Open AccessCase Report Beyond the Usual: Breast, Pituitary and Gastric Metastases from Clear Cell Renal Cell Carcinomas—A Case Series with Review of Literature by Yin Ping Wong Yin Ping Wong SciProfiles Scilit Preprints.org Google Scholar 1,*, Nur Liyana Khairuddin Nur Liyana Khairuddin SciProfiles Scilit Preprints.org Google Scholar 1, Jegan Thanabalan Jegan Thanabalan SciProfiles Scilit Preprints.org Google Scholar 2 and Geok Chin Tan Geok Chin Tan SciProfiles Scilit Preprints.org Google Scholar 1,* 1 Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia 2 Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia * Authors to whom correspondence should be addressed. Diagnostics 2026, 16(12), 1773; https://doi.org/10.3390/diagnostics16121773 (registering DOI) Submission received: 3 May 2026 / Revised: 4 June 2026 / Accepted: 6 June 2026 / Published: 9 June 2026 Abstract Background and Clinical Significance: Clear cell renal cell carcinoma (ccRCC) is notorious for its aggressiveness and great propensity to metastasize to virtually any organ, with a dismal five-year survival rate. While metastases from ccRCC typically occur in the lungs, lymph nodes, bones and liver, involvement of atypical locations such as the breast, pituitary gland and stomach is extremely rare. These unusual metastases can masquerade as primary tumours at their respective sites, posing significant diagnostic challenges. Case Presentation: Here, we describe three cases of metastatic ccRCC to unusual anatomical sites following nephrectomy: (1) a patient who presented with a suspicious left-sided breast mass and synchronous liver and lung metastases six months following the initial diagnosis of ccRCC; (2) a patient who presented with diplopia, found to have a pituitary lesion four months after nephrectomy; and (3) a patient with known pre-existing lung metastases who developed upper gastrointestinal bleeding one year post-nephrectomy, in whom oesophagogastroduodenoscopy (OGDS) revealed an 8 mm pedunculated gastric polyp. Histopathological examination following biopsies of these lesions showed compact nests and sheets of malignant cells with clear to eosinophilic cytoplasm and distinct membranes. Immunohistochemically, these malignant cells demonstrated CD10 immunopositivity, and were negative for CK7 and CK20, in keeping with the diagnosis of metastatic ccRCC. Conclusions: This case series illustrates the rare metastatic behaviour of ccRCC with its potential to spread to uncommon sites. Awareness of such presentations is crucial, particularly in patients with a known history of ccRCC, as these lesions may clinically and radiologically mimic primary tumours of the affected sites. Careful evaluation of its histomorphological features and judicious use of immunohistochemical panels, together with clinical and radiological correlations, is the key to arriving at an accurate diagnosis. Keywords: clear cell; renal cell carcinoma; metastasis; breast; pituitary gland; stomach; gastric polyp; unusual sites; case series 1. Introduction The classical sites of RCC metastases are lung (70%), lymph node (45%), bone (32%), liver (18%), adrenal gland (10%) and brain (8%) [ 5]. In contrast, metastasis to atypical sites such as pituitary, gastrointestinal tract, breast, thyroid, pancreas, skin, salivary gland and muscle is exceedingly rare, yet has been previously documented [ 5]. Importantly, these metastatic lesions frequently mimic primary tumours of the involved organs both clinically and radiologically, posing significant diagnostic challenges and potentially leading to misdiagnosis and inappropriate clinical management. 3. Discussion Renal cell carcinoma is the 14th most common malignancy and the 16th leading cause of cancer-related death worldwide, with an estimated 434,840 new cases diagnosed in a year. It accounts for approximately 2–3% of all adult cancers [ 80]. The incidence is about twice as high in men compared to women. Notably, higher incidence rates are observed in developed regions including North America and Europe, while lower incidence is seen in Asia and Africa. In Malaysia, the age-standardised incidence rate (ASR) is relatively low at 2.7 cases per 100,000 population per year. However, despite this low incidence, outcomes appear less favourable, with a relatively high mortality-to-incidence ratio (MIR 0.52 in 2018), suggesting later-stage presentation and potential disparities in access to early diagnosis and treatment [ 81]. Among the many recognised risk factors for RCC, hypertension, insulin resistance/diabetes mellitus, obesity, cigarette smoking and chronic kidney disease are the most strongly and consistently associated with RCC development. In addition to these modifiable risk factors, hereditary factors play a significant role in determining genetic predisposition to RCC. Several genes have been implicated in RCC pathogenesis and hereditary RCC syndromes, including VHL, ELOC, TSC1/2, MET, FLCN, FH, SMARCB1, BAP1, CHEK2 and PTEN [ 82]. These genetic alterations serve as the linchpin in cancer initiation and progression. RCC demonstrates a spectrum of gross appearances corresponding with its histological subtype. Classically, ccRCC exhibits a golden-yellow cut surface due to its high lipid content, often accompanied by areas of haemorrhage, necrosis, cystic degeneration and occasional calcification. In contrast, papillary RCC typically appears brown to haemorrhagic and granular, while chromophobe RCC often shows a mahogany-brown appearance. Most RCCs are well-circumscribed and cortical-based [ 85]. Histologically, RCC encompasses several subtypes with distinct morphological characteristics. ccRCC, the most common pathological subtype, accounts for 70–80% of cases. It is composed of nests and alveolar arrangement of neoplastic cells with abundant clear cytoplasm due to intracytoplasmic lipid and glycogen, separated by a delicate network of thin-walled vasculature. Papillary RCC, comprises 7–14% of tumours, is characterised by papillary or tubulopapillary architecture lined by neoplastic cells with eosinophilic or basophilic cytoplasm, often accompanied by foamy macrophages and psammoma bodies. Chromophobe RCC, representing approximately 2–4% of RCCs, shows large polygonal neoplastic cells with pale to eosinophilic cytoplasm, prominent cell borders and perinuclear halos. Several histopathological features such as high nuclear grade, tumour necrosis and lymphovascular invasion are associated with more aggressive behaviour. Furthermore, sarcomatoid and rhabdoid differentiation represent high-grade transformation and confer an adverse prognosis [ 85]. Tumour invasion is essential for metastatic spread, but not all invasive tumours metastasize. RCC demonstrates a greater propensity for haematogenous spread, facilitated by its rich sinusoidal vasculature and frequent early invasion of the renal vein [ 86, 87]. The so-called tumour thrombi (TT) in the renal vein, reported in approximately 15% of cases, provide a direct conduit for tumour cells to access the systemic circulation. This vascular route of spread partly explains the diverse and sometimes unpredictable metastatic patterns observed in RCC. Mechanistically, the progression of metastasis is driven by dysregulation of key oncogenic signalling pathways, including phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), Ras/MAPK (mitogen-activated protein kinase) and Wnt/β-catenin pathways. These oncogenic pathways promote tumour cell proliferation, survival and migratory cues, besides enabling tumour cells to withstand adverse microenvironments and to establish secondary growth at distant sites [ 88]. In RCC metastasis, these pathways work synergistically to induce epithelial–mesenchymal transition (EMT), enabling tumour cells to detach, invade surrounding stroma and enter the circulation. Concurrent extracellular matrix (ECM) remodelling, mediated by matrix metalloproteinases, further facilitates invasion and metastatic seeding [ 87]. Successful metastasis of cancer cells depends on the ability of circulating tumour cells to adapt to and to colonise distant organ microenvironments. RCC exhibits a unique form of organotropism, reflected by its capacity to metastasize to nearly any site in the body, including rare locations such as the pituitary gland, breast and stomach. Based on the existing literature, this behaviour is thought to be mediated by tumour–stroma interactions, chemokine signalling and exosome-mediated intercellular communication. For instance, CXCR4/CXCL12 axis plays a pivotal role in directing tumour cell migration and homing to specific metastatic niches [ 89], while tumour-derived exosomes contribute by conditioning pre-metastatic niches through modulation of the local immune milieu, extracellular matrix remodelling and promotion of a pro-tumourigenic environment that facilitates tumour cell engraftment [ 90]. The exact molecular underpinnings dictating why ccRCC cells home to rare sites remain incompletely elucidated, requiring further mapping of these unique organotropic pathways. Accurate diagnosis of metastatic RCC relies on a high index of suspicion and meticulous histopathological evaluation, especially when it presents at unusual sites. Morphologically, metastatic RCC often recapitulates the features of the primary tumour, with ccRCC demonstrating nests or alveolar arrangements of tumour cells with abundant clear to eosinophilic cytoplasm and a delicate capillary network [ 85]. In metastatic sites such as the breast, stomach and pituitary gland, these lesions may closely mimic primary neoplasms native to the organ, making recognition of subtle architectural and cytoplasmic features critical. Immunohistochemistry plays a pivotal role in confirming renal origin in metastatic lesions. PAX8 is the most sensitive and widely used marker, supporting renal epithelial differentiation and serving as a key discriminator from most primary tumours at these sites [ 92]. CcRCC typically demonstrates diffuse membranous CAIX expression with a characteristic “box-like” pattern, along with CD10 and vimentin positivity. In contrast, CK7 is usually negative or only focally positive in ccRCC, aiding distinction from primary breast and gastric adenocarcinomas, which are typically CK7 positive. For papillary and chromophobe RCC metastases, CK7 and CD117 may be contributory [ 92]. Judicious use of site-specific immunohistochemical markers cannot be overemphasised to exclude a primary tumour at the metastatic site. For instance, in breast lesions, the absence of immunomarkers such as GATA3, mammaglobin and gross cystic disease fluid protein 15 (GCDFP-15) supports a non-mammary origin and helps steer the diagnosis away from primary breast carcinoma [ 93]. Similarly, in gastric lesions, lack of CK20 and CDX2 expression argues against a primary gastrointestinal adenocarcinoma, especially when the morphology is not classic for a gastric primary. In the pituitary, immunonegativity for neuroendocrine markers such as synaptophysin and chromogranin further supports a metastatic disease rather than primary pituitary neoplasm [ 94], especially in lesions lacking the usual adenohypophyseal differentiation. Notably, a panel-based immunohistochemical approach remains essential, as no one single marker is entirely specific. Careful correlation with clinical history remains indispensable, particularly in patients with a history of prior RCC and the often strikingly long disease-free interval before metastatic presentation. This case series has several limitations that should be acknowledged. First, the retrospective, single-centre design and small sample size preclude drawing definitive conclusions regarding the clinical behaviour of ccRCC. Furthermore, our cases reflect heterogeneous follow-up and incomplete outcome data; specifically, the patients in Cases 1 and 3 succumbed to their disease shortly after diagnosis, while the patient in Case 2 was lost to long-term follow-up. As these cases were sourced from archived pathology records, there is inherent selection bias. Additionally, the immunohistochemical panels performed were variable across the cases, limiting direct comparability. Notably, PAX8 staining—considered the most sensitive marker for renal epithelial origin—was not performed due to unavailability of the antibody at the time of diagnosis. However, the combination of classic histomorphology and alternative immunohistochemical markers adequately supported the final diagnoses in these patients. 4. Conclusions Metastatic ccRCC to the breast, pituitary gland, and stomach is exceedingly rare. Awareness of such presentations is crucial, particularly in patients with a known history of ccRCC, as these lesions may clinically and radiologically mimic primary tumours. This case series serves as a reminder of the importance of considering metastatic disease in unusual locations, and highlights the pivotal role of careful histopathological evaluation and judicious use of immunohistochemistry panels in arriving at an accurate diagnosis. Supplementary Materials The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/diagnostics16121773/s1, Table S1: Summary of Previous Reported Cases (from Year 2016–2026) of ccRCC Metastasis to Atypical Sites, Pertaining to Stomach, Pituitary Gland and Breast. Author Contributions Conceptualisation, Y.P.W.; methodology, N.L.K.; investigation, N.L.K. and J.T.; writing—original draft preparation, N.L.K.; writing—review and editing, Y.P.W. and G.C.T.; funding acquisition, Y.P.W. All authors have read and agreed to the published version of the manuscript. Funding This case series was funded by the Faculty of Medicine, Universiti Kebangsaan Malaysia via the Fundamental Grant Faculty of Medicine UKM (grant code FF-2025-472). Institutional Review Board Statement Ethical review and approval were waived for this study due to the retrospective nature of this case series utilising completely anonymised, archival medical data. Informed Consent Statement Patient consent was waived direct contact with the patients was impossible, as two patients are deceased and one was lost to follow-up. This study was conducted in accordance with the Declaration of Helsinki that supports waiving consent when data are fully anonymised and patients cannot be contacted. Formal editorial approval was obtained. Data Availability Statement The original contributions presented in the study are included in the article/ Supplementary Material, further inquiries can be directed to the corresponding author. Acknowledgments The authors used ChatGPT (GPT-4) to improve the language and readability of the manuscript. The authors take full responsibility for the content and have reviewed and approved the final version of the manuscript. Conflicts of Interest The authors declare no conflicts of interest. References Figure 1. Histopathological examination of the breast mass. ( A) Diffuse infiltration by malignant cells in infiltrating nest, separated by delicate, thin-walled sinusoidal vasculature (Haematoxylin & Eosin (H&E), ×200). ( B) The malignant cells display pleomorphic hyperchromatic nuclei with occasional conspicuous nucleoli and abundant clear to eosinophilic cytoplasm (H&E, ×400). ( C) The malignant cells show CD10 immunopositivity (CD10, ×400). Figure 1. Histopathological examination of the breast mass. ( A) Diffuse infiltration by malignant cells in infiltrating nest, separated by delicate, thin-walled sinusoidal vasculature (Haematoxylin & Eosin (H&E), ×200). ( B) The malignant cells display pleomorphic hyperchromatic nuclei with occasional conspicuous nucleoli and abundant clear to eosinophilic cytoplasm (H&E, ×400). ( C) The malignant cells show CD10 immunopositivity (CD10, ×400). Figure 3. Histopathological examination of the gastric polyp. ( A) Infiltrating malignant cells in solid nests, interspersed with a delicate, arborising capillary network (H&E, ×200). ( B) The malignant cells demonstrate CD10 immunopositivity (CD10, ×400) and ( C) CK7 immunonegativity (CK7, ×400). Figure 3. Histopathological examination of the gastric polyp. ( A) Infiltrating malignant cells in solid nests, interspersed with a delicate, arborising capillary network (H&E, ×200). ( B) The malignant cells demonstrate CD10 immunopositivity (CD10, ×400) and ( C) CK7 immunonegativity (CK7, ×400). Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Share and Cite MDPI and ACS Style Wong, Y.P.; Khairuddin, N.L.; Thanabalan, J.; Tan, G.C. Beyond the Usual: Breast, Pituitary and Gastric Metastases from Clear Cell Renal Cell Carcinomas—A Case Series with Review of Literature. Diagnostics 2026, 16, 1773. https://doi.org/10.3390/diagnostics16121773 AMA Style Wong YP, Khairuddin NL, Thanabalan J, Tan GC. Beyond the Usual: Breast, Pituitary and Gastric Metastases from Clear Cell Renal Cell Carcinomas—A Case Series with Review of Literature. Diagnostics. 2026; 16(12):1773. https://doi.org/10.3390/diagnostics16121773 Chicago/Turabian Style Wong, Yin Ping, Nur Liyana Khairuddin, Jegan Thanabalan, and Geok Chin Tan. 2026. "Beyond the Usual: Breast, Pituitary and Gastric Metastases from Clear Cell Renal Cell Carcinomas—A Case Series with Review of Literature" Diagnostics 16, no. 12: 1773. https://doi.org/10.3390/diagnostics16121773 APA Style Wong, Y. P., Khairuddin, N. L., Thanabalan, J., & Tan, G. C. (2026). Beyond the Usual: Breast, Pituitary and Gastric Metastases from Clear Cell Renal Cell Carcinomas—A Case Series with Review of Literature. Diagnostics, 16(12), 1773. https://doi.org/10.3390/diagnostics16121773 Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here. Article Metrics Article metric data becomes available approximately 24 hours after publication online.
