Cytological features and nuclear scores: Diagnostic tools in preoperative fine needle aspiration of indeterminate thyroid nodules with RAS or BRAF K601E mutations?

INTRODUCTION: The cytological diagnosis of follicular-patterned thyroid lesions is challenging, especially since the World Health Organisation classification has recognised non-invasive follicular thyroid neoplasm with papillary-like features. These entities are often classified as indeterminate on cytology. Molecular testing has been proposed to help classify indeterminate nodules. RAS and K601E BRAF mutations are mostly encountered in follicular-patterned lesions, but their diagnostic value is not well established. Nuclear scores have also been proposed to help classify indeterminate lesions. OBJECTIVE: To investigate the correlation between cytological features and histology and to assess nuclear scores in a series of indeterminate RAS or BRAF K601E positive thyroid nodules. METHODS: The cytological parameters of 69 indeterminate RAS or BRAF K601E-positive thyroid nodules were evaluated. The Strickland and Maletta scores and a new nuclear score were assessed. Diagnosis of malignant, benign or indolent neoplasms was confirmed in each case by histology. Malignant and indolent nodules were considered surgical nodules, and adenomas non-surgical nodule. RESULTS: Surgical nodules were associated with the presence of ground glass nuclei (P = .001), grooves (P < .001) or irregular nuclear membranes (P = .01) on cytology. Nuclear scores were more often ≥2 in surgical nodules compared to benign ones (P < .001), with high sensitivity, but a low negative predictive value. CONCLUSIONS: Analysis of nuclear features is useful to distinguish non-surgical from surgical nodules in indeterminate FNAs. Although nuclear scores are not ideal rule-out tests for indeterminate RAS or BRAF K601E positive nodules, they seem useful to screen non-molecular tested or non-mutated indeterminate FNAs. This work shows that meticulous analysis of nuclear features on cytological specimens can be useful to distinguish non-surgical nodules (adenoma) from surgical nodules in indeterminate FNAs. Although nuclear scores are not rule-out tests for indeterminate RAS or BRAF K601E positive nodules, they are useful in screening non-molecular tested or non-mutated indeterminate FNAs for surgery.

Challenges in the treatment of BRAF K601E-mutated lung carcinoma: a case report of rapid response and resistance to dabrafenib and trametinib.

We report a case of limited effectiveness of dabrafenib and trametinib in a 59-year-old man with poorly differentiated lung carcinoma and a rare BRAF K601E mutation. The patient, unresponsive to chemotherapy and immunotherapy, received these targeted agents as second-line treatment. Despite a notable initial response, tumor regression lasted only 52 days. A subsequent liquid biopsy revealed additional alterations (BRAF amplification, KIT amplification, TP53 S241F), indicating a complex resistance mechanism. This case underscores the challenges in treating BRAF K601E-mutant lung carcinoma, emphasizing the need for advanced molecular diagnostics, personalized approaches, and further research into more effective therapies for unique genetic profiles.

BRAF K601E-mutated metastatic colorectal cancer in response to combination therapy with encorafenib, binimetinib, and cetuximab: A case report.

BACKGROUND: BRAF mutation has been recognized as a negative prognostic marker for metastatic colorectal cancer (mCRC), but these data are from common BRAF V600E-mutated mCRC. Combination therapy of BRAF inhibitor and anti-epidermal growth factor receptor (EGFR) antibody has been approved for BRAF V600E-mutated mCRC. However, BRAF non-V600 mutations are rare mutations, and their clinical behavior is not understood. Moreover, the BRAF K601E mutation is extremely rare in mCRC, and there have been no reports on its specific treatment. CASE SUMMARY: Herein, we report the case of a 59-year-old female with super aggressive mCRC with multiple metastases, which extended to whole body including mediastinal to abdominal lymph nodes, bones, pleura, and peritoneum. The companion diagnostics of tumor tissues showed RAS/BRAF wild-type without microsatellite instability. She received chemotherapy with mFOLFOX6 (oxaliplatin plus infusional 5-fluorouracil [5-FU] and leucovorin) plus panitumumab, following FOLFIRI (irinotecan plus infusional 5-FU and leucovorin) plus ramucirumab. For the next regimen selection, a comprehensive genomic profiling panel was performed and revealed a BRAF K601E mutation, which was not covered in the initial companion diagnostics. After disease progression, a combination of encorafenib, binimetinib, and cetuximab was selected as third-line chemotherapy. The serum levels of tumor markers were immediately decreased accompanied by improvements in pleural effusion and ascites. However, the disease progressed again, and best supportive care was done instead. CONCLUSION: This case offers novel insights into the clinical behaviors of BRAF non-V600E-mCRC, potentially advancing personalized therapy for rare and aggressive cases.

Metastatic Small Bowel Adenocarcinoma Mimicking a Primary Ovarian Mucinous Tumour - Clinical, Radiologic, Pathologic and Molecular Correlation.

We describe an interesting case of a patient who presented with a large adnexal mass, first favored to be mucinous carcinoma of the gynecologic origin. The primary tumour site was ascertained after the patient's small bowel was resected by identifying an adenomatous component evolving into an invasive adenocarcinoma identical in morphology and immunophenotype to the ovarian tumour. Notably, both tumours were found to harbor a BRAF K601E mutation, which is extremely rare for a primary of the ovary. BRAF mutations are present in a subset of large bowel and small bowel adenocarcinoma, but our case shows the first instance of a BRAF K601E mutation being present in a small bowel adenocarcinoma, to the best of our knowledge. This case serves as a great illustration of the pivotal role of molecular diagnostics in modern pathology in arriving at the correct diagnosis. Additionally, it is an excellent example of how clinical-radiologic-pathologic-molecular correlation plays into the landscape of molecular pathology to deliver optimal care for the patient.

BRAF K601E Mutation in Oncocytic Carcinoma of the Thyroid: A Case Report and Literature Review.

BACKGROUND: Thyroid carcinoma (TC) is the most common endocrine cancer, with papillary thyroid carcinoma (PTC) being the most common subtype. BRAF and RAS oncogene were characterized as the most frequently altered genes in PTC, with a strong association between genotype and histotype. The most common mutation in BRAF gene is V600E and is prevalent in classic and aggressive variants of PTC, while BRAF K601E mutation is the most common among the other rare BRAF mutations. BRAF K601E mutated thyroid carcinomas are usually characterized by low aggressiveness, except for anecdotal cases of poorly differentiated TC. CASE PRESENTATION: We described a case of oncocytic carcinoma of the thyroid (OCA) with an aggressive clinical course, including widespread metastasis and resistance to radioiodine treatment. Molecular analysis revealed the exclusive presence of the BRAF K601E mutation in both primary tumor and metastatic lesions. Accordingly, a revision of the literature about aggressive TC cases carrying BRAF K601E mutation was performed. CONCLUSION: Although rare, this case emphasizes the relevance of considering BRAF K601E mutation in advanced non-PTC thyroid carcinomas, since it can be considered an actionable mutation for target therapies.

Durable Response to Combined Dabrafenib and Trametinib in a Patient With BRAF K601E Mutation-Positive Lung Adenocarcinoma: A Case Report.

Targeted therapy with combined dabrafenib and trametinib has been proven to provide clinical benefits in patients with NSCLC with a BRAF V600E mutation. Nevertheless, the treatment strategy for patients with NSCLC with BRAF non-V600E mutations remains limited. Here, we present a patient with NSCLC with a BRAF K601E mutation, a class II BRAF mutation, who had a durable response to targeted therapy with combined dabrafenib and trametinib.

Metastatic BRAF K601E-mutated melanoma reaches complete response to MEK inhibitor trametinib administered for over 36 months.

BACKGROUND: The BRAF K601E mutation occurs in 5% of patients with melanoma, and is the third most common type of BRAF mutation. However, treatment with BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is only approved in patients with BRAF V600-positive melanoma, and patients with K601E-mutated melanoma do not have access to such drugs. CASE PRESENTATION: A female patient was diagnosed with high tumor burden metastatic melanoma harboring the BRAF K601E mutation. After chemotherapy failure, she underwent compassionate treatment with trametinib. Trametinib showed good activity and efficacy, with 48% shrinkage of a metastatic lymphadenopathy after 4 months' treatment. However, the patient reported treatment-related skin toxicity that required dosage reduction and a personalized intermittent trametinib dosing schedule. After over 36 months from the first trametinib administration, and resection of a metastatic lymphadenopathy, the patient experienced complete response. CONCLUSIONS: This case report shows that trametinib could be a valid therapeutic option in patients with metastatic melanoma harboring the rare BRAF K601E mutation.

BRAFK601E Mutation in a Follicular Thyroid Adenoma: A Case Report.

BRAF mutations represent the most common genetic alteration in papillary thyroid carcinoma (PTC). The p.V600E mutation is specific for the classic and tall-cell variants of PTC and has been associated with a more aggressive biologic behavior. On the other hand, the p.K601E mutation is peculiar to the follicular variant of PTC, and seems to be a favorable prognostic indicator. A 12-year-old boy presented with a 10-mm left-sided thyroid nodule. Fine-needle aspiration cytology reported the lesion as suspicious for a follicular neoplasm (Bethesda category IV). The patient underwent lobectomy, and histopathology revealed a follicular adenoma with normal surrounding tissue. The cytological smear was found to be positive for BRAF p.K601E mutation, and this was later confirmed on the corresponding paraffin block. This case was independently revised by 4 expert pathologists, all of whom confirmed the benign nature of the thyroid lesion. This article describes the presence of a BRAF mutation in a benign thyroid lesion. To the authors' knowledge, this is the fourth case of follicular adenoma carrying BRAFK601E reported in literature to date. BRAFK601E mutation can occur in benign thyroid lesions. This finding, in the context of the current literature and the recently proposed reclassification of the noninvasive encapsulated follicular variant of papillary thyroid carcinoma into a benign lesion, confirms the importance of preoperative BRAF p.K601E testing in offering patients a tailored treatment plan and avoiding overtreatment.

Clinicopathological characteristics associated with BRAF(K601E) and BRAF(L597) mutations in melanoma.

BRAF mutations at codons L597 and K601 occur uncommonly in melanoma. Clinical and pathological associations of these mutations were investigated in a cohort of 1119 patients with known BRAF mutation status. A BRAF mutation was identified in 435 patients; Mutations at L597 and the K601E mutation were seen in 3.4 and 3.2% of these, respectively. K601E melanomas tended to occur in male patients, a median age of 58 yr, were generally found on the trunk (64%) and uncommonly associated with chronically sun-damaged (CSD) skin. BRAF L597 melanomas occurred in older patients (median 66 yr), but were associated with CSD skin (extremities or head and neck location - 73.3%, P = 0.001). Twenty-three percent of patients with V600E- and 43% of patients with K601E-mutant melanomas presented with nodal disease at diagnosis compared to just 14% of patients with BRAF wild-type tumors (P = 0.001 and 0.006, respectively). Overall, these mutations represent a significant minority of BRAF mutations, but have distinct clinicopathological phenotypes and clinical behaviors.

A Case of Multifocal Papillary Thyroid Carcinoma Consisting of One Encapsulated Follicular Variant with BRAF K601E Mutation and Three Conventional Types with BRAF V600E Mutation.

Multifocal papillary thyroid carcinoma (mPTC) comprises about 20-30% of PTC. In mPTC, individual tumor foci can be identical or frequently composed of different histological types including follicular, solid, tall-cell or conventional patterns. We report a case of mPTC consisting of one encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) and three conventional PTCs in a 44-year-old woman. This case genetically demonstrates unique features including the simultaneous presence of the BRAF V600E (T1799A) mutation and the BRAF K601E (A1801G) mutation in conventional PTC and FVPTC, respectively.

A Case of Multifocal Papillary Thyroid Carcinoma Consisting of One Encapsulated Follicular Variant with BRAF K601E Mutation and Three Conventional Types with BRAF V600E Mutation

Multifocal papillary thyroid carcinoma (mPTC) comprises about 20-30% of PTC. In mPTC, individual tumor foci can be identical or frequently composed of different histological types including follicular, solid, tall-cell or conventional patterns. We report a case of mPTC consisting of one encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) and three conventional PTCs in a 44-year-old woman. This case genetically demonstrates unique features including the simultaneous presence of the BRAF V600E (T1799A) mutation and the BRAF K601E (A1801G) mutation in conventional PTC and FVPTC, respectively.