Medullary Carcinoma Research Articles

Thyroid carcinomas: the role of systemic therapies in internal medicine

The molecular pathogenesis of thyroid carcinoma is well studied and of importance for the treatment of advanced stages. Differentiated, poorly differentiated and anaplastic carcinomas originate in the follicular cells, while medullary carcinomas derive from the C‑cells. The prognosis of differentiated thyroid carcinoma is generally very favourable after surgery and radioiodine therapy. Where tumours progress and lose the ability to enrich iodine, curative treatment is usually not possible. Astrategy of watchful waiting is often appropriate. Activating mutations in BRAF or gene fusions of RET and NTRK provide opportunities for targeted therapies. These may be applied with the aim of restoring iodine uptake (redifferentiation). In the absence of molecular therapy targets, multityrosine kinase inhibitors (MKI) are the therapy of choice. If anaplastic thyroid carcinoma is suspected, rapid diagnostic workup including molecular pathology is warranted. Surgery where possible and radiochemotherapy are essential components of therapy. In the presence of aBRAF mutation, inhibition of BRAF and MEK is effective, even if it is not approved in Germany. Where molecular targets are lacking, combination therapy with the MKI lenvatinib and immune checkpoint inhibition is highly effective. Mutations in RET are present in the vast majority of cases of medullary thyroid carcinoma. In aggressive advanced disease, selective RET inhibition has recently been approved as first-line therapy and often leads to an objective response and long-lasting disease stabilisation. In summary, thyroid carcinomas are among the tumour entities for which molecularly targeted therapies can be used most frequently. The involvement of specialised centres is advisable.

Mismatch repair deficiency: how reliable is the two-antibody approach? A national real-life study.

Traditionally, mismatch repair (MMR) status is determined by a panel of four antibodies (MLH1, PMS2, MSH2, MSH6). If all proteins are retained, cases are MMR proficient (pMMR), while loss of one or more proteins is indicative of MMR deficiency (dMMR). This approach has been challenged in favour of a two-antibody approach, using PMS2 and MSH6 as a first screening. Their retainment is deemed sufficient to declare cases pMMR. In this study we aim to verify the validity of the two-antibody approach. We performed a nationwide study in colorectal cancer (CRC) and endometrial cancer (EC) diagnosed between 2016 and 2023, including 47,657 patients to evaluate the two-antibody approach. In 0.17% and 0.4% of cases of CRC and EC, respectively, dMMR cases would be missed with the two-antibody approach. Subgroup analyses pointed towards slightly increased miss rates in younger patients (under the age of 50 years) in both groups and identified special subtypes (signet ring cell carcinoma, medullary carcinoma, and mucinous carcinoma in CRC and clear cell carcinoma in EC) with increased miss rates. For these specific subgroups, a low threshold should be used for further testing. In case of ambiguous or heterogeneous staining patterns, four antibodies should be used. In general, the application of a two-antibody MMR testing strategy does not lead to considerable failure of dMMR identification and saves costs.

Clinical T1/2 renal cell carcinoma: multiparametric dynamic contrast-enhanced MRI features-based model for the prediction of individual adverse pathology

BackgroundThe detection of renal cell carcinoma (RCC) has been rising due to the enhanced utilization of cross-sectional imaging and incidentally discovered lesions with adverse pathology demonstrate potential for metastasis. The purpose of our study was to determine the clinical and multiparametric dynamic contrast-enhanced magnetic resonance imaging (CEMRI) associated independent predictors of adverse pathology for cT1/2 RCC and develop the predictive model.MethodsWe recruited 105 cT1/2 RCC patients between 2018 and 2022, all of whom underwent preoperative CEMRI and had complete clinicopathological data. Adverse pathology was defined as RCC patients with nuclear grade III-IV; pT3a upstage; type II papillary RCC, collecting duct or renal medullary carcinoma, unclassified RCC; sarcomatoid/rhabdoid features. The qualitative and quantitative CEMRI parameters were independently reviewed by two radiologists. Univariate and multivariate binary logistic regression analyses were utilized to determine the independent predictors of adverse pathology for cT1/2 RCC and construct the predictive model. The receiver operating characteristic (ROC) curve, confusion matrix, calibration plot, and decision curve analysis (DCA) were conducted to compare the diagnostic performance of different predictive models. The individual risk scores and linear predicted probabilities were calculated for risk stratification, and the Kaplan–Meier curve and log-rank tests were used for survival analysis.ResultsOverall, 45 patients were pathologically confirmed as RCC with adverse pathology. Clinical characteristics, including gender, and CEMRI parameters, including RENAL score, tumor margin irregularity, necrosis, and tumor apparent diffusion coefficient (ADC) value were identified as independent predictors of adverse pathology for cT1/2 RCC. The clinical-CEMRI predictive model yielded an area under the curve (AUC) of the ROC curve of 0.907, which outperformed the clinical model or CEMRI signature model alone. Good calibration, better clinical usefulness, excellent risk stratification ability of adverse pathology and prognosis were also achieved for the clinical-CEMRI predictive model.ConclusionsThe proposed clinical-CEMRI predictive model offers the potential for preoperative prediction of adverse pathology for cT1/2 RCC. With the ability to forecast adverse pathology, the predictive model could significantly benefit patients and clinicians alike by providing enhanced guidance for treatment planning and decision-making.

SMART: A phase II study of sacituzumab govitecan (SG) with or without atezolizumab immunotherapy in rare genitourinary (GU) tumors such as small cell, adenocarcinoma, and squamous cell bladder/urinary tract cancer, renal medullary carcinoma (RMC) and penile cancer.

TPS4627 Background: Rare tumors of the GU tract often exhibit aggressive clinical behavior, yet lack effective standard of care treatment options. SG is an antibody-drug conjugate (ADC) targeting trophoblastic cell surface antigen 2 (Trop2) with a payload of SN-38, a topoisomerase inhibitor. SG monotherapy gained accelerated approval in pts with metastatic urothelial carcinoma (mUC) post platinum and immune-checkpoint inhibitor (ICI) therapy based on the TROPHY-U-01 trial (Tagawa S et al., JCO 2021). Atezolizumab is an anti-PD-L1 ICI approved for use in multiple solid tumors. SMART will evaluate the efficacy and safety of SG monotherapy or SG plus atezolizumab in select rare GU tumors. Methods: SMART is an open-label, non-randomized, Phase 2 trial. Pts must have locally advanced (unresectable) or metastatic GU tumors of the following histologies: small cell carcinoma, squamous cell carcinoma, or primary adenocarcinoma of the bladder or urinary tract, RMC, or squamous cell carcinoma of the penis. Pts may be treatment-naïve or have received any number of prior therapies; pts with small cell carcinoma must have received a platinum-based regimen. Pts treated with a PD-1/PD-L1 ICI will be assigned to Cohort A/Treatment Arm 1 and will receive SG monotherapy (10mg/kg IV, D1 and D8 of 21 day cycles). Pts without prior ICI treatment will be assigned to Cohort B/Treatment Arm 2 and will receive SG (10mg/kg IV, D1 and D8 of 21 day cycles) with concomitant atezolizumab (1200mg IV, D1 of 21 day cycles). Treatment will continue until disease progression (max duration of treatment 5 years) or intolerable side effects. The primary endpoint is objective response rate (ORR) (RECIST v1.1) for each Cohort, with restaging every 3 cycles. Secondary endpoints include safety, clinical benefit rate (CR+PR+SD), median PFS/OS for each Cohort, and ORR for each histology. Exploratory analyses include determination of baseline tumor mutation and transcriptional profile, Trop2 expression, ctDNA/CTCs, peripheral blood immune subsets and cytokine profile correlation with response, and correlation of UGT1A1 allele genotype with response and safety. This study utilizes a Simon minimax two-stage design, with enrollment of up to 43 evaluable pts (accrual ceiling of 60 pts). Cohort A will enroll 11 pts in Stage 1; if 1 or more of the first 11 pts has a response (unacceptably low rate of 5%, p0=0.05; alpha 0.10, beta=0.20), accrual will continue into Stage 2 up to 18 evaluable pts. Cohort B will enroll 16 evaluable pts in Stage 1; if 2 or more pts have a response (unacceptably low rate of 10%, p0=0.10; alpha 0.10, beta=0.10), accrual will continue in Stage 2 up to a total of 25 evaluable pts. This study is open at the NIH Clinical Center (CC); enrollment may open at 1-2 additional centers. Clinical trial information: NCT06161532 .

The machine learning-based model for lateral lymph node metastasis of thyroid medullary carcinoma improved the prediction ability of occult metastasis.

For medullary thyroid carcinoma (MTC) with no positive findings in the lateral neck before surgery, whether prophylactic lateral neck dissection (LND) is needed remains controversial. A better way to predict occult metastasis in the lateral neck is needed. From January 2010 to January 2022, patients who were diagnosed with MTC and underwent primary surgery at our hospital were retrospectively reviewed. We collected the patients' baseline characteristics, surgical procedure, and rescored the ultrasound images of the primary lesions using American College of Radiology (ACR) Thyroid Imaging, Reporting and Data System (TI-RADS). Regularized logistic regression, 5-fold cross-validation and decision curve analysis was applied for lateral lymph node metastasis (LLNM) model's development and validation. Then, we tested the predictive ability of the LLNM model for occult LLNM in cN0-1a patients. A total of 218 patients were enrolled. Five baseline characteristics and two TI-RADS features were identified as high-risk factors for LLNM: gender, baseline calcitonin (Ctn), tumor size, multifocality, and central lymph node (CLN) status, as well as TI-RADS margin and level. A LLNM model was developed and showed a good discrimination with 5-fold cross-validation mean area under curve (AUC) = 0.92 ± 0.03 in the test dataset. Among cN0-1a patients, our LLNM model achieved an AUC of 0.91 (95% CI, 0.88-0.94) for predicting occult LLNM, which was significantly higher than the AUCs of baseline Ctn (0.83) and CLN status (0.64). We developed a LLNM prediction model for MTC using machine learning based on clinical baseline characteristics and TI-RADS. Our model can predict occult LLNM for cN0-1a patients more accurately, then benefit the decision of prophylactic LND.

Risk factor analysis and nomogram development and verification for medullary carcinoma of the colon using SEER database

Medullary Carcinoma of the Colon (MCC) is a rare histological subtype of colon cancer, and there is currently no recognized optimal treatment plan for it, with its prognosis remaining unclear. The aim of this study is to analyze the independent prognostic factors for MCC patients and develop and validate nomograms to predict overall survival (OS). A total of 760 patients newly diagnosed with MCC from 2004 to 2020 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. All patients were randomly allocated to a training group and a validation group in a 7:3 ratio. Univariate and multivariable Cox regression analyses were conducted to identify prognostic factors and construct nomograms. The nomogram prediction model was evaluated and validated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The study found that elderly women are more susceptible to MCC, and the ascending colon and cecum are the most common sites of involvement. MCC is poorly differentiated, with stages II and III being the most common. Surgery is the primary treatment for MCC. The prognosis for patients with stage IV MCC is poor, with a median survival time of only 10 months. Independent prognostic factors for MCC include age, N stage, M stage, surgery, chemotherapy, and tumor size. Among them, age < 75 years and completion of chemotherapy were protective factors for colon medullary carcinoma, while N2 (HR = 2.18, 95%CI 1.40–3.38), M1 (HR = 3.31, 95%CI 2.01–5.46), no surgery (HR = 27.94, 95%CI 3.69–211.75), and tumor diameter > 7 cm (HR = 1.66, 95%CI 1.20–2.30) were risk factors for colon medullary carcinoma. The results of ROC, AUC, calibration curves, and DCA demonstrate that the nomogram prediction model exhibits good predictive performance. We have updated the demographic characteristics of colon medullary carcinoma and identified age, N staging, M staging, surgery, chemotherapy and tumor size as independent prognostic factors for colon medullary carcinoma. Additionally, we have established nomograms for prognostic prediction. These nomograms can provide personalized predictions and serve as valuable references for clinical decision-making.

NF-κB1 deficiency promotes macrophage-derived adrenal tumors but decreases neurofibromas in HTLV-I LTR-Tax transgenic mice.

Human T-cell leukemia virus type I (HTLV-I) is an oncogenic virus whose infection can cause diverse diseases, most notably adult T-cell leukemia/lymphoma (ATL or ATLL), an aggressive and fatal malignancy of CD4 T cells. The oncogenic ability of HTLV-I is mostly attributed to the viral transcriptional transactivator Tax. Tax alone is sufficient to induce specific tumors in mice depending on the promotor used to drive Tax expression, thereby being used to understand HTLV-I tumorigenesis and model the tumor types developed in Tax transgenic mice. Tax exerts its oncogenic role predominantly by activating the cellular transcription factor NF-κB. Here, we report that genetic deletion of NF-κB1, the prototypic member of the NF-κB family, promotes adrenal medullary tumors but suppresses neurofibromas in mice with transgenic Tax driven by the HTLV-I Long Terminal Repeat (LTR) promoter. The adrenal tumors are derived from macrophages. Neoplastic macrophages also infiltrate the spleen and lymph nodes, causing splenomegaly and lymphadenopathy in mice. Nevertheless, the findings could be human relevant, because macrophages are important target cells of HTLV-I infection and serve as a virus reservoir in vivo. Moreover, the spleen, lymph nodes and adrenal glands are the most common sites of tumor cell infiltration in HTLV-I-infected patients. These data provide new mechanistic insights into the complex interaction between Tax and NF-κB, therefore improving our understanding of HTLV-I oncogenic pathogenesis. They also expand our knowledge and establish a new animal model of macrophage neoplasms and adrenal tumors.

False-Negative 68 Ga-FAPI PET/CT in Pediatric Thyroid Medullary Carcinoma Seen With 68 Ga-DOTATOC PET/CT and 18 F-FDG PET/CT.

In adults, 68 Ga-FAP inhibitor ( 68 Ga-FAPI) PET/CT outperforms 68 Ga-radiolabeled somatostatin analog peptides ( 68 Ga PET/CT) and 18 F-FDG PET/CT in detecting thyroid lesions. This is the case of a 13-year-old boy newly diagnosed with medullary thyroid cancer with high calcitonin level. 68 Ga PET/CT revealed the presence of only a primary thyroid lesion. Proven to be superior in detecting metastasis, 68 Ga-FAPI PET/CT was performed. The results came out negative for primary and potential metastatic lesions. This case sheds shed light on false-negatives reported in 68 Ga-FAPI PET/CT scans in pediatric patients, emphasizing the need for alternate radiotracers when a negative study is met.

A pediatric and young adult case of unclassified renal cell carcinoma with medullary phenotype (RCCU-MP): Clinical course and treatment

Renal cell carcinoma (RCC) is the most common kidney tumor in adults. RCC is rare in children, although its incidence increases in the second decade of life. Renal medullary carcinoma (RMC) is a rare and often aggressive RCC subtype characterized by complete loss of SMARCB1/INI1, predominantly diagnosed in patients with sickle cell disease or -trait. Here, we describe a pediatric and a young adult patient with clinicopathological characteristics similar to RMC but without hemoglobinopathies. These tumors are currently classified as “RCC unclassified with medullary phenotype” (RCCU-MP). Both our patients had an infiltrating, rather small kidney tumor with SMARCB1/INI1 deficiency. Remarkably, the aggressiveness and clinical course and treatment differed greatly between these two cases. So far, only nine patients, predominantly adults, have been reported. In a literature overview, most cases were metastatic and progressed or relapsed after varying treatment approaches, with low survival. Whereas the classification of these tumors remains a topic of debate, case reports add to the current knowledge of RMCs without hemoglobinopathies, stressing the importance of sharing experience concerning rare renal neoplasms with often poor outcomes, also concerning younger age categories.

Abstract PO3-02-09: Breast cancer in women under the age of 40 years.A south Wales UK reflection on incidence, tumour biology and outcomes over 10 years

Abstract Introduction: The incidence of breast cancer in the under 40-year-old age group is approximately 7% (Anders et al., 2009). Studies suggests that the management of Breast cancer in adolescent and young women is more challenging, with this age group under-represented in clinical trials. We investigated the management and outcomes of a cohort of 98 patients seen between 2013 and 2023 in the Hywel Dda NHS University Health Board, Wales, UK. Methods: A retrospective review was performed. Demographic, surgical and outcome data for patients under the age of 40 years was collated and analysed. Results: The cohort size was 98, representing 2.45% of the breast cancer population treated in the Health Board during this timeframe. The age of the cohort ranged from 23 years to 40 years, 12 out of 98 (12.24%) were under 30 years. Mean age was 35.28 years. Unfortunately, 8.16% (8/98) of the cohort died between 12 months to 96 months. Two patients were lost to follow up. Tumour biology results confirmed that most of the cohort had invasive ductal carcinoma (IDC), with 13.27% Grade 1, 37.76 % Grade 2 and 40.82% Grade 3. There were 4 (4.08%) invasive lobular carcinomas (ILC) in the cohort, 2 Grade 2 and 2 Grade 3. The remaining tumour groups were, 1 case of DCIS (Grade-2 intermediate grade), Grade-1 mucinous carcinoma, 1 Grade-1 ductal-lobular breast cancer and 1 medullary carcinoma. 10.20% of the cohort had triple negative cancers (ER, PR, Her-2 negative) and 10.20% were ER, PR, HER2 positive [Triple positive]. 40.82% metastatic axillary lymph nodes involvement on histology either on presentation or following sentinel node biopsy. Operative details confirmed that the 51.02% (50/98) of the cohort underwent mastectomy. 10 out of those 50 patients underwent contralateral risk reducing mastectomy .46 patients had breast conservation surgery. One patient is awaiting surgery, the other has been diagnosed with metastatic breast cancer at diagnosis. Patients received both neoadjuvant and adjuvant chemotherapy depending on initial assessment and MDT discussion [ACP, FEC, Taxane and platinum-based chemotherapy, Anti Her-2]. NAC was provided for all HER-2+ patients. Endocrine treatment and ovarian function suppression, and adjuvant Radiotherapy was also given. Some patients had a complete pathological response to NAC; however, some did not respond well. In addition, 10.20% of the cohort underwent bilateral salpingo-oophorectomy during their treatment and follow up. Genetic assessment confirmed that 3/98 (3.06%) of the cohort were BRCA2 positive, one BRCA1 carrier, 2 patients were BRCA negative, two have been referred for genetics assessment and two still awaiting consultation with genetics. In one patient somatic mutation was found in PTEN, BIRC3, HRAS, TP53, PMS, (5 gene panel). In one patient, panel was reassuring. PALB-2, TP53 was also reassuring in one patient. One patient who passed away at the age of 34 did not have any alteration in 5 gene panel. Three patients developed other malignancies during the 10-year period: 1 uterine, 1 cervix, 1 papillary thyroid cancer. 6/98 (6.12%) developed metastatic disease and one developed a local recurrence. One patient developed metastasis while pregnant, and by contrast one patient gave birth to a baby after stopping her endocrine treatment. One patient who passed away had no response to neoadjuvant chemotherapy (NAC). Discussion: The results from the cohort confirm that the incidence of TNBC and triple positive cancers is like that found in the general breast cancer population (10-15%). Our engagement with the genetics team has increased since the initial 2013 cohort. There is now an established system for referrals for young women with breast cancer. It is probably not surprising that other primary invasive cancers were found, whilst on follow up. Citation Format: Sohail Khan, Saira Khawaja, Yousef Sharaiha, Asma Munir, Anita Huws. Breast cancer in women under the age of 40 years.A south Wales UK reflection on incidence, tumour biology and outcomes over 10 years [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-02-09.

Abstract PO4-07-12: Concordance of Breast ultrasound (US) and breast Magnetic resonance imaging (MRI) for local (tumor size and node involvement) staging in patients with breast cancer before neoadjuvant chemotherapy treatment (NACT)

Abstract Introduction Breast cancer is the main cause of cancer-related deaths in Colombia, with many patients diagnosed with locally advanced (LABC) or metastatic disease. In the locally advanced setting, the use of NACT offers the opportunity of downstage BC and allows to adjust therapy based on the response, but, considering emerging therapies available in LACB as immunotherapy in triple negative BC (TNBC), dual HER2 blockade in HER2 positive BC or adjuvant iCDK 4/6 in luminal BC the importance of accurate pre NACT staging has become critical, we aim to explore the concordance of US and MRI as a method of BC staging in the NACT setting. Methods: EVA (Evidence – Verification – Analysis) is a prospective institutional multi-tumor registry that aims to gather demographic, clinical, and genomic variables from patients treated at Fundación CTIC, in Bogota Colombia, based on this registry, we recover the data from the patients that were treated with NACT and were staged with a US and an MRI before the initiation of treatment, dis concordance between the two methods was establish if a different Tumor size (change from T2 to T3 for example), a different node stage (chance from N2 to N2) or the discordant detection of multifocal disease, a descriptive analysis were performed. Results: 30 Patients were included in the analysis, The mean age was 51,7 years (28 – 79), 15/30 patients were ER of PgR positive BC, 11/30 HER2 positive BC (7/11 HER2 positive and 4/11 Luminal B HER2 positive) and 4/30 were TBNC. 28/30 patients were ductal carcinoma, with 1/30 lobular carcinoma and 1/30 medullary carcinoma. Mean ADC in luminal A-like BC was 0,9, 0,66 (0,4 – 0,9) in luminal-B HER2 negative BC, 0,77 (0,4 – 0,9) in HER2 positive BC, and 0,83 (0,7 – 0,9) in TNBC Concordance between US and MRI was only seen in 14/30 patients. The causes of discordance were Tumor size on 9/16 (change from T2 to T3 or evidence of pectoral muscle involvement), node staging on 11/16 (8/11 patients were node down staged based on MRI image), and evidence of multifocal disease not seen in the US on 2/16. Conclusion: Considering the high discordance rate between US and MRI, and the implications of accurate staging before NACT, we think that MRI should be considered as a routine evaluation before NACT. This is a small sample so a larger cohort would be needed for confirmation of this observation, based on the design of EVA, we expect to further evaluate the significance and uses in the NACT setting. Citation Format: Aura Pareja, Sergio Cervera, Maria Bravo, Sandra Franco, Jose Caicedo, William Mantilla. Concordance of Breast ultrasound (US) and breast Magnetic resonance imaging (MRI) for local (tumor size and node involvement) staging in patients with breast cancer before neoadjuvant chemotherapy treatment (NACT) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-07-12.

Collecting duct (Bellini duct) renal cell carcinoma: a clinical case and literature review

A rare subtype of renal cell carcinoma (RCC) is Bellini collecting duct carcinoma, also known as medullary renal carcinoma or distal nephron carcinoma, which accounts for 0.4-2.0% of all RCC cases. This subtype has the poorest prognosis of all RCC subtypes, typically presenting as a low-grade tumor at the pT3 or higher stage. Consequently, many patients have distant metastases at diagnosis and 60% develop metastases following radical treatment. There have been approximately 400 literature-reported cases of Bellini ductal carcinoma to date. We present a case report of a patient with early-stage Bellini duct cancer and a literature review of published reports on this condition.

New strategy for intraoperative phonosurgical management of recurrent laryngeal nerve infiltrated by thyroid carcinoma

PurposeTreating an infiltration of the recurrent laryngeal nerve (RLN) by thyroid carcinoma remains a subject of ongoing debate. Therefore, this study aims to provide a novel strategy for intraoperative phenosurgical management of RLN infiltrated by thyroid carcinoma.MethodsForty-two patients with thyroid carcinoma infiltrating the RLN were recruited for this study and divided into three groups. Group A comprised six individuals with medullary thyroid cancer who underwent RLN resection and arytenoid adduction. Group B consisted of 29 differentiated thyroid cancer (DTC)patients who underwent RLN resection and ansa cervicalis (ACN)-to-RLN anastomosis. Group C included seven patients whose RLN was preserved.ResultsThe videostroboscopic analysis and voice assessment collectively indicated substantial improvements in voice quality for patients in Groups A and B one year post-surgery. Additionally, the shaving technique maintained a normal or near-normal voice in Group C one year post-surgery.ConclusionThe new intraoperative phonosurgical strategy is as follows: Resection of the affected RLN and arytenoid adduction is required in cases of medullary or anaplastic carcinoma, regardless of preoperative RLN function. Suppose RLN is found infiltrated by well-differentiated thyroid cancer (WDTC) during surgery, and the RLN is preoperatively paralyzed, we recommend performing resection the involved RLN and ACN-to-RLN anastomosis immediately during surgery. If vocal folds exhibit normal mobility preoperatively, the MACIS scoring system is used to assess patient risk stratification. When the MACIS score > 6.99, resection of the involved RLN and immediate ACN-to-RLN anastomosis were performed. RLN preservation was limited to patients with MACIS scores ≤ 6.99.

Selpercatinib for treating recurrent mixed medullary and follicular cell-derived thyroid carcinoma: a case report

BackgroundMixed medullary and follicular cell-derived thyroid carcinoma (MMFCC) is characterized by the coexistence of follicular and C cell–derived tumour cell populations within the same lesion. Due to its rarity, its etiology and clinical course remain unclear, and treatment for advanced or recurrent cases has not been established.Case presentationWe report a case of MMFCC treated with selpercatinib. The patient was a 69-year-old male presenting with tumors in the right thyroid lobe and in the upper mediastinum. Fine-needle aspiration (FNA) cytology of the right thyroid lobe tumor revealed a medullary carcinoma; germline RET mutations were not detected. After resection of the right thyroid lobe with central node dissection, rapid intraoperative diagnosis of the mediastinal mass confirmed malignancy, leading to total thyroidectomy with excision of the upper mediastinal tumor. Histologically, the tumor in the right thyroid lobe and the pretracheal lymph node revealed a mixture of medullary and follicular carcinoma components, diagnosed as MMFCC. The mediastinal lymph node exhibited only medullary carcinoma components. At 11 months postoperatively, computed tomography scans showed enlargement of the right supraclavicular and upper mediastinal lymph nodes. FNA cytology of the right supraclavicular lymph node suggested the recurrence of medullary thyroid carcinoma. The gene panel testing (The Oncomine Dx Target Test Multi-CDx system®, Thermo Fisher SCIENTIFIC) of metastatic lymph node revealed RET somatic mutation (M918T). Treatment with selpercatinib was initiated, and both the cervical and mediastinal lymph nodes showed a reduction in size.ConclusionsWe report a rare case of selpercatinib use for MMFCC. Since RET mutations may occur frequently in MMFCC, selpercatinib could be effective in treating MMFCC.

Primary medullary adenocarcinoma of the colon: Literature review and case series

Aims: Medullary carcinoma of the colon is a rare subtype of adenocarcinoma, first described in 1999. Clinically known to have a favorably prognosis in comparison to poorly differentiated cancers, it is invariably associated with mismatch gene repair. This is an observational study of Hobart’s patient population with medullary cancer, and compares data with the current literature. Methods: We performed a search of the pathological database at our institution for medullary adenocarcinomas between the years of 2016 and 2023 and reviewed their clinical information to collect all relevant data including patient history, hospital admissions, surgery and clinic visits. We then performed a literature search using PubMed for search terms medullary cancer/carcinoma of the colon/colorectum. Results: Eleven patients were found in our database, 34 papers in the literature (19 retrospective cohort studies and 13 case reports). 81.8% (vs. 73.22% in cohort studies) were females. 8/11 patients had lymphovascular invasion (LVI) with 2/11 patients had perineural involvement (PNI). The immunohistochemistry (IHC) results showed that in all (11/11) patients’ tumors, there was a loss of MLH1 and PMS2 proteins, while MSH2 and MSH6 proteins were present. Cohort studies demonstrated 302/1897 (15.92%) patients had perineural invasion (PNI) with 1133/2151 (52.67%) demonstrating LVI. MLH1 testing was available for 192 patients, with 93.75% having loss of MLH1. Conclusion: Our cohort of medullary cancer patients was similar to that in the literature, with regard to demographic, staging, and tumor characteristics. A longer follow-up time is required for our cohort to produce comparable survival outcomes.

Characteristics of Triple Negative Subtype Breast Cancer in Dr. Hasan Sadikin General Hospital for 5 Years (2019-2023): An Observational Study

Background: Triple-negative breast cancer has a percentage of 15% to 20% in breast cancer patients at the time of first diagnosis. Guidelines from St. Gallen guidelines, the American Society of Clinical Oncology, and the American College of Pathology state that triple-negative breast cancer is breast cancer with ER and PR expression &lt;1%. As an aggressive subtype, outcomes are poor when compared with hormone receptor-positive. Methods: This research is an observational study. The research subjects in this study were triple-negative breast cancer patients in Dr. Hasan Sadikin General Hospital, Surgical Oncology division, West Java, Indonesia, from October 2018 - November 2023. There were 702 research subjects who would be studied. Characteristics of triple-negative breast cancer were taken from medical records. Results: The results showed that the average age of the subjects was 47 years. Based on histology, the most common was Invasive Carcinoma of no special type (86.75%), followed by Invasive lobular carcinoma (7.26%), medullary carcinoma (1.7%), micropapillary carcinoma (0.99%), metaplastic carcinoma (2.36%) and the least amount is Pleomorphic invasive lobular carcinoma (0.71%). The side of the breast affected is not significant, and the highest grade is 3. The involvement of lymph node metastases is due to aggressive tumor subtypes and lymphovascular invasion. Lymphovascular invasion is known to be a negative prognostic factor. It is a late stage for metastasis and local recurrence. Conclusion: Triple-negative breast cancer is breast cancer that has histopathological heterogeneity; most of the tumors are grade 3 and have significant metastases in regional lymph nodes. There is no significant relationship between grading and regional lymph node metastases. there is a significant relationship between lymphovascular invasion and regional lymph nodes metastases.

EBV-Associated Gastric Cancer; An In Situ Hybridization Assay on Tissue Microarray: A Multi-Region Study from Four Major Provinces of Iran.

Gastric cancer is the fourth leading cause of cancer-related deaths in the world. The identification of gastric cancer subtypes related to recognizable microbial agents may play a pivotal role in the targeted prevention and treatment of this cancer. The current study is conducted to define the frequency of Epstein-Barr virus (EBV) infection in gastric cancers of four major provinces, with different incidence rates of gastric cancers, in Iran. Paraffin blocks of 682 cases of various types of gastric cancer from Tehran, South and North areas of Iran were collected. Twelve tissue microarray (TMA) blocks were constructed from these blocks. Localization of EBV in tumors was assessed by in situ hybridization (ISH) for EBV-encoded RNA (EBER). Chi-squared test was used to evaluate the statistical significance between EBV-associated gastric cancer (EBVaGC) and clinicopathologic tumor characteristics. Fourteen out of 682 cases (2.1%) of gastric adenocarcinoma were EBER-positive. EBER was positive in 8 out of 22 (36.4%) of medullary carcinomas and 6 out of 660 (0.9%) of non-medullary type, which was a statistically significant difference (P<0.001). The EBVaGCs were more frequent in younger age (P=0.009) and also showed a trend toward the lower stage of the tumor (P=0.075). EBV-associated gastric adenocarcinoma has a low prevalence in Iran. This finding can be due to epidemiologic differences in risk factors and exposures, and the low number of gastric medullary carcinomas in the population. It may also be related to gastric tumor heterogeneity not detected with the TMA technique.

Clinical, Histopathological, and Radiological Profile of Patients Presenting With Thyroid Malignancies Among the Kerala Population.

Thyroid cancer, though relatively uncommon among all cancer types, stands as the primary form of endocrine tumor. Over the last 20 years, there has been a significant uptick in its occurrence. Papillary thyroid carcinoma (PTC), which is well-differentiated, emerges as the dominant subtype,in regions where iodine levels are deemed adequate. The study aimed to study the clinicopathological profile of patients diagnosed with thyroid malignancies at the Muslim Educational Society (MES) Medical CollegePerinthalmanna. This is a retrospective study undertaken at the MES Medical College by the Department of General Surgery and Endocrine Surgery. The study focuses on patients who have been diagnosed with thyroid cancer through a biopsy. Case sheets of all those patients diagnosed with thyroid malignancy were referred from the Medical Records Library to collect the relevant medical and sociodemographic data. This data was entered in the proforma, which was transferred to the Excel sheet and processed inIBM SPSS Statistics for Windows, Version 20 (Released 2011; IBM Corp., Armonk, New York, United States). The study included predominantly middle-aged individuals (40-60 years), with 22 (55%) falling within this age range, followed by 14 (35%) aged between 20 and 40 years, and only four (10%) above 60 years. Female patients constituted 82.5% of the study group. Most cases presented with swelling lasting less than six months 23 (57.5%), while only four (10%) had swelling lasting more than five years. Compression symptoms were rare, with only three (7.5%) experiencing dysphagia or dyspnea. Pain was reported in two (5%) of the cases. Hypothyroidism, toxic manifestations, or hoarseness were observed in one (2.5%) of the patients. Regarding swelling characteristics, most were greater than 4 cm in size (29, 72%) and firm in consistency (25, 62.5%). Nodular surfaces were present in 19 (47.5%) of the cases, while 38 (95%) of the swellings were mobile. Palpable lymph nodes were noted in 13 (32.5%) of cases. Radiologically, hypoechoic lesions were observed in 26 (65%) of cases, with microcalcification in 29 (72.5%) and peripheral vascularity in 31 (77.5%). Papillary carcinoma was the most common histological type (34, 85%), with medullary and follicular carcinomas accounting for five (12.5%) and one (2.5%), respectively. An association was found between the duration of swelling and histological type (p = 0.05) and between the mobility of swelling and histological type (p < 0.05). However, no significant associations were observed between imaging findings and histological type (p > 0.05). The gender distribution did not show a statistically significant association with histological type. The findings of the study revealed a statistically insignificant association between age, gender, clinical features, and the histological type of thyroid malignancy. Additionally, there was no statistically significant association between the histological type of thyroid malignancy and the size or type of surface or consistency of thyroid swelling or ultrasonographic findings of the swelling like echogenicity, microcalcification, increased peripheral vascularity, or loss of peripheral halo.

Abstract 2702: Hyperprogression due to myeloid mimicry in renal medullary carcinoma treated with nivolumab plus ipilimumab

Abstract Renal medullary carcinoma (RMC) is a rare but highly aggressive SMARCB1-deficient kidney cancer that mainly afflicts young individuals of African descent and has few treatment options. Despite the advancements in immune checkpoint therapy (ICT) for other kidney cancers, its efficacy against RMC remains elusive. The majority of RMC patients treated with ICT have experienced aggressively progressive disease as the best response. This hyperprogression was confirmed in our prospective clinical trial of nivolumab plus ipilimumab specifically designed for RMC patients (ClinicalTrials.gov identifier: NCT03274258). To elucidate the mechanisms of resistance to ICT in RMC, we generated high-quality single-cell RNA sequencing data on 23,880 cells from 7 patients at baseline and 2 patients exhibiting hyperprogression after ICT intervention. Our analysis revealed that RMC tumor cells undergo a distinct transcriptional reconfiguration following ICT therapy. This reconfiguration is manifested by upregulation of S100A9 and activation of the MEK/ERK pathway, indicating that RMC tumor cells adopt myeloid-affiliated transcriptional circuits, potentially promoting cell proliferation and leading to hyperprogression. Using a mouse model of RMC, we further demonstrated in a controlled setting that ICT causes hyperprogressive disease via activation of MEK/ERK pathway and an increase of S100A9 positive tumor cells. This process can be reversed by inhibiting master regulators of this “myeloid mimicry” mechanism, such as the CEBPB/p300 complex in our mouse model of RMC, thus restoring sensitivity to ICT. These findings provide novel insights into RMC resistance to ICT and suggest valuable directions for the development of therapeutic strategies. Citation Format: Melinda Soeung, Xinmiao Yan, Li Zhang, Luigi Perelli, Jianfeng Chen, Becky Slack Tidwell, Hania Khan, Courtney N. Le, Truong N. Lam, Nirjar Bhattacharya, Rutvi Shah, I-Lin Ho, Ziheng Chen, Sebastian R. Lundgren, Ningping Feng, Ciro Zanca, Menuka Karki, Niki Marie Zacharias Millward, Rong He, Rahul A. Sheth, Bathala K. Tharakeswara, Priya Rao, Najat C. Daw, Durga N. Tripathi, Cheryl L. Walker, Guangchun Han, Yanshuo Chu, Ruiping Wang, Minghao Dang, Enyu Dai, Fuduan Peng, Yunhe Liu, Akshaya S. Jadhav, Wenhua Lang, Claudio A. Arrechedera, Leticia Campos Clemente, Edwin R. Parra-Cuentas, Hsinyi Lu, Cara Haymaker, Ignacio I. Wistuba, Andrew Futreal, Timothy Heffernan, Andrea Viale, Giulio F. Draetta, Nizar M. Tannir, Jianjun Gao, Linghua Wang, Giannicola Genovese, Pavlos Msaouel. Hyperprogression due to myeloid mimicry in renal medullary carcinoma treated with nivolumab plus ipilimumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2702.

Abstract 4627: Metastatic renal cell carcinoma with occult primary: Clinical and biological evidence for a new entity of cancers of unknown primary that beneficiates from tissue-tailored treatment

Abstract Background: Cancers of unknown primary (CUP) is a heterogenous group of malignancies characterized by distant metastases in the absence of detectable primary. Specifics subgroups of CUP that share similarities with cancers of known primary beneficiate from tissue-tailored therapeutic strategies. The objective of this study was to characterize the clinical and biological presentation of a cohort of patients with suspected CUP of renal origin (rCUP) and to evaluate their optimal therapeutic management. Methods: All Patients with rCUP identified prospectively between 2020 and 2023 within the French National Multidisciplinary Tumor Board for CUP were included. Centralized pathological review and immunohistochemical stainings were performed. Whole Exome Sequencing (WES), whole transcriptomic sequencing (RNAseq) and application of the deep-learning based algorithm TransCUPtomics for prediction of tissue of origin, and DNA methylation analysis were performed and compared to public renal cell carcinomas (RCC). Progression Free Survival (PFS) and Overall Survival (OS) were calculated using Kaplan-Meier estimates. Results: 23 patients were included. The median age at diagnosis was 57 yo and 17/23 were male. The most common metastatic sites were the bones (N=17) and the lymph nodes (N=14). 19/23 patients presented with at least two distinct distant metastatic sites. Genomic analyses performed in 10 patients led to the identification of recurrent inactivating mutations in genes commonly altered in RCC, including NF2 (N=7), SETD2 (N=3), or VHL (N=1). 10/11 samples analyzed by RNAseq were predicted as RCC by the TransCUPtomics classifier based on their gene expression profiles. DNA methylation profiling performed in 7 samples showed major similarity with known RCC subtypes.Centralized pathological review and integration of molecular characteristics led to the final diagnoses of papillary RCC (N=2), clear cell RCC (N=7), renal medullary carcinoma (N=1), TFEB-amplified RCC (N=1) and unclassified RCC (N=12). 20/23 patients received at least one line of systemic treatment based on the renal origin, including anti-angiogenic TKI, anti-PD1/PDL1 antibody, anti-CTLA4 antibody or mTOR inhibitor. The median PFS under the first renal-oriented systemic treatment was 5 months and 10 patients remained progression-free for more than 6 months under tailored-treatment. The median OS was 31 months, and 11 patients are still alive in October 2023. Conclusions: This study shows that rCUP represent a new entity within CUPs that shares major similarities with classical RCC despite the more frequent presentation of unfavorable prognostic factors. Prolonged survival can be observed with renal-tailored systemic treatment, supporting the individualization of these patients within CUP. Citation Format: Nicolas Jacquin, Julien Masliah-Planchon, Guillaume Grisay, Ronan Flippot, Riwan Brillet, Célia Dupain, Maud Kamal, Isabelle Guillou, Nadège Gruel, Nicolas Servant, Pierre Gestraud, Jennifer Wong, Vincent Cockenpot, Andreia Goncalves, Janick Selves, Hélène Blons, Etienne Rouleau, Oliver Delattre, Christophe Le Tourneau, Ivan Bièche, Yves Allory, Laurence Albigès, Sarah Watson. Metastatic renal cell carcinoma with occult primary: Clinical and biological evidence for a new entity of cancers of unknown primary that beneficiates from tissue-tailored treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4627.