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Cancer Discovery Aug 2023A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many...
UNLABELLED
A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. We report here that Hürthle cell carcinoma of the thyroid (HTC) models harboring mitochondrial DNA-encoded defects in complex I of the mitochondrial electron transport chain exhibit impaired respiration and alterations in glucose metabolism. CRISPR-Cas9 pooled screening identified glycolytic enzymes as selectively essential in complex I-mutant HTC cells. We demonstrate in cultured cells and a patient-derived xenograft model that small-molecule inhibitors of lactate dehydrogenase selectively induce an ATP crisis and cell death in HTC. This work demonstrates that complex I loss exposes fermentation as a therapeutic target in HTC and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration.
SIGNIFICANCE
HTC is enriched in somatic mtDNA mutations predicted to affect complex I of the electron transport chain (ETC). We demonstrate that these mutations impair respiration and induce a therapeutically tractable reliance on aerobic fermentation for cell survival. This work provides a rationale for targeting fermentation in cancers harboring irreversible genetically encoded ETC defects. See related article by Gopal et al., p. 1904. This article is highlighted in the In This Issue feature, p. 1749.
Topics: Humans; Fermentation; Thyroid Neoplasms; Adenoma, Oxyphilic; DNA, Mitochondrial; Adenocarcinoma; Carcinoma
PubMed: 37262072
DOI: 10.1158/2159-8290.CD-22-0982 -
The American Journal of Dermatopathology Dec 2021Oncocytomas are benign neoplasms that are most often found in the salivary glands and kidneys. Ocular oncocytoma typically present as an asymptomatic dark blue papule on...
Oncocytomas are benign neoplasms that are most often found in the salivary glands and kidneys. Ocular oncocytoma typically present as an asymptomatic dark blue papule on the lacrimal caruncle. Histologically, the tumor is composed of oncocytes, cells notable for eosinophilic cytoplasmic granules representing large quantities of dysfunctional mitochondria. The neoplastic proliferation may be partially or totally encapsulated and may be surrounded by myoepithelial cells. Discussed is the pathophysiology and histopathology of an ocular oncocytoma from the right lacrimal caruncle of a 68-year-old man. The patient complained of a foreign body sensation and tearing associated with a purpuric 1 × 1-mm papule of the right caruncle that had been present for 6 months. An excisional biopsy showed an oxyntic neoplasm with small cystic glandular spaces associated with goblet cells and mucin, confirmed by mucicarmine stain. Given the rarity of ocular oncocytomas and presence of mucin, exclusion of an endocrine mucin-producing sweat gland carcinoma was necessary. Peripheral myoepithelial cells noted on p63 immunostaining are seen in both endocrine mucin-producing sweat gland carcinoma and oncocytomas. However, endocrine mucin-producing sweat gland carcinoma is excluded by the presence of goblet cells, the uniform oxyphilic cytoplasm of the epithelial cells, and the negative immunohistochemical staining for neuron-specific enolase, chromogranin, synaptophysin, estrogen receptor, and progesterone receptor. Complete surgical excision is the treatment of choice for oncocytomas. This case highlights the clinical and histopathological presentation of ocular oncocytomas and raises awareness of this rare entity for both the practicing dermatologist and dermatopathologist.
Topics: Adenoma, Oxyphilic; Aged; Eye Neoplasms; Humans; Lacrimal Apparatus Diseases; Male
PubMed: 33989220
DOI: 10.1097/DAD.0000000000001975 -
Experimental Oncology Sep 2020The morbidity rate of kidney cancer has been increasing. Management of patients and their prognosis depend on the specific histological type of tumor. Unfortunately,...
BACKGROUND
The morbidity rate of kidney cancer has been increasing. Management of patients and their prognosis depend on the specific histological type of tumor. Unfortunately, different renal tumors can have similar histological features, making differential diagnostics challenging. Among the most challenging tasks is differential diagnosis of renal oncocytoma (RO) and chromophobe renal cell carcinoma (ChRCC).
AIM
To analyze different histological features of renal oncocytomas and specify their pathognomonic characteristics that may be advantageous for the confirmation of the diagnosis.
MATERIALS AND METHODS
The medical records and histopathological reports of 197 patients with diagnosis of either RO or ChRCC were analyzed. 37 histological parameters were then evaluated and their prevalence in RO or ChRCC was compared by performing a contingency table analysis. Odds ratio was also calculated.
RESULTS
The most common growth patterns of ROs were solid (53%), nested (47%), cystic (29%), and alveolar (28%). A combination of two or more growth patterns was seen in 82% of cases mostly composing of nested, cystic, alveolar or solid structures. Most tumors exhibited granular inclusions (70%) and dense cytoplasm (58%).
CONCLUSION
With more than 95% confidence, the nested pattern, myxoid stroma, granular cytoplasm and round nuclei are likely indicative of RO, whereas the varying nuclear size, raisinoid nuclei and reticular cytoplasm indicate higher likelihood of ChRCC. Therefore, these features should be analyzed for RO confirmation.
Topics: Adenoma, Oxyphilic; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Combined Modality Therapy; Diagnosis, Differential; Disease Management; Female; Humans; Immunohistochemistry; Kidney Neoplasms; Male; Middle Aged; Multimodal Imaging; Neoplasm Staging; Odds Ratio; Prognosis; Treatment Outcome; Tumor Burden
PubMed: 32996740
DOI: 10.32471/exp-oncology.2312-8852.vol-42-no-3.14968 -
International Journal of Surgical... Oct 2022Renal tumors with oncocytic or chromophobe-like morphology can be a common source of diagnostic difficulty. In some series, they constitute the largest group of... (Review)
Review
Renal tumors with oncocytic or chromophobe-like morphology can be a common source of diagnostic difficulty. In some series, they constitute the largest group of unclassified renal cell carcinomas, a term used for neoplasms that do not fit the current classification of renal tumors. We describe the histological, immunohistochemical, and molecular findings of an eosinophilic renal neoplasm which presented with rib and liver metastases, and provide a review of the literature. The possibility of a renal oncocytoma with metastases was initially considered but excluded on the basis of several morphological and immunohistochemical features. Additionally, the tumor did not correspond with other traditional or newly emerging categories of renal neoplasms. It was therefore regarded as an unclassified oncocytic renal neoplasm which demonstrated evidence of malignant potential due to the presence of multiple metastases.
Topics: Adenoma, Oxyphilic; Biomarkers, Tumor; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Liver Neoplasms; Ribs
PubMed: 35274993
DOI: 10.1177/10668969221084265 -
Radiology Apr 2023
Topics: Humans; Retrospective Studies; Adenoma, Oxyphilic; Watchful Waiting; Reproducibility of Results; Kidney Neoplasms; Carcinoma, Renal Cell; Biopsy
PubMed: 36692404
DOI: 10.1148/radiol.223108 -
Urology Sep 2020Renal oncocytoma is an uncommon tumor that exhibits numerous features which are characteristic but not necessarily unique. Percutaneous biopsy is a safe method of... (Review)
Review
Renal oncocytoma is an uncommon tumor that exhibits numerous features which are characteristic but not necessarily unique. Percutaneous biopsy is a safe method of diagnosis. However, differentiation from other tumor subtypes often requires sophisticated analysis and is not universally feasible. This is why, surgical management can be considered as a first-line treatment or after surveillance. Potential triggers for change in management are: tumor size >3 cm, stage progression, kinetics of size progression (>5 mm/y), and clinical change in patient or tumor factors. Long-term follow-up data are lacking and greater centralization should be considered to reach adequate management.
Topics: Adenoma, Oxyphilic; Algorithms; Biopsy; Diagnosis, Differential; Humans; Kidney Neoplasms; Medical Oncology; Neoplasm Staging; Nephrectomy; Practice Guidelines as Topic; Urology; Watchful Waiting
PubMed: 32512107
DOI: 10.1016/j.urology.2020.05.047 -
Clinical & Experimental Ophthalmology May 2020
Topics: Adenoma, Oxyphilic; Diagnosis, Differential; Eyelid Neoplasms; Eyelids; Humans
PubMed: 32011066
DOI: 10.1111/ceo.13722 -
Current Opinion in Urology May 2023This review provides a summary of recent developments in classification of renal oncocytic neoplasms that were incorporated in the fifth edition WHO classification of... (Review)
Review
PURPOSE OF REVIEW
This review provides a summary of recent developments in classification of renal oncocytic neoplasms that were incorporated in the fifth edition WHO classification of renal tumors, released in 2022.
RECENT FINDINGS
Besides the distinct entities of renal oncocytoma and chromophobe renal cell carcinoma, the WHO now acknowledges a heterogeneous group of oncocytic tumors of the kidney that can be reported as 'oncocytic renal neoplasms of low malignant potential'. Case series by multiple institutions have revealed recurrent patterns of morphological features, protein marker expression, and genetic alterations within these neoplasms that may permit further subclassification in the future.
SUMMARY
The new classification system provides pathologists with the opportunity to simplify the diagnostic workup and reporting of morphologically equivocal oncocytic neoplasms.
Topics: Humans; Kidney Neoplasms; Kidney; Carcinoma, Renal Cell; Mutation; Adenoma, Oxyphilic; Biomarkers, Tumor; Diagnosis, Differential
PubMed: 36660966
DOI: 10.1097/MOU.0000000000001079 -
JAMA Otolaryngology-- Head & Neck... Mar 2024Oncocytic (Hürthle cell) thyroid carcinoma is a follicular cell-derived neoplasm that accounts for approximately 5% of all thyroid cancers. Until recently, it was... (Review)
Review
IMPORTANCE
Oncocytic (Hürthle cell) thyroid carcinoma is a follicular cell-derived neoplasm that accounts for approximately 5% of all thyroid cancers. Until recently, it was categorized as a follicular thyroid carcinoma, and its management was standardized with that of other differentiated thyroid carcinomas. In 2022, given an improved understanding of the unique molecular profile and clinical behavior of oncocytic thyroid carcinoma, the World Health Organization reclassified oncocytic thyroid carcinoma as distinct from follicular thyroid carcinoma. The International Thyroid Oncology Group and the American Head and Neck Society then collaborated to review the existing evidence on oncocytic thyroid carcinoma, from diagnosis through clinical management and follow-up surveillance.
OBSERVATIONS
Given that oncocytic thyroid carcinoma was previously classified as a subtype of follicular thyroid carcinoma, it was clinically studied in that context. However, due to its low prevalence and previous classification schema, there are few studies that have specifically evaluated oncocytic thyroid carcinoma. Recent data indicate that oncocytic thyroid carcinoma is a distinct class of malignant thyroid tumor with a group of distinct genetic alterations and clinicopathologic features. Oncocytic thyroid carcinoma displays higher rates of somatic gene variants and genomic chromosomal loss of heterozygosity than do other thyroid cancers, and it harbors unique mitochondrial DNA variations. Clinically, oncocytic thyroid carcinoma is more likely to have locoregional (lymph node) metastases than is follicular thyroid carcinoma-with which it was formerly classified-and it develops distant metastases more frequently than papillary thyroid carcinoma. In addition, oncocytic thyroid carcinoma rarely absorbs radioiodine.
CONCLUSIONS AND RELEVANCE
The findings of this review suggest that the distinct clinical presentation of oncocytic thyroid carcinoma, including its metastatic behavior and its reduced avidity to radioiodine therapy, warrants a tailored disease management approach. The reclassification of oncocytic thyroid carcinoma by the World Health Organization is an important milestone toward developing a specific and comprehensive clinical management for oncocytic thyroid carcinoma that considers its distinct characteristics.
Topics: Humans; Iodine Radioisotopes; Thyroid Neoplasms; Adenoma, Oxyphilic; Adenocarcinoma, Follicular; Lymphatic Metastasis
PubMed: 38206595
DOI: 10.1001/jamaoto.2023.4323 -
Mayo Clinic Proceedings Mar 2024
Topics: Humans; Adenoma, Oxyphilic; Thyroid Neoplasms
PubMed: 38432755
DOI: 10.1016/j.mayocp.2023.11.002