Rare Renal Tumors A Clinico-pathologic Conference
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1 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 1
2 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 2
3 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 3
4 Investigations - CT Investigations - CT 4
5 Investigations - CT Investigations - CT 5
6 Investigations - CT Investigations - CT 6
7 Investigations - CT Investigations - CT 7
8 Investigations - CT Investigations - CT 8
9 Investigations - CT Investigations - CT 9
10 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 10
11 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 11
12 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) 12
13 MEST Pathology (Dr. Jones) MEST Pathology (Dr. Jones) 13
14 MEST Pathology (Dr. Jones) MEST Pathology (Dr. Jones) 14
15 MEST Pathology (Dr. Jones) MEST Pathology (Dr. Jones) 15
16 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 16
17 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 1 st 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) 17
18 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) 18
19 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 19
20 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 20
21 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 21
22 MEST - Imaging MEST - Imaging 22
23 MEST - Imaging MEST Imaging 23
24 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 24
25 Differential Diagnosis of Complex Cystic Renal Lesions! Cystic RCC! Benign complex cyst! Adult cystic nephroma! MEST! Abscess! MCDK! Obstructed duplicated collecting system Questions? 25
26 Case #2 Renal Sarcoma Objectives! Epidemiology of retroperitoneal sarcoma! Diagnosis " Imaging " Role for biopsy?! Management " Peri-operative radiation therapy " Wide resection margin " Re-resection 26
27 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 27
28 Case # 2-71 F, 20 cm RCC in Horseshoe Kidney Case # 2-71 F, 20 cm RCC in Horseshoe Kidney 28
29 Case # 2-71 F, 20 cm RCC in Horseshoe Kidney Case # 2-71 F, 20 cm RCC in Horseshoe Kidney 29
30 Case # 2-71 F, 20 cm RCC in Horseshoe Kidney Case # 2-71 F, 20 cm RCC in Horseshoe Kidney 30
31 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 31
32 Renal Sarcoma Dr. Jones Renal Sarcoma Dr. Jones 32
33 Renal Sarcoma - Dr. Jones Renal Sarcoma Dr. Jones 33
34 Renal Sarcoma Dr. Jones Renal Sarcoma Dr. Jones 34
35 Retroperitoneal Sarcoma! 1-2 % of all solid malignancies are sarcoma! <10% of these are retroperitoneal sarcoma! 5 th 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 35
36 Tumour Staging AJCC Tumour Staging AJCC 36
37 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 37
38 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
39 Surgical Management! Complete resection will improve survival! Incomplete resection has limited benefit " No role for cytoreductive surgery Bonavat, JCO, 2009 Surgical Management! Tumour pseudocapsule 39
40 Surgical Management! 75% resection at least one adjacent organ Bonavat, JCO, 2009 Radiation Therapy:! Pre-operative! Intra-operative! Post-operative Vorde, Cancer
41 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)! Likely increased radiation toxicity Fixed bowel in operative field Larger radiation field Stoeke, Cancer
42 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
43 RMB - Complications! Lane, J Uro 2008 " 2500 renal mass biopsies " Significant complications 0.3% " Minor complications 4.7% " Deaths 0 Volpe, EUR J UROL 2012 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 43
44 Questions? Case #3 Epithelioid AML 44
45 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
46 46
47 47
48 48
49 49
50 Case #3! Intraoperatively: " Right Thoraco-abdominal incision, 10 th 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 metastasis 1-3 1) Aydin H, Am J Surg Path ) Nese Am J Surg Path ) Brimo, Am J Surg Path
51 Epithelioid AML Pathology (Dr. Jones) Epithelioid AML Pathology (Dr. Jones) 51
52 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 setting 1 1) Bissler Lancet
53 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? 53
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