Ki-67 Labeling Index Research Articles

Multilineage Pituitary Neuroendocrine Tumors Expressing TPIT and SF1: A Clinicopathological Series of Six Tumors.

Tumors of adenohypophysial hormone-secreting cells, now classified as pituitary neuroendocrine tumors (PitNETs), have been subclassified based on cell differentiation. Normal adenohypophysial cells have three lineages of differentiation driven by the transcription factors PIT1, TPIT, and SF1 which are responsible for the regulation of hormone gene expression; PIT1 drives expression of GH, PRL, and TSH, TPIT is required for POMC expression that gives rise to ACTH, and SF1 is the transcription factor responsible for FSH and LH expression. The vast majority of PitNETs follow these three lineage differentiation pathways but rare PitNETs show either no lineage differentiation or express biomarkers of more than one lineage. The recent WHO classification continued the terminology "plurihormonal" for tumors that have features of more than one lineage but a better term is "multilineage" since some tumors may express more than one lineage-specific transcription factor without the hormones that are driven by those factors. Recent data indicate that tumors with expression of PIT1 and SF1 are the most common multilineage PitNETs. Here we report the existence of rare PitNETs that express TPIT and SF1. The 6 patients (5 female, 1 male; mean age 54.8years; range 35-84years) represent less than 1% of patients in our series of PitNETs. Most patients had clinically silent tumors with no evidence of hormone excess and variable degrees of hypopituitarism; two had Cushing disease. All patients had macrotumors with a mean tumor size of 2.46cm (range 1.1-5.0cm). Crooke's hyaline change was identified in the nontumorous adenohypophysis of the two patients with Cushing disease. The mean Ki67 labeling index was 2.91% (range 2.03-3.94%). All tumors were negative for PIT1 and PIT1-lineage hormones (GH, PRL, and TSH). TPIT was focal in one tumor, and the remaining tumors had diffuse reactivity in more than 50% of tumor cells. SF1 expression was focal in 5 tumors and diffuse in one. Three tumors had variable expression of at least one gonadotropin (FSH or LH). GATA3 was expressed in two tumors. Variable ER-alpha expression was noted in three tumors. CAM5.2 was positive in all tumors. With the exception of two tumors causing Cushing disease, p27 expression was intact. Our study confirms that multilineage PitNETs expressing TPIT and SF1 occur but are extremely rare; they can be clinically non-functional or can cause Cushing disease. Irrespective of functional status of a PitNET, routine application of pituitary transcription factors is warranted to identify these tumors. Data on the molecular correlates and clinical significance are still needed for these rare multilineage PitNETs.

SURG-50. CLINICAL EXPERIENCE AND PATHOLOGICAL FEATURES IN AUTOPSY CASES TREATED WITH TUMOR TREATING FIELDS

Abstract BACKGROUND Since 2017 Tumor Treating Fields (TTF) was approved for primary glioblastoma in Japan. In this study, we reviewed clinical experience and the pathological characteristics of autopsy cases treated with TTF. METHODS From March 2018 to April 2022, 67 patients (36 males and 31 females, median age 68 years) with primary glioblastoma, IDH-wild type treated at our institution were included in the analysis. RESULTS Twenty-eight patients (19 males and 9 females, median age 66 years) met the TTF indication criteria for induction, 19 cases (67.9%) were 65 years or older, and 14 cases (50.0%) indicated MGMT promoter methylation. The mean duration of TTF treatment was 7.2 months. The main reasons for discontinuation were tumor recurrence in 11 patients (40.7%), skin symptoms in 8 patients (29.6%), and psychological distress in 6 patients (22.2%). Only 12 patients (42.9%) underwent TTF treatment over 18 hours per day, because of discomfort of wearing pad and concern about srrounding. Median PFS and OS in the used patients were 9.9 and 17.7 months, respectively. Autopsies were performed in 3 of the 16 deaths. Histopathological examination of tumor specimen indicate that the Ki-67 labeling index was higher in brainstem (33.6%) than in the supratentorial primary lesion (23.6%). DISCUSSION Comparing to the previous report (Stupp R et al., JAMA. 2017), our cases contained a large number of patients over 65 years old with shorter mean duration of TTF treatment, and shorter OS. After TTF treatment, the Ki-67 labeling index was higher on infratentorial than on supratentorial in the autopsy specimens, suggesting the anti-tumor effect of TTF for the supratentorial lesion. RESULTS High proliferative activity of infratentrial lesion was suggested as a typical form of progression for TTF treatment.

EXTH-81. A RARE CASE OF RELENTLESSLY PROGRESSIVE METASTATIC PINEOCYTOMA MANAGED WITH SEQUENTIAL MULTIMODAL THERAPY

Abstract BACKGROUND Pineocytoma is a rare pineal parenchymal WHO grade 1 tumor, typically well-managed with surgical resection alone. With gross total resection (GTR), 91% 1-year and 84% 5-year survival rates have been reported. Recurrent pineocytoma is rare and optimal management in that setting is unknown, in part owing to the rarity of the condition. METHODS We report an atypical course of pineocytoma in a 58-year-old male involving metastatic disease. RESULTS A pineal mass was identified upon MRI of the brain obtained for vision changes. Patient underwent GTR, pathology was consistent with pineocytoma, WHO grade 1. Ki-67 labeling index was low at 1-2%. Despite low-grade pathology, two years later, surveillance imaging demonstrated recurrence in the pineal region and a second lesion in the right thalamus. The patient underwent gamma knife surgery (GKRS) to both lesions. Three years later, he developed three new lesions in the right cerebellum and again underwent GKRS. Subsequent surveillance imaging identified new lesions in the right cerebellum and along ventricular walls, treated with further GKRS. Nine years after initial diagnosis, focal nodular leptomeningeal metastases were discovered, along with progression at the primary tumor site. Patient was treated with GKRS to the nodular deposits followed by pembrolizumab. Further disease progression as noted despite immunotherapy. Patient was treated with 6 cycles of temozolomide chemotherapy and at further progression 3 cycles of lomustine. Upon additional progression, further radiation therapy was administered with bevacizumab to reduce risk of radiation necrosis. Patient remains on surveillance 13 years after initial diagnosis with visual changes and mild headache representing only clinical issues. CONCLUSIONS Although exceedingly rare, pineocytoma is capable of metastasizing to brain parenchyma and the leptomeninges, as demonstrated in our patient. However, our case demonstrates prolonged survival is possible even in the setting of relentlessly progressive metastatic disease with utilization of multimodality treatment.

Association Between Gross Features and Coexistence of BRAFV600E and TERT Promoter Mutations in Papillary Thyroid Carcinomas: A Combined Analysis Incorporating Clinicopathologic Features.

Background: The coexistence of v-Raf murine sarcoma viral oncogene homolog B1 (BRAFV600E) and telomere reverse transcriptase promoter (TERT-p) mutations is considerably associated with aggressiveness and poor prognosis in papillary thyroid carcinoma (PTC). However, the association between gross findings and genetic alterations in PTC remains unknown. We aimed to investigate the association between clinicopathologic features, including macroscopic features, and the coexistent BRAFV600E and TERT-p mutations in patients with PTC. Methods: We retrospectively analyzed 375 cases of PTC surgically resected between January 2018 and October 2023 at a single institution, based on the presence of BRAFV600E and TERT-p double mutation. Clinicopathologic features, including gross features on the cut surface of tumors, were evaluated. Subsequently, the association between clinicopathologic features and mutation status was statistically examined. Cox proportional hazard models were used to analyze the impact of molecular pathological features on disease-free survival (DFS). Results: The BRAFV600E and TERT-p double mutation was identified in 78 (20.8%) patients among the PTC cases and was significantly correlated with shorter DFS. Multivariable analysis revealed that factors such as relatively older age (≥55 years) (odds ratio [OR] = 12.083, 95% confidence interval [CI] 4.498-32.456), larger tumor size (>2.0 cm) (OR = 2.722, CI 1.104-6.712), lobulated tumor margins (OR = 16.114, CI 3.155-82.296), papillary excrescences on the cut surface (OR = 17.573, CI 3.462-89.201), solid-cut surface (OR = 4.012, CI 1.084-14.849), minimal extrathyroidal extension (ETE) (OR = 4.156, CI 1.209-14.282), gross ETE (OR = 6.517, CI 1.734-24.490), and Ki-67 labeling index (LI) (≥5%, OR = 12.145, CI 4.354-33.877) were significantly associated with the double mutation. Conclusions: The BRAFV600E and TERT-p double mutation in PTC was significantly associated with relatively old age, larger tumor size, lobulated configuration in tumor margin, papillary excrescences on the cut surface, solid-cut surface, ETE, and high Ki-67 LI. These features are suggestive of the presence of the double mutation and should be analyzed at the molecular level in patients with PTC.

Programmed Death-Ligand 1 (PD-L1) and Ki-67 Labeling Index: Correlation with Tumor Grade and Recurrence

Background: Meningiomas are common primary brain tumors with variable clinical behavior. While most are benign, a subset exhibits aggressive characteristics and a high recurrence rate. This study aimed to investigate the association of Programmed Death-Ligand 1 (PD-L1) and Ki-67 labeling index with histopathological grade and recurrence in meningioma. Methods: A retrospective study was conducted on 139 cases of meningioma diagnosed between January 2020 and December 2023. PD-L1 expression was evaluated using immunohistochemistry (IHC) and scored using the combined positive score (CPS). Ki-67 labeling index was determined as the percentage of tumor cells with positive nuclear staining. The association of PD-L1 and Ki-67 with histopathological grade and recurrence was analyzed. Results: PD-L1 expression was positive in 66.7% of cases and was significantly associated with recurrence (p = 0.006). A higher Ki-67 labeling index (>4%) was observed in 68.9% of cases and was also significantly associated with recurrence (p = 0.013). No significant association was found between PD-L1 expression or Ki-67 labeling index and histopathological grade. Conclusion: PD-L1 expression and Ki-67 labeling index may serve as potential prognostic markers for predicting recurrence in meningioma. Further studies are needed to validate these findings and explore their potential therapeutic implications.

Rare presentations of glioblastoma multiforme in the septum pellucidum: illustrative case.

Glioblastoma multiforme (GBM), a high-grade primary brain tumor, presents a formidable challenge in neuro-oncology because of its aggressive nature, infiltrative growth, and limited response to treatment. The septum pellucidum represents an uncommon and unexpected location for GBM, adding complexity to the diagnosis and management of this rare intracranial malignancy. A 69-year-old male with a previous history of prostate carcinoma presented to an outside hospital with a 2-week history of a "trance-like state" and cognitive decline. Initial head computed tomography showed prominent ventricles without distinct mass lesions. Upon admission, magnetic resonance imaging demonstrated a mass within the inferior septum pellucidum extending to the third and both lateral ventricles. Biopsy findings indicated a GBM, World Health Organization central nervous system tumor grade 4, with immunopositivity for glial fibrillary acidic protein and a Ki-67 labeling index of 60%-70%. Identifying only 5 cases in more than 60 years of literature, this systematic review illustrates the diverse clinical presentations, diagnostic advancements, and management approaches for septum pellucidum GBM. https://thejns.org/doi/10.3171/CASE23770.

The role of the Ki-67 labelling index as an independent prognostic factor in indonesian glioma patients.

Gliomas are the most common type of brain tumor. However, interpreting glioma morphology is subjective, and identifying mitosis can be challenging. This can impact the determination of the patient's tumor grade, therapy, and prognosis. In addition, the Ki-67 expression level, which reflects the tumor cells' ability to proliferate, is closely related to the patient's survival. This study aims to find a correlation between Ki-67 expression and the overall survival (OS) of glioma patients in the Indonesian population. Ninety-one glioma patients from Sardjito General Hospital were collected for formalin-fixed embedded paraffin (FFPE) samples, and the Ki-67 labeling index (LI) was calculated by determining the percentage of labeled nuclei per 1000 cells using a 40x objective lens in a randomized area (average method). The OS was calculated from the day of pathology diagnosis until death or the last follow-up (for censored cases). Kaplan-Meier survival analysis was used to analyze the OS. Individuals aged ≥60 with high-grade tumors, infratentorial gliomas, and a Ki-67 LI ≥10% had a shorter OS. The p-values associated with these factors were 0.001, 0.018, and 0.006, respectively. In multivariate analysis, age and tumor grade did not significantly correlate with OS. Glioma patients with a Ki-67 LI ≥10% have a significantly shorter OS than those with a lower Ki-67 LI, indicating that Ki-67 LI is an independent prognostic factor in Indonesian glioma patients.

Role of Advanced Magnetic Resonance Imaging in Differentiating among Glioma Subtypes and Predicting Tumor-Proliferative Behavior

Abstract Objective Gliomas are a devastating and heterogeneous group of primary brain tumors. Previously, the source of glioma was undetermined. Recent literature indicates that neural stem cells, or progenitors, are proposed to be the source of glioma. The prognosis of different types of gliomas differs due to their various biological tissue types. Besides the histological grade, the two useful immunohistochemistry markers that show the tumor's biological behavior are isocitrate dehydrogenase (IDH) labeling and the Ki-67 labeling index. We sought to determine the magnetic resonance imaging (MRI) characteristics associated with IDH mutational status and ascertain whether MRI combined with IDH mutational status, can better predict the clinical outcomes of gliomas. Materials and Methods This period study was conducted in the Department of Radiology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India for 5 years (May 2016–May 2021). The study cohort included 30 patients diagnosed with gliomas who underwent preoperative MRI followed by surgical resection and histopathological examination. Preoperative MRI images were done to assess qualitative tumor characteristics such as location, margin of tumor, extent, cortical involvement, cystic component, mineralization or hemorrhage, and contrast enhancement. Discussion Differences in MRI features between IDH-mutant (MT) and IDH-wild-type (WT) groups were analyzed using the chi-square test for categorical variables and the Mann–Whitney U test for continuous variables. Statistical analysis was conducted using SPSS software. Results Among the 30 patients evaluated, 18 had IDH-WT and 12 had IDH-MT type gliomas. Male predominance (73.33%) was noted in our study. Brainstem location, indistinct borders (83.33%), less cortical involvement (72.22%), less cystic changes (88.89%), more area of necrotic component (44.44%), significantly increased choline/creatine (Cho/Cr) ratio, and choline/N-acetyl aspartate (Cho/NAA) ratio favors IDH-WT tumors. Positive T2-fluid-attenuated inversion recovery mismatch sign is more frequently seen in IDH-MT (7/12; 58.33%) tumors than in IDH-WT (4/18; 22.22%) tumors. Whereas well-defined contours (66.67%), more cortical involvement (83.33%), more cystic changes (58.33%), and less area of necrotic component favor IDH-MT type tumors. Conclusion MRI is a very promising and valuable tool for differentiating among glioma subtypes and predicting tumor-proliferative behavior in glioma cases. The combination of MRI characteristics with IDH mutation status enhances the predictive accuracy for clinical outcomes in glioma patients. This approach could potentially guide treatment planning and improve prognostic assessments.

High-Grade Progression, Sarcomatous Transformation, and/or Metastasis of Pituitary Neuroendocrine Neoplasms (PitNENs): The UCSF Experience.

Pituitary neuroendocrine tumors (PitNET) that metastasize comprise ~ 0.2% of adenohypophyseal tumors are aggressive and are challenging to treat. However, many non-metastatic tumors are also aggressive. Herein, we review 21 specimens from 13 patients at UCSF with metastatic PitNETs (CSF or systemic, N = 7 patients), high-grade pituitary neuroendocrine neoplasms (HG-PitNEN, N = 4 patients), and/or PitNETs with sarcomatous transformation (PitNET-ST, N = 5 patients). We subtyped cases using the World Health Organization (WHO) and International Agency for Research on Cancer (IARC) criteria for neuroendocrine neoplasms (NENs). Lineage subtypes included acidophil stem cell, null cell, thyrotroph, corticotroph, lactotroph, and gonadotroph tumors. The median Ki-67 labeling index was 25% (range 5-70%). Lack of p16 was seen in 3 cases, with overexpression in 2. Strong diffuse p53 immunopositivity was present in 3 specimens from 2 patients. Loss of Rb expression was seen in 2 cases, with ATRX loss in one. Molecular analysis in 4 tumors variably revealed TERT alterations, homozygous CDKN2A deletion, aneuploidy, and mutations in PTEN, TP53, PDGFRB, and/or PIK3CA. Eight patients (62%) died of disease, 4 were alive at the last follow-up, and 1 was lost to the follow-up. All primary tumors had worrisome features, including aggressive lineage subtype, high mitotic count, and/or high Ki-67 indices. Additional evidence of high-grade progression included immunohistochemical loss of neuroendocrine, transcription factor, and/or hormone markers. We conclude that metastatic PitNET is not the only high-grade form of pituitary NEN. If further confirmed, these histopathologic and/or molecular features could provide advanced warning of biological aggressiveness and be applied towards a future grading scheme.

Sinonasal adenoid cystic carcinoma: preoperative apparent diffusion coefficient histogram analysis in prediction of prognosis and Ki-67 proliferation status.

To investigate the value of preoperative apparent diffusion coefficient (ADC) histogram analysis in predicting the prognosis of patients with sinonasal adenoid cystic carcinoma (ACC) and the correlation between ADC histogram parameters and Ki-67 labeling index (LI). The study enrolled 66 patients with sinonasal ACC who were surgically resected and confirmed by histopathology. The disease-free survival (DFS) was evaluated with clinical-pathologic and radiologic characteristics using the Cox proportion hazard model. Spearman correlation analysis was used to evaluate the correlation between ADC histogram parameters and Ki-67 LI. The predictive performance of ADC histogram parameters for Ki-67 LI was assessed using the receiver operating characteristic (ROC) curve. Multivariable analysis showed Ki-67 LI (hazard ratio: 9.279; 95% confidence interval 1.099-78.338; P = 0.041) and ADCskewness (hazard ratio: 5.942; 95% confidence interval 1.832-19.268; P = 0.003) were significant independent predictors of DFS. The combination of these two variables achieved the predictive ability with a C-index of 0.717 (95% confidence interval 0.607-0.826). ADCmean and all ADC percentiles (10th, 50th, and 90th) significantly and inversely correlated with Ki-67 LI of ACC (Correlation coefficients = -0.574 to -0.591, Ps < 0.001). Among the ADC histogram parameters, the ADC50th showed superior performance for the differentiation of the high from low Ki-67 LI groups with an area under the curve (AUC) of 0.834 and an accuracy of 80.30%. ADC histogram analysis had predictive value for DFS and Ki-67 LI, which may be a valuable biomarker for prognosis and proliferation status for ACC in clinical practice.

Nodule-specific NRF2-targeted upregulation in patients with KEAP1 mutations and familial nontoxic multinodular goiter.

Kelch-like ECH-associated protein 1 (KEAP1) is associated with nuclear factor erythroid-2 related factor 2 (NRF2) and promotes NRF2 degradation in normal conditions. Genetic abnormality in KEAP1 is a rare disease and presents with familial multinodular goiter. This study assessed the clinical and molecular findings concerning nodular formation in the thyroid gland of patients harboring KEAP1 germline mutations. Next-generation sequencing analysis targeting goiter-associated genes was performed on 39 patients with familial multinodular goiter. The expression of NRF2-targeted genes from surgical thyroid specimens of patients with KEAP1 mutations were analyzed using a whole transcript expression array and immunohistochemistry. We found five probands with pathogenic heterozygous mutations in KEAP1 (p.Q86*, p.L136P, p.V411fs, p.R415C, and p.R483H), which had no meaningful concomitance with mutations of other goiter-associated genes in germline and somatic levels. Their common histopathological features showed multinodular goiters in the entire thyroid gland with few degenerative lesions or complications of malignancy and slow proliferation indicating < 1% at the Ki-67 labeling index. Among 42 NRF2-targeted genes, antioxidant genes were most frequently upregulated (11/12) in the nodule, followed by detoxification genes (6/11). Immunohistochemical analysis showed relatively high expression of glutathione peroxidase 2 and NAD(P)H quinone oxidoreductase 1 (representative NRF2-targeted genes) in the nodules of various patients harboring KEAP1 mutations. KEAP1 germline heterozygous mutations exert excessive NRF2 activity in the thyroid gland and may confer cytoprotective effects even under abundant reactive oxygen species associated with thyroid hormone production, resulting in thyroid hyperplasia with scarce degradation.

6436 Adrenal Venous Congestion Clinically Mimicking Carcinoma In A Large Degenerated Adrenocortical Adenoma

Abstract Disclosure: K. Ishiwata: None. S. Suzuki: None. S. Watanabe: None. Y. Yamazaki: None. H. Sasano: None. K. Yokote: None. Introduction: A large heterogenous adrenal tumor is often malignant. Only eight reported cases of adrenal adenoma harboring hemorrhage or venous thrombosis have been reported but their details not. We encountered a case of large degenerated adrenocortical adenoma harboring adrenal venous congestion mimicking adrenocortical carcinoma. Case: Adrenal tumor was incidentally detected in a 71-year-old woman with a history of hypertension, dyslipidemia, and osteoporosis in her regular health check-up. Abdominal CT and MRI demonstrated a heterogenous mass measuring 7.6 cm with peripheral enhancement in the left adrenal gland. [1]3[1]I-adosterol scintigraphy revealed accumulation only in the left tumor margins with no accumulation in [1]8F-FDG-PET scan. Results of endocrinologic evaluation were consistent with subclinical Cushing syndrome. The large size and heterogeneous nature of the mass clinically suggested adrenocortical malignancy, and left laparoscopic adrenalectomy was subsequently performed. The resected left adrenal lesion was encapsulated and measured 6.5 x 6.3 x 5.8 cm appearing almost black and partially yellow on the cut surface. Microscopically, the nodule was composed of SF-1 positive, clear cortical cells with abundant hyaline stroma containing numerous dilated veins with CD31/34-positive endothelial cells, and no foci of necrosis or hemorrhage were detected. The tumor cells above were positive for steroidogenic enzymes including CTP17, HSD3β and CYP11B1 but negative for CYP11B2. Ki-67 labeling index was &amp;lt;2% in the tumor. The criteria of Weiss (0 out of 9) revealed that the tumor was cortisol-producing adrenocortical adenoma. Discussion: In this case, clusters of SF1-positive cortisol producing adrenocortical adenoma cells were present in the hyalinized stroma containing many dilated blood vessels. These findings indicated that those histological features were caused by ischemic degeneration due to intratumoral circulatory disturbance, which clinically simulated adrenocortical carcinoma. Conclusion: We have experienced a very rare case of cortisol-producing adrenocortical adenoma with adrenal venous congestion, resulting in marked enlargement of the lesion. Presentation: 6/3/2024

7211 Clinical and Molecular Characterization Of An Aldosterone-Producing Adenoma Harboring Double Somatic Mutations In CTNNB1 and GNA11

Abstract Disclosure: A. Blinder: None. K. Nanba: Grant Recipient; Self; AstraZeneca. A. Udager: None. Y. Hirokawa: None. T. Miura: None. H. Okuno: None. K. Moriyoshi: None. Y. Yamazaki: None. H. Sasano: None. A. Yasoda: None. N. Satoh-Asahara: None. W.E. Rainey: None. T. Tagami: None. Background: Somatic activating mutations in CTNNB1, encoding β-catenin, have been detected in a small subset of aldosterone-producing adenomas (APAs). As a possible pathogenesis, an association of CTNNB1-mutated APA with pregnancy and menopause has been proposed. A recent study reported double somatic mutations in CTNNB1 and GNA11/Q, encoding guanine nucleotide-binding protein subunits alpha-11 and alpha-Q, in APA. However, due to its rare incidence, clinical and molecular features of APA associated with these mutations have not been well characterized. Herein, we report a case of APA harboring somatic CTNNB1 and GNA11 mutations. Clinical Case: A 46-year-old Japanese woman presented with hypertension and hypokalemia. She had two pregnancies in the past but had no history of pregnancy-induced hypertension. She had regular menstrual cycles at presentation. Laboratory testing showed elevated plasma aldosterone concentration with suppressed plasma renin activity. She was diagnosed as having primary aldosteronism based on the results of a captopril challenge test. Adrenal computed tomography revealed a 2 cm right adrenal mass. Adrenal venous sampling indicated excess aldosterone production from the right adrenal gland. She underwent right laparoscopic adrenalectomy. Histologic diagnosis of the resected tumor was adrenocortical adenoma based on the criteria of Weiss. Notably, Ki-67 labeling index was high (6% at hotspots). After surgery, her blood pressure and serum potassium both normalized. According to the primary aldosteronism surgical outcome (PASO) study criteria, PA remained clinically and biochemically cured at follow-up 2.5 years after surgery. Results: Immunohistochemistry (IHC) showed high and diffuse expression of aldosterone synthase (CYP11B2) within the tumor, whereas immunoreactivity of 17α-hydroxylase (CYP17A1) and 11β-hydroxylase (CYP11B1), both required for cortisol biosynthesis, was markedly low. VSNL1, a marker for the zona glomerulosa (ZG) where physiologic aldosterone biosynthesis occurs, was highly expressed within the tumor. CYP11B2 IHC-guided tumor capture followed by targeted next-generation sequencing identified double somatic CTNNB1 (p.D32Y) and GNA11 (p.Q209H) mutations. Quantitative real-time RT-PCR revealed high tumor expression of LHCGR (LH receptor) and GNRHR (GNRH receptor) mRNA levels compared with those in adjacent normal adrenal (148-fold and 56-fold, respectively). Immunofluorescence staining of the tumor revealed the presence of activated β-catenin, consistent with features of the normal ZG. Conclusions: Our study indicates that an APA with double somatic mutations in CTNNB1 and GNA11 has characteristics of the ZG and could occur in adults with no clear association with pregnancy or menopause. Presentation: 6/3/2024

6419 Cushing’s Syndrome due to Metastatic Pancreatic Neuroendocrine Neoplasm With Incidental Pituitary Microadenoma

Abstract Disclosure: A. Ibrahim: None. L. Esper: None. R. Jain: None. N. El Asmar: None. Introduction: Pancreatic neuroendocrine neoplasms (PNENs) are rare with a reported incidence of 1-2/100,000. While the majority are non-functional, insulinomas and gastrinomas are the most common functional PNENs. Our case of ACTH-producing PNENs is extremely rare. Case presentation: A previously healthy 47-year-old female was hospitalized for worsening dyspnea. Her symptoms included rapid weight gain, skin hyperpigmentation, and lower extremity edema. Her exam was notable for elevated blood pressure of 181/120 mmHg, moon facies, purple abdominal striae, and proximal myopathy. Her lab analysis showed a cortisol level of 42 mcg/dL (6.2-19.4), ACTH of 254 pg/ml (7.2-63), DHEA sulfate of 171 mcg/dl (41-243), HbA1C 7%, K of 3 mmol/l and 24H urine cortisol &amp;gt;2100 mcg/24hrs. A post low-dose DST cortisol level was 42.7 mcg/dl. CT chest demonstrated an ill-defined hypodense lesion in the region of the pancreatic head. MRI abdomen revealed a 3 x 2.3 x 2.3 cm mass in the pancreatic head and many small enhancing lesions within the right lobe of the liver. Adrenal glands appeared normal. Subsequent PET CT scan with GA 68 DOTOTATE showed increased uptake in the pancreatic head mass and in the right hepatic lobe. Her pituitary MRI revealed a right pituitary gland 6 mm hypointense lesion, possibly a microadenoma. A high dose DST resulted in a cortisol level of 80 mcg/dl mostly consistent with ectopic ACTH secretion. EUS-guided biopsy of the pancreatic mass showed a well-differentiated neuroendocrine tumor that stained positive for ACTH, chromogranin, synaptophysin, and CD56. Treatment with Ketoconazole 600mg q6h and Octreotide 50mg q6h was started 3 days before surgery to control acute hypercortisolism as she developed acute psychosis. The patient subsequently underwent a Whipple procedure with successful resection of the pancreatic mass. Post-op, her ACTH levels dropped to 19 pg/ml with a cortisol level of 6 mcg/dl. Final pathology showed a well-differentiated grade 3 neuroendocrine tumor with a KI-67 labeling index greater than 20%. After surgery, the patient received a short course of stress dose hydrocortisone which was tapered off over the following 2 months. The patient is being followed for planning further intervention given the aggressive grade of the tumor and hepatic metastases. Conclusion: Ectopic ACTH-producing PNENs are rare. An accurate and timely diagnosis, while challenging, is key. Patients usually present with rapidly progressing symptoms that could cause life-threatening complications such as thrombosis and sepsis. We demonstrated the importance of utilizing a multidisciplinary team approach and starting cortisol-lowering medications early given the complexity of the disease, requiring rapid intervention and lifelong follow-up. Presentation: 6/3/2024

Catching the Silent Culprits: TERT Promoter Mutation Screening of Minimally Invasive Follicular and Oncocytic Thyroid Carcinoma in Clinical Practice.

De-escalation of thyroid cancer treatment is crucial to prevent overtreatment of indolent disease, but it remains important to identify clinically aggressive cases. TERT promoter mutations are molecular events frequently associated with high-risk thyroid tumors with poor outcomes and may identify cases at risk of dissemination. In various international guidelines, small minimally invasive follicular thyroid carcinoma and oncocytic thyroid carcinoma (miFTC/miOTC) are classified as low-risk lesions and are not recommended adjuvant treatment. Our study aimed to explore the association between size-based risk assessment and TERT promoter mutations. Between 2019 and May 2024, 84 miFTCs/miOTCs diagnosed at our department underwent digital droplet PCR analysis targeting TERT promoter mutational hotspots C228T and C250T in clinical routine. TERT promoter mutations were found in 10 out of 84 cases (11.9%). Mutated cases were pT1 (n = 1), pT2 (n = 3), or pT3 (n = 6). Patients with mutated tumors were older compared to patients with wild-type tumors (median age of 71years vs. 57years, p = 0.041). There were no significant differences regarding patient sex, tumor size, Ki-67 labeling index, or the presence of distant metastases. Notably, 30% of mutations displayed variant allele frequencies < 10%, possibly suggesting subclonal events. To conclude, TERT promoter mutations in miFTCs and miOTCs were associated with higher patient age and were often suspected to be subclonal. However, they did not affect clinical outcomes, possibly due to short follow-up. Reflex testing for this genetic alteration in miFTCs and miOTCs could be justified regardless of tumor size, though the clinical benefit remains uncertain.

Correlation of Androgen Receptor Expression With Ki67 Proliferative Index and Other Clinicopathological Characteristics in Invasive Mammary Carcinomas.

Introduction The clinical importance of androgen receptor (AR) status in breast cancer is uncertain. The existing knowledge regarding the association of androgen receptor expression with clinicopathological factors of breast cancer is also limited. The main aim of this study is to evaluate the AR expression in breast cancer and to correlate it with the Ki67 proliferative index and other clinicopathological prognostic factors. Methods Theexpression of AR was evaluated in 192 invasive mammary carcinoma cases and the expression patterns were correlated with various clinicopathological prognostic factors such as age, tumor size, pathological primary tumor (pT) stage, nodal status,histological grade, estrogen receptor (ER) expression, progesterone receptor (PgR) expression, human epidermal growth factor receptor 2 (Her2) status, molecular subtype, and Ki67 labeling index. Immunohistochemistry was performed to assess AR, ER, PgR, Her2, and Ki67 expression. The clinicopathological data required for the analysis were obtained from the laboratory information system. Results Out of the 192 breast carcinoma cases, 139 (72.4%) showed AR-positive expression. The average age of the AR-positive cases was slightly higher than the AR-negative cases. AR-positive tumors tended to have a lower histological grade and positive ER and PgR expression. The expression of ARdid not correlate with tumor size, pT stage, nodal status, Her2 status, and Ki67 labeling index. Conclusion The expression of AR is noted in a significant proportion of breast carcinoma cases. AR expression may be related to good prognostic factors such as ER expression, PgR expression, and lower histologic grade. We also observed that AR expression did not have any association with the Ki67 proliferative index.

An unusual pattern of endometrial involvement: superficial spreading squamous cell carcinoma of the cervix.

Cervical squamous cell carcinoma (SCC) is the most common type of cervical carcinoma. Usually, the cancer metastasizes through lymphatic or hematogenous dissemination. However, it is uncommon for a superficial spreading of cervical cancer to reach the endometrium, fallopian tubes, and the ovaries. In the present study, we report 15 cases of superficial spreading SCC and discuss the possible mechanism involved. We collected 15 samples diagnosed by histopathology after surgery. Immunostaining, which included P16, P63, CD138, CD34, D2-40, and Ki-67, were performed for all samples. All patients were postmenopausal or perimenopausal women. The commonest clinical presentation was vaginal bleeding in 66.67%. All patients were infected with HPV 16. The endometrium was replaced by high-grade squamous intraepithelial lesion (HSIL), which involved the endometrial gland, even squeezing into the myometrium and forming SCC. Bilateral fallopian tubes and ovaries involvement was in 1/15. A total of 10/15 (66.67%) of the women had disease of stage 1B or less. All SCCs were moderately or poorly differentiated. Immunohistochemistry revealed that the tumor cells were positive for P63 and P16, with a high Ki-67 labeling index. There was CD138 positive expression in varying degrees, which was strongly and diffusely expressed in 6/15 (40.00%). Superficial spread of cervical cancer towards the endometrium is a rare but cognizable phenomenon, and a guideline for the management of these cases has not been established. Our present findings suggest that multiple factors may interact with each other simultaneously, contributing to this rare disease.

Gastric-type extremely well-differentiated adenocarcinoma of the stomach: A rare tumor with diagnostic difficulties and high inter-observer variation in endoscopic pinch biopsies

Extremely well-differentiated gastric-type adenocarcinoma (EWDGA) is a rare type of gastric cancer composed of deceptively bland-looking malignant cells resembling normal foveolar or pyloric epithelium. The histological features of this tumor have not been recognized by many pathologists, and inter-observer variation studies are lacking. Here, we report seven EWDGAs and inter-observer variation of six preoperative biopsies was evaluated by 11 pathologists in a single institute. Based on the pathological diagnosis of the endoscopic biopsy slides, the average rate of definite malignancy diagnosis was 15.2 %, and the overall diagnostic concordance rate was 34.9 % among 11 pathologists. Microscopically, the surface epithelium was preserved and only a few atypical tumor glands were scattered in most endoscopic biopsies. Structural atypia was minimal, and the tumor glands were barely distinguishable from normal glands. Although nuclear atypia was minimal, enlarged nuclei, relatively large glands with irregular shapes, and abundant cytoplasmic mucin were observed in gastric pinch biopsies. In preoperative biopsies, no cases showed p53 overexpression, and Ki-67 labeling index ranged from 3 % to 35 % and was higher compared to non-neoplastic glands in 3 cases. After gastrectomy, four (57.1 %) patients had advanced gastric cancer and three (42.9 %) had lymph node metastasis. Genomic profiling of the four patients revealed mutations of TP53, BRAF, KRAS, STK11, and MDM2/CCND1 amplification. Immunohistochemistry for p53 was not helpful while Ki-67 may be helpful when staining pattern is distinct from the non-neoplastic mucosa. In conclusion, it is challenging to diagnose EWDGA using biopsy specimens. Recognizing and addressing this rare entity will increase diagnostic accuracy to ensure the early diagnosis of cancer.

Spectrum of Ductal Carcinoma In Situ (DCIS) Lesions of the Breast: From Morphology to Molecular Characteristics.

Background Specific molecular characteristics of invasive breast cancer have been linked to an increased risk of early relapse. Similarly, ductal carcinoma in situ (DCIS) displays a comparable molecular profile, although their prevalence and implications are not yet fully understood. Aims and objectives The study design defined a multivariable statistical approach aimed at describing the interplay between the histopathological features of ductal carcinoma in situ (DCIS) and their molecular profile. The objective was to explore the correlations between the histopathological features of DCIS (tumor location, DCIS grade, DCIS type, and presence or absence of comedo necrosis) and various biomarkers like estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2/neu), androgen receptor (AR), and epidermal growth factor receptor (EGFR), in addition to the Ki-67 labeling index. Methods In this retrospective study, we selected and analyzed 100 diagnosed cases of ductal carcinoma in situ (DCIS) to represent various subtypes, grades, and morphological characteristics. A detailed histopathological review and immunohistopathological staining for ER, PR, HER2/neu, AR, EGFR, and Ki-67 were performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks. Molecular subtyping was done based on the biomarker analysis into luminal A, luminal B, luminal HER2/neu, HER2/neu enriched, and triple-negative subtypes. Statistical analysis was done to examine the correlation between tumor location, histopathological features of ductal carcinoma in situ (DCIS), and the expression of the immunohistochemical markers and the molecular subtypes. Results The majority of cases exhibited positivity for estrogen receptor (ER) and progesterone receptor (PR). A strong association was observed between histopathological features (DCIS grade, type, and comedo necrosis) of DCIS and ER/PR status. Additionally, a significant correlation was found between ductal carcinoma in situ (DCIS) grade and HER2/neu status. However, no association was identified between histopathological features and AR or EGFR status. Contrary to expectations, triple-negative DCIS did not show the most aggressive behavior, whereas HER2/neu-positive tumors, particularly high-grade ones, exhibited more aggressive features. No low-grade cases of luminal HER2/neu and HER2/neu-enriched tumors were found. A higher Ki-67 labeling index was found in cases with grade 3 and solid and comedo architectural types of DCIS, while low-grade tumors had a lower Ki-67 labeling index. Conclusion These findings suggest that hormone pathways play a crucial role in ductal carcinoma in situ (DCIS) progression, but the molecular interactions are complex and extend beyond simple binary associations. The complex relationship between the histopathological features of ductal carcinoma in situ (DCIS) and its hormone receptor status warrants further investigation with a larger sample size to fully understand the underlying mechanisms. The results challenge the expectation that triple-negative DCIS is the most aggressive subtype, highlighting the need for further research into the prognostic significance of different DCIS subtypes.

Successful outcome achieved with adjuvant chemotherapy with irinotecan plus cisplatin in rectal neuroendocrine carcinoma: a case report

BackgroundRectal neuroendocrine carcinomas (NECs) are rare and associated with poorer prognoses compared to conventional adenocarcinomas. The efficacy of adjuvant chemotherapy for resectable rectal NECs remains uncertain. Herein, we present a case of rectal NEC successfully treated with postoperative chemotherapy using irinotecan plus cisplatin.Case presentationA 48-year-old woman with a history of endometrial cancer presented with an intramural rectal tumour detected on follow-up imaging. Colonoscopy revealed a 30 mm submucosal tumour, and laparoscopic low anterior resection was performed. Histopathological examination showed poorly differentiated atypical cells with solid growth patterns. Metastasis from the uterine cancer was ruled out due to histological differences between the primary uterine tumour and the rectal lesion, as well as the absence of hormone receptor immunohistochemical expression. Further immunohistochemical analysis revealed diffuse CD56 positivity, a high mitotic rate (> 20/10 high power fields) and a Ki-67 labelling index exceeding 70%. Based on these findings, a diagnosis of rectal NEC, T3N0M0, Stage IIB (UICC 8th edition), was established. Given the aggressive nature of the tumour evidenced by a high Ki-67 labelling index, adjuvant chemotherapy comprising six cycles of irinotecan plus cisplatin was administered to mitigate the risk of recurrence. At the 3-year follow-up, the patient was free of disease recurrence.ConclusionThis case highlights the importance of multidisciplinary surgical interventions followed by adjuvant chemotherapy in managing rectal NECs.