A case of Carney triad complicated by renal cell carcinoma and a germline SDHA pathogenic variant

Summary Succinate dehydrogenase deficiency has been associated with several neoplasias, including renal cell carcinoma (RCC) and those associated with hereditary paraganglioma (PGL)/ pheochromocytoma (PHEO) syndromes, Carney dyad, and Carney triad. Carney triad is a rare multitumoral syndrome characterized by co-existing PGL, gastrointestinal stromal tumor (GIST), and pulmonary chondroma (CHO). We report a case of a 57-year-old male who presented with para-aortic and gastroesophogeal masses, and a right renal superior pole lesion, which were classified as multiple PGLs, a GIST, and a clear cell renal carcinoma, respectively, on pathology following surgical resection. Additionally, a CHO was diagnosed radiologically, although no biopsy was performed. A diagnosis of Carney triad was made. SDHB immunohistochemical staining was negative for the PGL and the GIST, indicating SDH-deficiency. Interestingly, the renal cell carcinoma (RCC) stained positive for both SDHB and SDHA. Subsequent genetic screening of SDH subunit genes revealed a germline inactivating heterozygous SDHA pathogenic variant (c.91 C>T, p.R31X). Loss of heterozygosity was not detected at the tumor level for the RCC, which likely indicated the SDHA variant would not be causative of the RCC, but could still predispose to the development of neoplasias. To the knowledge of the authors this is the first reported case of an SDHA pathogenic variant in a patient with Carney triad complicated by RCC. Learning points The succinate dehydrogenase enzyme is encoded by four subunit genes (SDHA, SDHB, SDHC, and SDHD; collectively referred to as SDHx), which have been implicated in several neoplasias and are classified as tumor suppressor genes. Carney triad is a rare multiple-neoplasia syndrome presenting as an association of PGLs, GISTs, and CHOs. Carney triad is most commonly associated with hypermethylation of SDHC as demonstrated in tumor tissue, but approximately 10% of cases are due to pathogenic SDHx variants. Although SDHB pathogenic variants are most commonly reported in SDH-deficient renal cell carcinoma, SDHA disease-causing variants have been reported in rare cases.

Download Full-text

A Case of Carney Triad Complicated by Renal Cell Carcinoma and a Germline SDHA Pathogenic Variant

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.2015 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A985-A985

Author(s):

Rachel Wurth ◽

Abhishek Jha ◽

Crystal Kamilaris ◽

Anthony J Gill ◽

Nicola Poplawski ◽

...

Keyword(s):

Blood Pressure ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Systolic Pressure ◽

Pathogenic Variant ◽

Renal Lesion ◽

Positive Staining ◽

Carney Triad ◽

18F Fdg

Abstract Background: Carney triad is a rare multiple-neoplasia syndrome presenting as an association of paragangliomas (PGL), gastrointestinal stromal tumors (GIST), and pulmonary chondromas (CHO). Succinate dehydrogenase deficiency has been associated with several neoplasias, including Carney triad, renal cell carcinoma (RCC) and those associated with hereditary PGL/ pheochromocytoma (PHEO) syndromes. Clinical Case: A 57-year-old male diagnosed with hypertension at age 49, presented with a gradual increase in blood pressure over a period of 12 months. For seven years following his diagnosis of hypertension, the patient experienced episodic increases in blood pressure, to a systolic pressure greater than 180 mmHg associated with a tight band sensation around his forehead lasting half a day. Abdominal computed tomography (CT) revealed a left adrenal adenoma, a 5.1 cm para-aortic mass, and a right renal superior pole lesion measuring 2.5 cm, which was suspicious for a carcinoma. 123I-metaiodobenzylguanidine (123I-MIBG) and 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) scans were performed, which suggested the para-aortic mass to be consistent with a PGL. Additionally, 18F-FDG uptake was noted in the gastroesophageal region and was suspicious for a GIST. The left adrenal mass was not associated with 123I-MIBG or 18F-FDG activity. Chest CT demonstrated a right middle lobe lung lesion suggestive of a CHO, although no biopsy was performed. A diagnosis of Carney triad was made. The patient underwent surgical resection of the PGL and GIST, as well as a partial right nephrectomy. The PGL and GIST were positive for SDHA and negative for SDHB by immunohistochemical (IHC) staining. Pathology from the renal lesion was consistent with a 2.3 cm conventional clear cell renal carcinoma, with positive staining for SDHA and SDHB by IHC. The patient was found to harbor a germline heterozygous pathogenic variant (c.91 C>T, p.R31X) in SDHA which has been previously reported and results in loss of function of SDHA. SHDC hypermethylation was not detected in the PGL, GIST, or RCC. Additionally, DNA sequencing of the RCC did not indicate loss of heterozygosity at the variant region of interest. Although the SDHA disease-causing variant is responsible for the patients Carney triad phenotype, it is unclear if this variant is causative of the RCC. Conclusion: This is a novel presentation of a germline inactivating SDHA pathogenic variant in a patient with Carney triad complicated by RCC. However, an SDHA disease-causing variant was previously reported in a patient with comorbid GIST and RCC. This case provides further support to the increasing evidence that SDHx pathogenic variants may predispose patients to develop renal neoplasms.

Download Full-text

Succinate Dehydrogenase-Deficient Renal Cell Carcinoma

Encyclopedia of Pathology ◽

10.1007/978-3-030-41894-6_4954 ◽

2020 ◽

pp. 402-404

Author(s):

Anna Caliò ◽

Diego Segala ◽

Guido Martignoni

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Succinate Dehydrogenase ◽

Renal Cell

Download Full-text

Succinate Dehydrogenase Deficiency in a Child with Bilateral Renal Cell Carcinoma

Journal of Pediatric Surgery Case Reports ◽

10.1016/j.epsc.2017.08.018 ◽

2017 ◽

Vol 26 ◽

pp. 18-21

Author(s):

Tanya Marié Schickerling ◽

Kamusisi Chinyundo ◽

Simon Nayler ◽

Jerome Alexander Loveland ◽

Alan Randall Anderson

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Succinate Dehydrogenase ◽

Renal Cell ◽

Dehydrogenase Deficiency ◽

Bilateral Renal Cell Carcinoma ◽

Succinate Dehydrogenase Deficiency

Download Full-text

Incidence of succinate dehydrogenase and fumarate hydratase–deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC

Human Pathology ◽

10.1016/j.humpath.2019.07.004 ◽

2019 ◽

Vol 91 ◽

pp. 114-122 ◽

Cited By ~ 7

Author(s):

Sounak Gupta ◽

Amy A. Swanson ◽

Ying-Bei Chen ◽

Tilcia Lopez ◽

Dragana Milosevic ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Succinate Dehydrogenase ◽

Renal Cell ◽

Fumarate Hydratase

Download Full-text

Succinate Dehydrogenase–Deficient Renal Cell Carcinoma

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2018-0024-rs ◽

2018 ◽

Vol 143 (5) ◽

pp. 643-647 ◽

Cited By ~ 6

Author(s):

Tsung-Heng Tsai ◽

Wen-Ying Lee

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Succinate Dehydrogenase ◽

Renal Cell ◽

World Health ◽

Low Grade ◽

Long Term Follow Up ◽

Health Organization

Succinate dehydrogenase (SDH)–deficient renal cell carcinoma is a recently recognized distinct subtype of renal cell carcinoma in the 2016 World Health Organization classification. It is associated with SDH gene germline mutations, which also cause paraganglioma/pheochromocytoma, gastrointestinal stromal tumor, and pituitary adenoma. The tumor most commonly presents in young adulthood. The tumors are arranged in solid nests or in tubules and frequently show cystic change. The tumors are composed of cuboidal to oval cells with round nuclei, dispersed chromatin, and inconspicuous nucleoli. The cytoplasm is eosinophilic or flocculent but not truly oncocytic. The most distinctive histologic feature is the presence of cytoplasmic vacuoles or inclusions. Loss of SDH subunit B immunostaining is needed for a definite diagnosis. The prognosis is good for low-grade tumors but worse for tumors with high-grade nuclei, sarcomatoid change, or coagulative necrosis. Long-term follow-up is indicated.

Download Full-text

Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma

Modern Pathology ◽

10.1038/modpathol.2014.86 ◽

2014 ◽

Vol 28 (1) ◽

pp. 80-94 ◽

Cited By ~ 108

Author(s):

Sean R Williamson ◽

John N Eble ◽

Mahul B Amin ◽

Nilesh S Gupta ◽

Steven C Smith ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Succinate Dehydrogenase ◽

Renal Cell ◽

Detailed Characterization

Download Full-text

Treatment of Metastatic Renal Cell Carcinoma With a Combination of Bevacizumab and Erlotinib

Journal of Clinical Oncology ◽

10.1200/jco.2005.01.8234 ◽

2005 ◽

Vol 23 (31) ◽

pp. 7889-7896 ◽

Cited By ~ 223

Author(s):

John D. Hainsworth ◽

Jeffrey A. Sosman ◽

David R. Spigel ◽

Donna L. Edwards ◽

Cara Baughman ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Growth Factor ◽

Cell Carcinoma ◽

Skin Rash ◽

Renal Cell ◽

Renal Carcinoma ◽

Clear Cell ◽

Targeted Agents ◽

Clear Cell Renal Carcinoma ◽

Cell Renal Carcinoma

Purpose To evaluate the efficacy and toxicity of combined treatment with two targeted agents, an antibody against vascular endothelial growth factor (bevacizumab) and an epidermal growth factor receptor tyrosine kinase inhibitor (erlotinib), in the treatment of patients with metastatic clear-cell renal carcinoma. Patients and Methods Sixty-three patients with metastatic clear-cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks and erlotinib 150 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients who responded continued treatment until they experienced tumor progression. Results Fifteen (25%) of 59 assessable patients (95% CI, 16% to 37%) had objective responses to treatment, and an additional 36 patients (61%) had stable disease after 8 weeks of treatment. Only eight patients' (14%) disease had progressed at this time point. The median and 1-year progression-free survivals were 11 months and 43%, respectively. After a median follow-up of 15 months, median survival has not been reached; survival at 18 months was 60%. Treatment was generally well tolerated; only two patients discontinued treatment because of toxicity (skin rash). Grade 1/2 skin rash and diarrhea were the most frequent treatment-related toxicities. Conclusion The combination of bevacizumab and erlotinib is an effective and well-tolerated treatment for patients with advanced renal cell carcinoma. The efficacy of these two drugs in combination suggests that targeting of separate pathways critical to tumor growth and dissemination may achieve results superior to either drug as a single agent. Additional development of this and other combinations of targeted agents is warranted.

Download Full-text

Synchronous Renal Cell Carcinoma and Gastrointestinal Malignancies

Case Reports in Urology ◽

10.1155/2016/7329463 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Tamer J. Dafashy ◽

Cameron K. Ghaffary ◽

Kyle T. Keyes ◽

Joseph Sonstein

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Surgical Intervention ◽

Clear Cell ◽

Case Series ◽

Cell Renal Cell Carcinoma ◽

Gastrointestinal Malignancies ◽

Gastrointestinal Malignancy ◽

Cell Renal Carcinoma

While renal cell carcinoma is the most commonly diagnosed neoplasm of the kidney, its simultaneous diagnosis with a gastrointestinal malignancy is a rare, but well reported phenomenon. This discussion focuses on three independent cases in which each patient was diagnosed with renal cell carcinoma and a unique synchronous gastrointestinal malignancy. Case1explores the diagnosis and surgical intervention of a 66-year-old male patient synchronously diagnosed with clear cell renal cell carcinoma and a carcinoid tumor of the small bowel. Case2describes the diagnosis and surgical intervention of a 61-year-old male found to have clear cell renal cell carcinoma and a mucinous appendiceal neoplasm. Lastly, Case3focuses on the interventions and management of a 36-year-old female diagnosed with synchronous clear cell renal carcinoma and hereditary nonpolyposis colorectal cancer. This case series examines each distinct patient’s presentation, discusses the diagnosis, and compares and contrasts the findings while discussing the literature on this topic.

Download Full-text