Papillary RccEdit
Papillary renal cell carcinoma (papillary RCC) is a distinct histologic subtype of renal cell carcinoma, differing in appearance, genetics, and clinical behavior from the more common clear cell RCC. It accounts for roughly 10 to 15 percent of renal cell carcinomas and often presents as smaller, less vascular tumors than clear cell tumors. In many cases, papillary RCC is detected incidentally during imaging for unrelated reasons, but it can also present with hematuria, flank pain, or a palpable mass. The management of papillary RCC emphasizes accurate classification, preservation of renal function when possible, and the use of targeted therapies when disease is advanced or metastatic. Renal cell carcinoma Papillary renal cell carcinoma
Classification and pathogenesis
Papillary RCC is most frequently divided into two major histologic subtypes, each with characteristic features and genetic drivers.
Type 1 papillary RCC: This form features small, uniform cells with scant cytoplasm arranged in papillary or tubular architectures. Type 1 tumors tend to have a lower nuclear grade and a comparatively better prognosis. Genetic alterations are commonly seen in this subtype, including MET gene abnormalities such as activating mutations or copy-number changes, and aneuploidies such as trisomy 7 and trisomy 17. The constellation of these changes supports the concept of a relatively indolent biological behavior in many Type 1 tumors. MET proto-oncogene Trisomy 7 Trisomy 17
Type 2 papillary RCC: Type 2 tumors are generally larger, with higher nuclear grade and a more aggressive clinical course. They show greater histologic heterogeneity and are more likely to harbor diverse genetic alterations, including alterations in genes such as CDKN2A, SETD2, and BAP1, among others. In hereditary conditions such as hereditary leiomyomatosis and renal cell cancer (HLRCC), fumarate hydratase (FH) mutations drive a distinct, aggressive papillary-appearing phenotype. The Type 2 category therefore encompasses a spectrum of biology, with some tumors behaving aggressively despite appearing superficially similar to Type 1. Hereditary leiomyomatosis and renal cell cancer FH mutation CDKN2A SETD2 BAP1
Hereditary papillary RCC is a recognized syndrome with germline mutations that predispose to papillary histology, most commonly involving MET in certain families. These hereditary forms illustrate how genetic testing can inform risk assessment and management for patients and relatives. Hereditary papillary renal cell carcinoma MET proto-oncogene
Immunohistochemistry and ancillary testing can aid differentiation from other renal neoplasms. Papillary RCC frequently expresses cytokeratin 7 (CK7) and AMACR (P504S) and shows a distinct pattern compared with clear cell RCC, which commonly demonstrates different vascular and cytoplasmic features. These patterns, together with morphology and genetics, support the tumor classification used in contemporary practice. Immunohistochemistry Cytokeratin 7 AMACR
Clinical features and diagnosis
Most patients with papillary RCC present in middle age, with a slight male predominance reported in several series. However, tumors can occur across a broad age range. Many cases are discovered incidentally during imaging for other reasons, reflecting the broader use of cross-sectional imaging in modern medicine. When symptoms occur, they may include visible blood in the urine (hematuria), flank pain, or a palpable lump, though these features are less common in small, early-stage tumors. Risk factors that have been associated with renal cell carcinoma in general—such as tobacco exposure, obesity, and hypertension—also apply to papillary RCC, though the strength of these associations can vary by population and tumor subtype. Renal cell carcinoma Hematuria
Diagnosis integrates imaging, histology, and, when appropriate, genetic testing. On imaging, papillary RCCs are often less vascular than clear cell tumors and may display characteristic enhancement patterns on contrast-enhanced CT or MRI, though imaging alone cannot reliably distinguish subtypes. Definitive classification rests on pathologic examination of the tumor tissue, often supplemented by immunohistochemical and molecular studies. Computed tomography Magnetic resonance imaging Pathology Immunohistochemistry
Imaging and pathology
Imaging features: Papillary RCCs tend to enhance less intensely than clear cell RCCs after contrast administration and may appear as well-circumscribed, exophytic masses with a propensity toward a more papillary architecture on cross-sectional imaging. The precise appearance can vary with tumor size and subtype. Renal mass Contrast-enhanced CT
Histology: Type 1 tumors show small, uniform cells with basophilic cytoplasm arranged in papillary fronds or tubules, often with foamy macrophages in the papillary stalk. Type 2 tumors display larger cells with eosinophilic cytoplasm and higher-grade nuclei, with more diverse architectural patterns. The differences in histology align with divergent clinical behavior and prognosis. FH-deficient tumors in the hereditary setting can resemble papillary RCC but carry distinctive aggressive features. Histology Foamy macrophages Fumarate hydratase
Immunohistochemistry: CK7 positivity is common in papillary RCC and helps distinguish it from some other RCC subtypes, though the full diagnostic workup relies on a combination of morphology and markers. Cytokeratin 7 AMACR Vimentin
Genetic and molecular features
Type 1: MET pathway activation is a recurring theme, with MET alterations driving tumorigenesis in many Type 1 papillary RCCs. This has spurred clinical trials of MET inhibitors in MET-driven papillary RCC. MET proto-oncogene
Type 2: More genetically heterogeneous, with alterations in several tumor-suppressor and chromatin-modifying genes (e.g., CDKN2A, SETD2, BAP1) that correlate with higher grade and worse prognosis. FH mutations define a hereditary subset (HLRCC) with particularly aggressive behavior. CDKN2A SETD2 BAP1 FH
Hereditary syndromes: Hereditary papillary RCC and HLRCC highlight how germline changes influence tumor biology and inform surveillance for patients and families. Hereditary papillary renal cell carcinoma Hereditary leiomyomatosis and renal cell cancer
Management
Localized disease: When feasible, nephron-sparing approaches such as partial nephrectomy are favored to preserve renal function, especially for smaller tumors. Active surveillance is an option for very small, indolent lesions or in patients with competing health risks. The choice among surgery, ablation, and surveillance depends on tumor size, growth rate, patient comorbidity, and preferences. Partial nephrectomy Active surveillance
Advanced or metastatic disease: Systemic therapy is guided by tumor biology and biomarker status. TKIs that target VEGF pathways have been used historically, while MET inhibitors are explored for MET-driven papillary RCC. Immunotherapy, including checkpoint inhibitors, has become part of the treatment landscape for advanced RCC, alone or in combination with anti-angiogenic agents. The therapeutic approach is individualized based on pathology, molecular profiling, and patient factors. Sunitinib Sorafenib Nivolumab
Genetic considerations: For patients with hereditary predispositions (e.g., MET mutations in HPRCC or FH mutations in HLRCC), targeted surveillance and counseling for family members are essential, and management plans may differ from sporadic cases. Hereditary papillary renal cell carcinoma Hereditary leiomyomatosis and renal cell cancer
Controversies and debates
Screening and incidental detection: The rise of cross-sectional imaging has increased incidental detection of small renal masses, including papillary RCC. Proponents of a prudent, value-based approach argue for risk-stratified management—favoring surveillance or nephron-sparing surgery when appropriate to avoid overtreatment and preserve renal function, while ensuring oncologic control. Critics of overtesting worry about costs and patient burden, but many clinicians emphasize tailoring decisions to tumor behavior and patient health. Active surveillance
Management of small renal masses: There is ongoing discussion about when to operate versus surveil for small papillary renal tumors. The conservative, patient-centered approach—prioritizing kidney function, quality of life, and cost-effectiveness—has gained traction, though tumor biology must remain a central guide. Partial nephrectomy Active surveillance
Targeted therapy and cost considerations: The advent of MET inhibitors and other targeted agents offers hope for patients with metastatic, MET-driven papillary RCC. However, the high cost of targeted therapies and immunotherapies raises questions about value, access, and payer policies. Advocates for cost-conscious policy frameworks argue for evidence-based adoption of therapies with proven benefit in defined molecular subgroups, while ensuring access for patients with proven need. MET proto-oncogene Nivolumab
Health equity and access: In any nation, the distribution of advanced treatments can reflect broader policy choices about insurance coverage, rural health access, and public-private care dynamics. Proponents of market-based, patient-choice frameworks emphasize clinical merit and cost control, while critics caution that disparities in access can lead to worse outcomes for underserved populations. The conversation centers on balancing innovation, affordability, and fairness in care delivery. Health care policy
Classification and prognosis: As molecular profiling advances, the boundaries between papillary RCC subtypes and other RCC forms continue to be refined. This has implications for prognosis and treatment selection, including decisions about when to pursue aggressive therapy in Type 2 or FH-deficient cases. Molecular profiling Prognosis