Moderators: John R. Srigley and Rodolfo Montironi
Case 1 -
Renal Medullary Carcinoma
Athanase Billis MD
School of Medicine
University of Campinas
A 25-year-old black male was hospitalized due to macroscopic hematuria. A computerized tomography
(CT) revealed a 7cm solid, expansile mass in the lower pole of the right kidney. The patient underwent a
radical nephrectomy. Three metastatic nodules in the liver were seen during the surgical procedure.
After surgery, hemoglobin electrophoresis showed 41.8%HbS and 0.5% HbF. A bone scintigraphy showed
several metastatic lesions.
Case 1 - Slide 1
The tumor measured 7.8cm in maximum diameter and was located in the lower pole of the right kidney.
The cut surface was white-yellowish with focal hemorrage. The adrenal gland showed a whitish irregular
area in the medulla. Twenty retroperitoneal lymph nodes were dissected.
The microscopic findings were characteristic of this tumor. The prevalent arrangement was a reticular
pattern of growth in which tumor cell aggregates formed spaces of variable size reminiscent of the yolk
sac testicular tumors of reticular type. Other areas included adenoid cystic appearance, microcystic
arrangement usually with micropapillations, tubular, trabecular and solid patterns. Cytologically the
cells showed dark eosinophilic cytoplasm, and nuclei with conspicuous and sometimes very prominent
nucleoli. The tumor diffusely infiltrated the renal parenchyma as seen in urothelial carcinomas but
there was no histologic resemblance to this kind of neoplasia. Stromal desmoplasia was prominent and
composed a considerable bulk of the tumor showing several appearances: dense, loose, mucoid and myxoid.
A peculiar finding was presence of focal suppurative necrosis typically resembling microabscesses within
epithelial aggregates. Sickled cells were seen in blood vessels. The tumor cells were positive for
35βH11 (low molecular weight cytokeratin) and vimentin; negative for 34βE12 (high molecular
weight cytokeratin); and, positive in a single focus for CK7. Electron microscopy from the paraffin
blocks disclosed two tumoral cell types: one with electron dense cytoplasm rich in microfilaments and
another one with clear cytoplasm and few organelles. Intracytoplasmic lumens with short microvilli and
intercellular junctions were seen. The adrenal gland was invaded by the tumor and 18/20 lymph nodes
dissected showed metastases.
Renal medullary carcinoma
In 1995, Davis, Mostofi and Sesterhenn , reported 34 cases of a very aggressive neoplasm with a
microscopic morphology highly predictive of finding sickled erythrocytes in the tissue. The authors
labeled this tumor renal medullary carcinoma and considered it as the seventh sickle cell nephropathy.
Berman , in 1974, enumerated the six nephropathies seen in patients with sickle cell disease or trait:
gross hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate the
urine and pyelonephritis. All of them can be attributed to the vascular stagnation associated with the
sharp-pointed sickle cells or the reduced oxygen pressure and interstitial hypertonicity of the renal
medulla that are associated with them.
Renal medullary carcinoma is a rare, rapidly growing tumour of the renal medulla associated almost
exclusively with sickle cell trait . Only one of the 34 patients reported by Davis, Mostofi and
Sesterhenn  had sickle cell disease. Over a period of 22 years the Armed Forces Institute of
Pathology had collected only 34 cases 
and over the next 5 years only 15 more had been described .
The incidence of sickle cell trait in Brazil is 6.7% in African-Brazilians, 5.4% in mulattos (persons of
mixed white and black ancestry), and 0.21% in whites . Considering the large black population at
risk, the tumor is very rare.
The tumor is seen in young people with sickle cell trait and exceptionally with sickle cell disease,
between ages 10 and 40 (mean age 22 years) and chiefly in males by 2:1 . In the series of Davis,
Mostofi and Sesterhenn , most of the carcinomas were on the right side. The most frequent symptoms
are gross haematuria and flank or abdominal pain. Considering that the tumor has a predilection for the
right kidney it is interesting that the benign bleeding associated with sickle cell disease (Berman's
first sickle cell nephropathy) occurs on the left side.
Morphologic Features, Immunoprofile, Genetic Analysis and Pathogenesis
Generally, the tumor arises centrally in the kidney, is poorly circumscribed and ranges in size from
4-12cm. Hemorrhage and necrosis are common . The microscopic findings of the case previously
described are characteristic of this tumor. Electron microscopy may disclose intracytoplasmic lumens
with short microvilli, lipid vacuoles and intercellular junctions
but no finding is specific for
Keratin AE1/AE3 is nearly always positive as is EMA but typically less strong and CEA is usually
positive. Some studies showed strong expression for low molecular weight cytokeratin (CAM 5.2) but
negative high molecular weight cytokeratin
Of the 15 tumors analyzed by Swartz et al. ,
cytokeratins 7 and 20 and CEA were heterogeneous and variable, and Ulex was focally positive in a
minority of cases.
Of nine tumors analyzed for genetic gains and losses using comparative genomic hybridization, eight
showed no changes and one showed loss of chromosome 22 .
Yang et al.  analyzed the gene
expression profiles of 2 renal medullary carcinomas from patients with sickle cell trait using
microarrays containing 21,632 cyclic DNA (cDNA) clones and compared them with gene expression profiles of
64 renal tumors. Based on global gene clustering with 3583 selected cDNAs, the authors found a distinct
molecular signature of renal medullary carcinoma, which clustered closely with urothelial (transitional
cell) carcinoma of the renal pelvis, rather than renal cell carcinoma (RCC). This finding of a
significant difference in the gene expression patterns of renal medullary carcinoma compared with RCC
suggests that this tumor should not be treated as a conventional RCC but rather as a special malignancy.
Medullary renal carcinoma probably originates in or near the renal papillae. This origin is suggested
by accumulated radiographic and pathologic findings in individuals with sickle cell disease and sickle
cell trait. Curiously, most of the spontaneous bleeding is from the left kidney, and most of the
carcinomas are on the right. Positivity for vascular endothelial growth factor (VEGF) and hypoxia
induced factor (HIF) suggests that chronic hypoxia secondary to the hemoglobinopathy may be involved in
the pathogenesis of medullary carcinoma .
Mostofi et al.  studied 22 patients with sickle cell
trait and unilateral hematuria. They observed epithelial proliferation of the terminal collecting ducts
in 12 cases and of the adjacent papillary mucosa in 14. Davis, Mostofi and Sesterhenn  hypothesized
that renal medullary carcinomas may originate in such areas of cellular activity. Of interest is a case
of this tumor associated with invasive pelvic urothelial carcinoma reported by Figenshau et al. .
The authors speculated whether the finding represents a collision tumor or dedifferentiation of the
pelvic urothelial carcinoma.
The main differential diagnosis is carcinoma of the collecting ducts of Bellini (or collecting duct
carcinoma of the kidney) . The peculiar histology of the renal medullary carcinoma precludes the
diagnosis of usual collecting duct carcinoma. The latter shows a predominantly tubulopapillary pattern,
the inflammatory infiltrate is not prominent, and dysplastic lesions are seen in the adjacent collecting
ducts. Both tumors involve young patients with a wider variation of age for the collecting duct
carcinoma . The overlap of immunohistochemical findings between these tumors favors the possibility
that they may represent a spectrum of the same neoplasm . It is now regarded that renal medullary
carcinoma may be a more aggressive variant of collecting duct carcinoma .
The prognosis is very poor. Metastases are both lymphatic and hematogenous with lymph nodes, liver
and lungs most often involved. In the series of Davis, Mostofi and Sesterhenn , 25/33 (75%) patients
had metastases to one or more lymph nodes; the tumor extended to the adrenal gland in eight, to the
perinodal retroperitoneal tissue in nine, to the peritoneum in two, and in six and seven patients,
respectively, it had metastasized to the liver and lungs. The mean duration of survival after surgery
has been 15 weeks .
Chemotherapy may prolong survival by a few months  but generally,
chemotherapy and radiotherapy has not altered the course of the disease .
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