1. March 18 th, 2014 Prostate Pathology Dr. Syeda NaghmanaTauqir

2. Normal prostate gland ~ weighs approx 30 gm ~ is funnel shaped ~ acts as a functional conduit that allows urine to pass from urinary bladder to urethra ~ adds nutritional secretion to sperm to form semen during ejaculation ~ many secretory products, including prostate-specific antigen (PSA)

4. Prostate Gland WHO Classification Epithelial tumours Glandular neoplasms Adenocarcinoma (acinar) 8140/31 Atrophic Pseudohyperplastic Foamy Colloid Signet ring Oncocytic Lymphoepithelioma-like Carcinoma with spindle cell differentiation (carcinosarcoma, sarcomatoid carcinoma) Prostatic intraepithelial neoplasia (PIN) Prostatic intraepithelial neoplasia, grade III (PIN III) Ductal adenocarcinoma Cribriform Papillary Solid Urothelial tumours Urothelial carcinoma Squamous tumours Adenosquamous carcinoma Squamous cell carcinoma Basal cell tumours Basal cell adenoma Basal cell carcinoma

5. Neuroendocrine tumours Endocrine differentiation within adenocarcinoma Carcinoid tumour Small cell carcinoma Paraganglioma Neuroblastoma Prostatic stromal tumours Stromal tumour of uncertain malignant potential Stromal sarcoma Mesenchymal tumours Leiomyosarcoma Rhabdomyosarcoma Chondrosarcoma Angiosarcoma Malignant fibrous histiocytoma Malignant peripheral nerve sheath tumour Haemangioma Chondroma Leiomyoma Granular cell tumour Haemangiopericytoma Solitary fibrous tumour Hematolymphoid tumours Lymphoma Leukaemia Miscellaneous tumours Cystadenoma Nephroblastoma (Wilms tumour) Rhabdoid tumour Germ cell tumours Yolk sac tumour Seminoma Embryonal carcinoma & teratoma Choriocarcinoma Clear cell adenocarcinoma Melanoma Metastatic tumours Prostate Gland WHO Classification

6. Classification: Tumours of the seminal vesicles Epithelial tumours Adenocarcinoma Cystadenoma Mixed epithelial and stromal tumours Malignant Benign Mesenchymal tumours Leiomyosarcoma Angiosarcoma Liposarcoma Malignant fibrous histiocytoma Solitary fibrous tumour Haemangiopericytoma Leiomyoma Miscellaneous tumours Choriocarcinoma Male adnexal tumour of probable Wolffian origin Metastatic tumours

7. Prostatic adenocarcinoma: facts Most cancers arise in the peripheral zone Transition zone enlargement sufficient to cause bladder outlet obstruction usually indicates hyperplasia. However, 8.0% of contemporary transurethral resection specimens disclose carcinoma, and rarely, urinary obstruction results from large-volume periurethral tumour

8. Prostatic adenocarcinoma: diagnosis Prostate needle core biopsy - gold standard! Methods of tissue diagnosis Needle biopsies Transurethral resection of the prostate Suprapubic or Retropubic Enucleation (Subtotal Prostatectomy) Radical Prostatectomy

9. Prostatic adenocarcinoma: diagnosis Submission of Tissue for Microscopic Evaluation in Transurethral Resection and Radical Prostatectomy Specimens Transurethral resection specimens weight 12 g or less submitted in their entirety, usually in 6 to 8 cassettes weight >12 g initial 12 g submitted (6 to 8 cassettes), and 1 cassette/every additional 5 g may be submitted. random chips are submitted generally; (firmer, yellow or orange- yellow appearance, submitted preferentially. If an unsuspected carcinoma found in tissue submitted, involving 5% or less of the tissue examined, the remaining tissue submitted for microscopic examination, especially in younger patients.

10. Radical Prostatectomy A radical prostatectomy specimen: entirety or partially sampled in a systematic fashion – - partial sampling (in the setting of a grossly visible tumor) - tumor, associated periprostatic tissue, margins - entire apical and bladder neck margins - junction of each seminal vesicle with prostate - partial sampling (in the setting of no grossly visible tumor) - submitting the posterior aspect of each transverse slice - along with a mid anterior block from each side - anterior sampling detects the T1c cases arising in the transition zone and extending anteriorly - entire apical and bladder neck margins - junction of each seminal vesicle with prostate

11. Prostatic adenocarcinoma features The histopathology of prostatic cancer, and its distinction from benign glands, rests on a constellation of ~ architectural, ~ nuclear, cytoplasmic and ~ intraluminal features

12. Prostatic adenocarcinoma: diagnosis Tissue diagnosis - gold standard! Architecture ~ infiltrative, small, large or cribriform glands Cell morphology ~ nuclear enlargement ~ nucleolar prominence ~ absence of basal cells (single cell layer)

13. Prostatic adenocarcinoma features Stromal features Ordinary acinar adenocarcinoma lacks a desmoplastic or myxoid stromal response, such that evaluation of the stroma is typically not useful in the diagnosis of prostate cancer. Typically adencarcinoma of the prostate does not elicit a stromal inflammatory response.

14. Prostatic adenocarcinoma features All of the above can be seen in benign mimickers of prostate with the exception of three malignant specific features which have not been described in benign prostate: ~ perineural invasion ~ mucinous fibroplasia (collagenous micronodules), ~ glomerulations

15. Perineural invasion perineural indentation by benign prostatic glands has been reported, the glands in these cases appear totally benign and are present at only one edge of the nerve rather than circumferentially, involving the perineural space, as can be seen in carcinoma

16. Mucinous fibroplasia or collagenous micronodules It is typified by very delicate loose fibrous tissue with an ingrowth of fibroblasts, sometimes reflecting organization of intraluminal mucin.

17. Glomerulations The final malignant specific feature is glomerulations, consisting of glands with a cribriform proliferation that is not transluminal. Rather, these cribriform formations are attached to only one edge of the gland resulting in a structure superficially resembling a glomerulus.

18. Adenocarcinoma with mucinous fibroplasia (collagenous micronodules). Adenocarcinoma with perineural invasion Prostate cancer with glomerulations

19. A. Collagenous micronodules B. Glomeruloid formations C. Perineural invasion

20. intraluminal pink, acellular, dense secretions crystalloids Blue-tinged mucin

21. Criteria Diagnostic of cancer (Major criteria) - Glomerulations - Collagenous micronodules (mucinous fibroplasia) - Perineural invasion Favor cancer (Minor criteria) - Lack basal cells - Nuclei enlarged and uniform prominent nucleoli! hyperchromasia mitotic figures - Cytoplasm amphophilic/basophilic straight luminal borders - Luminal content pink granular/dense secretions basophilic mucin crystalloids

22. Scanning Scan at low magnification (x4) ~ crowded, irregularly shaped or darker glands ~ examine all levels systematically ~ attention at edges (TGiF) ~ examine ALL fragments

23. Microscopic exam Higher magnification - evaluate glands systematically from periphery Basal cells, nuclei, nucleoli, cytoplasm, luminal border, content Compare with adjacent benign glands

24. ~ Atrophy ~ Atypia ? ~ Cancer ?

25. Histoanatomic structuresReactive atypia Seminal vesicle/ejaculatory duct Inflammatory Ischemic Cowper's gland Radiation Paraganglion Verumontanum mucosal glands (hyperplasia) Metaplasia Mucinous Mesonephric gland remnants (hyperplasia) Nephrogenic (adenoma) AtrophyProstatic hyperplasia Simple (lobular) Basal cell hyperplasia Sclerotic Cystic Linear (streaming) Benign nodular hyperplasia, small gland pattern (Clear cell) cribriform hyperplasia Sclerosing adenosis Post-atrophic hyperplasia (partial atrophy) InflammationAtypical adenomatous hyperplasia (adenosis) Usual prostatitis with preservation artifacts Granulomatous prostatitis, nonspecific Xanthogranulomatous prost atitis (xanthoma) Malakoplakia Modern Pathology (2004) 17, 328–348, advance online publication, 13 February 2004;doi:10.1038/modpathol.3800055 Benign mimickers of adenocarcinoma

26. (a) Low-power photomicrograph showing seminal vesicle with dilated central glands and peripheral small 'adenotic' glands. (b) High-power photomicrograph of seminal vesicle glands showing nuclear atypia within luminal cells and focal cytoplasmic lipofuscin pigment.

27. Cowper's gland. Note uniform collection of mucinous acini with excretory duct (left).

28. Atrophy in association with antiandrogen effects—note prominent basal cell layer and tiny irregular acini with pseudoinfiltrative growth pattern.

29. Patterns of atrophy (a) Simple lobular(b) Sclerotic (c) Cystic(d) Linear or streaming

30. Patterns of atrophy (a) Atrophy with pseudoinfiltrative growth pattern. (b) High molecular weight keratin stain showing prominent basal cell staining.

31. Post-atrophic hyperplasia (a) Low-power photomicrograph showing mixture of shrunken atrophic glands and ones with more abundant clear cytoplasm. At the periphery there are some tiny apparent neoacini. (b) High-power photomicrograph showing admixture of small atrophic and hyperplastic glands—note absence of significant nuclear atypia.

32. Chronic prostatitis Active chronic prostatitis with reactive glandular atypia. (a) Low-power of needle biopsy. (b) High-power— note nuclear atypia in some glands.

33. Prostatic infarct with reactive atypia (a) Low power (b) High power showing glands at edge of infarcted area—note squamoid features and nuclear atypicality.

34. Basal cell hyperplasia in needle biopsy (a) Low-power appearance showing prominent basophilic glands. (b) High-power photomicrograph showing budding and proliferation of small, uniform, dark basal cells

35. Benign nodular hyperplasia Small gland pattern of benign nodular hyperplasia. Note several small- to medium-sized, irregular acini embedded in a cellular stroma.

36. Prostatic adenocarcinoma BEWARE !!! Variants of prostatic adenocarcinoma

37. Prostatic adenocarcinoma: variants Atrophic carcinoma Cancer acini with round dilated and distorted lumina Higher magnification shows acini lined by flattened cells with scant cytoplasm and enlarged nuclei with prominent nucleoli

38. Prostatic adenocarcinoma: variants Pseudohyperplastic carcinoma type A. Branching and papillary type of growth is typical. B. Perineural invasion. C Higher magnificati on,showing prominent nucleoli.

39. Prostatic adenocarcinoma: variants Foamy gland and mucinous (colloid) types A.Pale eosinophilic finely vacuolated cytoplasm, distinct cell membranes, basal nuclei and small punctuate nucleoli. B Clear finely vacuolated cytoplasm and hyperchromatic nuclei with indistinct nucleoli. C & D Mucinous (colloid carcinoma). Abundant luminal mucin expands the malignant acinar lumina.

40. Prostatic adenocarcinoma: variants Foamy gland type

41. Prostatic adenocarcinoma: variants Signet ring like and sarcomatoid Signet-ring-like cancer cells display nuclear displacement and indentation by clear cytoplasmic vacuoles This sarcomatoid prostate carcinoma is biphasic, with a glandular component and a sarcomatoid component exhibiting malignant spindle cell proliferation

42. ASAP In case of ATYP Glands, Suspicious (ASAP) What steps to take

43. ATYP Glands, Suspicious (ASAP) Proper work-up (immunos, levels) Consultation (intra or extra-departmental) Remember: Not an entity, but diagnostic uncertainty, seen in ~5% of biopsies ~40% of repeat biopsies show carcinoma Sign out with comment/note: - Insufficient findings for definitive diagnosis - Clear recommendation for a repeat biopsy

44. ASAP Repeat biopsy recommendations: Within 3 months Increased sampling from “atypical” sites Increased diagnostic yield on repeat biopsy If repeat negative – close follow-up Additional biopsies as necessary Cancer usually detected on 1st or 2nd biopsy

45. Cancer How many glands for cancer diagnosis? Only one? - if around a nerve (PNI) - appropriate morphology - confirmatory immunos! Depends on the features, location, immunos Three glands – reasonable minimum! Algaba et al. Cancer 1996; 78: 376

46. Protocol for the Examination of Specimens from Patients with Carcinoma of the Prostate Gland Protocol applies to invasive carcinomas of the prostate gland. Based on AJCC/UICC TNM, 7th edition Protocol web posting date: Feb, 2011 PROSTATE GLAND: Needle Biopsy The Gleason grade and score and tumor extent measures should be documented for each positive specimen (container). The essential information in each specimen could be conveyed with a simple diagnostic line such as, “Adenocarcinoma, Gleason grade 3 + 4 = score of 7, in 1 of 2 cores, involving 20% of needle core tissue, and measuring 4 mm in length.” (See “Explanatory Notes.”) Histologic Type Adenocarcinoma (acinar, not otherwise specified) Other (specify): __________________________ Histologic Grade (Note B) Gleason Pattern (If 3 patterns present, use most predominant pattern and worst pattern of remaining 2) ___ Not applicable ___ Cannot be determined Primary (Predominant) Pattern Secondary (Worst Remaining) Pattern Total Gleason Score: ____ Tumor Quantitation (Note C) Number cores positive: ____ Total number of cores: ____ And Proportion (percent) of prostatic tissue involved by tumor: ____% or Total linear millimeters of carcinoma: ___ mm or Total linear millimeters of needle core tissue: ___ mm or Proportion (percent) of prostatic tissue involved by tumor: ____% and Total linear millimeters of carcinoma: ___ mm Total linear millimeters of needle core tissue: ____mm *Proportion (percentage) of prostatic tissue involved by tumor for core with the greatest amount of tumor: ____% Periprostatic Fat Invasion (document if identified) (Note D) Seminal Vesicle Invasion (document if identified) (Note D) *Lymph-Vascular Invasion *Perineural Invasion (Note E) *Additional Pathologic Findings *___ None identified *___ High-grade prostatic intraepithelial neoplasia (PIN) (Note F) *___ Atypical adenomatous hyperplasia (adenosis) *___ Inflammation (specify type): ___________________________ *___ Other (specify): ___________________________ *Comment(s) http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Pr ostate_11protocol.pdf HGPIN significance Pts with 4 or more cores with HGPIN appear to be at increased risk of subsequent detection of prostatic adenocarcinoma.

47. Squamous cell carcinoma Basaloid (basal cell) adenoid cystic carcinoma Urothelial (transitional cell) carcinoma Small cell carcinoma Lymphoepithelioma-like carcinoma Sarcomatoid carcinoma

48. Protocol for the Examination of Specimens from Patients with Carcinoma of the Prostate Gland Protocol applies to invasive carcinomas of the prostate gland. Based on AJCC/UICC TNM, 7th edition Protocol web posting date: February 1, 2011 PROSTATE GLAND: Needle Biopsy The Gleason grade and score and tumor extent measures should be documented for each positive specimen (container). The essential information in each specimen could be conveyed with a simple diagnostic line such as, “Adenocarcinoma, Gleason grade 3 + 4 = score of 7, in 1 of 2 cores, involving 20% of needle core tissue, and measuring 4 mm in length.” (See “Explanatory Notes.”) Histologic Type Adenocarcinoma (acinar, not otherwise specified) Other (specify): __________________________ Histologic Grade (Note B) Gleason Pattern (If 3 patterns present, use most predominant pattern and worst pattern of remaining 2) ___ Not applicable ___ Cannot be determined Primary (Predominant) Pattern Secondary (Worst Remaining) Pattern Total Gleason Score: ____ Tumor Quantitation (Note C) Number cores positive: ____ Total number of cores: ____ And Proportion (percent) of prostatic tissue involved by tumor: ____% or Total linear millimeters of carcinoma: ___ mm or Total linear millimeters of needle core tissue: ___ mm or Proportion (percent) of prostatic tissue involved by tumor: ____% and Total linear millimeters of carcinoma: ___ mm Total linear millimeters of needle core tissue: ____mm *Proportion (percentage) of prostatic tissue involved by tumor for core with the greatest amount of tumor: ____% Periprostatic Fat Invasion (document if identified) (Note D) Seminal Vesicle Invasion (document if identified) (Note D) *Lymph-Vascular Invasion *Perineural Invasion (Note E) *Additional Pathologic Findings *___ None identified *___ High-grade prostatic intraepithelial neoplasia (PIN) (Note F) *___ Atypical adenomatous hyperplasia (adenosis) *___ Inflammation (specify type): ___________________________ *___ Other (specify): ___________________________ *Comment(s) http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Pr ostate_11protocol.pdf HGPIN significance Pts with 4 or more cores with HGPIN appear to be at increased risk of subsequent detection of prostatic adenocarcinoma.

49. Well circumscribed nodule; Glands: single, separate, closely packed, uniform, back to back, no infiltration into adjacent benign tissue; Rounded/oval, medium-sized glands (larger than pattern 3), more abundant and pale-staining cytoplasm than other patterns. Fairly circumscribed nodules of single, separate glands; minimal infiltration at the edge of the tumor nodule; Glands are more loosely arranged and not as uniform as pattern 1. Discrete glandular units; Smaller glands than in Gleason pattern 1 or 2; Clear infiltrates into normal prostate glands; Marked variation in size and shape with amphophilic cytoplasm; Smoothly circumscribed small cribriform nodules of tumor. Fused glands in chains, nests, or masses; Ill-defined glands with poorly formed lumina; Large cribriform glands; Cribriform glands with an irregular border; Hypernephromatoid. No glandular differentiation; Solid sheets, cords, or single cells; Comedocarcinoma: central necrosis surrounded by papillary, cribriform, or solid masses