—  SPECIALTY CONFERENCE  —

Surgical Pathology

Case 2 - Invasive High-grade Urothelial Carcinoma of Upper Urinary Tract with Extensive Glandular Differentiation

L. Priya Kunju
University of Michigan
Ann Arbor, MI





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Clinical History
A 59 Y male underwent work-up for painless gross hematuria. Cystoscopy was negative. CT urogram showed a large(6 cm) renal mass. There was no evidence of retroperitoneal adenopathy. The patient underwent excision of kidney as definitive treatment. Can a definitive diagnosis be rendered based on the provided representative HE images and immunohistochemical stains? Are additional immunohistochemical stain(s) needed? If yes, which stains would be useful?


Case 2 - Slide 1
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Case 2 - Figure 1
Low-power view of tumor composed predominantly of glands with high-grade cytologic atypia infiltrating into renal parenchyma between glomeruli.
Case 2 - Figure 2
Tumor with solid areas composed of variably sized nests
Case 2 - Figure 3
Glands showing hobnail morphology
Case 2 - Figure 4
CK 7 : positive

Case 2 - Figure 5
High-molecular weight cytokeratin: Positive
Case 2 - Figure 6
CD10: Positive
Case 2 - Figure 7
p63: Positive
Case 2 - Figure 8
PAX8: Negative

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The patient is a 59 year old gentleman who underwent work- up for gross painless hematuria. Cystoscopy was negative. CT Urogram demonstrated a large renal mass in the renal sinus region. Ureteroscopy revealed an obstructing lesion in lower pole calyx of the right kidney and he underwent nephro-ureterectomy as definitive therapy. The kidney shows a large high-grade carcinoma involving the renal pelvis and extending into the adjacent renal parenchyma as well as renal sinus fat. The tumor is composed predominantly of glands and focal variably sized nests infiltrated between glomeruli of the kidney. Hobnail morphology is noted in some foci. The tumor cells are positive with CK 7, high-molecular weight cytokeratin, CD10, and p63 and negative with vimentin and PAX8.

Differential Diagnoses:
The critical differential diagnosis in this case includes collecting duct carcinoma of the kidney vs. invasive high- grade urothelial carcinoma involving upper urinary tract. Both these entities can have overlapping morphologic and immunohistochemical features.

Final Diagnosis:
Invasive high-grade urothelial carcinoma of upper urinary tract with extensive glandular differentiation

Case Discussion:
High-grade neoplasms that involve the renal sinus region include collecting duct carcinomas (CDC) of the kidney, renal medullary carcinomas, invasive high-grade urothelial carcinomas (UC) of the upper urinary tract, clear cell type renal cell carcinoma (RCC), and papillary RCC (type 2). Of these, CDC, renal medullary carcinomas and UC of the upper urinary tract are usually centered in the renal medullary/sinus region while clear cell type RCC and papillary Type 2 RCC are commonly cortical based and may extend centrally into the renal sinus region. CDC and UC can have considerable overlapping morphology. Although careful morphologic evaluation using hematoxylin and eosin stained sections will allow for correct diagnosis in the majority of cases, there is sufficient overlap between these two entities such that immunohistochemisty (IHC) is often required to arrive at the correct diagnosis with confidence. Accurate characterization of CDC from UC is critical as therapeutic approaches as well as prognostic implications differ. CDC is a rare type of RCC occurring predominantly in adults. It is an extremely aggressive tumor with a poor prognosis with many patients presenting with metastatic disease (1). CDCs primarily arise in the renal medulla and are usually located in the central region of the kidney. They usually show a tubular/glandular or tubulo- papillary architecture infiltrating renal parenchyma between intact glomeruli and are typically associated with a desmoplastic stroma; however a spectrum ranging from solid sheets to sarcomatoid morphology have been described in these tumors. The tumor cells are frequently high-grade (Fuhrman nuclear grade 3-4) with eosinophilic cytoplasm and may show hobnail morphology. The central location of tumor and associated tubular epithelial dysplasia are helpful clues in supporting this diagnosis. The diagnosis of this entity is often problematic and requires that UC involving the upper tract has been excluded [1, 2]. Urothelial carcinomas, particularly high-grade tumors have a peculiar capacity for "divergent" or "mixed histology" differentiation. In a large series of histologic evaluation of 448 consecutive TURBT by our group [3], UC with mixed histologic features was identified in 25% of all TURBT specimens. The most common mixed histologic components were squamous (40%) and glandular (18%). In a recent study [4] examining 108 high-grade UC of the upper urinary tract/renal pelvis, mixed histologic component was noted in 40% of cases including two cases with glandular differentiation. These cases can have significant overlapping morphology with CDC causing diagnostic difficulties. CDC and UC also share overlapping IHC. Immunostains used in the past including high-molecular weight cytokeratin (HMWCK) and Ulex europaeus lectin agglutinin have not been effective in distinguishing these entities as both CDC and UC can be positive [5, 6]. We recently presented a study [7] evaluating the utility of an optimal IHC panel to accurately differentiate high- grade RCCs (Clear cell type RCCs, Type 2 Papillary RCCs and CDCs) involving the renal sinus region from UC of the upper urinary tract. UC and CDC share overlapping IHC and are frequently positive with CK7, HMWCK and predominantly negative with vimentin. This is distinct from clear cell type RCCs and Type 2 Papillary RCCs which tend to be predominantly negative with CK7 and positive with vimentin. CD 10 has some utility when it is positive, as CDCs are usually negative with CD10 while a majority of clear cell type RCCs, Type 2 Papillary RCCs and 50% of UC are positive with this marker. These findings are in agreement with previous studies [6]. PAX 8, a recently described member of the PAX gene transcription factors family, is essential for thyroid, metanephron and Mullerian duct lineage commitment [8]. PAX 8 is strongly positive (nuclear expression) in normal kidney within collecting ducts and differentiating nephrons. The utility of p63 as a sensitive and specific marker of UC with diffuse nuclear expression has been well documented. [9, 10]. A panel of PAX 8 and p63 is most optimal in distinguishing UC from CDC. Based on the findings of two recent studies [7, 11], which combined have analyzed a large series of CDCs with these markers, PAX 8 is sensitive marker of CDC and stains the majority of CDC (88-100%). The majority of UC involving the upper tract (83-91%) are negative for PAX8; a finding confirmed by other studies [12, 13]. Our experience with p63 in UC involving upper urinary tract supports previous studies [10] which shows p63 to be a useful marker in distinguishing UC from high-grade RCC including CDC (100% specificity for UC with no staining of any RCC with p63). However, the recent study by Albadine et al [11], which evaluated a large cohort of CDC cases (21 CDCs) found p63 positivity in a small subset (3/21, 14%) of CDC. Thus, an immunoprofile of PAX8 (-)/p63 (+) supports the diagnosis of UC involving upper urinary tract (sensitivity 83-88%, specificity 100%) while a PAX8 (+)/p63 (-) immunoprofile supports a diagnosis of CDC (sensitivity 85-88%, specificity 100%). In the unusual scenario of PAX8 (+)/p63(+) immunoprofile, IHC alone may not be able to definitively distinguish these two entities; additional clinical information including positive urine cytology, presence of urothelial carcinoma in-situ along the renal pelvis, etc may be useful features to support a diagnosis of UC in these situations.

Conclusion(s):
The combined morphologic and immunohistochemical features support a diagnosis of invasive urothelial carcinoma involving the upper urinary tract.

References:
  1. Srigley JR and Moch H. carcinoma of the collecting ducts of Bellini. In: Eble JN, Sauter G, Epstein JI, et al, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: IARC Press; 2004:33–34.

  2. Srigley JR, Eble JN. Collecting duct carcinoma of kidney. Semin Diag Pathol. 1998; 15:54-67.

  3. Wasco M, Daignault S, Zhang Y et al. Urothelial Carcinoma with Divergent Histological Differentiation (Mixed Histology) Predicts the Presence of Locally Advanced Bladder Cancer when Detected at Transurethral Resection. Urology. 2007; 70(1):69-74.

  4. Perez-Montiel D, Wakely PE, et al: High-grade urothelial carcinoma of the renal pelvis: clinicopathologic study of 108 cases with emphasis on unusual morphologic variants. Mod Pathol. 2006;19: 494–503.

  5. Gupta R, Paner GP, Amin MB. Neoplasms of the upper urinary tract: a review with focus on urothelial carcinoma of the pelvicalyceal system and aspects related to its diagnosis and reporting. Adv Anat Pathol. 2008;15:127-139.

  6. Kobayashi N, MatsukaiO, Shirai S et al. Collecting duct carcinoma of kidney; an immunohistochemical evaluation of the use of antibodies for differential diagnosis. Hum Pathol.2008; 39:1350-1359.

  7. Carvalho JC, Thomas DG, JB McHugh et al. P63 is useful in Distinguishing Collecting Duct Renal carcinomas from its morphologic mimics. Mod Pathol. 2010; 23:182A (806).

  8. Lang D, Powell SK, Plummer RS et al. PAX genes: roles in development, pathophysiology and cancer. Biochem Pharmacol.2007; 73:1-14.

  9. Kunju LP, Mehra R, Snyder M et al. Prostate Specific Antigen (PSA), High Molecular Weight Cytokeratin (clone 34βE12) and/or p63: An Optimal Immunohistochemical Panel to Distinguish Poorly Differentiated Prostate Adenocarcinoma from Urothelial Carcinoma. American J of Clin Pathol. 2006; 125:675-681.

  10. Langner C, Ratschek M, Tsybrovskyy O et al. p63 immunoreactivity distinguishes upper tract transitional cell carcinomas and renal cell carcinoma even in poorly differentiated renal tumors. J Histochem Cytochem. 2003;51:1097-1099.

  11. Albadine R, Schultz L, Illei P et al. Pax8 (+)/p63 (-) immunostaining pattern in Renal Collecting Duct carcinoma (CDC). A Useful Immunoprofile in the Differential Diagnosis of CDC vs. Urothelial Carcinoma of the Upper Urinary Tract. Am J Surg Pathol. 2010;34(7):965-969.

  12. Tong GX, Yu WM, Beaubier NT et al. Expression of PAX8 in normal and neoplastic renal tissues: an immunohistochemical study. Mod Pathol.2009;22:1218-1227.

  13. Albadine R, Schultz L, Fajardo DA, et al. PAX8 expression in urothelial neoplasia- an immunohistochemical study of 236 cases. Mod Pathol.2010;23:174A.