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New Frontiers in Pathology GU case presentation

New Frontiers in Pathology GU case presentation. Rajal B. Shah, M.D. Associate Professor - Pathology and Urology. Case 13. A 65 year-old white American male with serum PSA of 4 ng/ml, underwent extended 12 core biopsies. 34 β E12 + p63. P504S. P504S. Summary of atypical findings.

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New Frontiers in Pathology GU case presentation

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  1. New Frontiers in PathologyGU case presentation Rajal B. Shah, M.D. Associate Professor - Pathology and Urology

  2. Case 13 • A 65 year-old white American male with serum PSA of 4 ng/ml, underwent extended 12 core biopsies

  3. 34βE12 + p63

  4. P504S

  5. P504S

  6. Summary of atypical findings • Disorganized growth pattern • Presence of some round and poorly formed small glands • Micro nucleoli • Lack of basal cell staining in some glands • AMACR reactivity

  7. Diagnosis • Benign prostate parenchyma with focus of partial atrophy

  8. Diagnosis of Limited Cancer in Prostate Biopsy: Critical Issues • Recognize cancer and avoid under-diagnosis (false negative) • Recognize benign mimics and avoid over-diagnosis (false positive)

  9. Mimics of Prostate Cancer Pattern 1 Small glandular growth pattern Pattern 2 Cribriform/large growth pattern Pattern 3 Fused gland/solid growth pattern

  10. Pattern 1-Small gland mimics Seminal vesicle/ejaculatory duct epithelium Cowper’s glands Verumontenum hyperplasia Crowding of small glands Mucinous metaplasia Mesonephric gland hyperplasia Post atrophic hyperplasia/atrophy Partial atrophy Adenosis Radiation atypia Nephrogenic adenoma Basal cell hyperplasia

  11. PA: Among the most common reasons for second opinion Herawi M et al, AJSP, 2005

  12. Partial atrophy (PA) - Background • Experts have utiized various terms to describe partial atrophy • Some have used the term post atrophic hyperplasia (PAH) to describe similar lesions (Amin MB et al, 1999, Srigley JR et al, 2004) • Recently PA and PAH recognized as a distinct types of focal atrophy in the Working Group Classification of Focal Prostate Atrophy Lesions (De Marzo et al, 2006)

  13. Partial atrophy - Significance • Potential for confusion with prostatic adenocarcinoma (PCa) • Among the most common reasons for second opinion in a consultation practice (Herawi et al, 2005) • Potential immunohistochemical (basal cell markers and P504S (monoclonal antibody to AMACR)) overlap with PCa • Association with inflammation and proliferation found in certain forms of atrophy such as post atrophic hyperplasia (Ruska et al, 1998; De Marzo et al, 1999; Shah R et al, 2001)

  14. Architectural indices Gland size Gland shape Circumscription Stromal characteristics Associated completely atrophic glands within the focus Luminal secretions Inflammation Cytological indices Character of cytoplasm Nuclear size in relation to benign glands Micronucleoli (visible only at 40x) and macronucleoli (visible easily at 10X) AJSP, 32(1), 2008

  15. Basal cell marker “cocktail”(34βE12 + p63) • Completely positive • Patchy positive • Completely negative • P504S - Rabbit monoclonal antibody to AMACR (Zetacorporation, Sierra Madre, CA) • Negative • Weak • Moderate-to-strong (Expression evaluated in relation to benign glands) AJSP, 32(1), 2008

  16. Study design - Proliferation status • Ki-67 (MIB-1 clone) immunohistochemistry • Quantitative analysis by ChromaVision ACIS • Measurement of stain intensity of PA foci compared with benign glands (range 0-225, 0%-100%) • Manual delineation of foci

  17. Results - Morphology (architectural features) N=73 foci

  18. Circumscribed focus with stellate – “star” shaped glands

  19. Disorganized poorly formed round glands

  20. Results - Morphology (architectural features) FEATURES % CASES

  21. Complete dark atrophic glands within the focus

  22. Results - Morphology (cytologic features) FEATURES % CASES

  23. “Micro” nucleoli visible at high power

  24. Other benign conditions known to contain nucleoli: > Basal cell hyperplasia > Post atrophic hyperplasia > Adenosis > Radiation atypia > Benign glands associated with inflammation

  25. Clear cytoplasm similar to adjacent benign glands, placed laterally to Nuclei giving them partially atrophic look

  26. Results: IHC – Basal cell markers cocktail 34βE12 + p63

  27. Other lesions with patchy/negative basal cell reactions • PIN • Adenosis Lack of basal cell staining in few atypical glands is not necessarily diagnostic of cancer

  28. Results: IHC – P504S

  29. Comparison with published literature • AMACR results • 79% (15/19 cases)(Herawi et al, 2005) • Series consisting of selected consultation cases with AMACR staining performed at multiple institutions • 31% (38/122 foci)(Adley et al, 2006) • Hospital based series, AMACR staining using the triple antibody (P504S + CK 903+ p63)

  30. AMACR-specificity issues PIN= Prostatic intraepithelial neoplasia, NA= Nephrogenic adenoma NS= Not studied

  31. Results - Basal cell markers and P504S antibody as a panel

  32. Results - Proliferation status • N=54 foci • Mean proliferative indices: • PA foci=5.5 (range 0-30) • Benign glands=5.6 (range 0-31) • P=0.97 (paired t-test)

  33. Summary - Features that potentially mimic prostate cancer • Morphology • Disorganized growth pattern • Small, round, poorly-formed glands • Visible nucleoli • Immunohistochemistry • Very patchy/negative staining for basal cells • Possible AMACR positivity

  34. Summary - Reliable morphologic features of PA • Stellate/undulated gland lumina • Pale cytoplasm similar to adjacent benign glands • Presence of completely atrophic glands within the focus • Lack of nuclear enlargement or macronucleoli

  35. Morphological low-power comparison of PAH and PA PAH PA PAH = post atrophic hyperplasia, PA = partial atrophy

  36. So where to draw a line between partial atrophy and atypia/cancer? • Infiltrative glands • Amphophilic cytoplasm • Macronucleoli • Presence of blue mucin • Lack of basal cell markers and/or AMACR positivity with any of the above features

  37. Architectural/cytological features not specific but suggest the benign diagnosis:

  38. Architecture Lobular/circumscribed growth

  39. Pseudo infiltrative appearance – “patch” like growth pattern

  40. Benign glands as reference Similar cytoplasmic character Benign gland

  41. Cellular spindle cell stroma BCH Adenosis Sclerosing adenosis

  42. Complete atrophy BCH Nuclei occupy full cell height

  43. SV Radiation atypia “Random” cytological atypia

  44. Radiation atypia Random cytological atypia, smudgy nuclei, prominent nucleoli, cytoplasmic vacuolization

  45. Conclusions • A systemic approach using constellation of architectural and cytological features necessary to work up atypical small glandular proliferations • Diagnosis relies on constellation of features • Use markers to support your impression, use them as a panel • An expert second opinion can help reduce atypia rate

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