Biopsy interpretation of prostate disease

Inflammatory, benign, malignant, mimics

1. Interpretation of prostate biopsy Presenter: Dr.Shwetha.B Moderator: Dr.Anisha.T.S

2. PROSTATE The prostate is exocrine, pear-shaped, accessory structure of the male reproductive system that weighs up to 20 g in the normal adult male that surrounds the urethra in the pelvic cavity . It lies immediately inferior to the bladder, posterior to the pubic symphysis , and anterior to the rectum. It is shaped like an inverted rounded cone with a larger base, which is continuous above with the neck of the bladder, and a narrower apex, which rests below on the pelvic floor .

3. There is a partial capsule enclosing the posterior and lateral aspects of the prostate but the anterior surfaces are bounded by the a fibromuscular stroma . The anterior fibromuscular stroma contains no glandular tissue, only of collagenous stroma and muscle fibres . Prostate has a number of ill-defined lobes ,which are described as four zones of unequal size.

4. • The transition zone surrounds the proximal prostatic urethra and comprises about 5% of the glandular tissue. • The central zone (20%) surrounds the ejaculatory ducts. • The peripheral zone makes up the bulk of the gland (approximately 70%).

5. Peripheral and central zones collectively referred to as outer prostate; transition zone and anterior fibromuscular layer termed inner prostate .

6. The different zones of the prostate are important because they tend to be the sites of different disease processes. Most cases of carcinoma of the prostate arise in the peripheral zone, while the transition zone harbours almost all cases of benign nodular hyperplasia Secretions from the prostate, together with secretions from the seminal vesicles, contribute to the formation of semen , which helps in liquification of semen.

7. HISTOLOGY The prostate gland is composed of glands and stroma . The stroma is a mixture of collagenous fibrous tissue and smooth muscle fibres . The branched tubulo acinar glands,show a convoluted pattern with the epithelium thrown up into folds, sometimes into almost a papillary pattern.

8. The main epithelial cell type is the tall columnar secretory cell with prominent round basal nuclei, reddish granular chromatin and pale-staining cytoplasm. There is also small, flat, basal cells with blue-grayish, semi-transparent chromatin at the base of the gland in contact with the basement membrane and scattered neuroendocrine cells.

9. These basal cells act as stem cells . Distinction between a prostatic duct and acinus primarily is based on its architecture . Ducts consist of elongated tubular structures with branching and the proximal portions of the ducts are lined by urothelium similar to the urethra as opposed to acini , which are more rounded structures grouped in lobular units. Smaller ducts cut on cross section are indistinguishable from acini

10. Inspissated secretions may accumulate in some glands to form well circumscribed round to oval concentric lamellar rings called - corpora amylacea .

11. Lipofuscin pigment seen in secretory cells considered as“wear and tear” products in aging cells with brown purple appearance.

12. Peripheral nerves are of importance because of the high frequency with which the loose connective space that surrounds them is involved by adenocarcinomas .

13. SAMPLING TECHNIQUES Needle biopsy Transurethral resection of prostate (TURP) Radical Prostatectomy

14. NEEDLE BIOPSY It is obtained by an 18-guage spring driven biopsy gun introduced transrectally or transperineal with or without radiologic guidance. TECHNIQUES Sextant Extended Saturation

15. Prostate biopsy Routine sextant biopsies sample the parasagittal midlobe region of the prostate Disadvantage -It misses a substantial proportion of clinically significant cancers (approximately 20%) because of sampling errors, especially in the anterior horns” and the lateral aspects of the peripheral zone. 12-core biopsy that includes a standard sextant sampling , six additional cores from the lateral peripheral zone on each side is taken in extended.

16. This approach is supported by the zonal anatomy of the prostate and the origin of the tumor . Saturation biopsy is an infrequently utilized extensive sampling approach and is utilized for staging minute focus of Gleason score 6 prostate cancer. Transition zone of the prostate is also regularly sampled. On average, 23 (range, 14–45) biopsy cores are taken. Specimens should be considered unsatisfactory if only minimal or no prostatic glandular or stromal tissue is present. Cores of prostatic tissue containing only stroma are not necessarily unsatisfactory specimens.

17. CLINICAL CORRELATES WITH BIOPSY DIGITAL RECTAL EXAMINATION - Asymmetry, induration , and discrete hard nodules are findings on digital rectal examination (DRE) that are suspicious for cancer. IMAGING TECHNIQUE - Transrectal ultrasound (TRUS) prostate cancers appear as hypoechoic relative to the normal peripheral zone, although tumors may also be hyperechoic or isoechoic but has poor sensitivity and specificity. Over the last decade, endorectal magnetic resonance imaging (MRI) and, more recently, multiparametric MRI ( mpMRI ) have increasingly been used in clinical staging of localized prostate cancer patients.

18. PROSTATE-SPECIFIC ANTIGEN PSA is a serine protease synthesized in the ductal epithelium and prostatic acini . PSA is secreted into the lumina of the prostatic ducts to become a component of the seminal plasma. It reaches the serum by diffusion. It is used as a screening tool, has remained the mainstay biomarker for the prostate cancer diagnosis and management.

19. Total Serum Prostate-Specific Antigen The risk of cancer is proportional to the serum PSA level. The most commonly used cutoff for PSA is 4 ng /Ml USE: Following radical prostatectomy, the serum PSA should drop to undetectable levels. Elevated serum PSA levels following radical prostatectomy (0.2 ng / mL ) indicate recurrent or persistent disease .

20. Benign prostate conditions like prostatitis , infarct, instrumentation of the prostate, and ejaculation also produces serum PSA. Many patients screened have PSA values in the 2-10 ng / mL range, and total PSA does not perform well in this so-called as grey zone. To overcome this different types of PSA measurements are used in clinical practice :

21. Prostate-Specific Antigen Velocity (Rate of Change of Prostate-Specific Antigen) A higher rate of PSA increase is more suspicious for malignancy than a single PSA measurement; used in patients with PSA levels of 4–10  ng / mL If baseline PSA is 4–10  ng / mL , increase of ≥0.75  ng / mL per year is considered as suspicious. Those men who were diagnosed as prostate cancer had an increased rate of rise in PSA as compared to men who did not have prostate cancer.

22. PSA density Calculated by dividing the total serum PSA level by the estimated gland volume determined by transrectal ultrasonography measurement. Serum PSA density reflects the PSA produced per gram of prostate tissue. Benign prostate tissue also contributes to serum PSA levels, although not to the same extent as does cancer. Men with enlarged hyperplastic prostate glands will have higher total serum PSA levels than men with small glands.

23. Age-related PSA 40–49 y; ≤2.5  ng / mL 50–59 y; ≤3.5  ng / mL 60–69 y; ≤4.5  ng / mL 70–79 y; ≤6.5  ng /Ml Useful in younger men who generally have lower baseline PSA levels.

24. Emerging Biomarkers PSA derivatives -Various forms of PSA in blood, including free PSA ( fPSA ), complex PSA ( cPSA ), ProPSA and benign PSA (BPSA). Prostate cancer antigen 3 α- Methylacyl-CoA racemase (AMACR) Glutathione s- transferase π 1 ( GSTP1)

25. Categories of prostatic diseases are : Inflammatory lesions Nodular hyperplasia Carcinoma

26. INFLAMMATORY CONDITIONS Acute and chronic prostatic inflammation Granulomatous prostatitis Mycobacterial prostatitis Nonspecific granulomatous prostatitis Abscess Malakoplakia

27. ACUTE AND CHRONIC PROSTATIC INFLAMMATION Acute bacterial prostatitis Cause :E. coli, other gram-negative rods, enterococci , and staphylococci. Intraprostatic reflux of urine from the posterior urethra or from the urinary bladder,occasionally lymphohematogenous route, catheterization, cystoscopy , or resection procedures.

28. . Signs and Symptoms: fever, chills, and dysuria . On rectal examination the prostate is exquisitely tender and boggy. Microscopy: It consists of sheets of neutrophils within and around acini , intraductal desquamated cellular debris, stromal edema, and hyperemia. The diagnosis can be established by urine culture and clinical features.

29. Chronic bacterial prostatitis Symptoms:Low back pain, dysuria , and perineal and suprapubic discomfort. history of recurrent urinary tract infections. Chronic abacterial prostatitis is the most common form of prostatitis seen it is indistinguishable from chronic bacterial prostatitis in terms of signs and symptoms, but there is no history of recurrent urinary tract infection. Expressed prostatic secretions contain more than 10 leukocytes per high-power field, but bacterial cultures are uniformly negative. Diagnosis of chronic bacterial prostatitis depends on the demonstration of leukocytosis in the expressed prostatic secretions, along with positive bacterial cultures.

30. It is preferable to diagnose inflamed prostate specimens as showing “acute or chronic inflammation” as opposed to “acute or chronic prostatitis .”

31. Benign Prostatic Hyperplasia or Nodular Hyperplasia Most common benign prostatic disease. It results from nodular hyperplasia of prostatic stromal and epithelial cells Age group : Histologic evidence of BPH can be seen in approximately 20% of men 40 years of age, that increases to 70% by age 60 and to 90% by age 80. Site: Periurethral region of the prostate.

32. Etiology and Pathogenesis: Androgens , which are required for the development of BPH, not only increase cellular proliferation, but also inhibit cell death.

33. Symptoms: Urinary obstruction Increased urinary frequency Nocturia Difficulty in starting and stopping the stream of urine Overflow dribbling Dysuria (painful micturition ) Microscopy: Glandular component is made up of small and large acini , some showing papillary infoldings and projections containing central fibrovascular cores .

34. In Stroma identification of nodules is diagnostic for hyperplasia. Which is composed of loose mesenchyma containing prominent small round vessels. pure stromal nodules composed almost entirely of smooth muscle.

35. Within hyperplastic areas, there often is an infiltrate of lymphocytes and plasma cells around the glands. The histologic diagnosis of nodular hyperplasia does not relate to specific histologic findings but to the clinical findings of an enlarged prostate resulting in obstructive symptoms.

36. Needle biopsy specimens should not be diagnosed as showing hyperplasia. Because: Needle biopsy specimens do not even sample the transition zone. Histologic findings on needle biopsy, with the exception of stromal nodules, do not correlate with size of the prostate or urinary obstructive symptoms. Falsely reassure the urologist that he has sampled the palpable or hypoechoic lesion of concern. Hence the diagnosis as “benign prostate tissue” is used.

37. Treatment: Surgical : Transurethral resection of the prostate (TURP) has been the gold standard in terms of reducing symptoms Medical : α- blockers, Inhibitors of 5- α- reductase

38. Intraepithelial Proliferative Lesions PIN consists of architecturally benign prostatic acini or ducts lined by cytologically atypical cells. PIN is subcategorized into two grades, low- and high-grade PIN, distinction between LGPIN and HGPIN is the finding of prominent nucleoli in HGPIN. Only high-grade PIN is diagnosed and reported in modern practice. First, pathologists cannot reproducibly distinguish between LGPIN and benign prostate tissue. Second, when LGPIN is diagnosed on needle biopsy, these patients are at no greater risk of having carcinoma on repeated biopsy than are men with a benign biopsy finding .

39. Low-grade prostatic intraepithelial neoplasia

40. High-grade prostatic intraepithelial neoplasia HGPIN is most commonly found in the peripheral zone of the prostate, and coexists with cancer in > 85% of cases

41. Prognosis and predictive factors The clinical importance of recognizing HGPIN and extent of HGPIN in needle biopsies is a strong predictor of cancer on subsequent biopsy. The cancer yield in repeat biopsies after an initial diagnosis of isolated HGPIN is 20-25%,

42. For men with an isolated HGPIN involving only one biopsy core, repeat biopsy may not be necessary within the first year in the absence of other clinical indicators of cancer. However, follow-up biopsy is recommended for patients with multifocal HGPIN (more than one core with HGPIN) within 1 year. HGPIN alone should not lead to definitive therapy

43. General Approach to Prostate Needle Biopsy Evaluation Use benign glands as reference, and study their low-power architectural features and high-power cytological features. Scan biopsy cores to look for glands that appear different from and do not fit in with benign glands Evaluate low-power architectural features and high-power cytological features of atypical glands

44. WHO classification of tumours of the prostate Epithelial tumours Glandular neoplasms Acinar adenocarcinoma - Atrophic Pseudohyperplastic Microcystic Foamy gland Mucinous (colloid) Signet ring-like cell Pleomorphic giant cell Sarcomatoid Prostatic intraepithelial neoplasia - high grade Intraductal carcinoma Ductal adenocarcinoma Urothelial carcinoma Squamous neoplasms Basal cell carcinoma

45. Neuroendocrine tumours - Adenocarcinoma with neuroendocrine differentiation Well-differentiated neuroendocrine tumour Small cell neuroendocrine carcinoma Large cell neuroendocrine carcinoma Mesenchymal tumours - Stromal tumour of uncertain malignant potential Stromal sarcoma Leiomyosarcoma Rhabdomyosarcoma Leiomyoma Angiosarcoma Haematolymphoid tumours -Diffuse large 8-cell lymphoma Chronic lymphocytic leukaemia Follicular lymphoma Mantle cell lymphoma Miscellaneous tumours -Cystadenoma Nephroblastoma Rhabdoid tumour

46. Acinar adenocarcinoma It is an invasive carcinoma consisting of neoplastic prostatic epithelial cells with secretory differentiation Patient age is strongly related to the detection of prostate cancer, with most cancers detected in men aged > 60 years.

47. Etiology : Prostate cancer, develops as the result of multiple, complex molecular events of initiation, which includes: Loss of specific genomic sequences that lead to inactivation of tumor suppressor genes Gain of specific chromosome regions that are associated with activation of oncogenes . In prostate carcinogenesis, androgen receptor is believed to play a central role. The most common chromosomal aberrations demonstrated in prostatic carcinoma are TMPRSS2: ETS gene fusions, PTEN deletion, TP53 gene mutation, Gain of chromosome 7.

48. Signs and symptoms Clinical symptoms are usually a manifestation of locally advanced or metastatic disease. Manifestations of locally advanced prostate cancer include urinary frequency and difficulty urinating, which can simulate benign prostatic hyperplasia, acute urinary retention, and haematuria . Metastatic prostate cancer can produce bone pain, pathological fractures, lower extremity oedema , and neurological symptoms

49. Histological Features Considered Specific for diagnosis of Cancer Three features have not, been reported in benign glands and are considered specific for prostate cancer : Mucinous fibroplasia ( collagenous micronodules ) Glomerulation Perineural invasion

50. Mucinous fibroplasia ( collagenous micronodules ) It consists of delicate loose fibrous tissue with an ingrowth of fibroblasts often associated with intraluminal blue mucinous secretions.

51. Glomerations It is cribriform proliferation which are attached to only one edge of the gland resulting in a structure superficially resembling a glomerulus

52. Perineural invasion Tight circumferential or near circumferential encircling of a nerve fiber by cancer glands

53. In the majority of prostate biopsies, the diagnosis of cancer relies on histological features other than cancer specific features Architectural features Presence of crowded small glands compared to larger benign glands is suspicious but not diagnostic of carcinoma.

54. More specific feature of carcinoma is the presence of a linear row of atypical glands spanning the width of the core.

55. Small atypical glands on both sides of a benign gland.

56. Mimickers of cancer may appear infiltrative, as a collection of glands between benign glands, but they do not intercalate as isolated glands between and around benign glands. It is uncommon for a diagnosis of tumour to be based solely on the architectural presence of small glands situated next to larger benign glands

57. Nuclear features The most widely recognized cytological feature of prostate adenocarcinoma is prominent nucleoli.

58. However, it should not be the sole criterion used to establish the diagnosis. Because prominent nucleoli may be seen in various mimickers of cancer. A lack of prominent nucleoli may reflect a Sampling problem-for example, if areas of the tumour with prominent nucleoli are not biopsied or are overstained , or thick sections obscure nuclear detail..

59. Additional nuclear features : Nuclear enlargement and hyperchromasia . Mitotic figures and apoptotic bodies are more common in carcinoma than in benign glands

60. Cytoplasmic features Prostate cancer may show more amphophilic cytoplasm than the surrounding benign glands, which have pale to clear cytoplasm . Abundant cytoplasm with straight luminal borders in glands is also a feature of cancer.

61. Intraluminal contents Luminal contents can also aid in the diagnosis of prostatic adenocarcinoma . Crystalloids are dense eosinophilic crystal-like structures that appear in various geometric shapes such as rectangular, hexagonal, triangular, and rodlike structures .

62. Other diagnostic intraluminal criteria are blue-tinged mucinous and pink dense amorphous acellular secretions , seen either alone or in combination amorphous secretions should be distinguished from corpora amylacea .

63. Retraction artefact is more commonly seen around prostate cancer glands is stromal response to carcinoma but is not entirely specific for malignancy. Tumour spread The infiltration of periprostatic fat is clear evidence of extraprostatic extension, often associated with perineural invasion. Metastatic spread to regional lymph nodes and distant sites occurs secondarily to lymphovascular or venous invasion,

64. Diagnosis of /limited (minimal) adenocarcinoma on needle biopsy: Limited adenocarcinoma are those measuring < 1 mm or involving < 5% of needle core tissue.

65. The adjunctive study for the confirmation of a diagnosis of small adenocarcinomas is immunohistochemistry with antibodies directed against basal cells. Antibodies reactive with high-molecular weight cytokeratins (such as 34ßE12 , also known as CK903) and p63 are the most widely used. These antibodies may be used singly or combined in a cocktail known as a triple stain, containing antibodies for AMACR (also called P504S and racemase ), p63 , and 34ßE12.

66. IDENTIFICATION OF BASAL CELLS ON HEMATOXYLIN AND EOSIN–STAINED SECTIONS The problem of identifying basal cells on H&E-stained sections is that there may be cells that closely mimic basal cells like fibroblast. Consequently, in a focus that is consistent with cancer architecturally and which has other features supportive of the diagnosis of carcinoma at higher power, a search for basal cells by light microscopy may be counterproductive. Immunohistochemistry may be necessary to more definitively identify basal cells.

67. Prognosis and predictive factors Reporting of prognostic factors of prostate cancer in needle biopsies serves to predict histological findings and risk for disease progression in the radical prostatectomy specimen. The College of American Pathologists (CAP) recommends reporting Histological type Number of cores positive for cancer Total number of cores Linear cancer extent and/or proportion of prostatic tissue involved by carcinoma. Gleason score Extraprostatic extension, and seminal vesicle invasion.

68. The most important tissue-based predictive and prognostic factor is Gleason grade . Prostate cancer grading Recent significant changes were introduced in 2005 International Society of Urologic Pathology Consensus Conference, and further modifications were done in 2014. The resulting grading system has been termed as “ modified Gleason grading system.” Two unique aspects of the Gleason grading system are that it is based solely on the architectural pattern of the tumour and that the grade is defined as the sum of the two most common grade patterns (the Gleason score).

69. The primary (predominant) and secondary (second most prevalent) architectural patterns are assigned a number from 1 (the most differentiated) to 5 (the least differentiated). On biopsy, the most common and highest grade patterns on a given core are added to result in the Gleason score Gleason score ranges from 2 to 10.

70. The 2005/2014 Modifications of Gleason Grading System The definitions of patterns 1 and 2 are the same as Gleason’s original description . Gleason patterns 1 and 2 consist of fairly circumscribed nodules of closely packed glands which are uniform in their size and shape with slightly more variation in pattern 2 than pattern 1.

71. Scores 2-5 and Gleason pattern 1 or 2 are no longer assigned on biopsy, and only rarely on other specimens. Because (1) there is poor reproducibility, even among experts; (2) there is poor correlation with radical prostatectomy grade, with almost all cases showing higher grade at resection; and (3) a diagnosis of Gleason score 2-5 may mislead clinicians and patients into believing that the patient has an indolent tumour needle biopsy. (4) one may not see the border of the entire lesion.

72. Gleason Pattern 3 Consists of variably sized individual glands,smaller than Gleason patterns 1 and 2 that are present in well- formed and discrete units.

73. The presence few poorly formed glands at high magnification,which could represent a tangential section off of adjacent small well-formed glands, Is still consistent with Gleason pattern 3 .

74. Key differences from previous grading system : “ Cribriform glands” are not allowed in Gleason pattern 3 “Individual cells” are not allowed in Gleason pattern 3 Application The most common pattern encountered in needle biopsy specimens Minute foci of individual, infiltrating tumor glands seen frequently in needle biopsy represent Gleason score 3 + 3 = 6 Pure Gleason score 3 + 3 = 6 at radical prostatectomy is incapable of regional lymph node metastasis; same however does not apply in the biopsy settings.

75. Gleason Pattern 4 Fused glands -ill-defined glands or cluster with poorly formed glandular lumina where tangentially sectioning is ruled out

76. Cribriform glands Glomeruloid glands, a variant of cribriform glands, are also graded as pattern 4

77. Application in clinical practice Presence of >5% Gleason pattern 4 typically is considered clinically significant prostate cancer and usually necessitates definitive therapy. Cribriform Gleason pattern 4 is specifically considered unfavorable as it is associated with clinically aggressive disease and independently predicts adverse outcomes and hence should be documented in the report

78. Gleason Pattern 5 Consists of sheets of tumor, individual cells, and cords of cell Comedonecrosis , defined by intralumi - necrotic cells and/or karyorrhexis , even if present in cribriform glands.

79. Application in clinical practice Any amount of pattern 5 is clinically significant and puts the patient in the high-risk group category. In needle biopsy, pattern 5 should be included in the final Gleason score as secondary pattern even when present in an amount less than the secondary pattern

80. REPORTING GLEASON GRADE ON BIOPSY Pathologists to report the grades of each core separately as long as the cores are submitted in separate containers or the cores are in the same container yet specified by the urologist as to their location (i.e., by different color inks). As a consequence, the core with the highest grade tumor can be selected by the clinician as the grade of the entire case to determine treatment. In cases with multiple fragmented cores provided in a jar, only an overall Gleason score for the jar can be assigned.

81. Gleason grading system has several deficiencies that may have misleading clinical implications. Gleason score 6 is in the middle of the 2–10 numerical scale, patients may assume that they have moderately aggressive cancer even though Gleason score 6 prostate cancer is the least aggressive tumor. A Gleason score of 7 can be derived from either 3 + 4 or 4 + 3: yet treatment decisions for prostate cancer have often relied on the simplified single Gleason score of 7

82. Benign Mimics of Prostate Carcinoma Adenosis /Atypical Adenomatous Hyperplasia The diagnosis of adenosis on needle biopsy is more difficult, since it is more difficult to appreciate the architectural pattern on needle biopsy .

83. ATROPHY It is considered to be a process affecting the elderly. There are distinct histologic variants of atrophy, which can be classified as (1)simple atrophy; (2) simple atrophy with cyst formation; (3) postatrophic hyperplasia; and (4) partial atrophy.

84. Postatrophic hyperplasia Lobulated collection of small basophilic and round acini surrounding a central dilated “feeder” duct. Stroma is sclerotic and contains inflammation. Acini lined by low cuboidal cells with scant cytoplasm, nuclei are regular and devoid of hyperchromasia , but the nucleoli may be prominent. Compared to atrophy, gland-forming adenocarcinomas of the prostate typically have a greater amount of cytoplasm, neoplastic glands are not as basophilic.

85. Partial atrophy Most common benign mimicker of prostatic carcinoma on needle biopsy. It is composed of crowded pseudoinfiltrative glands with reduced luminal cytoplasm. The glands are often angulated and preserved lateral cytoplasm is characteristic . Nucleoli may be enlarged and some cases have visible nucleoli.

86. The presence of crowded glands with pale cytoplasm may lead to an overdiagnosis of low-grade adenocarcinoma . At higher power, however, the glands have benign features characterized by undulating luminal surfaces with papillary infolding .

87. Basal cell hyperplasia Basal cell hyperplasia is typically seen as a part of the spectrum of benign prostatic hyperplasia in transition zone specimens, may also affect the peripheral zone and may be encountered in needle biopsies .

88. Clear Cell Cribriform Hyperplasia Nodular proliferation of crowded cribriform glands, Strikingly prominent basal cell layer around many cribriform glands an important clue in the differential diagnosis with invasive carcinoma

89. SCLEROSING ADENOSIS A well-circumscribed nodule composed of variably sized and shaped (often compressed) glands and small clusters of epithelial cells embedded in a cellular, often myxoid stroma . The clusters contain both a continuous basement membrane and a layer of basal cells.

90. A rather unique feature of sclerosing adenosis is the presence of a hyaline sheath–like structure around some of the glands . The glands in ordinary adenocarcinoma lack such a collarette and have a “naked” appearance as they infiltrate the stroma .

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