Focal Squamous Differentiation Research Articles

SMARCA4 Deficient Gastric Carcinoma With Squamous Differentiation in a Young Patient With Aggressive Clinical Course

Inactivation of SMARCA4 (BRG1), a subunit of SWI/SNF complex, has been reported in malignancies from various sites, including the thorax, uterus, ovary, and gastrointestinal tract, and is usually associated with aggressive clinical course. These tumors have been reported primarily in elderly patients and on histology demonstrate high-grade morphology, often with rhabdoid differentiation. SMARCA4 loss is exceedingly rare in primary gastric cancers. Here, we present a unique example of SMARCA4 deficient gastric carcinoma in a 28-year-old male patient with molecular confirmation which showed a poorly differentiated histology and focal squamous differentiation. Despite multidisciplinary management, including FOLFOX chemotherapy, immunotherapy (nivolumab), and surgical resection, the patient succumbed to his disease within 2 years of diagnosis. This case report highlights the aggressive nature of SMARCA4-deficient carcinomas, which are often resistant to conventional chemotherapy, and underscores the importance of early diagnosis and exploring alternative therapeutic approaches for such malignancies.

7928 A "PTH-Mediated" Hypercalcemia Of Malignancy

Abstract Disclosure: N. Sekhon: None. R.J. Bingham: None. Background: We present a challenging diagnostic case of a 73-year-old female with PTH-mediated hypercalcemia in the presence of new metastatic uterine cancer. Case: A 73-year-old female with a past medical history of hypertension and abdominal aortic aneurysm was seen in the hospital for hypercalcemia. She endorsed constipation, fatigue, and generalized weakness for the past few weeks. This was the second hospitalization related to hypercalcemia over the period of 10 days. During the previous hospitalization, her admission calcium was 17 mg/dL and was treated with IV fluids, calcitonin, and zoledronic acid. There was a history of intentional weight loss of about 30-40 lbs in the last 3 months by reducing carbohydrate intake. The patient had a 40-pack years of smoking history. There was no family history of calcium disorders or cancers. Home medications included amlodipine 10 mg QD, docusate sodium 100 mg BID, senna 1 tab QHS, and Vit D 5000 U QD. On physical examination, she was hemodynamically stable but appeared confused and lethargic. The rest of the examination was unremarkable. Laboratory results were remarkable for hypercalcemia (Ca: 13.3 mg/dL), hypophosphatemia (Phosphorus: 2.3 mg/dL), and elevated PTH of 418.3 pg/mL (Ref. Range: 18.4-80.1 pg/mL). CT abdomen/ pelvis revealed innumerable ill-defined hypodense lesions throughout the liver concerning metastatic disease and a 5 cm mass in the uterine fundus. The patient was worked up with the view of hypercalcemia related to malignancy. However, PTHrP (PTH-related peptide) came back normal, which was checked twice during both hospitalizations. Liver biopsy showed metastatic high-grade carcinoma highly suspicious for GYN malignancy with negative PTH staining. Imaging studies for localization including CT soft tissue neck and CT 4D parathyroid with and without contrast failed to show any parathyroid lesions. Endometrial biopsy obtained during subsequent hospitalization showed high-grade adenocarcinoma with focal squamous differentiation. Immunohistochemical staining identified scattered positivity for PTH. The patient was managed as per hypercalcemia of malignancy guidelines with IV fluids and denosumab. Discussion: Hypercalcemia of malignancy due to ectopic PTH secretion has been reported in < 1% of cases. Only two endometrial cancer cases with ectopic PTH have been reported in the literature. PTH-mediated hypercalcemia is seen in primary hyperparathyroidism, parathyroid cancers, or ectopic PTH. In all cases of hypercalcemia of malignancy, primary hyperparathyroidism should be ruled out in the presence of elevated PTH. Diagnosing ectopic PTH secretion by tumor can be challenging due to constant changes in cells with metastasis. Conclusion: This is a rare case of endometrial cancer with liver metastasis and ectopic PTH secretion by primary tumor leading to recurrent hospitalizations related to hypercalcemia. Presentation: 6/2/2024

Colorectal adenocarcinoma with enteroblastic differentiation: a clinicopathological analysis of eight cases

Objective: To investigate the clinicopathological features of colorectal adenocarcinoma with enteroblastic differentiation (CAED). Methods: Eight cases of CAED diagnosed at the Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China from January 2017 to August 2023 were collected. The histopathological, immunohistochemical, molecular and prognostic features of 8 CAED cases were analyzed. The relevant studies were also reviewed. Results: Among the eight patients, there were six males and two females, with an average age of 58 years (range: 29-77 years, median age: 61.5 years). Preoperative serum alpha-fetoprotein levels were elevated in five patients (14.0-286.6 μg/L). Four tumors were located in the colon, and four tumors in the rectum. Two patients were clinically staged as advanced stage (stage Ⅳ), and distant metastasis occurred at the initial diagnosis (one case had liver metastasis, and the other had lung, bone and multiple lymph nodes metastases). Six patients were clinically staged as locally-advanced stage (Stage Ⅱ-Ⅲ). Three of them developed distant metastases after surgery (one case had liver metastasis, one case had lung metastasis, and one case had peritoneal metastasis). Additionally, two patients died at 9 months and 24 months after surgery, respectively. The tumors were composed of various proportions of adenocarcinoma components with enteroblastic differentiation (30%-100%) and classical tubular adenocarcinoma components. The component with enteroblastic differentiation exhibited morphology similar to embryonic intestinal epithelium: cuboidal or columnar tumor cells arranged in tubular, papillary, cribriform, or solid nest patterns, with clear cytoplasm. Immunohistochemical studies showed that tumor cells expressed at least one oncofetal protein (SALL4, Glypican-3, and AFP). In addition, focal squamous differentiation was observed in 3 cases (3/8). Compared to the primary tumor, both CAED and squamous differentiation components were increased in the metastatic tumors. Based on the sequencing results of KRAS, NRAS and BRAF of the primary and/or metastatic tumors, 5 cases were wild-type, while KRAS exon 2 (G13D) mutations were identified in 2 cases. Conclusions: CAED is a rare colorectal malignancy with a dismal prognosis. Accurate pathological diagnosis is prognostically valuable. The histological features of enteroblastic differentiation, elevated serum AFP levels, and the expression of oncofetal proteins play an important role in the tumor diagnosis.

Submucosal gland differentiation and implications in esophageal basaloid squamous cell carcinomas.

Esophageal basaloid squamous cell carcinoma (BSCC) is a heterogenous entity with multilineage differentiation. It lacks systematical analysis on submucosal gland differentiation (SGD) due to the histological diversity and low incidence of esophageal BSCC. This study aims to find the correlation of SGD and clinicopathological features. A total of 152 esophageal BSCCs were separated into three histological groups: pure, mixed, and borderline group. The clinicopathological features were compared between different groups. The prevalence of SGD was also compared between cases of different groups. A panel of antibodies were used to identify SGD. The pure group differed from the mixed and borderline groups in many aspects, lymph node metastasis (LNM), cancer embolus, perineural invasion, and advanced stage occurred less frequently in the pure group (P<0.01). The pure group had a better but statistically insignificant overall survival (P=0.097). The squamous cell carcinoma (SCC) component or focal squamous differentiation was present in metastatic lymph nodes in almost all mixed BSCCs (95.7%, 22/23) with LNM. The LNM rate of superficial (T1b) BSCCs (17.6%, 6/34) was comparable to that of superficial (T1b) SCCs (18.5%, 57/308). However, LNM exclusively occurred in superficial mixed (3/5) and borderline (3/10) BSCCs. The IHC results demonstrated a prevalence of SGD in pure group (77%, 43/56). SGD is considered to be a favorable factor, while the squamous differentiation or invasive SCC component is an adverse factor in esophageal BSCCs. Refinement of classification is a promising way to improve patient management.

An Extraordinary Location of Sentinel Lymph Nodes in a Patient with Endometrial Cancer

To show dissection of sentinel lymph nodes. A step-by-step demonstration of the technique with narration. Endometrial cancer (EC) is the most common gynecologic malignancy worldwide. Sentinel lymph node biopsy with indocyanine green (ICG) has become more widely used and has been featured in recently published guidelines for EC [1]. Minimally invasive approaches with the sentinel lymph node concept (conventional laparoscopy, laparoscopic-assisted vaginal surgeries or robotic) to EC staging have resulted in lower rates of peri- and postoperative complications than conventional staging procedures [2]. No video article has been published in the literature about high pelvic, para-aortic sentinel lymph node dissection. An informed consent form was obtained from the patient. An institutional review board approval was not required. A 45-year-old female with gravidity 0, parity 0, and body mass index of 23.4 kg/m2 presented with complaints of abnormal uterine bleeding (spotting). Increased endometrial thickness was detected on transvaginal ultrasound (10 mm) in the postmenstrual period. Endometrioid-type endometrial adenocancer with focal squamous differentiation International Federation of Gynecology and Obstetrics grade I was detected on endometrial biopsy. The patient had hepatitis B virus positivity and no other chronic disease. A laparotomic myomectomy had been performed in 2016. Laparoscopic high pelvic, low para-aortic sentinel lymph node dissection with ICG and hysterectomy (without uterine manipulator)+bilateral salpingo-oophorectomy were performed (Supplemental Video 1). The operation time for the procedure was 110 minutes and the estimated blood loss was <20 mL. No major complications occurred during or after the surgery. The patient stayed in the hospital for 1 day. The final pathology result showed an International Federation of Gynecology and Obstetrics grade I, endometrioid-type endometrial adenocancer with focal squamous differentiation, as a 1.5×1 cm tumorous mass invading less than one-half of the myometrium. Neither lymphovascular invasion nor sentinel lymph node metastasis was detected. A multicenter, prospective study showed that sentinel lymph node dissection with ICG in clinical stage 1 EC is feasible and has a high degree of diagnostic accuracy in detecting EC metastases. In that study, isolated para-aortic sentinel lymph node was detected in 3 of 340 patients (<1%) [2]. Another study reported the detection rate of isolated para-aortic sentinel lymph node to be 1.1% in patients with intermediate- and high-risk EC [3]. There are in some cases 2 distinct channels emanating from one side, and it is important to follow each and to acknowledge there may be more than one sentinel, one of which is lower in a typical location and one higher as in this case. This video article is the first video demonstration of bilateral isolated high pelvic, para-aortic sentinel lymph node dissection in EC.

Desmoglein 3 (Dsg3) expression in cancer: A tissue microarray study on 15,869 tumors.

Desmoglein-3 (Dsg3) is a transmembrane glycoprotein which is preferably found in desmosomes of keratinocytes in squamous epithelium. Both loss and upregulation of Dsg3 have been implicated in cancer progression. To comprehensively evaluate Dsg3 expression in normal and neoplastic tissues, a tissue microarray containing 15,869 samples from 137 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Dsg3 immunostaining was detectable in 47 (34.3%) tumor categories including 15 (10.9%) tumor types with at least one strongly positive case. The highest rate of Dsg3 positivity was found in squamous cell carcinomas from various sites (71.2-97.3%), basal cell carcinomas of the skin (41.9%), various tumors from salivary glands (12.9-38.9%), and in urothelial neoplasms (2.1-20.7%). Dsg3 positivity in less than 10% of cases was seen in 23 additional cancer categories. Dsg3 staining was almost always weak and rarely moderate in these tumors. High Dsg3 expression was linked to invasive growth in urothelial carcinoma (p<0.0001), as well as to advanced pT stage (p=0.0102), nodal metastasis (p=0.0162), blood vessel infiltration (p=0.0189) and lymph vessel infiltration (p=0.0151) in colorectal cancer. Reduced Dsg3 expression was linked to high grade in a cohort of 599 squamous cell carcinomas from 11 different sites of origin (p<0.0001). Associations between Dsg3 immunostaining and clinicopathological features were not found in invasive breast cancer of no special type, ductal adenocarcinomas of the pancreas and in gastric adenocarcinomas. In summary, Dsg3 expression predominates in squamous cell carcinomas and loss of Dsg3 immunostaining goes along with dedifferentiation of these tumors. The identification of focal squamous differentiation in other neoplasms may constitute a diagnostic application of Dsg3 immunohistochemistry.

Non-small cell lung carcinomas with diffuse coexpression of TTF1 and p40: clinicopathological and genomic features of 14 rare biphenotypic tumours.

Thyroid transcription factor 1 (TTF1) and p40 are widely-utilized diagnostic markers of lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), respectively. Diffuse coexpression of TTF1 and p40 has been described in only rare case reports. In a multi-institutional study, we collected the largest cohort of these unusual tumours to-date (n = 14), with the goal of elucidating their clinicopathological and genomic characteristics. Lung tumours with diffuse coexpression (labelling 50-100% tumour cells) of TTF1 clone 8G7G3/1 and p40 clone BC28 were identified. Detailed clinicopathological and immunohistochemical parameters were analyzed. Eight tumours were analyzed by next-generation sequencing (NGS) and the results were compared to those in > 9 K LUAD and > 1 K LUSC. All tumours with diffuse TTF1/p40 coexpression were poorly differentiated non-small cell lung carcinomas (NSCLC), 42% of which had basaloid features. Some tumours exhibited focal keratinization (14%), napsin A and/or mucicarmine labelling (46%) or both squamous and glandular features (7%). NGS revealed a uniquely high rate of FGFR1 amplifications (70%) compared to either LUAD (0.7%, P < 0.0001) or LUSC (11%, P = 0.001). LUAD-type targetable driver alterations were identified in 38% of cases (one EGFR, two KRAS G12C). The tumours were clinically aggressive, exhibiting metastatic disease in most patients. Lung carcinomas with diffuse TTF1/p40 coexpression represent poorly differentiated NSCLCs with frequent basaloid features, but some show evidence of focal squamous, glandular or dual differentiation with a distinctly high rate of FGFR1 amplifications. The presence of targetable LUAD-type alterations (EGFR, KRAS G12C) emphasizes the importance of molecular testing in these tumours.

A BCC masquerading as a fungating breast mass

A 55-year-old female presented with a growth on her left chest that was increasing in size. The growth had been present for several years. The patient had no complaints of pain; just concerns about the presence of the mass. Upon examination, the patient had a polypoid, lobulated, violaceous, and red fungating mask measuring approx. 7.0 cm x 6.0 cm (Fig. 1a). Malignant breast disease encompasses many histologic types that include, ductal or lobular carcinoma, infiltrating ductal or lobular carcinoma, and inflammatory carcinoma. Benign masses can include fibroadenoma, intraductal papilloma, and abscess. Patient was referred to a general surgeon for removal due to the uncertain nature of this growth (Fig. 1b). Pathology was positive for a basal cell carcinoma with focal squamous cell differentiation, nodular type (Fig. 2). All resected margins were negative. Recovery was uneventful. Basal cell carcinomas located on the trunk account for only 10 percent of all cases. The majority are in sun exposed areas such as the face and neck [1,2].

Diagnosis, Treatment and Prognosis of Primary Pulmonary NUT Carcinoma: A Literature Review.

NUT carcinoma is a rare, highly lethal cancer characterized with the rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14, which primarily occurs in the midline organs. Primary pulmonary NUT carcinoma (NC) lacks characteristic clinical manifestations, which leads to the high rate of misdiagnose and nonstandard treatment. To date, fewer than one hundred cases have been reported worldwide. Here, a comprehensive literature search involving a total of 35 articles with 55 patients was conducted in this paper. We reviewed and analyzed the associated clinical and pathological characteristics, the efficacy of various treatment options and the prognosis. Pulmonary NC mainly occurred in middle young-aged men (median age, 36) with no smoking history (2:1) and would present with symptoms of cough (63.6%), dyspnea (29.5%), chest pain (18.2%) and hemoptysis (18.2%). The initial imaging frequently revealed large and irregular lesions in the lower lobe (46.5%) of the left or right lungs; lymph node metastasis was also prevalent (91.9%). A focal squamous differentiation with abrupt keratinization often occurred in the undifferentiated or poorly differentiated (93.75%) tumor cells, with abundant necrosis and numerous neutrophils infiltrated. The mean overall survival (OS) in patients of this malignant disease was 6.21 months, and the median OS was 4.4 months. According to our results, this disease is sensitive to radiotherapy, and chemoradiotherapy (either concurrent chemoradiotherapy or sequential chemoradiotherapy) was the most efficient therapeutic regimen to prolong the OS of patients with pulmonary NC.

Cytokeratin 10 (CK10) expression in cancer: A tissue microarray study on 11,021 tumors

Cytokeratin 10 (CK10) is a type I acidic low molecular weight cytokeratin which is mainly expressed in keratinizing squamous epithelium of the skin. Variable levels of CK10 protein have been described in squamous carcinomas of different sites and in some other epithelial neoplasms. To comprehensively determine the prevalence of CK10 expression in normal and neoplastic tissues, a tissue microarray containing 11,021 samples from 131 different tumor types and subtypes was analyzed by immunohistochemistry. CK10 immunostaining was detectable in 41 (31.3 %) of 131 tumor categories, including 18 (13.7 %) tumor types with at least one strongly positive case. The highest rate of positive staining was found in squamous cell carcinomas from various sites of origin (positive in 18.6 %–66.1 %) and in Warthin tumors of salivary glands (47.8 %), followed by various tumor entities known to potentially exhibit areas with squamous cell differentiation such as teratomas (33.3 %), basal cell carcinomas of the skin (14.3 %), adenosquamous carcinomas of the cervix (11.1 %), and several categories of urothelial neoplasms (3.1 %–16.8 %). In a combined analysis of 956 squamous cell carcinomas from 11 different sites of origin, reduced CK10 staining was linked to high grade (p < 0.0001) and advanced stage (p = 0.0015) but unrelated to HPV infection. However, CK10 staining was not statistically related to grade (p = 0.1509) and recurrence-free (p = 0.5247) or overall survival (p = 0.5082) in 176 cervical squamous cell carcinomas. In the urinary bladder, CK10 staining occurred more commonly in muscle-invasive (17.7 %) than in non-invasive urothelial carcinomas (4.0 %–6.0 %; p < 0.0001). In summary, our data corroborate a role of CK10 as a suitable marker for mature, keratinizing squamous cell differentiation in epithelial tissues. CK10 immunohistochemistry may thus be instrumental for a more objective evaluation of the clinical significance of focal squamous differentiation in cancer.

A surgical case of high-grade urothelial carcinoma of the renal pelvis complicated with giant hydronephrosis, giving rise to diagnostic difficulties on a cytological examination

BackgroundWe report a surgical case of urothelial carcinoma of the renal pelvis, resulting in diagnostic difficulties on cytological examination.Case presentationA man in his late 70s underwent nephrectomy for giant hydronephrosis and renal cysts after nephrostomy and renal cyst puncture and drainage. On all cytological examinations performed before surgery, including nephrostomy urine, renal cyst fluid, catheterized bladder urine, and bladder washings, we were unable to make any conclusive diagnosis of malignancy. The pathological diagnosis of the surgical specimen concluded that this was a case of high-grade urothelial carcinoma of the renal pelvis with focal squamous differentiation (pT4). Liver and lung metastases were identified 3 months after surgery, and the patient died 2 months later.ConclusionIt was very difficult to make a conclusive diagnosis using cytological specimens because of the presence of a small number of atypical cells with severe degenerative changes. Since clinicians cannot predict the potential for malignancy on preoperative imaging findings, it is critical to consider the difficulties in clinically making a correct diagnosis of urothelial carcinoma of the upper urinary tract, especially in cases complicated with giant hydronephrosis.

Squamoid Eccrine Ductal Carcinoma of the Eyelid: Clinicopathologic Correlation of a Case

Squamoid eccrine ductal carcinoma (SEDC) is a rare cutaneous neoplasm that often manifests as a plaque or nodule in sun-exposed areas of older patients. Herein, the authors report the first case of SEDC in the eyelid. A 76-year-old man presented with a 2.5 × 1.5 mm area of left upper eyelid erythema, thickening, ulceration, and scaling with madarosis superotemporally just above the lash line. Full-thickness wedge biopsy demonstrated irregular epithelial tubules with nuclear atypia and focal squamous differentiation, consistent with SEDC. The patient underwent Mohs resection and has had no recurrence approximately 27 months after surgical removal. The authors present this case to raise awareness of SEDC to ophthalmologists as all previous cases have been described in the nonophthalmic literature. A full-thickness biopsy is recommended to avoid misdiagnosing SEDC as squamous cell carcinoma (SCC), a less aggressive tumor. With greater awareness, there may be increased recognition of this likely underreported, more malignant entity.

Cytomorphologic findings of thyroid carcinoma showing thymus-like (CASTLE) differentiation: A case report

Abstract Introduction/Objective Thyroid carcinoma showing thymus-like differentiation also known as intrathyroidal thymic carcinoma is a rare thyroid neoplasm arising from either an ectopic intrathyroidal thymic tissue or from remnants of thymobranchial pouches. On fine needle aspiration (FNA) its diagnosis can be challenging due to overlapping morphologic features with other aggressive thyroid carcinomas. Methods/Case Report A 31-year-old female consulted for 6-month history of neck swelling and tenderness. Thyroid ultrasound demonstrated a 2.6 x 2.5 x 2.1 cm nodule in the right lobe with punctate calcifications. FNA showed cellular smears composed of loosely cohesive and single basaloid neoplastic cells exhibiting significant cellular and nuclear pleomorphism. Focal squamous differentiation with keratinization was noted on the cell block sections. Immunocytochemical stains showed that the tumor was positive for cytokeratin AE1/AE3, p40, p63, CD117 and CD5 consistent with intrathyroidal thymic carcinoma. The Ki67 proliferative index was approximately 40%. A right thyroidectomy with central neck dissection confirmed the diagnosis and showed a 3.0 cm tumor with invasion into skeletal muscle, lymphovascular invasion and positive lymph nodes. The patient completed adjuvant radiotherapy and remain in remission at 3-months follow-up. Results (if a Case Study enter NA) NA Conclusion Intrathyroidal thymic carcinoma is a rare thyroid neoplasm that frequently shows squamous differentiation and therefore overlaps with papillary thyroid carcinoma with squamous morulae, squamous cell carcinoma and anaplastic carcinoma. The coexpression of squamous markers together with CD5 and CD117 allows the recognition of CASTLE on FNA samples.

Clinicopathological and molecular characterizations of pulmonary NUT midline carcinoma.

IntroductionPulmonary nuclear protein of the testis (NUT) midline carcinoma (NMC) is a aggressive cancer with t (15, 19) translocation. Here we present the clinicopathological characteristics and molecular genetics alterations of primary pulmonary NMC.MethodsFluorescence in situ hybridization (FISH) assay was performed to evaluate NUT translocation. Next generation sequencing (NGS) was performed to investigate genomic landscape. A panel of 289 lung cancer tissues with undifferentiation was retrospectively screened for NUT expression by immunohistochemical (IHC) assay.ResultsOverall, 2136 lung cancer samples were reviewed. We consecutively identified 12 cases of primary pulmonary NMC. Computed tomography revealed centrally located bulky lung mass with ipsilateral mediastinal lymph node and pleural involvements. Tumor cells presented diffuse poor differentiation and focal squamous differentiation with positive NUT expression. NUT rearrangement was confirmed by FISH assay. Ten NMC samples were investigated by NGS. The most common alterations identified were P53, PIK3CA, AUTS2, ITIH2, and CDKL5 genes. Pulmonary NMC exhibited increased activity of PI3K/AKT pathway. In the screening study, BRD4‐NUT rearrangement was identified in two cases.ConclusionNUT rearrangement remains the gold standard in the diagnosis of pulmonary NMC. PI3K inhibition is a potential targeted therapy for pulmonary NMC.

Glassy cell carcinoma of cervix: A case report

Glassy cell carcinoma of the cervix is a rare subtype of adenosquamous carcinoma associated with aggressive course and poor prognosis. It is considered to originate from the subcylindrical reserve cells of the cervix and has been associated with human papillomavirus. Histologically glassy cell carcinoma is composed of nestes of large cells with ground glass cytoplasm and large vesicular nuclei with prominent nucleoli. Nuclear pleomorphism and tumor giant cells are frequently seen. Mitotic activity is brisk. Infiltration by eosinophils and plasma cells with admixture of lymphocytes is a characteristic feature. Focal squamous and glandular differentiation may be seen. The immunohistochemistry markers are positive for squamous cell carcinoma (p63, CK34) and adenocarcinoma(MUC1, MUC2, CEA).Here we present a case of 49 year old female diagnosed as glassy cell carcinoma histologically and immunohistochemically.

Case Report: Invasive Endometrial Cancer in a Trans Man and Risk of Testosterone Therapy

Abstract Background: Only one case of uterine cancer in a trans man on testosterone is noted in literature prior to this case. No clinical evidence nor guidelines exist regarding testosterone therapy for this subset of patients. Clinical Case: A 41-year-old trans man was seen by Gynecology for vaginal bleeding, with work-up revealing thickened endometrium and biopsy with endometrial adenocarcinoma. Testosterone therapy was held, and patient underwent total hysterectomy with BSO and bilateral pelvic/aortic lymph node dissection. Pathology demonstrated stage IIIA invasive adenocarcinoma, endometrium type with focal squamous differentiation, low grade. The tumor extended into the endocervical stroma with small metastasis to one ovary. He received adjunct pelvic radiation and sandwich chemotherapy with carboplatin and taxol. Concurrently, he was referred to Endocrinology for management of hormone replacement therapy (HRT). He originally started weekly testosterone injections and anastrozole at an outside facility in 2016 and underwent bilateral mastectomy in 2017. Testosterone was held perioperatively and during chemoradiation, for a total duration of 9 months. The patient experienced worsening gender dysphoria during this time. Discussion was held on goal to restart HRT in the setting of a theoretical risk of testosterone conversion to estradiol with increased risk of cancer recurrence; thus, patient initially chose to delay re-initiation of HRT. Following the completion of chemotherapy, he started on low-dose (30mg) weekly IM testosterone with plans for continued monitoring of testosterone and estradiol levels. Conclusion: Research is needed in monitoring the effects of testosterone therapy on reproductive organs in patients assigned female at birth, and whether anastrozole therapy has protective effects for estrogen-driven cancers. Further, guidance is needed on monitoring of uterine lining in trans men and whether this should be standard of practice.

Responses to the First Radioactive Iodine Treatment After Targeted Therapy for Aggressive Papillary Thyroid Cancers

Introduction: Tall cell variant (TCV) and columnar cell variant (CCV) are aggressive variants of papillary thyroid cancer (PTC) and they are overrepresented in radioactive iodine (RAI) refractory cases. Studies have reported using BRAF and/or MEK inhibitors to restore iodine avidity in patients with iodine refractory disease. There is much less experience of using targeted therapy pre-emptively to enhance iodine uptake for aggressive variants and advanced disease prior to the first RAI treatment (RAI-T). We present three patients with these variants and describe their responses to the first RAI-T after targeted therapy. Case 1: 64-year-old male with CCV-PTC and areas of poor differentiation (pT3aN1bM1) has somatic BRAF V600E, TERT and AJUBA mutations. Thyroglobulin (TG) 6 weeks post surgery was 21 ug/L, with negative TG antibodies (TGAb). PET-CT revealed FDG avid superior mediastinal lymphadenopathy and lung metastases. He received dabrafenib for 6 weeks followed by his first RAI -T(153 mCi) after thyroid hormone withdrawal (THW). Pre- and post-therapy scans showed uptake in the neck, right superior mediastinum and lung metastases. Three months post RAI, TG decreased to 5.1 ug/L. Chest CT revealed stable mediastinal lymphadenopathy and decreased size of lung metastases. Case 2: 41-year-old male with TCV-PTC containing areas of focal squamous differentiation and poor differentiation (pT4aN1bM1) has somatic BRAF V600E and TP53 mutations. PET-CT showed FDG avid neck lymph nodes and lung metastases. TG 8 weeks after surgery was 1.5 ug/L, TGAb 31.19 IU/L. He was treated with dabrafenib and trametinib for 4 weeks followed by his first RAI-T (150mCi) after THW. Pretreatment scan showed uptake in the thyroid bed and cervical lymph nodes. Post-therapy scan revealed additional uptake in the lung metastases. Chest CT 3 and 9 months after RAI-T revealed stable paratracheal lymph node and lung metastases. TGAb decreased to 7.04 IU/L; TG was 2.2 ug/L. Case 3: 33-year-old female with invasive TCV-PTC (pT3bN1aM1) has a somatic BRAF V600E mutation. CT chest showed multiple scattered lung nodules up to 4mm. Ten weeks post surgery, TG was 0.1 ug/L, TGAb 5.21 IU/ml. Patient received 1 month of dabrafenib and trametinib followed by his first RAI-T(125 mCi) after THW. Pre- and post-therapy scans revealed uptake in the neck and left supraclavicular areas, without uptake in lung nodules. Three months post RAI, chest CT revealed stable lung nodules. TG was 0.1 ug/L, and TGAb was 5.16 IU/L. Neck ultrasound showed no disease. Conclusion: These three patients with aggressive variants of PTC have advanced disease, and all were found to have a BRAFV600E mutation on genomic analysis. They tolerated BRAF targeted inhibition as an attempt to enhance iodine uptake preemptively with various responses to their first RAI-T. More studies will be needed to determine if this strategy will improve outcomes for these patients.

Cutaneous Spindle Cell Squamous Cell Carcinoma in Cats: Clinical, Histological, and Immunohistochemical Study.

This study describes the clinical and pathological characteristics of cutaneous spindle cell squamous cell carcinoma (SCSCC) in 18 cats. The average age of the cats was 11.8 ± 2.7 years, and all tumors were located in the facial skin, mainly affecting the pinna (13/18, 72%), followed by the periorbital area (4/18, 22%) and the dorsal muzzle (1/18, 6%). Tumors were composed of fusiform neoplastic cells with moderate atypia arranged in solid sheets or fascicles with foci of squamous differentiation. A panel of antibodies against cytokeratins, vimentin, S-100 protein, NSE, GFAP, Melan A, SMA, desmin, CD18, CD31, and p63 was used to help differentiate SCSCC from other spindle cell malignancies. SCSCCs expressed CK5/6 (17/18, 94%), AE1/AE3 (15/18, 83%), and p63 protein (18/18, 100%), but there was no immunolabeling for CK8/18. A role for sunlight exposure in the pathogenesis of the tumors was suggested by changes indicative of actinic keratosis, the location of the tumors in dorsal areas, and the absence of histomorphologic features of papillomavirus infection. Recurrence was not recorded in 14/18 cases (78%) during a follow-up period of 7 to 25 months. Three of 18 (17%) tumors recurred or led to humane euthanasia due to local progression, and one case (5%) had regional lymph node metastasis. Clinical outcome varied with cutaneous location, mitotic count, and invasion of surgical margins; thus, SCSCCs with a more aggressive behavior were located in the periorbital area (4/4 cases), had ≥14 mitoses in 10 high-power fields (2.37 mm2) (4/4 cases), and showed invasion of surgical margins (3/4 cases).

YAP1-NUTM1 Gene Fusion in Porocarcinoma of the External Auditory Canal

Gene fusions involving the NUTM1 gene (NUT) represent defining genetic markers of a highly aggressive carcinoma type with predilection for the midline structures of children and young adults, hence the original description as NUT midline carcinoma. Recent studies have increasingly documented involvement of the NUTM1 gene in the pathogenesis of other entities as well. We herein describe two cases of auditory canal carcinomas with features of porocarcinoma, both harboring a newly described YAP1-NUTM1 gene fusion. Patients were males aged 28 and 82 years who presented with slowly growing lesions in the external auditory canal. Histologic examination showed monomorphic basaloid and squamoid cells arranged into organoid solid aggregates, nests, ducts, small cysts, and focal pseudocribriform pattern with variable mitotic activity, infiltrative growth, and focal squamous differentiation, particularly in the most superficial part of the tumor. Immunohistochemistry revealed consistent reactivity for CK5, p63 and SOX10 and diffuse aberrant expression of TP53. CK7 expression was limited to a few luminal ductal cells. The androgen receptor and S100 were negative. Next generation sequencing (TruSight RNA fusion panel, Illumina) revealed the same YAP1-NUTM1 gene fusion in both tumors, which was subsequently confirmed by NUT-FISH and the monoclonal anti-NUT antibody. These cases represent a novel contribution to the spectrum of NUT-rearranged head and neck malignancies. This adnexal carcinoma variant should not be confused with the highly lethal NUT carcinoma based on NUT immunoreactivity alone.

Poorly Differentiated Large-Cell Neuroendocrine Carcinoma of the Cecum: A Rare Malignancy

Abstract Poorly differentiated neuroendocrine carcinomas (PDNECs) are rare tumors that can arise anywhere in the gastrointestinal tract. They often present at advanced stage and portend a poor prognosis when compared to adenocarcinomas of the same stage. A 65-year-old female presented with progressively worsening bilateral proximal muscle weakness of 3 months’ duration. It was associated with fatigue, decreased appetite, and unintentional weight loss (8 lbs). She was also found to have hypercalcemia (serum calcium 12.1 mg/dL), anemia (hemoglobin 9.9 g/L), and abnormal liver panel (Alk phos 336, AST 85, GGTP 737). CT abdomen showed abnormal thickening and mass-like enhancement in the cecum measuring 2.9 × 3.7 cm and an enlarged 22-cm liver with numerous rounded masses, the largest measuring 4.6 × 8.2 cm. Colonoscopy revealed a large ulcerated mass distal to the ileocecal valve and extending to the proximal ascending colon. Histology revealed an ulcerated invasive pleomorphic large cell neoplasm with focal squamous differentiation and a tubular adenoma. Initial positive immunostains were AE1/AE3, CK5, and p63. CK7, CK20, S100, and calretinin were negative. Strong, diffuse expression of synaptophysin confirmed neuroendocrine carcinoma; high Ki-67 (80%) confirmed grade 3. CDX2 and TTF1 were positive but are not lineage specific in PDNECs. A liver biopsy had identical histology with diffuse expression of CD56, another confirmatory neuroendocrine marker. Elevated random urine 5-hydroxyindoleacetic acid (5HIAA) supported the diagnosis. Mismatch repair (MMR) protein immunostains did not reveal deficient MMR. Colonic NECs are extremely rare, accounting for 0.6% of patients with colorectal carcinoma; of these, only 0.2% are classified as large cell NECs. A panel of immunostains confirms the diagnosis. They most often arise in the cecum or rectum with early liver metastases and median survival of 9 months. Rare cases have responded to checkpoint inhibitors, which may be a therapeutic option.