Clear Cell Carcinoma in Tuberous Sclerosis Complex: Case Report and Review of the Literature

International Journal of Medical Science and Clinical Research Studies ISSN(print): 2767-8326, ISSN(online): 2767-8342 Volume 05 Issue 11 November 2025 Page No: 1922-1927 DOI: https://doi.org/10.47191/ijmscrs/v5-i11-21, Impact Factor: 8.188 1922 Volume 05 Issue 11 November 2025 Corresponding Author: Elisael Meléndez Bautista Clear Cell Carcinoma in Tuberous Sclerosis Complex: Case Report and Review of the Literature Elisael Meléndez Bautista1, Miguel Humberto Gómez Lara2, José Antonio Narvaez Morales3, Luis Dorantes Carrillo4 1Fourth-Year Urology Resident, “Dr. Agustín O’Horán” General Hospital, Faculty of Medicine, Autonomous University of Yucatan, Mexico. 2,3,4Attending Physician, Department of Urology, Yucatán Health Services, “Dr. Agustín O’Horán” General Hospital, Merida, Yucatan, Mexico. BACKGROUND Tuberous sclerosis is a rare autosomal dominant genetic disorder caused by a mutation in either the TSC1 or TSC2 genes. It is classified within the group of phakomatoses, which include neurofibromatosis types I and II, von Hippel– Lindau syndrome, and Sturge–Weber disease (1). Its global incidence ranges from 1 in every 6,000 to 10,000 newborns, and it is therefore considered a “rare” disease, affecting approximately 2 million people worldwide. In Europe, its prevalence is estimated at 11,500 to 25,000 people, while in the United States, 40,000 to 80,000 cases have been reported (2). The exact pathophysiological mechanism of this disease is not fully understood; however, it is known that the TSC1 and TSC2 genes encode the proteins hamartin and tuberin, which form a complex that negatively regulates the mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cellular biosynthesis. This occurs through inactivation of the small protein Rheb by the GTPase-activating domain of hamartin. Loss of the hamartin–tuberin complex leads to aberrant activation of mTORC1, promoting the synthesis of lipids, nucleotides, and proteins, while inhibiting autophagy (3). Another function of these genes is related to embryonic development of the cerebral cortex and the regulation of neural growth (4). Approximately 60% of TSC gene mutations are de novo, while 40% are inherited. Tumors associated with tuberous sclerosis complex (TSC)—including angiomyolipomas and ABSTRACT ARTICLE DETAILS BACKGROUND: Tuberous sclerosis is a rare autosomal dominant genetic disorder caused by a mutation in either the TSC1 or TSC2 genes, with a global incidence ranging from 1 in every 6,000 to 10,000 newborns. Its pathophysiological mechanism is not fully understood; however, it is known that the TSC1 and TSC2 genes encode the proteins hamartin and tuberin, which form a complex that regulates mTOR, considered a key pathway in controlling cell growth. Clinical manifestations include cutaneous, neurological, cardiac, and renal abnormalities, among which the development of benign and/or malignant renal tumors stands out—particularly angiomyolipoma or clear cell renal carcinoma. CLINICAL CASE: A 31-year-old male patient presented to the emergency department with generalized abdominal pain (VAS 8/10) radiating to the right iliac fossa, unresponsive to analgesics, and accompanied by changes in bowel habits, fever, and a 20-kilogram weight loss over one month. A diagnostic work-up was performed, documenting a right renal tumor. CONCLUSIONS: Tuberous Sclerosis Complex (TSC) is known to predispose individuals to the formation of benign tumors in any organ of the body, with corresponding clinical consequences. However, the development of clear cell renal carcinoma is a rare finding, as most renal tumors in these patients tend to be angiomyolipomas, which are benign in the vast majority of cases. KEYWORDS: Tuberous sclerosis, clear cell carcinoma, renal cancer. Published On: 29 November 2025 Available on: https://ijmscrs.com Clear Cell Carcinoma in Tuberous Sclerosis Complex: Case Report and Review of the Literature 1923 Volume 05 Issue 11 November 2025 Corresponding Author: Elisael Meléndez Bautista renal cell carcinomas—develop after somatic inactivation of the second hit of the wild-type TSC1 or TSC2 allele (5). TSC is caused by an inactivating mutation in one allele of TSC1on 9q34 or TSC2 on 16p13.3, with this mutation appearing de novo in two-thirds of patients (6,7). Mutations occur much more frequently in TSC2 than in TSC1, and only 10–30% of mutations affect TSC1, the latter being more common in familial forms (8-9). The condition can present from birth to adulthood and often manifests during the first year of life as epileptic seizures, along with cutaneous, neurological, cardiac, pulmonary, ocular, and renal abnormalities (4). Renal manifestations of TSC include angiomyolipomas, renal cysts, and renal cell carcinoma (RCC). Angiomyolipomas occur in up to 80% of TSC patients, followed by renal cysts in 35–50% of cases, while RCC is the least common, with a prevalence of 2–4% (10). CLINICAL CASE This is a 31-year-old male patient of mestizo ethnicity who works as a construction laborer. He has a family history of tuberous sclerosis in his father and younger sister. His significant past medical history includes a diagnosis of tuberous sclerosis from the first months of life, manifested by cutaneous lesions and epilepsy, which has been managed with phenytoin 100 mg daily, as well as periodic follow-ups at another healthcare institution, although he has been lost to follow-up for the past 10 years. He presented to the Emergency Department with generalized abdominal pain (VAS 8/10) radiating to the right iliac fossa, unrelieved by analgesics, accompanied by changes in bowel habits, fever, and a 20-kilogram weight loss over one month. On physical examination, Pringle’s sebaceous adenomas were noted in the nasolabial folds, cheeks, chin, scalp, and neck. Cardiopulmonary examination was unremarkable. Abdominal examination showed present peristalsis and no signs of peritoneal irritation, with a palpable, painful mass in the right lumbar region. Periungual fibromas were observed on both lower extremities; the rest of the physical examination showed no abnormalities. A contrast-enhanced CT scan of the abdomen and pelvis was performed, documenting an enlarged right kidney with a heterogeneous, irregular mass measuring 177 × 180 × 132 mm, with enhancement up to 96 HU, arising from the upper pole and extending beyond Gerota’s fascia, in close contact with the liver and hepatic hilum, crossing the midline toward the contralateral side and displacing major vessels. A heterogeneous subcapsular collection was also noted. At the renal hilum, one artery and one vein were identified, with no evidence of renal vein thrombosis. Contrast uptake and excretion were preserved. The left kidney showed no apparent abnormalities and demonstrated adequate contrast uptake and excretion. Laboratory studies revealed severe WHO grade IV anemia (5.4 g/dL) and signs of hypovolemic shock. Once stabilized, the decision was made to perform an open right radical nephrectomy via a Chevron incision. Intraoperative findings included a right kidney with loss of normal morphology and a renal tumor arising from the lower pole measuring 20 × 15 cm, along with a subcapsular hematoma of approximately 1,500 mL, one artery and one vein, abundant neovascular vessels, and a 1-cm paracaval lymph node. No tumor thrombus was present. Surgery proceeded without intraoperative complications. The patient remained hospitalized postoperatively for strict monitoring, including surgical drain output, urine output, wound care, pharmacological and mechanical thromboprophylaxis, and laboratory parameters such as renal function, white blood cell count, and hemoglobin. His postoperative course was favorable, and he was discharged on postoperative day 5. During outpatient follow-up, histopathology revealed clear cell renal carcinoma ISUP grade 4, with sarcomatoid features (40%), rhabdoid features (40%), necrosis (20%), and lymphovascular invasion. The surgical bed was free of tumor. Perirenal fat was positive for tumor involvement, while the renal vein and ureteral margin were negative. Six lymph nodes showed positive neoplastic foci with moderate chronic interstitial inflammation. According to AJCC staging, the tumor was classified as pT2b pN2 Mx. The patient was referred to medical oncology for surveillance. He experienced recurrence-free survival for 11 months. A follow-up contrast-enhanced CT scan revealed oncologic recurrence in bone and retroperitoneal lymph nodes. Treatment with the tyrosine kinase inhibitor (TKI) sunitinib 50 mg in a 4/2 schedule was initiated; however, he developed hematologic toxicity (anemia, thrombocytopenia, and neutropenia), hepatic toxicity (elevated liver enzymes), and significant weight loss. The drug was discontinued, and sorafenib 400 mg every 12 hours was started, which he tolerated adequately, but disease progression was confirmed on a new CT scan showing hepatomegaly with multiple suspicious liver lesions. A second line of palliative treatment with pembrolizumab 200 mg every 15 days was added. Despite treatment, he experienced clinical deterioration and ultimately died due to mixed-origin shock. Clear Cell Carcinoma in Tuberous Sclerosis Complex: Case Report and Review of the Literature 1924 Volume 05 Issue 11 November 2025 Corresponding Author: Elisael Meléndez Bautista Figure 1. Axial projection arterial-phase computed tomography. A heterogeneous and irregular mass arising from the upper pole of the right kidney is visualized, showing contrast enhancement and extension beyond Gerota’s fascia. It extends toward the contralateral side, crossing the midline and displacing the major vessels. A heterogeneous subcapsular collection is observed, suggestive of a hematoma. Figure 2. Specimen from right radical nephrectomy. The right kidney is shown with a renal tumor arising from the upper pole, along with perirenal fat. Ligation of the renal vein and artery is also observed. Clear Cell Carcinoma in Tuberous Sclerosis Complex: Case Report and Review of the Literature 1925 Volume 05 Issue 11 November 2025 Corresponding Author: Elisael Meléndez Bautista Figures 3 and 4. Hematoxylin–eosin–stained images. Clear cytoplasm due to lipid-rich content, polygonal irregular nuclei with open chromatin, and visible nucleoli are observed. Figure 3 shows the sarcomatoid component, while Figure 4 shows the rhabdoid component. INFORMED CONSENT Prior to data collection and the preparation of this document, the patient’s relative—his mother (GAM)—was contacted by telephone. She reported that a few days before informed consent could be obtained, the patient had passed away due to complications secondary to mixed-type shock. Nonetheless, a detailed explanation was provided regarding the relevance of the case report, emphasizing that its dissemination may contribute to a deeper understanding of the clinical and oncological implications of clear cell renal carcinoma in the context of tuberous sclerosis complex. Furthermore, it was clarified that the report may serve as a reference for future scholarly work addressing this rare yet highly complex association. After granting authorization, the relative expressed appreciation that such a complex case was being considered for the purpose of generating knowledge that may benefit future patients, and she declared no conflicts of interest. In accordance with the Mexican General Health Law (LGS) and its secondary regulatory framework—including NOM004-SSA3-2012 on the Clinical Record and the Regulations of the LGS on Health Research—the procurement of informed consent is mandatory for all medical procedures and for research involving human subjects, including the publication of case reports. These regulations mandate not only that the purpose of the study be thoroughly explained to the patient or their representative, but also that the principles of autonomy, confidentiality, and privacy be upheld, as well Clear Cell Carcinoma in Tuberous Sclerosis Complex: Case Report and Review of the Literature 1926 Volume 05 Issue 11 November 2025 Corresponding Author: Elisael Meléndez Bautista as the right to withdraw participation from the project at any time. DISCUSSION This patient exhibits several features that render the case particularly unusual, including the mode of clinical presentation (sudden-onset abdominal pain, a palpable mass in the right flank, and signs of hypovolemic shock associated with tomographic findings of subcapsular hemorrhage) and the histological subtype (clear cell renal carcinoma with rhabdoid and sarcomatoid morphology). Tuberous Sclerosis Complex (TSC) is considered a hereditary genetic syndrome that predisposes individuals to the development of benign tumors in multiple organs. The occurrence of renal cell carcinoma (RCC) is uncommon, accounting for only 2–4% of patients with TSC and demonstrating a predominance in females (11). Various histological subtypes of RCC have been identified in patients with TSC, including clear cell, papillary, chromophobe, and renal oncocytoma (12). Nevertheless, given their high incidence in TSC, angiomyolipoma and renal hamartoma should always be considered the primary diagnostic possibilities. Approximately two-thirds of patients with TSC present detectable de novo germline mutations, while most of the remaining cases harbor hereditary mutations. Specifically, TSC2 mutations are detectable in approximately 70% of patients and are generally associated with a more severe disease phenotype compared to TSC1 mutations (12). Patients with TSC carry a hereditary or de novo germline mutation in one allele of TSC1 (hamartin) or TSC2 (tuberin). Tumorigenesis is most frequently associated with a “secondhit” event that mutates or eliminates the expression of the remaining wild-type allele (13–14). Given the two-hit pathogenesis of TSC-associated RCC, the phenotypic heterogeneity observed may be related to distinct secondary mutations within each tumor or, alternatively, to mutations affecting different renal cell types (15). Renal cell carcinoma with sarcomatoid and/or rhabdoid features exhibits aggressive behavior and typically portends an unfavorable prognosis. According to the 2022 WHO Classification, these patterns are considered transformational changes that may arise in the context of various RCC histological subtypes (16). Sarcomatoid differentiation is characterized by malignant spindle cells forming interlacing fascicles resembling undifferentiated pleomorphic sarcoma, whereas rhabdoid cells are epithelioid cells with eccentric vesicular nuclei, prominent nucleoli, and large eosinophilic intracytoplasmic inclusions—each displaying distinct molecular features. Sarcomatoid RCC demonstrates shared genomic alterations between carcinomatous and rhabdoid components, as well as enrichment of specific genomic changes within the sarcomatoid element, suggesting molecular pathways leading to sarcomatoid transformation from a common clonal precursor. Rhabdoid differentiation likewise arises through clonal evolution, although less is known about the specific genomic alterations underlying this phenotype (17). Wünderlich syndrome is an uncommon clinical entity characterized by the acute onset of spontaneous renal hemorrhage within the subcapsular, perirenal, or pararenal spaces, in the absence of trauma. It is frequently associated with renal neoplasms—most notably angiomyolipomas and clear cell RCC—which demonstrate an increased propensity for hemorrhage and rupture, accounting for approximately 60–65% of all reported cases (18). In patients with TSC, partial nephrectomy—and especially radical nephrectomy—should be avoided whenever possible, as renal lesions tend to continue developing, and repeated surgical interventions for lesion removal may progressively reduce functional renal parenchyma, potentially culminating in chronic kidney disease and ultimately death. According to the literature, the ideal approach involves obtaining a renal biopsy to determine the histological characteristics of the mass and subsequently providing targeted therapy. However, in this case, radical nephrectomy was selected due to the presence of Wünderlich syndrome. Surgical management of TSC-associated renal masses is reserved for highly specific scenarios (19). Consequently, current advances in the treatment of this disease focus on the development of systemic therapies aimed at eliminating rather than merely suppressing angiomyolipomas, cysts, and TSC-associated RCC. In the present case, the decision to perform radical nephrectomy was largely driven by the lifethreatening deterioration caused by the ongoing renal hemorrhage. Within our institutional setting, it is important to highlight significant limitations, notably the lack of access to molecular and immunohistochemical studies that would allow for appropriate characterization of these renal masses, as well as restricted availability of next-generation therapies that may improve recurrence-free survival and overall survival in patients with RCC (20). CONCLUSION In all patients with TSC, it is essential to conduct an initial screening in order to detect, in a timely manner, manifestations involving other organ systems (cardiovascular, neurological, dermatological, pulmonary), including the renal system. Renal involvement often presents as masses that are predominantly benign but exhibit uncertain behavior due to their intrinsic characteristics. Despite the low incidence of RCC in patients with TSC, its presence must never be discounted when a renal mass is identified. Therefore, it is necessary to perform detailed morphological, immunohistochemical, and molecular analyses of a substantial cohort of TSC-associated renal carcinomas to further investigate their characteristics, which may ultimately define a unique RCC subgroup. Clear Cell Carcinoma in Tuberous Sclerosis Complex: Case Report and Review of the Literature 1927 Volume 05 Issue 11 November 2025 Corresponding Author: Elisael Meléndez Bautista REFERENCES I. Ruiz Villaverde, R., Melguizo, B., Cruz, M., Sánchez, M., & Sintes, R. N. (2002). Esclerosis tuberosa. Enfermedad de Pringle Bourneville. In Actas Dermosifiliogr (Vol. 93, Issue 1). II. Uysal, S. P., & Şahin, M. (2020). Tuberous sclerosis: A review of the past, present, and future. In Turkish Journal of Medical Sciences (Vol. 50, Issue SI-2, pp. 1665–1676). Turkiye Klinikleri. https://doi.org/10.3906/sag-2002-133 III. Lam, H. C., Siroky, B. J., & Henske, E. P. (2018). Renal disease in tuberous sclerosis complex: pathogenesis and therapy. 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