1. An otherwise healthy 76 year-old man with h/o prostate cancer and renal cell carcinoma (s/p TURP and nephrectomy) was seen as part of his routine follow-up. Catheterized urine.

2. Dr. Davey

3. VERY cellular urine (SurePath prep). Some bland orderly groups in background mixed with dark bad looking cells.

5. Mitotic figures and lots of bizarre cells

6. Most cells with scant cytoplasm; molding appears to be present

8. ME ?SYED Syed offered me the chance to participate in this seminar last spring. I was trusting of him, until I got the slides…

9. Urothelial carcinoma Could the renal malignancy have been pelvic urothelial carcinoma? Metastatic prostate adenocarcinoma Metastatic renal cell carcinoma Small cell carcinoma Other malignancy: sarcoma, etc. Need to review previous cancers in this patient and special stains

10. Cellular specimen: Yes Pleomorphism: Yes Cell size enlarged: only in few cells Hyperchromatic nuclei: Yes Often vesicular chromatin: Only in few (most cells coarse chromatin) Nuclei usually have nucleoli: No Cytoplasm variable, but more defined: No

11. A known case of high grade urothelial carcinoma: bigger cells, more cytoplasm

12. More urothelial carcinoma, note pleomorphism of cells

13. Left: Urothelial Renal Pelvic Carcinoma, Fig 23-40 from Koss’ Diagnostic Cytology, 2008. Right: Case 2

14. I found a key article on small cell carcinoma published by Dr. Ali! Small cell neuroendocrine carcinoma of the urinary bladder: A clinicopathologic study with emphasis on cytologic features Syed Z. Ali, M.D., Victor E. Reuter, M.D., Maureen F. Zakowski, M.D. Cancer 1997

15. Very rare (<0.5%) but reported in urine Hypercellular specimen Background bloody, necrotic, inflamed Tumor cells small (2-3 X normal lymphs) Scant cytoplasm, may have molding Nuclei granular chromatin, mitoses Larger cancer cells corresponding to urothelial carcinoma can be seen Acs 2000, Ali 1997, Koss 2006

16. Small cell neuroendocrine Carcinoma of the bladder from Cancer 1997:79:356 Ali is the author!

17. Renal: <30% usual renal cell carcinomas shed cells in urine –Case 2 lacks nucleoli, vacuolated cytoplasm Prostate cancer: if aggressive and located centrally could see in urine (TURP history) –Case 2 lacks glandular features and nucleoli Either type would need to be high grade or small cell variant

18. Renal Adenocarcinoma in fluid (L) and urine (UR, from Koss’ Diagnostic Cytology 2008, Fig 23-54). LR from Case 2

19. Metastatic prostate carcinoma In urine (Courtesy of Yolanda Brill)

20. Immunocytochemistry for PSA showing prostate origin (Cell block)

21. Left: Metastatic prostate Cancer from ThinPrep Morphology Atlas Cytyc©. Right: Case 2 showing less nucleoli & cytoplasm more pleomorphism

23. Urothelial: usually + for P53, Thrombomodulin, UPIII, CK20 –these 4 markers are negative in most prostate and renal carcinomas –EMA also positive in urothelial and most renal but negative in prostate Prostate: + for AR, other prostate markers, CD-57, Lewis, EPCAM Renal: + for vimentin, GST-P*, EMA *Glutathione S Transferase Pi

24. If small cell neuroendocrine carcinoma admixed with urothelial, also can look for neuroendocrine markers like chromogranin and synaptophysin

25. Melanoma: always possible, need stains! Sarcomas: rhabdomyosarcoma can occur –Embryonal (botyroid): small primitive cells but usually see in children Photo from Arch Pathol Lab Med 2004;12:357

26. Lymphoma/leukemia: doubtful with history and definite clustering of cells Urine Photo from 70 year old with Burkitt-like lymphoma t(8;14) in marrow. Photo courtesy of Melissa Kesler. Note pseudo clusters !

28. Key features: Scant cytoplasm, molding, relatively small cell size

29. Positive for malignancy! Favor small cell type carcinoma (mixed with urothelial carcinoma) Other choice: high grade urothelial carcinoma Exclude metastatic carcinoma Compare with previous histology Special stains could help!

30. Now for the real answer…

31.  Panelist I – “High-grade urothelial carcinoma (?micropapillary type)”  Panelist II – “Urothelial carcinoma, papillary, low grade”  Panelist III – “Probable post-procedure instrumentation - reactive cells”

32.  52% - “Prostatic adenocarcinoma”  20% – “Urothelial carcinoma”  17% – “RCC”  Misc – Sq cell carcinoma, Reactive, BK (polyoma) virus, Nephrogenic adenoma, Other

38.  Prostatic Adenocarcinoma (core, Gleason grade 4+4=8)  Renal Cell Carcinoma (s/p Nephrectomy, Conven type)  Is it a 3 rd primary?  Or, one of the above two?  IPOX:  Positive – Chromogranin (focal), Synaptophysin  Negative – PSA, PSMA

39.  High-grade Carcinoma, morphologically and immunohistochemically c/w with Small Cell Carcinoma

40.  Patient was on Lupron and Casodex  A TURP was performed one month later

42. High-grade Prostatic ACA with a component of “Small Cell Ca”

43.  High-grade ACA of the prostate (80% of the tissue) with small cell carcinoma component

44.  INCIDENCE: < 1% of all prostate cancers  Phenotypic Spectrum  Pure – 50%  Mixed -25 to 50%  Initially Aca, Recur as SmCC – 25 to 40% after hormonal therapy. Interval -25 mo  Mean age of diagnosis – 65 to 69 yrs  Serum PSA - not elevated (mostly)  ~ 10% secrete hormones (ACTH or ADH), and may present with paraneoplastic syndromes  Risk factors, anatomic distribution, gross appearance is similar to conventional Aca Basic Facts

45. Morphology-Immunochemistry  Cyto-Histo similar to SmCC from other sites  In combined cancers;  Admixed-80%  Two distinct components-20%  Aca-High-grade, Gleason >7  Immunolabeling- e-medicine

46.  Prognosis is poor (median survival <1 yr. No significant survival difference between pure and mixed carcinomas  Do not respond to hormonal therapy or radiation therapy, and surgery is usually not curative.  Treatment- regimen of cisplatin and etoposide Management - Prognosis

47.  Primary bladder SmCC  Urothelial carcinoma  Metastatic SmCC  Metastatic RCC (Clin hx)

48.  Clinical history is important  Cyto-histo review is critical  Immunostaining plays a major role  SmCC cyto dx has a defining role in clinical management