planning.

Adrenal cortical carcinoma in children: a clinicopathological analysis of 25 cases

Objective: To investigate the clinicopathological features, diagnosis and differential diagnosis of adrenal cortical carcinoma (ACC) in children. Methods: Twenty-five children with ACC diagnosed in the Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China from March 2014 to August 2022 were retrospectively analyzed. The related literature was reviewed. Results: A total of 25 children with ACC were collected, including 11 males and 14 females, with a male to female ratio of 1.0∶1.3. The patient ages ranged from 8 months to 14 years (median, 4 years). Eighteen cases with clinical data had functional tumors (18/22, 81.8%) presenting with virilization or precocious puberty (15/18), symptoms related to hypercortisolism (8/18) or endocrine symptoms mixed with both (5/18), while 3 cases (3/22, 13.6%) had unknown clinical data. The clinical manifestations of four patients with nonfunctional tumors were an abdominal mass and/or abdominal pain, walking instability and others. Grossly, the average maximum diameter of the tumor was 9.4 cm. Most of the tumors were nodular and partially encapsuled. The cut surfaces were gray or gray brown, soft with hemorrhage. Histologically, the tumor cells were diffusely distributed, separated by a vascular-rich network. The tumor cells were large, with distinct nucleoli, abundant eosinophilic or clear cytoplasm, and round or oval nuclei. The mitotic index was high, and atypical mitoses were common. Necrosis, calcification, capsule invasion or/and venous invasion were present. In some cases, the tumor invaded the surrounding soft tissues or kidneys. Immunohistochemically, the tumor cells were diffusely positive for syn and SF1 and focally positive for α-inhibin, Melan A and Calretinin, but negative for CgA. Ki-67 proliferation index ranged from 2%-90%. TP53 gene status was examined in 7 cases, in which mutations were detected in 4 cases. Follow-up data was obtained in 21 patients, among whom 18 received chemotherapy and 3 received radiotherapy. Distant metastasis occurred in 13 patients. Median progression-free survival (PFS) was 11.2 months and median overall survival (OS) was 54.7 months. Patients aged less than 5 years had a better prognosis for OS (P<0.05) than the older ones (≥5 years), but a similar PFS (P>0.05). Male patients and Ki-67 proliferation index <15% had a better prognosis tendency for OS, but there was no statistically significant difference (P>0.05). Conclusions: ACC in children is a rare, often functional tumor associated with Li-Fraumeni genetic syndrome and has a poor prognosis. Diagnosis and differential diagnosis require a combination of morphological, phenotypic and clinical analysis.

Clinical and Pathological Predictors of Death for Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare and lethal disease with a poor prognosis. This study aims to share our 41-year experience as a referral center, focusing on identifying risk factors associated with ACC mortality. Our retrospective analysis included a cohort of 150 adult patients with ACC in all stage categories, treated between 1981 and 2022. Tumor hormonal hypersecretion was observed in 78.6% of the patients, and the median age of diagnosis was 40 years. The majority presented as European Network for the Study of Adrenal Tumors (ENSAT) III or IV (22.9% and 31.2%, respectively), and the overall mortality rate was 54.6%. Independent predictors of death were elevated secretion of cortisol (HR = 2.0), androstenedione (HR = 2.2), estradiol (HR = 2.8), 17-OH progesterone (HR = 2.0), and 11-deoxycortisol (HR = 5.1), higher Weiss (HR = 4.3), modified Weiss (HR = 4.4), and Helsinki scores (HR = 12.0), advanced ENSAT stage (HR = 27.1), larger tumor size (HR = 2.7), higher Ki-67 percentage (HR = 2.3), and incomplete surgical resection (HR = 2.5). Mitosis greater than 5/50 high-power field (HR = 5.6), atypical mitosis (HR = 2.3), confluent necrosis (HR = 15.4), venous invasion (HR = 2.8), and capsular invasion (HR = 2.4) were also identified as independent predictors of death. Knowing the risk factors for ACC's mortality may help determine the best treatment option.

Undifferentiated Embryonal Sarcoma of Liver- A Rare Case Entity

Undifferentiated Embryonal Sarcoma of the Liver (UESL) is a rare hepatic malignant mesenchymal neoplasm in the paediatric population, typically affecting children between 6-10 years of age without sex predilection. It accounts for 9-15% of paediatric liver malignancies, with an incidence of 0.6-1.2 cases per one million patients. Here, the authors present a case of an 11-year-old male, who presented with right upper quadrant pain, loss of appetite for the past one month, and high-grade fever for the past three days. On examination, a firm mass in the right hypochondrium and epigastrium, about 4 cm below the right costal margin, was noted, moving with respiration. Blood work showed normal values and normal alpha-fetoprotein levels. An ultrasonogram revealed a cystic lesion, while a contrast-enhanced Computed Tomography (CT) scan showed a large hepatic space-occupying lesion with cystic and solid architecture, with the following differential diagnosis as, embryonal sarcoma and hepatoblastoma. The patient underwent surgery for a hepatic hydatid cyst, and the procedure performed was percutaneous aspiration, irrigation and respiration. Gross examination revealed multiple grey-brown and grey-white fragments with a variegated appearance. Microscopic analysis showed a malignant neoplasm composed of spindle cells, stellate cells, multinucleated giant cells in a myxoid stroma, with many atypical mitoses present. Periodic Acid-Schiff (PAS) positive eosinophilic hyaline globules were observed in the tumour cell cytoplasm, along with extensive areas of haemorrhage and necrosis. The final diagnosis of embryonal sarcoma was made after a panel of Immunohistochemistry (IHC) markers. The present case is presented here due to its rarity and diagnostic challenge, arising from the lack of a characteristic clinical presentation, serological markers and inconclusive radiological findings.

Pediatric Pleomorphic Xanthoastrocytoma with Neoplastic Meningitis: A Case Report with Cytopathological Evidence with Literature Review

AbstractPleomorphic xanthoastrocytoma (PXA) was regarded as grade II tumor and considered to be associated with favorable outcome. The World Health Organization Central Nervous System 5 (WHO CNS5) has classified PXA under circumscribed astrocytic gliomas and graded 2 or 3 depending on histology. Cerebrospinal fluid (CSF) and leptomeningeal spread are observed rarely in these tumors. The present case report describes a PXA, grade 3 tumor in a young male with neoplastic meningitis. This 17-year-old male child presented with history of seizure, signs of raised intracranial pressure, and meningeal irritation. Well-defined, T2 heterogeneously hyperintense lesion (5.5*4.8 cm) was seen in right frontal lobe with mild heterogenous contrast enhancement and adjacent pachy-meningeal enhancement. Right frontal craniotomy and near total excision were done. Postoperative hydrocephalus was treated with CSF diversion. Histopathology showed epithelioid and rhabdoid morphology with significant cellular pleomorphism and atypical mitosis consistent with the PXA, grade 3. The CSF cytology showed numerous tumor cells with marked nuclear and cytoplasmic pleomorphism. PXA is a rare malignancy of children and young adults, commonly seen in the temporal lobes. BRAF point mutations of V600E type are most common in PXA, grade 2. Meningeal dissemination is uncommon in PXA and its presence marks poor outcome. PXA, grade 2 tumors could be followed with serial imaging following gross total resection. PXA, grade 3 tumors are managed with maximal-safe resection, radiotherapy, and/ or chemotherapy. PXA, grade 3 with CSF spread tends to have rapid decline in the clinical course and it is advisable to get routine baseline and follow-up craniospinal screening and needs aggressive management.

A Retrospective Multicenter Italian Analysis of Epidemiological, Clinical and Histopathological Features in a Sample of Patients with Acinic Cell Carcinoma of the Parotid Gland.

The acinic cell carcinoma (AciCC) of the parotid gland is a rare tumor with an indolent behavior; however, a subgroup of this tumor presents an aggressive behavior with a tendency to recur. The aim of this multicenter study was to identify and stratify those patients with AciCC at high risk of tumor recurrence. A retrospective study was carried out involving 77 patients treated with surgery between January 2000 and September 2022, in different Italian referral centers. Data about tumor characteristics and its recurrence were collected. The histological specimens and slides were independently reviewed by a senior pathologist coordinator (L.C.) and the institution's local head and neck pathologist. The patients' age average was 53.6 years, with a female prevalence in the group. The mean follow-up was 67.4 months (1-258, SD 59.39). The five-year overall survival (OS) was 83.2%. The 5-year disease-free survival (DFS) was 60% (95% CI 58.2-61.7). A high incidence of necrosis, extraglandular spread, lymphovascular invasion (LVI), atypical mitosis, and cellular pleomorphism was observed in the high-risk tumors compared to the low-risk ones. AciCC generally had an indolent behavior, optimal OS, DFS with few cervical node metastases, and rare distant relapses. This multicenter retrospective case series provides evidence of the need for clinical-epidemiological-histological stratification for patients at risk of poor outcomes. Our results suggest that the correct definition of high-risk AciCC should include tumor size, the presence of necrosis, extraglandular spread, LVI, atypical mitosis, and cellular pleomorphism.

Clinical and histopathological characteristics, diagnosis and treatment, and comorbidities of Bowen's disease: a retrospective study.

Bowen's disease (BD) is a slow-growing precancerous skin condition, often concurrent with other diseases, with a high misdiagnosis rate. Previous studies show that patients with BD in different populations have differentiated characteristics. A retrospective study was conducted in a tertiary hospital in Shenzhen, China. Data about demographic information, diagnosis and treatment, clinical and pathological characteristics, and comorbidities of 50 patients with BD were collected and analyzed. Clinical data of onset age and disease course of 43 patients with BD were available, the average onset age of male and female patients are 55.1 (standard deviation (SD) = 15.29) and 58.2 (SD = 15.59) years old, respectively; the average disease course of male and female patients are 25.3 (SD = 28.63) and 33.9 (SD = 49.65) months, respectively. The onset age (p = 0.52) and disease course (p = 0.49) between male and female patients are not significantly different. Interestingly, there is a negative correlation between onset age and disease course (r = -0.245, p = 0.11). The correct rate of clinical diagnosis is relatively low (54.00%); Some patients with BD are misdiagnosed as Bowenoid papulosis (10.00%), actinic keratosis (8.00%), basal cell carcinoma (8.00%), seborrheic keratosis (6.00%), and pigmented naevus (4.00%). Trunk and limbs are the most common distribution sites of BD lesions, and 94.00% patients with BD are treated with surgical resection; 66.00% patients with BD had comorbidities, including skin diseases (48.48%), cardiovascular diseases (39.39%), gastrointestinal diseases (30.30%), respiratory diseases (27.27%), and tumors (18.18%). The most commonly observed histopathological characteristics of BD are squamous-cell hyperplasia (86.00%), disordered maturation with atypical keratinocytes (74.00%), atypical mitoses (60.00%), hyperkeratosis with hypokeratosis (48.00%), dermal inflammatory cell infiltration (36.00%), and koilocytosis (22.00%). BD often occurs in middle-aged and elderly people and is easily misdiagnosed. The onset age and disease course of patients with BD are not significantly different between males and females, whereas there is a negative correlation between the onset age and disease course. BD is more likely to occur in trunk and limbs in the Chinese population, and most patients with BD are concurrent with comorbidities.

Embryonal Rhabdomyosarcoma: Rare Case Reports with Middle Ear Location

Background: Patients with embryonal rhabdomyosarcoma (EMRS) are dominated by boys. The peak incidence occurs in the small age group from one year to 4 years. Approximately 35% of all pediatric RMS occur in the head and neck.&#x0D; Case presentation: A 3-year-old male patient came to the ear, nose, throat-head neck (ENT-HNS) polyclinic at Dr. M. Djamil General Hospital Padang on February 25th, 2021, with complaints of a lump appearing in his right ear canal for 4 months. The patient also complained of slanting on the right side of his face and pain in his right ear since 2 weeks ago. History of bleeding from the ear 1 week ago. On the examination of House-Brackmann, the patient obtained a category House-Brackmann V. Histopathological results, microscopically visible pieces of tissue with part of the surface covered with keratinized squamous epithelium, part of the surface not keratinized. There are dense groups consisting of a proliferation of cells with round, oval nuclei, small to medium size, little cytoplasm, some cells with pleomorphic nuclei, hyperchromatic, irregular nuclear membranes, lots of eosinophilic cytoplasms, with the appearance of "tadpole”, atypical mitoses may be found. The underlying tissue stroma appears myxoid. Among them, fibrotic connective tissue septa containing partially hyperemic capillaries are visible. Necrotic areas and clusters of PMN leukocytes and cellular debris were also seen. This description is consistent with EMRS.&#x0D; Conclusion: The patient was diagnosed with right middle ear EMRS stage III with right peripheral facial nerve paresis House-Brackmann V.

SAT203 Parathyroid Adenoma Masquerading As Parathyroid Carcinoma

Abstract Disclosure: M. Fariduddin: None. A. Lupieri: None. H.L. Calero: None. A. Rubenfeld: None. Y. Eisenberg: None. Case: 22 y/o pregnant female (5 weeks gestation) presented to the endocrinology clinic after a hospital admission for nausea, vomiting, constipation, fatigue and joint pain with labs showing calcium (corrected) of 14 mg/dL and PTH of 1200 pg/ml. Labs in the clinic showed calcium at 16 mg/dL and PTH 1500 pg/ml. She was re-admitted for IV fluids, calcitonin and zoledronic acid. Severe hypercalcemia, young age, and extremely high PTH levels were highly suggestive of parathyroid cancer. CT of neck showed a 2 cm right inferior parathyroid mass abutting the esophagus with concern for esophageal invasion with no evident plane between the mass and the esophagus. No cervical adenopathy was noted. Patient in conjunction with her obstetrician made an informed decision to terminate the pregnancy as this was an undesired pregnancy. She underwent an urgent right inferior gland parathyroidectomy. The mass was not fixed to underlying structures and was resected in-toto. Pathology showed chief cells with clear cytoplasm, and homogeneously round nuclei. There were no atypical mitoses, lymphovascular invasion, perineural invasion, or other invasive features concluding the final pathology as parathyroid adenoma. Discussion: Primary hyperparathyroidism predominantly affects postmenopausal women. Most common cause is parathyroid adenoma (80-85%). Parathyroid carcinoma is a rare cause of primary hyperparathyroidism (1-2%).80% people with parathyroid adenoma and primary hyperparathyroidism are diagnosed incidentally with mildly elevated calcium. PTH elevation is around 1.5-2 times the upper limit of normal. Symptoms are mild sequelae of hypercalcemia. PTH levels 5-10 times upper limit of normal, severe hypercalcemia (Ca &amp;gt; 14 mg/dl) or a hypercalcemia crisis are highly suspicious for parathyroid cancer. Surgical resection is the mainstay of treatment. Clinical criteria play a key role in early identification of parathyroid carcinoma in order to get these patients to surgery before tumor spread and improve long term survival. Our patient with significantly elevated calcium and parathyroid hormone had an atypical presentation of a parathyroid adenoma thus uncovering the limitations of clinical criteria in identifying a parathyroid carcinoma. Most of the patients with a parathyroid adenoma will eventually require surgery, however the technique, extent and urgency of surgery is affected based on clinical situations like these. The timing of the surgery could be detrimental when coupled with a scenario like our patient’s pregnancy wherein you could delay the surgery until the second trimester had the patient wanted to continue the pregnancy. This case highlights the importance of awareness of atypical presentations of parathyroid adenomas and to have a cautious approach in patients with clinical concern for parathyroid carcinoma especially if there is a potential benefit to delay surgery. Presentation: Saturday, June 17, 2023