1. QA CONFERENCE Conf #1, May 23, 2012 By Dr. E. Ravinsky

2. CASE 1 54 year old female Right breast core biopsy Central calcs R/O DCIS Moderate probability Magnification x 4

3. CASE 1 Magnification x 20

4. CASE 1 Magnification x 20

5. Case 1

6. CASE 1 Magnification x 20

7. Case 1 DiagnosisPathologist or resident ADH versus florid UDH CK5/6 immuno will help 1 Pathologist ADH Do CK5/6 to rule out UDH 1 Pathologist ADH (at most)1 Pathologist Favour UDH over ADH Consider CK5/6 1 Resident Fibrocystic change with florid UDH Do CK5/6 1 Resident Florid duct hyperplasia1 Pathologist High grade DCIS1 Pathologist

8. CASE 1 Immunohistochemistry CK5/6

9. CASE 1 The answer is: Atypical duct hyperplasia

10. Case 2 50 year old female Right breast core biopsy Calcs lower aspect R/O DCIS Magnification x 2

11. Case 2 Magnification x 4

12. Case 1 Magnification x 20

13. Case 2 Magnification x 10

14. Case 2 Magnification x 20

15. Case 2 DiagnosisPathologist or Resident ADH3 Pathologists 1 Resident Columnar cell hyperplasia with atypia 1 Pathologist Low grade DCIS1Pathologist High grade DCIS Suspicious for invasion 1 Resident

16. Case 2 The answer is: Atypical duct hyperplasia

17. Atypical Duct Hyperplasia DEFINITION: A proliferative lesion that fulfills some, but not all, of the features of duct carcinoma in situ Diagnosis is based on quantitative and qualitative features

18. Atypical Duct Hyperplasia Quantitative features: One duct with qualitative features of DCIS Ducts with qualitative features of DCIS less than 2.0 mm across

19. Atypical Duct Hyperplasia Qualitative features: Presence of architectural or cytologic features of DCIS mixed with features of usual duct hyperplasia Can have a cribriform or solid pattern Can have cytologic atypia  Nuclear enlargement  Nuclear hyperchromasia  Irregular chromatin pattern  Enlarged pleomorphic nucleoli  Atypical cells have distinct cell borders

20. Atypical Duct Hyperplasia Usual duct hyperplasia Cellular proliferation has a syncytial appearance because individual cell borders are inconspicuous May have streaming appearance Microlumens are irregular in size, irregular in shape (slit- like, ovoid, crescentic, serpeginous) Cells surrounding lumens are not oriented. Ductal cells tend to be parallel to the lumina Atypical duct hyperplasia Monomorphic population of cells with distinct cell borders Can have solid growth pattern Can have cribriform growth pattern in which microlumens are round Ductal cells are oriented radially around the lumens In columnar cell hyperplasia with atypia, cells are columnar Atypia is architectural:  Cribriform  Cell bridges  Roman arches  Micropapillary  Radial orientation of nuclei

21. Atypical Duct Hyperplasia Usual duct hyperplasia: Cytoplasm may be reduced, giving the cells an increased nuclear/cytoplasmic ratio, but the nuclei are not enlarged Cell borders are indistinct Cytoplasm is amphophilic or weakly eosinophilic and homogenous Cytoplasm may be vacuolated, but true intracytoplasmic lumens are not identified Atypical duct hyperplasia: Nuclear enlargement leading to an increased nuclear/cytoplasmic ratio Nuclear hyperchromasia and an irregular chromatin pattern Enlarged, pleomorphic nucleoli Distinct cell borders May have intracytoplasmic lumena containing muin

22. Florid Duct Hyperplasia

23. Case 3 85 Year female Unguided core biopsy right breast Probable right breast cancer Large central mass and clinically positive node Magnification x 4

24. Case 3 Magnification x 10

25. Case 3 Magnification x 20

26. Case 3 DiagnosisPathologist or Resident Poorly differentiated malignancy Ddx: Poorly differentiated carcinoma;lymphoma; melanoma Immuno will help 1 Pathologist Favour poorly differentiated carcinoma Needs immuno 1 Pathologist 1Resident Needs immuno 1 Pathologist 1 Resident High grade invasive duct carcinoma 1 Pathologist

27. Case 3 Immunohistochemistry for CD45

28. Case 3 The answer is: Lymphoma breast

29. Lymphoma Breast Recognizing lymphoma of the breast can be problematic, particularly in a needle core biopsy Distinguishing large cell lymphoma from poorly differentiated carcinoma can be difficult. Large cell lymphoma may assume solid, diffuse and sometimes alveolar growth patterns Another problem is distinguishing lymphoma from lobular carcinoma Signet-ring cell lymphoma bears a striking resemblance to signet ring cell lobular carcinoma

30. Lymphoma Breast It has been noted, that when a tumour is poorly differentiated, the distinction between poorly differentiated carcinoma and high grade lymphoma cannot be made on H+E examination The tumour cells in this case are large and monotonous with a very high N/C ratio and scant cytoplasm The cells of high grade carcinoma tend to be pleomorphic with large vesicular nuclei and prominent nucleoli. Although they have high N/C ratio, they tend to have more cytoplasm than lymphoma cells

31. Lymphoma Breast A reactive lymphocytic infiltrate can be identified in association with lymphomas and carcinomas, but it’s presence together with other features can raise the possibility of lymphoma This is particularly true for infiltrating lobular carcinomas which tend not to be associated with a lymphocytic infiltrate In summary, we should be alert to the subtle signs that a breast tumour may be a lymphoma Immunohistochemistry for cytokeratin and CD45 should be performed in all cases where the morphologic features raise the possibility of lymphoma

32. Lymphoma Breast

33. Lymphoma Breast (signet-ring)

34. Lymphoma Breast

35. Lymphoma breast (angiocentric)

36. Solid papillary carcinoma

38. Case 4 Biopsy vulva 52 year old female Labial lesion R/O VIN Magnification x 2

39. Case 4 Magnification x 10

40. Case 4 Magnification x 20

41. Case 4 Magnification x 20

42. Case 4 DiagnosisPathologist or Resident Extramammary Paget disease1 Pathologist Paget disease vs melanoma Needs immuno 2 Residents 2 Pathologists Paget disease vs melanoma in situ vs squamous cell carcinoma in situ 1 Pathologist

43. Case 4 The neoplastic cells stain positive on mucicarmine and PAS diastase Immunohistochemical stain for CEA was done on the biopsy specimen and the neoplastic cells stain positive Immunohistochemical stains on the excision specimen are positive for CK7 and ER and negative for CK20 and CDX2

44. Case 4 THE ANSWER IS: Paget disease of vulva

45. Paget Disease of Vulva Primary Paget disease (primary cutaneous Paget disease) Paget disease as an intraepithelial neoplasm/in situ Paget disease Paget disease as an intraepithelial neoplasm with invasion/invasive primary Paget disease Paget disease as a manifestation of an underlying cutaneous neoplasm Secondary Paget disease (Paget disease of non-cutaneous origin) Paget disease as a manifestation of anal-rectal carcinoma Paget disease related to other adenocarcinomas Paget disease as a manifestation of urothelial carcinoma

46. Staining of Paget disease Primary Paget diseasePaget disease in anal- rectal adenocarcinoma Paget disease in urothelial carcinoma CK7+CK7-CK7+/- CK20-CK20+ CDX2-CDX2+CDX2+/- p63- p63+ ER+ER- Brst2+Brst2-

47. Morphology of Paget disease Paget disease MelanomaVIN Location of tumour cells Mainly located in the basal and parabasal layers compressing basal keratinocytes. Tumour cells may be present in the upper layers Located at the dermal-epidermal junction. Tumour cells may be present in the upper layers Evenly spaced throughout the epidermis singly and in nests Arrangement of tumour cells Larger than those of melanoma and have more cytoplasm May form glandular spaces Smaller than those of Paget disease and have less cytoplasm Resemble cells of Paget disease and are large with abundant pale cytoplasm, clear nuclei and prominent nucleoli PAS +-+ PAS-D +-- Mucicarmin +--

48. Immunohistochemical Staining Primary Paget DiseaseMelanomaVIN Mucin+/-Mucin- CK7+CK7-CK7+/- CK20- CEA+CEA- ER+ER- Brst2+Brst2- S100-S100+S100- Mart-1-Mart-1+Mart-1- HMB45-HMB45+HMB45- P63- P63+ P16- P16+

49. Case 5 25 year old female. ASCUS on recent pap smear. Colposcopic biopsy of an erythematous area, Slightly raised, No epithelial changes Magnification x 2

50. Case 5 Magnification x 10

51. Case 5 Magnification x 20

52. Case 5 DiagnosisPathologist or Resident Endometriosis2 Pathologists ? Endometriosis Do CD10 (1 pathologist) 2 Pathologists No malignancy Edematous stroma with PNMs and tubal metaplasia 1 Resident Focal moderate squamous dysplasia with stroma a bit hypercellular 1 Resident

53. Case 5 The answer is Endometriosis of cervix

54. Endometriosis of cervix is not uncommon It is usually confined to the superficial third of the cervical wall They appear as small blue or red nodules on the cervix Histologically, the glands and stroma resemble proliferative endometrium The mechanism responsible for the development of endometriosis is unknown, but it frequently develops following cervical trauma Cervical endometriosis occurs in 5-43% of patients who have had cautery, cone biopsy or LEEP excisions

55. Endometriosis of cervix Endometriosis can be mistaken for AIS The cells of normal proliferating endometrium are very active They are pseudostratified. They have large oval nuclei with numerous nucleoli Numerous mitoses are identified

56. Endometriosis of cervix How to identify endometriosis of cervix: The glandular cells of endometriosis have an endometriotic appearance with a moderate amount of basophilic cytoplasm and regular oval nuclei Endometriosis can be recognized by the presence of endometrial-type stroma, but the pathologist must be aware of the possibility or s/he might concentrate on the glands and not notice it In some cases, there may be abundant hemorrhage and the endometrial-type stroma might not be obvious The presence of small arterioles like the spiral arterioles can help identify the presence of endometrial-type stroma CD10 can confirm the endometrioid nature of the stroma

57. Case 6 37 year old female with 2 ASCUS diagnoses on cervico-vaginal smear Biopsy cervix taken at colposcopy Colposcopic impression “?CIN1” Magnification x 4

58. Case 6 Magnification x 10

59. Case 6 Magnification x 20

60. Case 6 Mangification x 20

61. Case 6 Magnification x 40

62. Case 6 DiagnosisPathologist or Resident Atypical endocervical epithelium ? Reactive vs in-situ Do P16, Ki67 1 Pathologist Not sure. Some glands at the edge that I would like to explore on deepers 1 Pathologist ASC-H (one edge of the biopsy) Favour tubo-endometrial metaplasia (vs endocervical glandular neoplasia/ AIS) 1 Pathologist Focal discohesive atypical squamous cells Order serials and deepers 1 Pathologist ? Presence of focal high grade squamous dysplasia and tubal metaplasia of endocervical glands 1 Resident Immature squamous metaplasia 1 Pathologist

63. Case 6 The answer is: Tubo-endometrioid metaplasia

64. Tubo-endometrioid metaplasia of the cervix is the type of metaplasia that is histologically similar to the tubal metaplasia that can develop in the endometrium in patients with unopposed estrogen The glands are lined by a pseudostratified epithelium composed of columnar cells with a high N/C ratio Many of the cells are ciliated or have secretory features with apical snouts The glands lack an associated endometrial stroma Tubo-endometrioid metaplasia occurs commonly after cervical conization

65. Tubo-endometrioid metaplasia Because of the pseudostratification and high N/C ratio, these glands can be misinterpreted as AIS Tubo-endometrioid or tubal metaplasia should not be misinterpreted as AIS because of the presence of bland nuclei and the absence of significant mitotic activity Immunohistochemical panels of p16, Ki-67, CEA are used by some in difficult cases

66. Adenocarcinoma in situ