What are the recommended diagnostic and treatment strategies for papillary renal cell carcinoma, including management of localized and metastatic disease?

Papillary Renal Cell Carcinoma: Diagnostic and Treatment Strategies

Overview and Biological Characteristics

Papillary renal cell carcinoma (pRCC) is the second most common RCC subtype, accounting for 10-20% of all renal cell carcinomas, and requires distinct diagnostic and therapeutic approaches compared to clear cell RCC. 1, 2

pRCC is fundamentally divided into two biologically distinct subtypes with different molecular drivers and prognoses 1, 3:

• Type 1 pRCC: Characterized by MET pathway alterations, typically presenting with more indolent, multifocal disease 1, 3
• Type 2 pRCC: Associated with activation of the NRF2-ARE pathway, CDKN2A silencing, SETD2 mutations, and TFE3 fusions, often presenting as solitary aggressive tumors with worse prognosis 1, 3

Type 2 pRCC further subdivides into at least three molecular subtypes, with a particularly aggressive subgroup characterized by CpG island methylator phenotype (CIMP) and fumarate hydratase (FH) mutations that convey poor survival 1, 3.

Diagnostic Approach

Initial Imaging and Staging

Contrast-enhanced CT of the chest, abdomen, and pelvis is mandatory for accurate staging of all suspected pRCC cases. 4, 5

• Over 50% of pRCC cases are detected incidentally on abdominal imaging 4, 6
• CT provides assessment of tumor size, local invasiveness, lymph node involvement, and distant metastases 4, 5
• MRI is recommended when evaluating venous tumor thrombus or when CT contrast is contraindicated 4, 5
• Bone scan and brain imaging are not routinely indicated unless clinical symptoms suggest involvement 5
• FDG-PET is not recommended for routine diagnosis or staging 6, 5

Laboratory Evaluation

Obtain baseline prognostic markers 4, 5:

• Serum creatinine and hemoglobin
• Lactate dehydrogenase (LDH)
• C-reactive protein (CRP)
• Serum-corrected calcium
• Leukocyte and platelet counts

Tissue Diagnosis

Core needle biopsy is mandatory before ablative therapies and before initiating systemic treatment in metastatic disease. 4, 6, 5

• Biopsy provides high diagnostic accuracy (>90%) with rare complications 4, 6
• Histopathological confirmation determines the specific pRCC subtype, which guides treatment selection 5
• Tumor seeding from biopsy is exceptional 4

Risk Stratification

Localized Disease

Use integrated prognostic scoring systems 1:

SSIGN Score (Stage, Size, Grade, and Necrosis) 1:

• Incorporates pathological T category, lymph node status, tumor size, nuclear grade, and presence of necrosis
• Risk groups: Low (0-2 points, 97.1% 5-year metastasis-free survival), Intermediate (3-5 points, 73.8%), High (≥6 points, 31.2%)

UISS Score (UCLA Integrated Staging System) 1:

• Provides prognostic predictions for both localized and metastatic disease
• Concordance with SSIGN: 0.68-0.89 for cancer-specific survival 1

Metastatic Disease

IMDC Score (International Metastatic RCC Database Consortium) is the preferred risk stratification tool 1:

Six prognostic factors 1:

• Karnofsky performance status <80%
• Hemoglobin below lower limit of normal
• Time from diagnosis to treatment <1 year
• Corrected calcium above upper limit of normal
• Platelets above upper limit of normal
• Neutrophils above upper limit of normal

Risk categories: Favorable (0 factors), Intermediate (1-2 factors), Poor (≥3 factors) 1

Treatment Strategies

Localized Disease (T1-T3, N0, M0)

Partial nephrectomy is the preferred first-line treatment for organ-confined tumors ≤7 cm (T1). 1, 4, 5

T1 Tumors (<7 cm):

• T1a (≤4 cm): Partial nephrectomy is recommended as the preferred option, preserving renal function with equivalent oncological outcomes 1, 4, 5
• T1b (>4-7 cm): Partial nephrectomy remains preferred if technically feasible 1
• Laparoscopic or robot-assisted approaches are acceptable alternatives to open surgery 1
• For poor surgical candidates with tumors ≤3 cm: thermal ablation (radiofrequency ablation or cryotherapy) is an option, but biopsy confirmation is mandatory before ablation 4, 6, 5

T2 Tumors (>7 cm, confined to kidney):

• Laparoscopic radical nephrectomy is the preferred option 1, 5
• Open radical nephrectomy remains standard for locally advanced disease 1

T3-T4 Tumors (locally advanced):

• Open radical nephrectomy is standard of care 1
• Systematic adrenalectomy is not recommended unless imaging shows adrenal involvement 1
• Extensive lymph node dissection is not recommended unless enlarged nodes are visible on imaging 1, 4

There is no recommended adjuvant systemic therapy for localized pRCC after complete surgical resection. 1

Metastatic Disease (M1)

The treatment landscape for metastatic pRCC has historically lagged behind clear cell RCC, as pRCC is less responsive to standard VEGF-targeted therapies 2, 7, 8. However, recent advances have emerged:

Cytoreductive Nephrectomy:

• Should be considered for selected patients with metastatic disease but not performed indiscriminately 4
• Best suited for patients with good performance status and limited metastatic burden 4

Metastasectomy:

• May be an option for patients with solitary or oligometastatic disease 4

Systemic Therapy Considerations:

The evidence for systemic therapy in pRCC is limited, as most trials enrolled predominantly clear cell RCC patients. 2, 7, 8

For patients requiring systemic therapy, consider 1, 2, 7, 8:

• MET inhibitors are particularly relevant for type 1 pRCC given MET pathway alterations 1, 7, 8, 3
• mTOR inhibitors (everolimus, temsirolimus) have shown activity in pRCC subsets 7, 8
• VEGF-targeted agents (sunitinib, pazopanib) may be considered, though response rates are lower than in clear cell RCC 7, 8
• Combination strategies with targeted therapies and immune checkpoint inhibitors are under investigation 2

Enrollment in clinical trials specifically designed for pRCC is strongly encouraged, as histology-based and biology-based trials are ongoing. 2, 7, 8

Palliative Radiotherapy:

• Recommended for symptomatic bone metastases, providing symptom relief in up to two-thirds of cases 4, 5
• Single fraction or fractionated radiotherapy is effective 5
• Whole-brain radiotherapy for brain metastases provides effective symptom control 5

Follow-Up Protocol

After Curative Treatment:

High-risk patients (SSIGN score ≥6 or UISS high-risk) 4, 5:

• CT chest and abdomen every 3-6 months for the first 2 years
• Then annually thereafter

Low-risk patients 5:

• Annual CT scan after curative treatment

During Systemic Therapy:

• CT imaging every 2-4 months to assess response 4, 5

Critical Pitfalls to Avoid

• Do not assume pRCC will respond similarly to clear cell RCC therapies—the molecular biology is fundamentally different 1, 2, 7, 3
• Do not skip tissue diagnosis before ablative therapy or systemic treatment—histological subtype confirmation is essential 4, 6, 5
• Do not use radiotherapy in the neoadjuvant or adjuvant setting for primary pRCC—four negative randomized trials demonstrate no benefit 5
• Do not perform systematic lymph node dissection or adrenalectomy without imaging evidence of involvement—this adds morbidity without survival benefit 1
• Do not delay surgical evaluation in operable candidates—surgery remains first-line for resectable disease 5
• Do not overlook genetic counseling for patients ≤46 years or those with multifocal/bilateral disease—hereditary syndromes may be present 4, 5