-
Cancer Research Communications Jul 2023Hürthle cell carcinoma (HCC) is a rare type of thyroid cancer with high rates of distant metastasis and recurrence. Along with the scarcity of effective systemic...
UNLABELLED
Hürthle cell carcinoma (HCC) is a rare type of thyroid cancer with high rates of distant metastasis and recurrence. Along with the scarcity of effective systemic therapies for HCC, these factors contribute to poor clinical outcomes. The immunologic features of HCC are poorly defined and response rates with immune checkpoint blockade have not been reported. A more comprehensive understanding of the immune landscape and factors that predict response to checkpoint inhibitors is needed. We performed RNA sequencing on 40 tumors to characterize the neoantigen landscape and immune microenvironment of HCC. We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T-cell activation/dysfunction and correlated these to genetic features such as tumor mutation burden, neoantigen burden, mitochondrial mutations, and LOH from chromosomal uniparental disomy. Finally, immune profiles of patients with recurrence were compared with those of patients without recurrence. HCC tumors exhibited low levels of immune infiltration, with the more aggressive widely invasive phenotype associated with more immune depletion. There was a negative correlation between tumor mutation burden, neoantigen burden, programmed cell death ligand 1 (PD-L1) expression, and the immune infiltration score. HCC tumors that exhibited a global LOH from chromosomal uniparental disomy or haploidization had the lowest level of immune infiltration. HCC tumors that recurred displayed an immune-depleted microenvironment associated with global LOH and aerobic glycolysis. These findings offer new insights into the functional immune landscapes and immune microenvironment of HCC. Our data identify potential immunologic vulnerabilities for these understudied and often fatal cancers.
SIGNIFICANCE
The immune landscape of HCC is poorly defined and response rates to immunotherapy have not been reported. The authors found the immune microenvironment in HCC to be depleted. This immunosuppression is associated with a global LOH from haploidization and uniparental disomy, resulting in whole chromosome losses across the genome.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Uniparental Disomy; Oxyphil Cells; B7-H1 Antigen; Tumor Microenvironment
PubMed: 37529400
DOI: 10.1158/2767-9764.CRC-23-0120 -
Cancer Discovery Aug 2023Oncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here,...
UNLABELLED
Oncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA sequencing and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging to be increased in HCC. A CRISPR-Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against lipid peroxides and ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity.
SIGNIFICANCE
HCC harbors abundant mitochondria, mitochondrial DNA mutations, and chromosomal losses. Using a CRISPR-Cas9 screen inspired by transcriptomic and metabolomic profiling, we identify molecular effectors essential for cell fitness. We uncover lipid peroxide stress as a vulnerability coupled to mitochondrial complex I loss in HCC. See related article by Frank et al., p. 1884. This article is highlighted in the In This Issue feature, p. 1749.
Topics: Humans; Thyroid Gland; Carcinoma, Hepatocellular; Lipid Peroxides; Fermentation; Oxyphil Cells; Liver Neoplasms; DNA, Mitochondrial
PubMed: 37262067
DOI: 10.1158/2159-8290.CD-22-0976 -
European Journal of Medical Research Jan 2024N-Nitrosomorpholine (NMO) is one of the most common N-nitroso compounds. An oncocytic transformation has been demonstrated in renal tubules of NMO-treated rats. In our...
BACKGROUND
N-Nitrosomorpholine (NMO) is one of the most common N-nitroso compounds. An oncocytic transformation has been demonstrated in renal tubules of NMO-treated rats. In our study, we aimed to investigate the potential transformation of oncocytic cells in 6 endocrine organs, i.e., thyroid, adrenal and pituitary glands, pancreas, testis, and bone, of NMO-exposed rats.
METHODS
Thirty male rats were born and raised. Fifteen of them were given a single dose of 320 mg NMO per kg body weight, dissolved in drinking water, by a gavage tube. At the end of 52 weeks, the animals in both series were killed. Right after the killing, 6 different endocrine organs (hypophysis, thyroid, pancreas, adrenal gland, bone [femur], and testicles) of each animal were excised.
RESULTS
There was no evidence of oncocytic cell development in the control group. In contrast, oncocytes were observed in 8 out of 13 NMO-treated rats: 2 in the adrenal sections, 1 in the thyroid sections, 3 in the pituitary sections, and 2 in the pancreas sections. Thesticle and bone sections were completely normal.
CONCLUSIONS
We showed that NMO induced an oncocytic change in pancreas, thyroid, pituitary, and adrenal glands. To date, no identified specific environmental risk factors that lead to an oncocytic transformation in endocrine glands have been reported previously. Given the increasing prevalence of endocrine-disrupting chemicals in the environment, personal care products, manufactured goods, and food sources, there is a need to advance our understanding of the pathological mechanisms underlying oncocytosis in endocrine organs.
Topics: Rats; Male; Animals; Oxyphil Cells; Nitrosamines; Thyroid Gland; Adrenal Glands
PubMed: 38245764
DOI: 10.1186/s40001-024-01654-5 -
Indian Journal of Pathology &... 2023Neoplastic lipomatous lesions of the salivary glands constitute ≤0.5% of all the salivary gland tumors. Oncocytic sialolipoma of the parotid glands is extremely... (Review)
Review
Neoplastic lipomatous lesions of the salivary glands constitute ≤0.5% of all the salivary gland tumors. Oncocytic sialolipoma of the parotid glands is extremely uncommon. We report a case of oncocytic sialolipoma of the parotid gland in a 59-year-old male who presented with a gradually increasing swelling of the right parotid. Excisional parotid biopsy performed in view of possible pleomorphic adenoma as suggested on ultrasonography showed histological features consistent with oncocytic sialolipoma. We also described the characteristics of 24 previously reported cases of oncocytic sialolipoma of the parotid gland. The median age of the patients including the present case was 56 years (range 7-89), and 14 were male. The largest and the least reported sizes of the tumor were 7.0 and 1.4 cm, respectively. The left-sided parotid gland was more commonly involved (14/23). Despite its rarity, oncocytic sialolipoma should be considered in lipomatous parotid lesions showing epithelial components with oncocytic changes.
Topics: Humans; Male; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Female; Parotid Gland; Adenoma; Salivary Gland Neoplasms; Oxyphil Cells; Lipoma; Parotid Neoplasms
PubMed: 37530346
DOI: 10.4103/ijpm.ijpm_323_21 -
The American Journal of Case Reports Oct 2023BACKGROUND Brain metastasis of papillary thyroid cancer (PTC) is rare. Treatment of these patients is challenging due to the lack of specific guidelines. Early diagnosis...
Thyroglobulin as a Rapid and Cost-Effective Biomarker for Diagnosis of Thyroid Carcinoma Brain Metastasis: A Case Report of a Patient with Metastatic Hurthle Cell Thyroid Carcinoma.
BACKGROUND Brain metastasis of papillary thyroid cancer (PTC) is rare. Treatment of these patients is challenging due to the lack of specific guidelines. Early diagnosis is accompanied by immediate treatment and less morbidity. Total resection of brain lesions may be unattainable when they include infiltration of eloquent areas. This report is of an 81-year-old man who had undergone total thyroidectomy for goiter in the past and presented with metastatic papillary thyroid carcinoma (PTC) to the neck after a gap of 16 years. After two years, the patient developed a solitary cystic brain PTC metastasis associated with raised thyroglobulin (Tg) inside the cystic lesion aspirated during brain surgery. CASE REPORT An 81-year-old male patient was admitted for a space-occupying brain lesion in the right frontal lobe. The patient's history included metastatic disease of PTC to the neck with cervical lymph node metastasis and local recurrence after surgery and radioactive iodine-131 treatment. The patient underwent craniotomy and removal of the lesion. The aspirated fluid was sent for cytological examination and measurement of Tg levels, which were interestingly high. Pathology of the brain lesion revealed infiltration of brain parenchyma from a metastatic lesion characterized by eosinophilic cells with irregular contours forming grooves, resulting in cytoplasmic pseudo-inclusions, an oncotic variant of PTC. CONCLUSIONS This report has shown that residual tissue may be present following total thyroidectomy and may be the origin of PTC with metastasis to the brain. The patient in this study suffered from a brain lesion that could be excised. However, aspiration of cystic compartments could provide a rapid diagnosis in patients with non-removable brain lesions.
Topics: Male; Humans; Aged, 80 and over; Thyroid Neoplasms; Thyroglobulin; Iodine Radioisotopes; Cost-Benefit Analysis; Oxyphil Cells; Carcinoma, Papillary; Thyroid Cancer, Papillary; Thyroidectomy; Brain Neoplasms; Biomarkers
PubMed: 37853680
DOI: 10.12659/AJCR.939025