Kidney

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 09, and is invasive urothelial carcinoma of the kidney.

The information provided in this case was accurate and correct at the time of publication in 2021.

Any changes in terminology since the time of publication may not be reflected in this case.

Histologic sections of the tumor demonstrate a nested and infiltrative pattern with focal papillary formations. The malignant cells demonstrate enlarged nuclei with moderate amounts of amphophilic to eosinophilic cytoplasm. Single prominent nucleoli are noted, and mitotic figures are frequent. Microscopically, the tumor involves the renal pelvis, with invasion into the renal medulla, cortex, and sinus fat. Areas of fibrosis and desmoplasia are noted. The tumor is positive for CK7, CK20, p63, and GATA3, while negative for PAX8. Based on the overall histologic and immunophenotypic profile, this is an invasive urothelial carcinoma (UC) of the renal pelvis.

UC involving the upper urinary tract accounts for approximately 5% - 10% of all UC and is the most common tumor arising in the renal pelvic-calyceal system. It also accounts for 7% - 8% of all kidney tumors. Approximately 50% of patients who have renal pelvic UC will also have lower urinary tract UC. UC generally arises in adults, with peak incidence in the sixth and seventh decades of life. There is a male predominance, representing 64% of cases. Symptoms of upper urinary tract urothelial carcinoma (UTUC) may mimic those of renal cell carcinoma, including flank pain, hematuria, and the presence of a renal mass. Known risk factors for developing UC include tobacco use, industrial chemical exposure, phenacetin use, chronic irritation, and family history.

UTUC shows similar morphology to UC in other parts of the urinary tract, which includes histologic subtypes (e.g., nested, micropapillary, sarcomatoid, plasmacytoid, microcystic, lymphoepithelioma-like, lipid-rich, clear cell, and giant cell) and those with divergent differentiation (e.g., squamous, glandular, trophoblastic, and Müllerian). The histology and immunoprofile can be specific for these different patterns and thus influence the differential diagnostic considerations.

Positive staining for CK7, CK20, cytokeratin 5/6, p63, and GATA3 may be of use when utilized in an appropriate differential immunopanel to determine urothelial origin. GATA3, a nuclear transcription factor expressed in 65% - 90% of UC, was originally touted as a sensitive and specific marker of urothelial differentiation. However, additional studies have shown a wider range of expression in multiple other tumor types, requiring judicious interpretation of this antibody’s results in the greater histologic context. Uroplakin III, which is a specific but less sensitive immunostain for urothelial differentiation, marks umbrella cells. Its newer cousin, uroplakin II, reportedly has equal specificity and increased sensitivity for urothelial differentiation. S100P (so-called “placental S100”) is a more sensitive and specific marker for urothelium but is also positive in pancreaticobiliary lesions.

Molecular analysis can be used for the diagnosis of urothelial carcinoma, as well as for prognosis and prediction. TERT promoter mutations is a reliable molecular diagnostic biomarker for urothelial carcinoma that can be helpful in distinguishing bland malignant processes from benign conditions and in establishing urothelial origin. Recent consensus molecularly classifies muscle invasive urothelial carcinoma into 6 subtypes with differing underlying oncogenic mechanisms, infiltration by immune and stromal cells, histologic and clinical features, such as prognostic outcomes. These include luminal-papillary, luminal non-specified, luminal-unstable, stroma-rich, basal-squamous, and neuroendocrine-like. The luminal-unstable, basal-squamous, and neuroendocrine-like subtypes are associated with worse overall survival. These 3 subtypes also frequently demonstrate TP53 mutations. The luminal-papillary subtype has high rates of FGFR3 mutations. The role of these molecular classes as predictors of therapeutic response is being investigated. Additionally, a number of novel prognostic and predictive biomarkers, including microRNA, DNA damage repair defects, and tumor immune microenvironment markers, are being explored.

Collecting duct carcinoma (CDC) arises within the renal medulla, and it can involve areas of the renal pelvis. CDC is a high-grade adenocarcinoma with an inflamed desmoplastic stromal response that can display a range of possible architectural patterns, including tubular, tubulopapillary, cording, and nesting. As such, CDC may show macroscopic and microscopic overlap with high-grade UTUC. Furthermore, the immunoprofile of CDC can also overlap with UTUC (CK7 positive, CK20 sometimes positive, CK5/6 positive). CDC is usually negative for UTUC markers p63, GATA3, and uroplakin II/III, which are therefore useful in this differential. PAX8 and PAX2 immunostains, positive in CDC and other renal epithelial lesions, can be positive in up to 20% of UTUC and should be interpreted with caution in these situations. Also, careful inspection of the background urothelium is critical to identify possible in-situ urothelial lesions to further aid in this differential diagnosis.

Metastatic carcinoma, NOS to the kidney or renal pelvis can mimic UC. The most common tumors metastatic to the kidney are from the lung, colon, stomach, uterus, pancreas, and skin (melanoma). History and imaging studies can be very helpful in this differential, particularly for those patients with a history of non-urothelial carcinoma, dominant masses in other organs, and multifocality. A panel of carefully considered immunostains may be of use in select circumstances, particularly for those tumors with glandular differentiation.

Renal cell carcinoma, NOS (RCC) should be included in the differential diagnosis of any invasive carcinoma within the kidney. RCC usually arises in the renal cortex but can extend into the renal medulla and pelvis. A variety of morphologic patterns are possible, which can overlap with the histology of high-grade UTUC. Immunostains can be very useful in this differential, as RCC are often positive for RCC antigen, PAX8, and PAX2 and are rarely dual CK7/CK20 positive.

SMARCB1-deficient renal medullary carcinoma (RMC) is a rare, aggressive malignancy thought to arise from the renal papillae or calyceal epithelium. In contrast to UTUC, RMC arises in a younger age group and develops almost exclusively in patients with the sickle cell trait or hemoglobin SC disease. A variety of morphologic patterns is again possible, including sarcomatoid and rhabdoid features. Desmoplastic stroma is often prominent. RMC variably express CK7 and CK20, however, they are PAX8 positive and may be OCT 3/4 positive. Additionally, RMC demonstrates loss of SMARCB1 (INI1) by immunohistochemistry.

1. Which of the following immunostain panels is most consistent with a urothelial carcinoma (UC) of the renal pelvis?
   
   
   1. CK7-, CK20-, PAX8-, p63+
   2. CK7-, CK20+, PAX8+, p63-
   3. CK7+, CK20-, PAX8-, p63+
   4. CK7+, CK20-, PAX8+, p63-
   5. CK7+, CK20+, PAX8-, p63+
2. Which of the following features is most helpful in distinguishing SMARCB1-deficient renal medullary carcinoma from invasive UC?
   
   
   1. CK7 positivity
   2. FGFR3 mutations
   3. High nuclear grade
   4. Loss of SMARCB1 (INI1)
   5. Sarcomatoid growth pattern
3. Which of the following is identified as a distinct molecular subtype of muscle invasive UC having potential prognostic and therapeutic implications?
   
   
   1. Inverted
      
   2. Luminal-papillary
   3. Microcystic
   4. Nested
   5. Urothelial carcinoma with squamous differentiation

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3. Paner GP, Kamat A, Netto GJ, et al. International Society of Urological Pathology (ISUP) consensus conference on current issues in bladder cancer. working group 2: grading of mixed grade, invasive urothelial carcinoma including histologic subtypes and divergent differentiations, and non-urothelial carcinomas. Am J Surg Pathol. 2023. doi: 10.1097/PAS.0000000000002077. Online ahead of print.
4. Reuter VE, Argani P, Zhou M, Delahunt B, et al. Best practices recommendations in the application of immunohistochemistry in the kidney tumors: report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol. 2014; 38(8):e35-49.
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1. CK7+, CK20+, PAX8-, p63+ (e)
2. Loss of SMARCB1 (INI1) (d)
3. Luminal-papillary (b)