Rare Renal Tumors – A Clinico

2014-03-26
Rare Renal Tumors –
A Clinico-pathologic Conference
Reza Hamidizadeh, MD and Michael J. Metcalfe, MD
David Harriman, MD and Ryan Flannigan, MD
Residents, Department of Urologic Sciences
Edward C. Jones, MD
Department of Pathology and Laboratory Medicine
Department of Urologic Sciences Grand Rounds
March 19, 2014
Objectives
!  Review
clinico-pathologic features and
management of several rare renal tumors
"  Mixed epithelial and stromal tumor (MEST)
"  Renal sarcoma
"  Epithelioid angiomyolipoma
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Case #1 – Mixed epithelial and
stromal tumor of kidney
Case #1
!  59
yo Asian female
!  Referred with asymptomatic microhematuria
(October 2012)
!  Urologic ROS negative
!  PMHx – T2DM, HTN, Dyslipidemia
!  Meds – Trandolapril, Statin, Metformin
!  FMHx – non-contributory
!  P/E – BMI 27, unremarkable
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Investigations
!  Cystoscopy
normal
!  Normal CBC, lytes. GFR > 90 ml/min
!  Renal U/S
"  4.5cm complex cystic left renal mass
"  Previously seen 11 years ago – stable
in size and appearance
Investigations - CT
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Investigations - CT
Investigations - CT
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Investigations - CT
Investigations - CT
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Investigations - CT
Investigations - CT
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Investigations - CT
Investigations - CT
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Investigations - CT
Investigations - CT
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Investigations - CT
Investigations - CT
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Investigations - CT
!  5x4x5
cm complex left renal cyst
!  1.2cm enhancing mural nodule - though to
be renal parenchyma trapped between 2
cysts
!  Called Bosniak III cyst by radiology
!  Normal contralateral kidney, renal vein
!  No lymphadenopathy
!  1.2cm liver hemangioma
!  No metastatic disease
!  Bulky uterus – ?leiomyomata
Management?
!  Follow
up imaging in 6 months
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6 month follow-up
!  Stable
appearance of cyst
!  Enhancing nodule visualized again
!  Bosniak IV
!  ?cystic RCC
!  In
the interval patient had flank pain and
gross hematuria
"  Repeat cysto negative
Management
! Options
discussed
"  MRI vs. biopsy vs. surgery
MIS left radical nephrectomy (October
2013) – no complications
! Discharged POD #1
! !
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Pathology
!  Multiloculated
cystic lesion
!  Spindle cell/smooth muscle stroma surrounding
atrophic renal tubular structures and microcysts
!  Tubular epithelium comprised of low cuboidal
cells with hobnail appearance
!  No atypia, mitotic activity, no necrosis
!  Negative margins
!  ! Mixed epithelial and stromal tumor (MEST)
MEST – Pathology (Dr. Jones)
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MEST – Pathology (Dr. Jones)
MEST – Pathology (Dr. Jones)
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MEST – Pathology (Dr. Jones)
MEST – Pathology (Dr. Jones)
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MEST – Pathology (Dr. Jones)
MEST – Pathology (Dr. Jones)
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Follow-up
!  NED
based on CT (Jan 2014)
!  Plan for
"  Annual CXR and US
"  CT q5 years
MEST – Review of literature
!  Pubmed
mixed epithelial and stromal tumor
kidney
!  All English language manuscripts with
full text accessible online (1998 –
present) reviewed
!  58 articles identified
! 
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MEST – Historical perspective
Michal and Syrucek first proposed MEST
designation (1998)
!  Tumors consisting of biphasic solid and
cystic morphology (spindle cell stroma,
cysts or tubules)
!  Previous terminology used for similar
tumors
! 
" 
" 
" 
" 
Cystic hamartoma of renal pelvis
Adult mesoblastic nephroma
Cystic nephroma
Mature/adult metanephric stromal tumor
•  1st study to publish a large number of cases diagnosed as mixed epithelial and
stromal tumor
•  12 cases
•  11 female, 1 male
•  Mean age 56
•  50% presented with symptoms
•  Most patients had hormonal history
•  1 male – 11 years of hormone therapy for prostate cancer (DES + lupron)
•  Females
•  6 HRT post TAH-BSO
•  2 with possible history of hormone use
•  1 vaginal bleeding + ovarian cyst (?high estrogen)
•  1 DM + obesity (?PCOS)
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MEST – Clinical presentation
!  132
cases identified in literature
!  Male 16, median age 58 (12 - 92)
!  Female 116, median age 54 (8-84)
!  6.7cm (0.3cm – 30.5cm)
!  Predilection for right side
!  50% symptomatic presentation
"  Pain
"  Gross hematuria
MEST – Clinical Presentation
Hormonal history
!  Males
"  2/16 with history of hormone therapy
"  Both patients on ADT for prostate cancer
!  Females
"  Not reported in most case reports
"  Breast cancer (4)
"  HRT/OCP (14)
"  Ovarian Sertoli cell tumor (1)
"  Uterine fibroids / DUB (7)
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MEST - Pathology
! 
Biphasic Histology
"  Stromal component: spindle cells, smooth muscle,
ovarian type stroma
"  Epithelial component: cysts, tubules lined with
flattened / cuboidal epithelium with hobnail
appearance
!  Immunohistochemistry
"  Epithelium: cytokeratin, epithelial membrane antigen
"  Stroma: Vimentin, Desmin, SMA, ER, PR
MEST – Pathogenesis
!  Embryological
proximity of mullerianderived and renal tissue
!  Appropriate hormonal milieu
(hyperestrogenemia) ! neoplastic
differentiation of renal stromal cells with
mullerian features ! entrapment of
normal renal tubules ! neoplastic
change in tubules ! cysts, primitive
tubules, glands
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MEST – Natural History
!  5
patients with malignant transformation on
original path – All followed benign course
"  1 received adjuvant chemotherapy
!  5 deaths
"  4 patients with local recurrence
○  3 early (4-6 months)
"  1 had tumor rupture intraoperatively
○  1 late (2 years post nephrectomy)
○  All had malignant stromal features on original path
"  1 metastasis
MEST – Pediatric Cases
3 cases reported
!  Male (1)
! 
"  12 years old, prepubertal
"  Hematuria
"  Partial nephrectomy
! 
Female (2)
"  1 patient with isolated clitoral hypertrophy –
negative hormonal workup
"  Both presented with abdominal fullness (15cm)
"  Nephrectomy
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MEST - Imaging
!  Complex
cystic (Bosniak III / IV) ! solid
with microcysts
!  +/- mural / septal calcifications
!  Rare
presentations
"  Containing fat resembling AML (2)
"  Resembling TCC (7)
MEST - Imaging
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MEST - Imaging
MEST - Imaging
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MEST - Imaging
MEST Imaging
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MEST and Adult Cystic Nephroma
! 
Cystic Nephroma (Bimodal age distribution)
"  Boys 2-3 years old
"  Women 40s-50s
! 
Recognized since 1800s
! 
Pediatric – continuum with cystic partially
differentiated nephroblastoma and cystic Wilms
"  Can contain blastemal elements
! 
Adult - ?continuum with MEST
"  Does not contain blastemal elements
MEST and Adult Cystic Nephroma
! 
Both rare
"  CN – 300 cases
"  MEST – 132
! 
Female preponderance
"  CN – 8:1
"  MEST – 10:1
! 
! 
Mainly benign course
Similar histologic/immunohistochemistry, gene expression
profiles
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Differential Diagnosis of Complex
Cystic Renal Lesions
!  Cystic
RCC
!  Benign complex cyst
!  Adult cystic nephroma
!  MEST
!  Abscess
!  MCDK
!  Obstructed duplicated collecting system
Questions?
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Case #2 – Renal Sarcoma
Objectives
!  Epidemiology
of retroperitoneal sarcoma
!  Diagnosis
"  Imaging
"  Role for biopsy?
!  Management
"  Peri-operative radiation therapy
"  Wide resection margin
"  Re-resection
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CASE # 2
! 
! 
! 
! 
! 
71 F
HPI
"  20 lbs weight loss in 2 months
"  Abdominal distension and discomfort
"  Bowel dysfunction
PMedHx
"  GERD, CRI (GFR 40)
PsurgHx
"  Ectopic pregnancy (lower midline incision)
O/E: Massive abdominal mass from right flank
crossing midline
Case # 2 -71 F, 20 cm RCC in Horseshoe Kidney
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Case # 2 -71 F, 20 cm RCC in Horseshoe Kidney
Case # 2 -71 F, 20 cm RCC in Horseshoe Kidney
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Case # 2 -71 F, 20 cm RCC in Horseshoe Kidney
Case # 2 -71 F, 20 cm RCC in Horseshoe Kidney
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Case # 2 -71 F, 20 cm RCC in Horseshoe Kidney
Case # 2 -71 F, 20 cm RCC in Horseshoe Kidney
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Case # 2 -71 F, 20 cm RCC in Horseshoe Kidney
Surgical management
!  Invasion
into liver, duodenum and pancreas.
!  Partial duodenectomy, partial pancreatectomy,
partial nephrectomy and partial hepatectomy x2
(HPB involvement)
!  Path demonstrated High Grade Leiomyosarcoma
"  Negative renal, duodenal, and pancreatic margin.
"  Liver Margin
"  1-Negative
"  2-Focal extension to margin
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Renal Sarcoma – Dr. Jones
Renal Sarcoma – Dr. Jones
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Renal Sarcoma - Dr. Jones
Renal Sarcoma – Dr. Jones
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Renal Sarcoma – Dr. Jones
Renal Sarcoma – Dr. Jones
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Retroperitoneal Sarcoma
!  1-2
% of all solid malignancies are sarcoma
!  <10% of these are retroperitoneal sarcoma
!  5th decade; equal M:F ratio.
!  Retroperitoneal sarcoma ddx (rcc, acc, germ
cell tumour, lymphoma)
Radiologic Signs of Renal Sarcoma
! 
! 
! 
! 
! 
Large soft tissue mass,
involving or derived from the
kidney
Absence of lymphadenopathy,
thrombus, or distant
metastasis.
Apparent origin from the
capsule or perisinous region.
Presence of fat or bone
suggests liposarcoma or
osteosarcoma.
Hypovascular
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Tumour Staging – AJCC
Tumour Staging – AJCC
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Tumour Staging – AJCC
Presentation
! 
Most RP sarcomas present large (> than 5cm) and
are deep to superficial fascia
"  Stage IIB- large, low grade and deep
"  Stage III – large, high grade and deep
! 
Symptoms
"  Vague abdominal pain
"  Bowel obstruction / complaints
"  Neurologic manefestations of spinal cord
compression
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Work-up
History & Physical
Labs - ? functional assessment if large, upper
pole and adrenal not identified
!  Imaging
! 
! 
!  CT Chest , Abdo & Pelvis.
!  ? MRI
"  Delineate margin between other organs
"  Vascular involvement
! 
? biopsy
"  May have a role in guiding neoadjuvant therapy if
diagnosis uncertain
"  Risk versus benefit
Determinants of prognosis
! 
Tumour grade and resectability
! 
Complete resection and low grade tumours have best
survival rates
! 
Most recurrences occur within 2 years
○  Local recurrence most common
○  May require re-resection
○  Median survival following resection of local
recurrence is 60 months vs. 20 months without
surgery
Windham, Cancer Control 2005
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Surgical Management
! 
Complete resection will improve survival
! 
Incomplete resection has limited benefit
"  No role for cytoreductive surgery
Bonavat, JCO, 2009
Surgical Management
!  Tumour
pseudocapsule
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Surgical Management
! 
75% resection at least one adjacent organ
Bonavat, JCO, 2009
Radiation Therapy:
!  Pre-operative
!  Intra-operative
!  Post-operative
Vorde, Cancer 2011
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Pre-operative RT
! 
Vorde, Cancer 2011
!  5-year LRR varied from 12 to 62%
!  5-year OS rate ranged from 50 to 74%
!  Conclusion: pre-operative RT improves LC and may improve OS
! 
Considerations
! 
! 
! 
! 
No RCT on radiotherapy and retroperitoneal sarcoma
Tissue diagnosis needed prior to RT
Need to wait 4-6 weeks before surgery
May limit radiation toxicity
!  Visceral organs do not tolerate radiation well
Post-operative RT
! Given
4-6 weeks post surgery
! Improved
local control
"  Decreased LRR (3.4x reduction)
"  Decreased time to local recurrence
"  No change in overall survival (49-54% 5 yr OS)
Stoeke, Cancer 2001
! Likely
increased radiation toxicity
○ Fixed bowel in operative field
○ Larger radiation field
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Chemotherapy
!  Adriamycin
and ifosfamide: partial
response in up to 50% of patients with
increased overall survival.
!  Complete responses are seen in less than
10% of patients.
!  Reserved primarily for metastatic setting
Raut, Pisters PW J Surg Oncol 2006
EUR J UROL 2012
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RMB - Complications
!  Lane,
Volpe, EUR J UROL 2012
J Uro 2008
"  2500 renal mass biopsies
"  Significant complications – 0.3%
"  Minor complications – 4.7%
"  Deaths – 0
A fine balance
•  Risks
•  <5% minor
complications
•  0.3% major
complications
•  RARE Seeding
•  Excision of tract
may be necessary
Benefits
•  Clinical information
•  Preoperative RT is a
potential benefit
•  Preoperative planning
for a potential
invasive tumour
possibly requiring
resection of adjacent
organs
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Questions?
Case #3 – Epithelioid AML
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CASE # 3
!  53
yr. male presents with vague abdominal
pain and bloating.
!  Otherwise healthy, no med s.
!  O/E: Thin, cachectic, massive palpable
abdominal mass from right flank crossing
midline.
!  Cr – 61
!  Hgb 103
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Case #3
! 
Intraoperatively:
"  Right Thoraco-abdominal incision, 10th rib resected.
"  No complications.
"  Tumor resected, negative margins, no vein
involvement.
"  <200cc blood loss.
! 
Post – Operatively:
"  D/c post-op day 4.
"  No complications.
"  Well at 6 week check up.
Diagnosis – Epithelioid AML
! 
2 types of AML
"  Classic
○  Major features:
"  Angio - thick walled vessels that lack a well-developed internal elastic lamina
"  Myo - varying amounts of spindle smooth muscle cells
"  Lipoma - adipose tissue
○  Benign, but can be locally invasive
○  May have epithelioid cells present (15% of AML s)1
! 
Epithelioid AML
"  Epithelioid cells – contain abundant eosinophilic and granular cytoplasm
"  # epithelioid cells required to make a dx of epithelioid variant uncertain
○  10 to 100%1,2
"  May undergo malignant transformation
○  0 to 36 % have local recurrence or distant metastasis1-3
1)  Aydin H, Am J Surg Path 2009
2)  Nese Am J Surg Path 2011
3)  Brimo, Am J Surg Path 2010
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Epithelioid AML Pathology (Dr. Jones)
Epithelioid AML Pathology (Dr. Jones)
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Epithelioid AML Pathology (Dr. Jones)
Epithelioid AML
!  Diagnosis
– Histological
"  + HMB 45 (AML),
"  + Melanocytic variant stain (epithelioid)
"  -ve cytokeratin (rule out RCC)
!  Treatment:
"  Surgical excision
"  Role of mTOR inhibitors (everolimus) - ?
potential in metastatic setting1
1)  Bissler Lancet 2013
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Everolimus for angiomyolipoma associated with tuberous
sclerosis complex or sporadic lymphangioleiomyomatosis
(EXIST-2): a multicentre, randomised, double-blind,
placebo-controlled trial
•  18 years or older with at least one angiomyolipoma 3 cm or larger in its longest
diameter and a definite diagnosis of tuberous sclerosis or sporadic
lymphangioleiomyomatosis.
•  2:1 randomisation to everolimus 10 mg po OD or placebo.
•  Primary endpoint: 50% reduction in total volume of target AML
•  118 patients, from 24 centres.
•  Response rate was 42% for everolimus and 0% for placebo (p<0·0001).
•  Everolimus reduced angiomyolipoma volume with an acceptable safety profile,
suggesting it could be a potential treatment for angiomyolipomas associated with
tuberous sclerosis.
Bissler, Lancet 2013
Questions ?
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