TEMPORARY REMOVAL: Spectrum of histopathologic findings in risk-reducing bilateral prophylactic mastectomy in patients with and without BRCA mutations.

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Atypical cystic hypersecretory lesions of the breast commonly harbour TP53 alterations.

AIMS: Cystic hypersecretory lesions are rare and include atypical cystic hypersecretory hyperplasia (A-CHH) and cystic hypersecretory carcinoma in situ (CHC-IS). Despite detailed morphological descriptions, little is known about the genetic landscape of these lesions. METHODS AND RESULTS: We identified four A-CHH and three CHC-IS from 2010 to 2022. Patients ranged from 39 to 65 (median 49) years. All lesions showed characteristic cystically dilated ducts with colloid-like secretions lined by enlarged cells with hyperchromatic nuclei and at least moderate cytological atypia. CHC-IS was remarkable for a greater degree of intraductal proliferation, typically with a micropapillary pattern. Four patients had concurrent ipsilateral invasive carcinoma. Next-generation sequencing (104 cancer-associated genes) was successful in four, showing variants in TP53 (3), KEAP1 (1) and MDM2 (1). p53 immunohistochemistry was concordant with molecular results with mutant-pattern staining in three TP53-mutants and wild-type in one. In three cases where sequencing failed, one showed mutant p53 staining, one was wild-type and one had no remaining lesion. The combined molecular and immunohistochemical results demonstrated p53 alterations in one A-CHH and three CHC-IS. CONCLUSION: Based on this limited cohort, atypical cystic hypersecretory lesions appear to commonly harbour TP53 alterations. To our knowledge, this is the first study to characterise molecular alterations in this rare subset of breast lesions.

Endometrial/Endometrioid Stromal Tumors With Extensive Whorling and CTNNB1 Translocation : A Report of 3 Cases.

Endometrial/endometrioid stromal tumors are rare and morphologically heterogenous, and their diagnosis may be challenging. We identified 3 endometrial/endometrioid stromal tumors with identical and previously undescribed histologic features and herein report their morphologic, immunohistochemical, and molecular profiles. Patients were 53, 62, and 79 years. Tumors were well-circumscribed, tan-yellow solid masses measuring 10.0, 11.0, and 18.7 cm, and were intramyometrial (n=2) or in the broad ligament (n=1). All showed small, tight whorls of epithelioid to slightly spindled tumor cells with minimal cytoplasm and negligible mitoses, multifocally associated with hyalinization and myxoid change set in a loose fibroblastic background with small, delicate vessels. This morphology was seen throughout in 1 tumor and in ∼20% and 70% of the 2 others with the remaining areas showing sex cord-like differentiation. Tumor cells expressed CD10 (3/3, 1 focal), calretinin (3/3 diffuse), WT1 (3/3 diffuse), estrogen receptor (1/1, diffuse). RNA-sequencing was successful in 1 tumor and revealed a GREB1-CTNNB1 in-frame fusion. All 3 tumors harbored a CTNNB1 translocation by fluorescence in situ hybridization correlating with nuclear ß-catenin expression. Whole-genome DNA methylation analysis classified all 3 tumors within the low-grade endometrial stromal sarcoma reference class with flat copy number profiles. One patient (79-y-old) died of unrelated causes 2 months after surgery and the other 2 were alive without disease after 13 and 75 months. We have described a rare subset of endometrial/endometrioid stromal tumors with extensive whorling and a CTNNB1 translocation, expanding the morphologic and molecular spectrum of these neoplasms.

TRK inhibitor in a patient with metastatic triple-negative breast cancer and NTRK fusions identified via cell-free DNA analysis.

Tissue-agnostic indications for targeted therapies have expanded options for patients with advanced solid tumors. The Food and Drug Administration approvals of the programmed death-ligand 1 inhibitor pembrolizumab and the TRK inhibitors larotrectinib and entrectinib provide rationale for next-generation sequencing (NGS) in effectively all advanced solid tumor patients given potential for clinical responses even in otherwise refractory disease. As proof of concept, this case report describes a 64-year-old woman with triple-negative breast cancer refractory to multiple lines of therapy, found to have a rare mutation on NGS which led to targeted therapy with meaningful response. She initially presented with metastatic recurrence 5 years after treatment for a localized breast cancer, with rapid progression through four lines of therapy in the metastatic setting, including immunotherapy, antibody-drug conjugate-based therapy, and chemotherapy. Germline genetic testing was normal. Ultimately, NGS evaluation of cell-free DNA via an 83-gene assay (Guardant Health, Inc.) identified two NTRK3 fusions: an ETV6-NTRK3 fusion associated with the rare secretory breast carcinoma, and CRTC3-NTRK3, a novel fusion partner not previously described in breast cancer. Liver biopsy was sent for whole exome sequencing and RNA-seq analysis of tissue (BostonGene, Inc., Boston, MA, USA), which provided orthogonal confirmation of both the ETV6-NTRK3 and CRTC3-NTRK3 fusions. She was started on the TRK inhibitor larotrectinib with a marked clinical and radiographic response after only 2 months of therapy. The patient granted verbal consent to share her clinical story, images, and data in this case report. This case demonstrates the significant potential benefits of NGS testing in advanced cancer and the lessons we may learn from individual patient experiences.

Metaplastic breast cancer: A review.

Metaplastic breast cancer (MpBC) is an uncommon aggressive malignancy that is associated with a poor prognosis. Due to its rarity, the relationships between the clinical and pathological features of MpBC, treatment approach, and clinical outcomes remain underexplored. In the following review article, we synthesize the existing data on the clinical, pathological and genomic features, management, and outcomes of MpBC. We also identify potential targets for future clinical trials.

Metastatic Uterine Leiomyosarcoma With Rhabdomyosarcomatous Heterologous Differentiation.

Heterologous differentiation has only been previously reported twice in metastatic uterine leiomyosarcomas. We report herein the first case of metastatic uterine leiomyosarcoma with rhabdomyosarcomatous differentiation. A 67-yr-old woman presented with femur, abductor magnus, and lymph node metastases 9 yr after the primary diagnosis. The metastatic sites showed rhabdomyosarcomatous morphologic features, and immunohistochemical studies confirmed skeletal muscle differentiation. Molecular testing revealed the same loss-of-function TP53 mutation in the uterine leiomyosarcoma and metastatic sites supporting heterologous differentiation of the primary tumor. Our case highlights the morphologic shifts metastatic tumors may manifest and the potential diagnostic problems that may arise.

Uterine Tumors Resembling Ovarian Sex Cord Tumors: A Clinicopathologic Study of 75 Cases Emphasizing Features Predicting Adverse Outcome and Differential Diagnosis.

Uterine tumors resembling ovarian sex cord tumors (UTROSCTs), first characterized by Drs Clement and Scully in 1976, are rare neoplasms showing clinical, morphologic, and immunohistochemical overlap with a number of other uterine tumors, most being mesenchymal. Criteria for aggressive behavior are not clearly established. We report 75 tumors from patients ranging from 21 to 84 (mean=52.4) years. Seventy-one patients were treated by hysterectomy and 4 by conservative total excision. Thirty-eight tumors were intramyometrial, 34 submucosal, and 3 cervical; they ranged from 0.6 to 20 (mean=4.9) cm and were typically tan-yellow. Sixty-eight neoplasms were well-circumscribed and 7 had infiltrative borders (4 only minimally). In 56 tumors, a smooth muscle component was intimately admixed with the neoplastic cells ("pseudoinfiltration"; extensive in 29). Architectural patterns included cords (n=53), diffuse (n=51), hollow tubules (n=48), nests (n=38), trabeculae (n=37), retiform (n=23), solid tubules (n=21), pseudoangiomatoid (n=11), pseudopapillary (n=4), and whorled (n=2); typically, more than 1 pattern was seen. Tumor cells were epithelioid (n=62), epithelioid and spindled (n=12), or spindled (n=1) and/or rhabdoid (n=20; extensive in 2). Cytologic atypia was absent to mild in 57, moderate in 16, and moderate to severe in 2 tumors. Fifty-seven UTROSCTs had ≤2mitoses/10 high power fields (HPF), 12 had 3 to 5/10 HPF, and 6 >5/10 HPF. Necrosis was present in 3 and lymphovascular invasion in 1. Tumor cells showed a polyphenotypic immunohistochemical profile (with positivity for sex cord, smooth muscle, and epithelial markers), most commonly inhibin (17/33+) and calretinin (22/31+) positive. Five of 58 patients with follow-up (22 to 192; mean=73.2 mo) had recurrences/metastases from 30 to 144 months, and 2 died of disease. Malignant tumors showed >3 of the following 5 features compared with benign tumors: size >5 cm, at least moderate cytologic atypia, ≥3 mitoses/10 HPF, infiltrative borders, and necrosis. One of the 5 malignant tumors showed an extensive rhabdoid morphology. UTROSCTs are uncommon, show a wide morphologic spectrum, often pose problems in differential diagnosis, and typically have a benign outcome. Rare tumors are associated with late recurrences and a combination of more than 3 of the 5 features listed above predicted aggressive behavior in this series.

Follicular Dendritic Cell Sarcoma of Uterine Corpus: Report of 2 Cases.

Follicular dendritic cell sarcoma is a rare dendritic/histiocytic tumor of intermediate malignant potential, which often involves extranodal sites, most commonly the gastrointestinal tract and mediastinum with only 5 cases reported in the female genital tract. We present the clinical and pathologic features of 2 such examples arising in the uterine corpus. Both patients (63 and 72-yr old) presented with postmenopausal bleeding and underwent an endometrial biopsy diagnostic of follicular dendritic cell sarcoma that was followed by hysterectomy. The tumors were polypoid, 3.5 and 5.0 cm, and were confined to the endometrium. Microscopically, ovoid to round to spindled tumor cells with pale eosinophilic cytoplasm and vesicular nuclei were arranged predominantly in sheets with an accompanying lymphocyte-rich inflammatory infiltrate. The tumor cells were positive for CD35, CD23, D2-40 in both tumors and additionally positive for CD21 in 1 tumor, all highlighting cell bodies and processes. Patients were alive without evidence of disease at 1 and 4 years with no adjuvant treatment. These cases highlight the importance of entertaining a broad differential diagnosis in lesions with epithelioid and/or spindled morphology involving the uterus.

Vulvar angiomyofibroblastoma is molecularly defined by recurrent MTG1-CYP2E1 fusions.

Angiomyofibroblastoma (AMF), a rare benign vulvovaginal mesenchymal tumour, poses a diagnostic challenge due to histologic and immunohistochemical overlap with other vulvar mesenchymal tumours. Recently, MTG1-CYP2E1 fusion transcripts were reported in 5/5 AMFs; no other genetic alterations have been described to date. Herein, we sought to investigate the frequency of the MTG1-CYP2E1 fusion and the presence of other potential genetic alterations in a cohort of AMFs (n = 7, patient age range: 28-49 years). Tumours demonstrated classic morphologic features including alternating hypo/hypercellular areas, capillary channels surrounded by epithelioid/spindled tumour cells, and variable amounts of mature adipose tissue. reverse transcription-polymerase chain reaction (RT-PCR) for MTG1-CYP2E1 fusion, performed in all seven cases, showed the fusion transcript in five of six cases (one case with technical failure). Two tumours, including the one lacking the fusion, were subjected to targeted next-generation sequencing (104 genes) and a sarcoma fusion assay (28 genes); the fusion negative AMF also underwent RNA sequencing. No additional mutations, copy number alterations, or fusion genes were identified with the assays employed. We conclude that the majority of AMFs harbour recurrent MTG1-CYP2E1 fusion transcripts and identification of this fusion may aid in the diagnosis.

Vasculopathy and Increased Vascular Congestion in Fatal COVID-19 and Acute Respiratory Distress Syndrome.

Rationale: The leading cause of death in coronavirus disease 2019 (COVID-19) is severe pneumonia, with many patients developing acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD). Whether DAD in fatal COVID-19 is distinct from other causes of DAD remains unknown. Objective: To compare lung parenchymal and vascular alterations between patients with fatal COVID-19 pneumonia and other DAD-causing etiologies using a multidimensional approach. Methods: This autopsy cohort consisted of consecutive patients with COVID-19 pneumonia (n = 20) and with respiratory failure and histologic DAD (n = 21; non-COVID-19 viral and nonviral etiologies). Premortem chest computed tomography (CT) scans were evaluated for vascular changes. Postmortem lung tissues were compared using histopathological and computational analyses. Machine-learning-derived morphometric analysis of the microvasculature was performed, with a random forest classifier quantifying vascular congestion (CVasc) in different microscopic compartments. Respiratory mechanics and gas-exchange parameters were evaluated longitudinally in patients with ARDS. Measurements and Main Results: In premortem CT, patients with COVID-19 showed more dilated vasculature when all lung segments were evaluated (P = 0.001) compared with controls with DAD. Histopathology revealed vasculopathic changes, including hemangiomatosis-like changes (P = 0.043), thromboemboli (P = 0.0038), pulmonary infarcts (P = 0.047), and perivascular inflammation (P < 0.001). Generalized estimating equations revealed significant regional differences in the lung microarchitecture among all DAD-causing entities. COVID-19 showed a larger overall CVasc range (P = 0.002). Alveolar-septal congestion was associated with a significantly shorter time to death from symptom onset (P = 0.03), length of hospital stay (P = 0.02), and increased ventilatory ratio [an estimate for pulmonary dead space fraction (Vd); p = 0.043] in all cases of ARDS. Conclusions: Severe COVID-19 pneumonia is characterized by significant vasculopathy and aberrant alveolar-septal congestion. Our findings also highlight the role that vascular alterations may play in Vd and clinical outcomes in ARDS in general.

Discerning subsets of breast cancer with very low and absent HER2 protein expression.

Breast cancers are currently eligible for treatment with anti-HER2 therapies if they exhibit amplification of the gene ERBB2 and overexpression of its protein product HER2. Recently, breast cancers with low HER2 expression have shown response to novel anti-HER2 antibody-drug conjugates, and the lower end of "low-HER2" tumors has not yet been clinically delineated. The historically binary approach to HER2 scoring will need to evolve and reporting of HER2 status may require refinement to better stratify low-HER2 statuses. We performed a quality review of HER2 immunohistochemical (IHC) scoring of breast carcinomas with low HER2 expression (71 core biopsies and 51 excisions). We also investigated the feasibility of discerning cases with total lack of HER2 expression from those cases with "very low" HER2 expression that did not meet current criteria for a HER2(1+) score. Rescoring HER2 achieved substantial agreement when performed at 200×, and near-perfect agreement at 400× magnification. Examination under 400× magnification led to recognition of more cases with HER2 expression. Less than 10% of cases showed complete lack of HER2 protein expression by IHC. Cases with "very low" expression were readily identified, and such a category would be feasible to implement in pathologist workflow.

How a woman's myomectomy saved her father's life: evidence of fumarate hydratase-deficient uterine leiomyoma and early detection of germline variants in fumarate hydratase.

Objective: To describe a case of a personal and family history of early uterine leiomyomatosis that revealed a pathogenic variant in the FH gene encoding fumarate hydratase. After the patient's diagnosis, a first-degree relative was detected with early-stage renal cell carcinoma. The patient decided to undergo preimplantation genetic testing to reduce the risk to her future children. Design: A case report of autosomal dominant hereditary leiomyomatosis and renal cell cancer syndrome where the patient underwent 2 cycles of in vitro fertilization with preimplantation genetic testing for monogenic disease/aneuploidy (PGT-MA) that resulted in 3 unaffected, euploid embryos. Setting: Large academic single-center hospital. Patients: A 35-year-old nulligravida woman with a personal history of an early-onset uterine leiomyomatosis and a family history of renal cell carcinoma and uterine leiomyomas, who is heterozygous for a pathogenic variant in FH and diagnosed with hereditary leiomyomatosis and renal cell cancer syndrome. Informed consent was obtained. Interventions: Two laparoscopic myomectomies were performed, and tissue was sent for histopathology and immunostaining. Hereditary leiomyomatosis and renal cell cancer syndrome was confirmed by germline testing, and 2 cycles of PGT-MA were performed. Main Outcome Measures: Through PGT-MA, the patient was able to mitigate the risk of passing a known familial variant to her future children. Results: After 2 cycles of in vitro fertilization with PGT-MA, 3 unaffected embryos were available for transfer. An unaffected, euploid embryo was transferred for pregnancy, and the patient is currently pregnant in her second trimester. Conclusions: Pathogenic variants in FH should be suspected in patients with early-onset uterine leiomyomas and a family history of cutaneous and/or uterine leiomyomas. Familial variant testing is crucial in identifying relatives at risk to start early screening.

Cystic Granulosa Cell Tumors of the Ovary: An Analysis of 80 Cases of an Often Diagnostically Challenging Entity.

CONTEXT.­: Granulosa cell tumors (GCTs) of both adult (AGCT) and juvenile (JGCT) types can rarely be completely or dominantly cystic, creating diagnostic difficulty because the cyst lining epithelium is often denuded. OBJECTIVE.­: To describe clinical, gross, microscopic, immunohistochemical, and molecular features of cystic GCTs with an emphasis on their differential diagnosis. DESIGN.­: We report 80 cystic GCTs (24 AGCTs and 56 JGCTs) in patients from ages 3 to 83 years (average ages, 35 years for AGCT and 22 years for JGCT). RESULTS.­: Nineteen of 43 patients with known clinical information (3 AGCT and 16 JGCT) had androgenic manifestations. All tumors were greater than 8 cm (average, 17 cm) with minimal to absent gross solid component. Denudation of cells lining the cysts was prominent. Invagination of the epithelium into the cyst walls was a key diagnostic feature, was present as cords, trabeculae, solid nests, and small and large follicles, and was identified in most tumors (17 AGCTs and 45 JGCTs). Cytologic atypia was essentially absent in AGCTs, whereas 14 JGCTs showed moderate to severe atypia of bizarre type. A theca cell component was present in all tumors and was extensive in 54. A FOXL2 hotspot mutation was identified in 1 of 4 AGCTs tested. CONCLUSIONS.­: Despite extensive denudation, the finding of typical architectural patterns and cytologic features as well as, in some cases, androgenic manifestations helps differentiate cystic GCTs from follicle cysts, the most common and challenging differential diagnosis, as well as other cystic neoplasms that may enter the differential diagnosis. FOXL2 sequencing may show a false-negative result in cystic AGCT because of the limited number of cells present within the tumor sample.

GLI1 Gene Alterations in Neoplasms of the Genitourinary and Gynecologic Tract.

We report 4 neoplasms of the kidney (2 cases) and uterus (2 cases) harboring rearrangements or amplifications of the GLI1 gene, which because of their unusual clinical presentation, morphology, and immunoprofile mimicked other neoplasms, causing significant diagnostic challenge. The neoplasms occurred in 4 female patients ages 33 to 88 years. Histologically they all demonstrated nodular growth, solid architecture, bland epithelioid to ovoid-spindle cells with pale cytoplasm set in a variably myxoid or hyalinized stroma. One uterine tumor also demonstrated a focal round cell pattern, while another demonstrated focal pleomorphism. Unlike most previously reported neoplasms with these genetic abnormalities, the neoplasms in the current series were negative for S100 protein and minimally reactive for actin. All labeled for CD10 and cyclin D1, while 2 labeled for estrogen receptor and BCOR and 1 labeled for desmin, raising consideration of endometrial stromal sarcoma, myxoid leiomyosarcoma, metastatic breast carcinoma, and glomus tumor. One renal neoplasm demonstrated a GLI1-FOXO4 gene fusion and the other harbored a GLI1 gene rearrangement (unknown partner). The 2 uterine neoplasms exhibited GLI1 gene amplifications. GLI1-altered neoplasms (particularly those with GLI1 amplification) show variable morphology and lack a consistent immunophenotype, and thus may trigger diagnostic challenges which can be resolved by molecular testing.

Spindle cell tumors of the pleura and the peritoneum: pathologic diagnosis and updates.

A diverse group of both benign and malignant spindle cell tumors can involve the pleura or the peritoneum. Due to their rarity and overlapping morphologic features, these tumors can pose considerable diagnostic difficulty in surgical pathology. As these tumors differ in their prognosis and clinical management, their correct pathologic diagnosis is critical. In addition to histologic assessment, select immunohistochemical and molecular tools can aid the distinction among these tumors. In this review, we consider some of the major histologic differential diagnosis of spindle cell tumors involving these serosal membranes. This list of tumors includes solitary fibrous tumor, inflammatory myofibroblastic tumor, desmoid fibromatosis, synovial sarcoma, sarcomatoid carcinoma, spindle cell melanoma, dedifferentiated liposarcoma, epithelioid hemangioendothelioma, and sarcomatoid mesothelioma. We describe their salient clinicopathologic and genetic findings, with a review on some of the recent discoveries on their molecular pathogenesis.

Cribriform-Morular Thyroid Carcinoma Is a Distinct Thyroid Malignancy of Uncertain Cytogenesis.

Tumors with papillary cribriform and morular architecture were initially considered to be variants of papillary thyroid carcinoma; however, recent observations have challenged this view. In this study, we reviewed the demographical, histopathological, and immunohistochemical features of the largest case series, consisting of 33 tumors. The age at time of pathological diagnosis ranged from 18 to 59 (mean 33) years, and all patients except one were female. Sixteen patients had multifocal and fifteen had unifocal disease. The status of focality was unavailable in two patients. Tumors were well-circumscribed, ranging in size from 0.1 to 8.0 cm. The cribriform component was admixed with morulae in the majority, except seven had a cribriform-predominant architecture and two had predominantly solid growth. Variable degrees of nuclear enlargement, elongation, overlapping, and grooves were seen but florid nuclear convolution, intranuclear pseudoinclusions, and optically clear nuclei due to chromatin margination were not appreciated. There was no or little colloid material within the cribriform spaces. Two solid tumors had high-grade features. Immunohistochemical studies showed beta-catenin nuclear and cytoplasmic positivity in all cases. The cribriform component was positive for TTF1 and negative for thyroglobulin. PAX8 was absent in half of these tumors and focal in the remainder. Morulae were positive for keratin 5 and CD5 and negative for p63, p40, TTF1, and PAX8. Molecular studies revealed germline APC mutations in 12 tumors and were negative in 5 sporadic tumors in a subset of tested tumors. Irrespective of the antibody used in this cohort, all cribriform-morular carcinomas express TTF1; however, PAX8 immunoreactivity is weak, focal or negative, and all tumors lack thyroglobulin reactivity; these findings raise questions about tumor cell origin and may indicate that these are not of thyroid follicular epithelial differentiation. We postulate that morulae may represent divergent thymic/ultimobranchial pouch-related differentiation. Given their unique cytomorphology, immunohistochemical profiles, and genetic features that have little overlap with traditional follicular cell-derived thyroid carcinomas, we propose that these tumors represent a distinct form of thyroid carcinoma unrelated to other neoplasms of thyroid follicular cells.

Clinicopathologic and molecular characterization of NTRK-rearranged thyroid carcinoma (NRTC).

Primary thyroid neoplasms with actionable NTRK rearrangements are rare, and their clinical behavior, histologic characteristics, and molecular landscape are not well understood. We report an institutional series of eleven NTRK-rearranged thyroid carcinomas (NRTC) by performing clinicopathologic review and next-generation sequencing for targeted mutations and gene rearrangements. The NRTC encompass a histomorphologic spectrum of ten papillary thyroid carcinomas (PTC), including one with high-grade features, and one secretory carcinoma (SC), in ten adults and one adolescent. All NRTC were characterized by an unusual multinodular growth pattern, extensive lymphovascular invasion, and cervical lymph node metastases at initial presentation. Immunophenotypically, while most cases were positive for TTF1 and PAX8, the SC case was negative/weak for these markers and instead diffusely expressed GATA3, mammaglobin and S100. Observed gene rearrangements included ETV6-NTRK3 (n = 4, including the SC), TPR-NTRK1 (n = 2), RBPMS-NTRK3 (n = 2), SQSTM1-NTRK1 (n = 1), SQSTM1-NTRK3 (n = 1), and EML4-NTRK3 (n = 1). Mutation profiling revealed a concurrent TERT promotor mutation C228T in two (22%) patients and a novel frameshift MEN1 deletion in one. All patients received total thyroidectomy and radioactive iodine. Despite frequent development of persistent/recurrent disease (9 cases, 82%) and distant metastases (6 cases; 55%), no tumor-related death occurred over a median (range) follow-up of 44 (11 to 471) months. Three patients received NTRK inhibitor therapy, with the SC case showing complete resolution and two other patients experiencing 33% and 69.7% decrease of disease burden. Although the range of features is variable, NRTC appear to be clinically aggressive tumors with high metastatic rate but relatively low mortality with NTRK inhibitor therapy. The histologic findings of multinodular growth and extensive lymphovascular spread, seen in all NRTC, including PTC and SC, may serve as useful histomorphologic clues to prompt NTRK status testing. We also present the first report of concurrent TERT promotor activating mutation which did not appear to confer entrectinib resistance to NRTC.