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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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
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.
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.
Invasive high-grade urothelial carcinoma of upper urinary tract with extensive glandular
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
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 , 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
 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
We recently presented a study
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 . PAX 8, a recently described member of the PAX gene transcription factors family,
is essential for thyroid, metanephron and Mullerian duct lineage commitment . 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
A panel of PAX 8 and p63 is most optimal in distinguishing UC from CDC. Based on
the findings of two recent studies
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
Our experience with p63 in UC involving upper urinary tract supports previous studies  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
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.
The combined morphologic and immunohistochemical features support a diagnosis of invasive urothelial
carcinoma involving the upper urinary tract.
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