Rare Malignancy Research Articles

Challenges in treating coexisting scrotal apocrine carcinoma and gastric cancer: insights from an elderly patient: a case report and literature review

BackgroundApocrine carcinoma associated with Paget’s disease is a rare malignancy that typically manifests in elderly individuals, predominantly affecting the geriatric population. It commonly arises in regions rich in apocrine glands and often exhibits an insidious onset, potentially requiring several years to be diagnosed.Case presentationAn 80-year-old male was simultaneously diagnosed with scrotal apocrine carcinoma (showing Paget changes) and early-stage gastric cancer. Whole-genome exome sequencing confirmed these as independent malignancies with minimal genetic overlap, indicating that they were two primary tumors. The patient initially underwent successful surgery but experienced recurrence and metastasis. Treatment with capecitabine and paclitaxel showed promising responses, highlighting similarities between breast and apocrine carcinomas. Challenges were noted in the use of genetic testing and drug susceptibility assessments for treatment guidance. Notably, HER-2 expression in metastatic lesions, a trait of apocrine carcinoma, has remained unexplored due to negative HER-2 FISH results and a lack of available targeted therapies in China.ConclusionElderly patients often exhibit a lesser degree of aggressiveness toward treatment following a diagnosis of malignant tumors. It is imperative to carefully consider how to strike a balance between effective treatment and maintaining a satisfactory quality of life for these patients. This case underscores the complexity of treating coexisting rare cancers in older adults and emphasizes the need for personalized treatments and continued innovation in cancer therapy. The insights gained offer significant value in understanding and managing such rare cancer cases.

The Great Mimicker: Goblet Cell Adenocarcinoma of the Appendix Mimicking Mammary Carcinoma in a Patient with a History of Metastatic Breast Cancer

Abstract Introduction/Objective Goblet cell adenocarcinoma of the appendix is a rare and aggressive malignancy with high- grade histological patterns that pose diagnostic challenges due to their resemblance to other tumors. Previous reports have indicated that high-grade goblet cell adenocarcinoma may exhibit similarities to well-differentiated neuroendocrine tumors, and metastatic high-grade goblet cell adenocarcinoma can manifest diverse histologic growth patterns within a single section. Methods/Case Report We present a case of an 82-year-old female with a known history of breast cancer with sacral metastasis, presenting with a left upper quadrant “pinching” sensation. Histopathological examination following colectomy showed features of metastatic mammary carcinoma with mixed lobular (pleomorphic and partial signet ring cell type) and ductal features (Figure 1); Notably, different histologic patterns were observed in two tumor deposits, highlighting the complexity of the diagnosis (Figure 2). However, further investigation of the tip of the appendix revealed goblet-like mucinous cells arranged in a tubular growth pattern (Figure 3). Immunohistochemical stains were performed with adequate controls, revealing positive staining for CK20, SATB2, and CDX2, while showing negativity for BRST2, SATB2, GATA3, CK7, PR, ER, and HER2 (Figure 4). These findings corroborate the diagnosis of goblet cell adenocarcinoma. Results (if a Case Study enter NA) NA Conclusion In our case, we observed morphological features of goblet cell adenocarcinoma that overlapped with those of established mammary carcinomas. This scenario underscores the diagnostic challenges posed by rare tumors and emphasizes the significance of identifying the low-grade component of goblet cell adenocarcinoma, particularly in patients with a history of metastatic breast cancer.

Cardiac Angiosarcoma with Unusual Cytologic Features Causing Cardiac Tamponade in a Young Adult Patient

Abstract Introduction/Objective Cardiac angiosarcoma is a rare endothelial malignancy with poor prognosis, frequent metastasis, and short median survival of only a few months. The disease has a wide age spectrum and can occur in young adult patients. The cytological diagnosis of cardiac angiosarcomas is challenging as cases are rare and its cytology is not extensively described or reported in literature. Here, we describe a rare case of cardiac angiosarcoma with unusual cytologic features. Methods/Case Report Our patient is a 30 year old male presenting with three days of worsening dyspnea and palpitations and was discovered on ultrasound to have large pericardial effusion compressing the right ventricle and causing cardiac tamponade. CT/MRI imaging revealed a 4.5 x 4.3 x 2.6 cm mass inside the right ventricle with extra- cardiac invasion through the pericardium and into the anterior mediastinum. Pericardiocentesis yielded 1.5 liters of hemorrhagic, brown, pericardial fluid with elevated LDH and protein levels. Cytology of the pericardial fluid revealed numerous tumor cells occurring singly or in monolayered, acinar clusters or cohesive spheres containing amorphous, eosinophilic cores made of collagen as evidenced on trichrome stain. The tumor cells possessed hyperchromatic, irregular, variably sized nuclei, prominent nucleoli, and cytoplasmic vacuoles. The tumor cells were positive for vimentin, CD31, and CD34, and showed high Ki67 proliferation index > 50%. A catheter-mediated biopsy of the right ventricular mass revealed spindled and epithelioid tumor cells strongly positive for CD31, CD34, and vimentin, focally positive for Factor VIII and AE1/AE3, and showing high Ki67 proliferation index of roughly 50%. The cytological, histological, and immunohistochemical findings were most consistent with cardiac angiosarcoma as the diagnosis. The patient eventually developed worsening chronic left chest pain and expired from cardiac arrest six months after his diagnosis. Results (if a Case Study enter NA) NA Conclusion We report a rare case of cardiac angiosarcoma with unusual cytologic features, manifesting as acinar clusters and cohesive spheres with collagenous cores that are not typical of malignant endothelial neoplasms. Currently there are no effective, standardized therapies that can significantly prolong survival for this malignancy, and treatment is often palliative. The cytological diagnosis of cardiac angiosarcoma is challenging given the rarity of this disease and the paucity of literature describing its cytology.

Navigating Secondary Breast Angiosarcoma: a case report

BACKGROUND AND PURPOSE: Secondary breast angiosarcoma is a rare and aggressive malignancy that poses significant diagnostic and therapeutic challenges. Arising either from metastasis or as a complication of previous radiation therapy, it presents distinct clinical characteristics and prognostic implications compared to primary breast angiosarcoma. Understanding the unique features of secondary breast angiosarcoma is essential for guiding clinical decision-making and optimizing patient outcomes in the management of this challenging malignancy. METHODS: Imaging modalities such as mammography, ultrasound, or MRI may be used to evaluate the extent of the tumor, assess lymph node involvement, and detect distant metastases. A tissue biopsy is essential for confirming the diagnosis of angiosarcoma. Histopathological examination of the biopsy specimen helps to differentiate angiosarcoma from another breast tumor and determine the tumor grade. RESULTS: As angiosarcoma is relatively rare, there is a lack of detailed information regarding its progression. However, when compared to more common types of breast cancer, angiosarcoma of the breast generally carries a worse outlook. This is largely attributed to its tendency to be diagnosed later and its higher likelihood of rapid spread to distant sites within the body. CONCLUSIONS: Breast secondary angiosarcoma is associated with poor prognosis, often due to its aggressive nature and limited treatment options. Close monitoring, aggressive treatment strategies, and supportive care are essential in managing this challenging malignancy.

Liver Metastasis Masking as Neuroendocrine Carcinoma (NEC) Predates Discovery of Intra/Peri-Thyroid Thymic Carcinoma (ITTC)

Abstract Introduction/Objective Intrathyroidal thymic carcinoma (ITTC) also known as Carcinoma showing Thymus-Like differentiation (CASTLE) is a rare malignancy comprising 0.1 to 0.15% of thyroid cancers. The WHO 5th Edition emphasizes that these tumors may also occur outside the thyroid typically at the lower pole Methods/Case Report Our aim is to show that NEC is a mimic of ITTC; that CD5, c-KIT (CD 117), p40, CK5/6 expression distinguishes ITTC from NEC, and that ITTC may at times express NE markers. Briefly, a 51-year-old man presented with hoarseness left neck mass and a PET avid liver lesion in 2016. Biopsy of the neck and liver masses revealed an infiltrating poorly differentiated “NEC” with similar morphology; positive for p53, chromogranin, and synaptophysin; negative for cam5.2, thyroglobulin, TTF-1, CD20, Pax5, CD3, CD5, S-100, calcitonin, CD56, p16, p63, c-KIT (CD117), AE1/3; and 100% staining for Ki-67. The patient underwent chemotherapy, responded well, remained under surveillance, and was symptom-free in the interim. A new 2.1 x 2.0 cm nodule appeared at the left thyroid lower pole after 6 years. The tumor was positive for CD5, CD117, p40, CK5/6, with > 95% Ki67 expression. Chromogranin, synaptophysin, CD56, thyroglobulin, calponin, TTF1, and Epstein Barr virus were negative and was overall diagnostic of ITTC Results (if a Case Study enter NA) NA Conclusion This shows the diagnostic dilemma of distinguishing ITTC from NEC which may share expression of neuroendocrine (NEC) markers and that positivity for CD5, c-KIT (CD117), p40, and CK5/6 are key diagnostic features of ITTC.

Unveiling the Unusual: Mediastinal Rhabdomyosarcoma in an Adult Patient

Abstract Introduction/Objective We present a case of a 55-year-old female with a history of hypertension, diabetes, hyperlipidemia, chronic kidney disease (CKD), and asthma, who presented with a mediastinal mass. Methods/Case Report A needle core biopsy of the mediastinal mass was performed. Microscopic examination showed a proliferation of primitive appearing, moderately pleomorphic cells with features suggestive of rare strap cells of rhabdomyosarcoma. Immunohistochemical staining was positive for desmin and myogenin, consistent with rhabdomyosarcoma. Further cytogenetic analysis for FOXO1 translocation, was performed. Results (if a Case Study enter NA) Cytogenetic analysis was negative for FOXO1 translocation by FISH, ruling out alveolar rhabdomyosarcoma. Despite negative cytogenetic findings, the morphology and immunoprofile were consistent with rhabdomyosarcoma. However, the possibility of rhabdomyosarcoma occurring within a mediastinal teratoma, germ cell tumor, or carcinosarcoma was noted. Conclusion This case highlights the challenge of diagnosing rhabdomyosarcoma in adults, especially when presenting as a mediastinal mass. The histologic and immunophenotype supported the diagnosis of rhabdomyosarcoma. However understanding the primary of the lesion in the hilum is more diffecult. physical examination releave no lesion on the extremities. CT scan of the abdomen and pelvis reveals no other lesion. making the metastasis unlikely.This case underscores the importance of thorough diagnostic evaluation, including histopathology and immunohistochemistry, in the assessment of unusual neoplasms, which can impact treatment decisions and prognosis. Further studies are warranted to elucidate the molecular mechanisms underlying rhabdomyosarcoma in adults and its association with other mediastinal tumors. This case report contributes to the evolving understanding of rare malignancies and their implications for pathology and laboratory medicine practice.

Regional distribution of anaplastic thyroid cancer in the United States

Abstract Introduction/Objective Anaplastic thyroid cancer (ATC) is an aggressive rare malignancy found in less than 2% of thyroid cancer patients. Its low occurrence rate presents challenges for collecting sufficiently large cohorts at a single institution, making statistical analysis about the disease’s spread, geographical distribution, and prevalence difficult. Nationwide data lakes such as Oracle EHR Real-World Data (ORWD, formerly Cerner Real World Data) offer a boost in cohort sizes and an opportunity to study ATC’s geographical distribution and assess regional differences. Methods/Case Report We searched ATC distribution across US regions defined by ZIP codes recorded in ORWD using multiple coding parameters, including ICD9, ICD10, and SNOMED as well as direct text searches for “anaplastic thyroid carcinoma”. We analyzed the geographical associations defined by ORWD (region) with sex, race, and age of ATC onset using the Fisher’s exact test. We combined 10 regions into 4 representative groups because of the small sample size. The groups are West Coast including the Rockies, Midwest from North Dakota to Texas, East Coast, and New England. Results (if a Case Study enter NA) Search for ATC condition codes in ORWD produced only 200 region-coded patient records across the US using multiple methods to try and identify cases. The mid-section of the US and coastal regions shows the highest numbers of ATC patients while New England and South regions show the lowest. While more women have ATC overall, the East Coast group has significantly more males (p value = 0.04). ATC is a predominantly white disease (79.8% overall) with black population increasing in East Coast group and other races (Asian/Undeclared) in West Coast (p-value < 0.001). There appears to be no significant association between age of ATC onset and the geographical groups. Conclusion The data shows geographic differences in distribution of ATC although this preliminary analysis neither explains the nature of these differences nor allows for a clearer view. The rarity of the disease complicates data analysis. This study was also limited by number of cases retrievable from the database itself and lack of granularity in coding available for ATC to find cases of interest, highlighting the difficulty of accurate tumor classifications in large data lakes. Further research into geographical distribution and environmental factors (radioactivity, pollution) of thyroid cancer using more advanced tools, such as GeoSpark, are planned.

Population-Based Cohort Study on Treatment and Overall Survival of Patients Clinically Diagnosed With T1 Ampullary Cancer.

To evaluate treatment outcomes, overall survival (OS), and prognostic factors for OS in patients diagnosed with T1 ampullary cancer. Ampullary cancer is a rare gastrointestinal malignancy with limited data from large cohorts, especially regarding T1 disease. Patients diagnosed with clinical (c) T1 ampullary cancer and patients with pathological (p) T1 in the case of cTx were included from the Netherlands Cancer Registry (2014-2021). Primary endpoint was OS, analyzed using the Kaplan-Meier estimator. Multivariable Cox proportional hazards regression was used to identify OS predictors. Overall, 244 patients with cT1 ampullary cancer were included, of whom 75% (n=184) underwent resection. Among these, 68% (n=125) were upstaged to a higher pathologically T classification (pT2:40%, pT3:22%, pT4:5%). Similarly, cN0 was upstaged to pN1 in 47% of patients (n=87). Next, 100 patients with pT1 and cTx ampullary cancer were included, making a total of 159 patients with pT1 tumor. 92% (146/159) underwent pancreatoduodenectomy while 8% (13/159) underwent endoscopic or local surgical resection. The 1- and 5-year OS for cT1N0 ampullary cancer were 72% and 36%, while for pT1N0 they were 94% and 75%. Independent poor prognostic factors for OS were pN1 classification (HR 2.12; 95%CI 1.15-3.94, P=0.017), pNx classification (i.e. locally resected patients) (HR 2.82; 95%CI 1.22-6.55, P=0.016), and poorly differentiated tumors (HR 4.05; 95%CI 1.33-12.40, P=0.014). In patients with cT1 ampullary cancer, more than two-thirds had a pathologically higher T classification, and almost half had a pathologically higher N classification. These findings suggest that pancreatoduodenectomy is recommended for cT1 ampullary cancer.

Expression of the large amino acid transporter SLC7A5/LAT1 on immune cells is enhanced in primary sclerosing cholangitis-associated cholangiocarcinoma and correlates with poor prognosis in cholangiocarcinoma

Biliary tract cancers (BTC) are rare lethal malignancies arising along the biliary tree. Unfortunately, effective therapeutics are lacking and the prognosis remains dismal even for patients eligible for surgical resection. Therefore, novel therapeutic approaches along with early detection strategies and prognostic markers are urgently needed. Primary sclerosing cholangitis (PSC) is a chronic disease of the bile ducts leading to fibrosis and ultimately cirrhosis. Patients with PSC have a 5–20% lifetime risk of developing BTC; yet the molecular mechanisms that underpin the development of PSC- associated biliary tract cancer (PSC-BTC) have not been fully elucidated. SLC7A5/LAT1, a large amino acid transporter, has been shown to modulate cell growth and proliferation as well as other intracellular processes in solid tumors. In this study, we evaluated SLC7A5 expression in PSC-BTC and in sporadic BTC (sBTC) and its role as a prognostic factor. Analysis of the TGCA cohort showed a significantly higher expression of SLC7A5 in tumor tissue compared with adjacent normal tissue (p = 0.0002) in BTC. In our cohort (comprised of 69 BTC patients including 16 PSC-BTC), SLC7A5/LAT1 expression was observed in both tumor and intratumoral immune cells. A significantly higher percentage of SLC7A5/LAT1 positive intratumoral immune cells was observed in PSC-BTC compared with sBTC (p = 0.004). Multiplex immunofluorescence co-detection by indexing (CODEX) analysis identified CD4+ regulatory T lymphocytes and CD68+ macrophages as the largest immune cell populations expressing LAT1.SLC7A5/LAT1 expression as well as a higher intratumoral infiltration of SLC7A5/LAT1-positive immune cells (≥2%) were associated with a shorter overall survival in our cohort (LogRank test, p = 0.04 and p = 0.008; respectively). SLC7A5/LAT1 expressing tumors are higher staged tumors (pT3/4 versus pT1/2, p = 0.048).These results underline the potential use of SLC7A5/LAT1 as a prognostic marker in BTC. Furthermore, the higher frequency of SLC7A5/LAT1 positive immune cells in PSC-BTC compared to sBTC may hint at the potential role of SLC7A5/LAT1 in inflammation-driven carcinogenesis.

Influence of Perineural (Pn), Lymphangio (L) and Vascular (V) Invasion on Survival after Resection of Perihilar Cholangiocarcinoma.

Perihilar cholangiocarcinoma is a rare malignancy of the biliary tract, for which surgery remains the treatment of choice. However, even after radical resection, the prognosis is poor. In addition to tumor size, depth of invasion and nodal/metastatic status, the TNM classification includes additional parameters such as perineural (Pn), lymphangio (L) and vascular (V) invasion. The prognostic impact of these factors is not yet fully understood. The aim of this study was to investigate the influence of these parameters on overall survival after resection of perihilar cholangiocarcinoma. Data from all patients who underwent surgical exploration for perihilar cholangiocarcinoma between January 2013 and December 2023 were included into an institutional database. The impact of perineural, lymphangio and vascular invasion on overall survival was analyzed. Over the 11-year period, a total of 214 patients underwent surgical exploration for perihilar cholangiocarcinoma. Curative intended resection was possible in 168 patients (78.5%). Perineural invasion, lymphangio invasion and vascular invasion were present in 79.2%, in 17.3% and in 14.3% of patients, respectively. Cross tabulation revealed a significant association between the presence of L1 and V1 (p = 0.006). There was also a significant association of Pn1, L1, and V1 with R-status (p = 0.010; p = 0.006 and p ≤ 0.001). While V1 was associated with significantly worse overall survival across the entire cohort, Pn1 alone showed only a tendency towards worse overall survival without reaching statistical significance. In Bismuth type IV, both L1 and V1, but not Pn1, were significantly associated with worse overall survival (p = 0.001; p = 0.017 and p = 0.065). Perineural invasion is very common in perihilar cholangiocarcinoma. Although Pn1 was associated with a tendency toward worse survival, it did not reach statistical significance. In contrast, vascular invasion significantly worsened overall survival in the entire cohort, and lymphangio invasion was linked to worse overall survival in Bismuth type IV tumors. The combination of perineural invasion with positivity of more than one additional factor (either L or V) was also associated with worse overall survival. In patients with Bismuth type IV, these pathological markers appeared to have even greater prognostic relevance.

Clear Cell Adenocarcinoma of the Urinary Tract Primary to the Renal Pelvis: A Multi-institutional Clinicopathologic and Molecular Study of Five Patients.

Clear cell adenocarcinoma (CCA) of the urinary tract is a rare malignancy and tumors involving the renal pelvis are notably sparse in the literature, with only 5 other patients reported. We present 5 patients, 4 women, and 1 man, with CCA of the renal pelvis. The age at presentation ranged from 29 to 81 years. The tumor size ranged from 4.5 to 8.0 cm. Tumors exhibited shared morphologic and immunohistochemical features with CCA of the female genital tract and those originating in the bladder and urethra, including cells with large nuclei, prominent nucleoli, nuclear hobnailing, and scant clear cytoplasm. Common immunohistochemical findings included reactivity for PAX8, CK7, HNF1β, and Napsin-A. One of the tumors arose in the background of a mixed epithelial and stromal tumor. Another tumor occurred in a renal allograft and tumor cells were positive for the BK virus, demonstrated by SV40 immunohistochemistry. All tumors were negative for TFE3 and TFEB rearrangement and lacked TERT alterations. Follow-up was limited with no recurrence in 4 patients at a maximum of 20 months follow-up and 1 patient died of an unrelated cause at 25 months of follow-up. Next-generation sequencing analysis of all 5 CCAs revealed mutations within genes implicated in DNA damage repair and chromatin remodeling pathways, including ATM, BRCA1, BRCA2, ARID1A, DICER1, SMAD4, NOTCH1, and MYC amplification. These molecular findings underscore the dysregulation of fundamental cellular processes essential for genomic integrity maintenance.

Altering Trends in Pathological Spectrum of Cholecystectomy Specimen: Time to be More Vigilant

Abstract Background: Gall bladder cancer is a rare, most common and aggressive malignancy of the biliary tree, accounting for 80%–90% of biliary tract cancers. Gallstones are one of the major causes of the development of cholecystitis and long-term malignancy in developing countries. Cholecystectomy specimens have a great value in documenting various entities with clinical significance. Early detection is the most important step in improving the prognosis of gall bladder carcinoma (GBC) screening. Aim: Clinico- pathological spectrum of cholecystectomy specimen and Incidence of malignancy and its precursor lesion with gallstones. Patient and Methods: We conducted a retrospective analysis of all gall bladder specimens (cholecystectomy, laparoscopic, open or radical) from the period of January 2019–January 2022, including demographic data of the patients such as age and sex. Additional findings, such as the presence of gallstones, cholesterolosis, gastric or intestinal metaplasia, dysplasia and histopathological type of GBC, were documented. Results: A total of 1221 gall bladder specimens were received, with a higher female preponderance and a female-to-male ratio of 2.6:1. The mean age of presentation was 45 years. The most common histopathological diagnosis made was chronic cholecystitis (97%), and malignant cases accounted for 3% of the total cases. Conclusions: The high propensity of GBC with non-cholelithiasis cases, more than half of cases with metaplasia and increased incidence of adenosquamous carcinoma indicate a high burden of tumours, alerting the clinician as well as the pathologist.

Immunotherapy for Treatment of Pleural Mesothelioma: Current and Emerging Therapeutic Strategies

Pleural mesothelioma is a rare malignancy associated with asbestos exposure and very poor prognosis, with a 5-year overall survival of 12%. Outcomes may vary according to stage at time of diagnosis and histologic subtype. Most recently, clinical trials utilizing dual checkpoint inhibitor regimens and chemotherapy in combination with immune oncologic agents have demonstrated impactful changes in outcomes. In this article, we review studies that have led to the successful implementation of immunotherapy in clinical practice for the treatment of this disease and highlight ongoing clinical trials exploring the use of different immunotherapy strategies for the treatment of pleural mesothelioma. We also discuss the challenges of immunotherapy-based approaches in the context of mesothelioma and future strategies currently being investigated to overcome them.

Role of 18F-FDG-PET/CT in the initial staging of very high-risk Ewing Sarcoma in a prospective multicentric Phase II Study: Is there still a place for bone marrow sampling?

The Ewing Sarcoma Family of Tumors (ESFT) constitutes a group of rare malignancies, wherein approximately one-third of cases exhibit metastatic spread, particularly impacting prognosis when bone and/or bone marrow (BM) are involved. Primary extra-pulmonary metastatic ESFT often necessitates intensified therapeutic approaches. Accurate staging plays a pivotal role in clinical decision-making, with fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) currently serving as a non-invasive modality for assessing ESFT's BM extent. In the French phase II COMBINAIR3 (NCT03011528) study, a comprehensive approach for patients with extra-pulmonary ESFT metastasis was evaluated. We prospectively compared the efficacy of PET/CT to BM aspiration and biopsy (BMAB) analysis in patients undergoing initial staging. Among the 42 patients analyzed (median age 14 y, 2:1 male/female ratio), 45% presented with pelvic primary tumors and 83% had bone/BM involvement at diagnosis. Our findings showed PET/CT had 100% specificity and 83.3% sensitivity in detecting initial BM involvement. Overall, PET/CT correctly classified 92.8% of patients, reaching 100% accuracy in patients identified with bone involvement, thus surpassing the standard BMAB. These results suggest that the conventional use of BMAB in the initial staging of high-risk ESFT patients can be omitted, promoting PET/CT as a non-invasive alternative, thus improving staging accuracy and treatment decisions in ESFT management.

7652 Functional Adrenocortical Carcinoma Presenting As Uncontrolled Hypertension

Abstract Disclosure: B.R. Bedell: None. M. Fariduddin: None. J. Sanchez Perez: None. S.C. Kukreja: None. R.M. Sargis: None. Adrenocortical carcinoma is a rare malignancy, with approximately 2,000 cases reported in the United States since 1970.[1] Many secrete excess adrenocortical hormones, adding to morbidity and mortality. Surgery can be curative or prolong survival if diagnosis is made early, but prognosis remains poor due to delayed detection.[2] We present a case of metastatic functional adrenocortical carcinoma that presented with consequences of long-standing uncontrolled hypertension. A 59-year-old male with history of hypertension and CAD presented to the hospital with worsening bilateral pitting edema, dyspnea on exertion, palpitations, headaches, and proximal muscle weakness over for multiple months. His hypertension (HTN) was noted to be uncontrolled despite use of multiple antihypertensives (daily Lasix 20 mg, Lisinopril 40 mg, Metoprolol Succinate 100 mg and Amlodipine 10 mg). Hypokalemia of 3.0 mmol/l (3.5 - 5.2 mmol/l) was noted. Echocardiogram revealed new heart failure with preserved ejection fraction. A subsequent nuclear stress test incidentally revealed a right-sided 15 cm retroperitoneal mass, invading the IVC and the right hepatic lobe. An AM dexamethasone suppression test was notable for a cortisol of 39 ug/dl (<1.8 ug/dl) and an undetectable ACTH level of <1.5 pg/ml (7.2 - 63.3 pg/mL), suggestive of primary hypercortisolism. 24-hour urine cortisol was 930.6 ug/d, (<=60.0 ug/d), DHEA-s 1105 ug/dL (52 - 295 ug/dL), Androstenedione 2.641ng/mL (0.230 - 0.890 ng/mL), and 17-Hydroxyprogesterone 299.87 ng/dL (<=138.00 ng/dL). Plasma metanephrines were normal and aldosterone levels were undetectable, confirming cortisol and its precursor excess as the cause of hypertension. Biopsy of the mass was consistent with adrenocortical carcinoma. Due to disease extent, the patient was not a candidate for surgical debulking, and radiation therapy was commenced. Ketoconazole 200 mg and Spironolactone 150 mg twice daily led to improvement in HTN and hypokalemia. His course was further complicated by bacteremia and acute pulmonary embolism. The patient eventually elected to pursue hospice care. Adrenocortical carcinoma remains challenging to detect at early stages given a paucity of symptoms. This case highlights the need to have a high index of suspicion for hypercortisolism in patients with uncontrolled HTN and hypokalemia, as this may be indicative of a functional adrenal cancer. This could be a potential strategy for earlier diagnosis, thereby increasing survival rates by improving disease amenability to surgical intervention. (1.) Sharma E, Dahal S, Sharma P, et al. The Characteristics and Trends in Adrenocortical Carcinoma: A United States Population Based Study. J Clin Med Res. 2018;10(8):636-640. doi:10.14740/jocmr3503w (2.) Vaidya A, Nehs M, Kilbridge K. Treatment of Adrenocortical Carcinoma. Surg Pathol Clin. 2019;12(4):997-1006. doi:10.1016/j.path.2019.08.010 Presentation: 6/2/2024

8592 Parathyroid Carcinoma: A Rare Cause of Primary Hyperparathyroidism

Abstract Disclosure: S.E. Koshy: None. C.F. Mulcahy: None. P.S. Kothari: None. E.M. Jacobi: None. T.D. Cubb: None. Introduction: Parathyroid carcinoma (PC) is a rare malignancy that accounts for <1% of cases of primary hyperparathyroidism (PHPT). Patients often present with symptoms of hypercalcemia, serum calcium (Ca) >14 mg/dL, large tumor size, and a very high parathyroid hormone (PTH) level. We report a case of an asymptomatic patient with incidentally found hypercalcemia consistent with PHPT who was ultimately diagnosed with PC. Clinical Case: A 31yo male was found to have elevated serum Ca of 12.7 mg/dL (8.6-10.3 mg/dL) on labs obtained during routine physical exam. He had no known significant medical or family history and notably had no laboratory evaluation within the prior 10 years. He denied constipation, polyuria, confusion, depression, bone pain, and history of fractures or nephrolithiasis. Workup showed an inappropriately elevated PTH of 505 pg/mL (16-77 pg/mL). Neck ultrasound demonstrated a left inferior 3.9 cm complex thyroid nodule. Sestamibi scan confirmed increased uptake in the inferior left thyroid. Left neck exploration was performed. Intraoperatively, a 3.7 cm left parathyroid mass weighing 13.0 grams was encountered and excised in an en bloc fashion. The left superior parathyroid gland was evaluated and found to be normal. Intraoperative PTH level decreased from 529 pg/mL to 48 pg/mL 10 minutes after excision. Left hemithyroidectomy was not performed. Surgical pathology revealed PC with lymphovascular invasion, suspected capsular invasion, and negative margins. Immunohistochemical staining showed a Ki67 proliferation index up to 5% and complete loss of nuclear staining for parafibromin. Next generation sequencing demonstrated a somatic CDC73 p.L8fs mutation, tumor mutational burden 4.7m/MB, and stable microsatellite instability. Germline testing was negative for a CDC73 mutation. Postoperative staging did not demonstrate evidence of metastatic disease in the neck or chest. Serum Ca remained within normal limits. After multidisciplinary discussion, no further surgical intervention was recommended and plan was for ongoing biochemical and imaging surveillance. Conclusion: Though rare, PC should be considered as a cause of PHPT. The primary treatment is complete surgical resection. Unfortunately, there is a high rate of recurrence, >50%, with most occurring 2-5 years after initial surgery with a median overall survival of 14 years. Thus, long-term surveillance is of utmost importance. Treatment of recurrent disease is surgical resection when feasible as well as medical management of hypercalcemia. Further research is needed to better understand the role of targeted systemic therapy in addition to immunotherapy. PC is most commonly sporadic but can be hereditary, thus genetic evaluation is recommended. Given its rarity and complexity, PC is best managed in a multidisciplinary setting. Presentation: 6/1/2024

8543 Non-Specific Uptake Of Magnetic Iron Oxide Nanoparticles Into Adrenocortical Carcinoma Cells, Endothelium And Primary Monocytes

Abstract Disclosure: R. Challapalli: None. A. Sorushanova: None. C. Hong: None. N.J. Mullen: None. S. Feely: None. O. Covarrubias-Zambrano: None. J. Covarrubias: None. S. Varghese: None. C. Hantel: None. P. Owens: None. M. O’Halloran: None. P. Prakash: None. S.H. Bossmann: None. M.C. Dennedy: None. Adrenocortical carcinoma (ACC), a rare malignancy with a poor prognosis and a survival rate of up to 24 months, requires varied treatments such as surgery, chemotherapy, or radiation. The high recurrence rate emphasizes the need for innovative therapies. Magnetic iron oxide nanoparticles have emerged as promising candidates for cancer treatment due to their versatility in size and shape and the ability to modify their surface for targeted cellular uptake. In our initial investigation, we assessed the uptake of magnetic iron oxide nanoparticles (IONP) by ACC (H295R, HAC15, and MUC1) cells, HUVECs and primary monocytes, incubated with 0, 5, 10, 20, and 50 µg/ml of IONP for 24 hours. The results demonstrated concentration and time-dependent nanoparticle uptake and its impact on cellular viability. The optimal concentration of IONP was identified as 10 µg/ml, subsequently used to evaluate the rate of uptake and intracellular location. The efficiency of IONP uptake by ACC cells decreased when exposed to primary monocytes and an HUVEC layer, as demonstrated through a Transwell migration system. This study revealed insights into the non-specific uptake of IONP by ACC, primarily attributed to the mechanism of macropinocytosis. These preliminary findings lay the groundwork for exploring potential modifications to enhance specific uptake by ACC cells, particularly for applications like magnet-induced thermal ablation or nanobiocontrast. Presentation: 6/2/2024

7036 Luteinizing Hormone/Human Chorionic Gonadotropin Receptor And Cyclooxygenase-2 Expression In Adrenocortical Carcinoma

Abstract Disclosure: R. Sheskier: None. A. Kirschenbaum: None. I. Zappi: None. S. Yao: None. A.C. Levine: None. Adrenocortical carcinoma (ACC) is a rare malignancy that has a poor prognosis. The current mainstays of therapy are surgical resection of primary and oligometastases, and systemic therapy with mitotane with or without combination of etoposide, doxorubicin, and cisplatin for more advanced disease. New therapeutic targets are needed to increase options for medical management of mitotane-resistant disease. Expression and function of the luteinizing hormone/human chorionic gonadotropin receptor (LH/hCG-R) have been demonstrated in non-gonadal tissues and malignancies (1). In the adrenal gland, LH/hCG-R expression has been noted in some secretory benign adenomas but its expression in ACC is underexplored (1, 2). Cyclooxygenase-2 (COX-2) is expressed in a variety of cancers, but has not been previously evaluated in ACC (3). We examined the immunohistochemical expression of LH/hCG-R and COX-2 in 15 tissue samples from 7 patients with ACC of varying ENSAT stages with 5 samples from primary ACC tumors and 10 metastatic samples from varying sites. LH/hCG-R was expressed in 13/15 ACC tissue samples (6/7 patients; 4/5 primary ACC; 9/10 metastases). COX-2 expression was demonstrated in 12/15 ACC tissue samples (6/7 patients; 4/5 primary ACC; 8/10 metastases with one metastasis post-mitotane negative for COX-2). Specimens from one patient were also examined for LH/hCG-R and COX-2 expression prior to and following treatment with mitotane. Compared to the primary ACC tumor pre-treatment with mitotane, the post-mitotane ACC metastasis showed an increase in LH/hCG-R expression and a decrease in COX-2 expression. In comparison, a liver ACC metastasis from a separate patient with mitotane-resistant disease demonstrated persistent LH/hCG-R and COX-2 expression. Our findings suggest that LH/hCG-R and COX-2 are expressed in the majority of ACC primary and metastatic lesions. Our results further imply that LH/hCG-R expression persists in mitotane-resistant disease and COX-2 expression initially decreases with mitotane therapy, but is re-expressed in mitotane-resistant disease. Both LH/hCG-R and COX-2 may therefore serve as potential therapeutic targets in the management of advanced ACC. (1) Carlson HE. Human adrenal cortex hyperfunction due to LH/hCG. Mol Cell Endocrinol. 2007 Apr 15;269(1-2):46-50. (2) Doroszko DM, Chrusciel M, Stelmaszewska J, Slezak T, Anisimowicz S, Plöckinger U, Quinkler M, Bonomi M, Wolczynski S, Huhtaniemi I, Toppari J, Rahman NA. GnRH antagonist treatment of malignant adrenocortical tumors. Endocr Relat Cancer. 2019 Jan 1;26(1):103-117. (3) Hu Z, Yang Y, Zhao Y, Huang Y. The prognostic value of cyclooxygenase-2 expression in patients with esophageal cancer: evidence from a meta-analysis. Onco Targets Ther. 2017 Jun 9;10:2893-2901. Presentation: 6/1/2024

8592 Parathyroid Carcinoma: A Rare Cause of Primary Hyperparathyroidism

Abstract Disclosure: S.E. Koshy: None. C.F. Mulcahy: None. P.S. Kothari: None. E.M. Jacobi: None. T.D. Cubb: None. Introduction: Parathyroid carcinoma (PC) is a rare malignancy that accounts for <1% of cases of primary hyperparathyroidism (PHPT). Patients often present with symptoms of hypercalcemia, serum calcium (Ca) >14 mg/dL, large tumor size, and a very high parathyroid hormone (PTH) level. We report a case of an asymptomatic patient with incidentally found hypercalcemia consistent with PHPT who was ultimately diagnosed with PC. Clinical Case: A 31yo male was found to have elevated serum Ca of 12.7 mg/dL (8.6-10.3 mg/dL) on labs obtained during routine physical exam. He had no known significant medical or family history and notably had no laboratory evaluation within the prior 10 years. He denied constipation, polyuria, confusion, depression, bone pain, and history of fractures or nephrolithiasis. Workup showed an inappropriately elevated PTH of 505 pg/mL (16-77 pg/mL). Neck ultrasound demonstrated a left inferior 3.9 cm complex thyroid nodule. Sestamibi scan confirmed increased uptake in the inferior left thyroid. Left neck exploration was performed. Intraoperatively, a 3.7 cm left parathyroid mass weighing 13.0 grams was encountered and excised in an en bloc fashion. The left superior parathyroid gland was evaluated and found to be normal. Intraoperative PTH level decreased from 529 pg/mL to 48 pg/mL 10 minutes after excision. Left hemithyroidectomy was not performed. Surgical pathology revealed PC with lymphovascular invasion, suspected capsular invasion, and negative margins. Immunohistochemical staining showed a Ki67 proliferation index up to 5% and complete loss of nuclear staining for parafibromin. Next generation sequencing demonstrated a somatic CDC73 p.L8fs mutation, tumor mutational burden 4.7m/MB, and stable microsatellite instability. Germline testing was negative for a CDC73 mutation. Postoperative staging did not demonstrate evidence of metastatic disease in the neck or chest. Serum Ca remained within normal limits. After multidisciplinary discussion, no further surgical intervention was recommended and plan was for ongoing biochemical and imaging surveillance. Conclusion: Though rare, PC should be considered as a cause of PHPT. The primary treatment is complete surgical resection. Unfortunately, there is a high rate of recurrence, >50%, with most occurring 2-5 years after initial surgery with a median overall survival of 14 years. Thus, long-term surveillance is of utmost importance. Treatment of recurrent disease is surgical resection when feasible as well as medical management of hypercalcemia. Further research is needed to better understand the role of targeted systemic therapy in addition to immunotherapy. PC is most commonly sporadic but can be hereditary, thus genetic evaluation is recommended. Given its rarity and complexity, PC is best managed in a multidisciplinary setting. Presentation: 6/1/2024

8180 Rare Variants Of Adrenocortical Carcinoma: A Retrospective Cohort Study

Abstract Disclosure: C.A. Villavicencio Torres: None. I. Bancos: None. Background: Adrenocortical carcinoma (ACC) is a rare malignancy with an estimated annual incidence of 0.7-2 cases per million per year. Scarce data are available on rare histological variants of ACC. Objective: To describe the clinical presentation and outcomes of patients diagnosed with oncocytic, sarcomatoid and myxoid ACC variants. Methods: Retrospective single center cohort study, 1992-2021 of patients with rare histological ACC variant. Results: A total of 20 patients were diagnosed with oncocytic (17, 85%), sarcomatoid (2, 10%), or myxoid (1, 5%) ACC. Median age of diagnosis was 47 years (range 17-80), and 14 (70%) were women. All patients had unilateral ACC (12, 60% left) with a median tumor size of 11 cm (range 4-29). Adrenal hormone excess was documented in 10 (50%) patients, mostly with either glucocorticoid or androgen excess. ENSAT stage I, II, III, and IV was documented in 2 (10%), 10 (50%), 6 (30%), and 2 (10%) patients, respectively. All patients were treated with adrenalectomy (laparoscopic in 5 and open in 15). In addition, patients were treated with mitotane (10, 50%), radiation (7, 35%), and chemotherapy (5,25%). Mitotane was administered for a median of 12 months (range 4-31) and was discontinued mainly due to side effects in 9 (90%) patients. Patients were followed for a median follow up of 6.5 years (range 0.4-12). In addition to 2 patients who presented with ENSAT stage IV metastatic disease, metastatic disease developed in additional 6 (30%) patients who initially presented with localized ACC (3 stage 2, 3 stage 3, 5 oncocytic, 1 sarcomatoid). Metastatic sites included lung (n=2), omentum (n=1), duodenum (n=1), liver (n=4), and bones (n=1). At the end of follow up, 11 (55%) patients remained disease free (53% oncocytic, 50% sarcomatoid, 100% myxoid), 5 (25%) patients were alive with metastatic ACC (23% oncocytic, 50% sarcomatoid), and 4 patients died of ACC (median time to death 21 months (range 10-50) post-adrenalectomy). Conclusions: Patients with oncocytic, sarcomatoid, and myxoid ACC may have a better prognosis than in reported literature. Larger multicenter studies are needed to identify patient and tumor-specific factors that guide management to assure improved outcomes in these very rare patients. Presentation: 6/2/2024