Overview of AJCC 8 th Staging in Pathologic Aspects

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1 Overview of AJCC 8 th Staging in Pathologic Aspects Jee Yeon KIM, M.D.,Ph.D. Department of Pathology, Pusan National University, College of Medicine, Pusan National University Yangsan Hospital, KOREA

2 Major Changes to AJCC 8 th edition Inclusion of biologic factors in staging Tumor grade, HER-2, ER, PR and genomic assays Two stage groups (anatomic and prognostic staging) options Lobular Carcinoma In Situ removed from ptis category

3 Contents Changes and clarification for T, N, M changes Clarifications for post-neoadjuvant therapy classification Inclusion of grade, HER2, ER, PR Inclusion of multigene panels Two stage group options: Anatomic for use where biomarker (grade, ER, PR, HER2) not available Prognostic for use on all USA pts

4 T, N, M Changes T Category

5 T Category Changes to AJCC 8 th edition LCIS is removed as a ptis category Pleomorphic LCIS ; also not included in a ptis category due to insufficient evidence for definitive treatment recommendations ptis (DCIS): ductal carcinoma in situ ptis (Paget): Paget disease of the nipple not associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma

6 T Category Changes to AJCC 8 th edition Rounding tumor size Do not apply for tumors between 1.0 and 1.5mm so as to not classify these cancers as microinvasive (T1mi) carcinomas (defined as invasive tumor foci 1.0mm or smaller) 1.0mm= pt1mi >1.0mm = pt1a Tumors > 1mm and < 2mm should be reported rounding to 2mm.

7 Microinvasion Most commonly seen in association with large, high-grade DCIS No focus more than 0.1 cm in greatest dimension Surrounded by dense lymphoid infiltrate or desmoplastic stroma As an indication for sentinel node biopsy or other forms of axillary node examination

8 T Category Clarification from AJCC 7 th edition Multiple tumors in same breast T category based on a single largest tumor focus Don t include satellite foci when measuring tumor size If multiple foci of microinvasion, report the number of foci and the size of the largest focus (don t combine) Use (m) modifier

9 Invasive carcinom a #1 Invasive carcinom a #2 DCIS

10 T Category Clarification from AJCC 7 th edition Multiple tumors in bilateral breast Stage each side separately

11 T Category Clarification from AJCC 7 th edition Skin involvement Satellite skin foci must be macroscopically identified and separate from the primary tumor (not contiguouse) Direct extension into skin and skin involvement only identified microscopically are NOT categorized as pt4b Such tumors are categorized based on tumor size

12 T Category Clarification from AJCC 7 th edition Skin involvement In the absence of clinical findings of inflammatory carcinoma (erythema and edema involving 1/3 of breast skin), dermal lymphatic tumor emboli are NOT categorized as pt4b

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14 T staging: pt3 (m) No inflammatory ca, no skin ulcer, not pt4

15 T, N, M Changes N Category

16 N Category Clarification from AJCC 7 th edition The criteria for pathological measurement of lymph node metastases are clearly defined. The dimension of the area containing several or multiple tumor deposits is NOT used to determined pn category. The largest contiguous tumor deposit is used for pn; adjacent satellite tumor deposits are not added.

17 N Category Clarification from AJCC 7 th edition pno (i) ITC (isolated tumor cell clusters) pn1mi, micrometast asis pn1 The largest contiguous tumor deposit must be no larger than 0.2mm. Multiple ITCs are often clustered and multiple foci are frequently present in a single node. The size of areas of noncontiguous adjacent ITCs are not added. When more than 200 singe tumor cells are present in a single lymph node cross section, this signifies that the size of the deposits= is likely greater than 0.2mm and this should be classified as a micrometastasis. At least one contiguous tumor deposit must be larger than 0.2mm and the largest contiguous tumor deposit must be no larger than 2.0mm. The sizes of noncontiguous adjacent tumor deposits are not added. Multiple micrometastases may be present in a single lymph node. At least one contiguous tumor deposit must be larger than 2.0mm

18 N Category Clarification from AJCC 7 th edition Assessment of N category Invasive tumor nodules in axillary fat without apparent nodal tissue are classified as regional lymph node metastases (pn)

19 N Category Clarification from AJCC 7 th edition Assessment of N category Metastasis to lymph nodes from the following sites are regional nodes and categorized as pn Axillary, intramammary, interpectoral, internal mammary and supraclavicular Metastases to any other lymph nodes (including cervical or contralateral internal mammary or contralateral axillary lymph nodes) are categorized as pm1

20 N Category Changes to AJCC 8 th edition (f) modifier added to the N category confirmation of metastasis by either FNA or core needle biopsy, with NO further resection of nodes Usually applies to cn staging before definitive resection or neoadjuvant therapy

21 S (Right Breast) S (Left Lymph Node) ctnm staging: Right ct1c (f) cn0 cm0 ctnm staging: Left ctx cn1(f) cm0 ptnm staging: pt1c pn0 (sn) pm1

22 N Category Clarification from AJCC 7 th edition Assessment of N category Nodes with isolated tumor cells (ITCs) only are not included in the overall count of positive nodes When measuring ITCs, report size of largest contiguous focus (NOT the overall area in which the ITCs are found) Example 10 nodes: 2 with macromets; 2 with ITCs No. of positive nodes is 2 out of 10 pn1a (not 4/10 = pn2a)

23 T, N, M Changes M Category

24 M Category Clarification from AJCC 7 th edition pm0 is not a valid category Valid M categories for clinical and pathological staging cm0: no signs or symptoms of distant metastasis cm1: signs, symptoms, or imaging evidence of distant metastasis pm1: microscopic confirmation of distant metastasis

25 Post Neoadjuvant Therapy Staging

26 Post Neoadjuvant Theraphy Staging Clarification from AJCC 7 th edition Assigined after neoadjuvant therapy and surgical resection ypt category Largest focus of residual tumor Treatment-related fiborosis near invasive tumor NOT used Multiple foci of residual tumor, use (m) modifier

27 Post Neoadjuvant Theraphy Staging Clarification from AJCC 7 th edition Assigined after neoadjuvant therapy and surgical resection ypn category Largest focus of residual tumor in nodes Treatment-related fiborosis near invasive tumor NOT used

28 Post Neoadjuvant Theraphy Staging Clarification from AJCC 7 th edition Assigined after neoadjuvant therapy and surgical resection M category If M1 prior to therapy, remains M1 following neoadjuvant therapy Regardless of observed response to therapy

29 Post Neoadjuvant Theraphy Staging Clarification from AJCC 7 th edition pcr pcr(pathological complete response) No sidual tumor ypt0 ypn0 cm0 any residual invasive carcinoma detected by pathological examination in the breast, including cancer within blood or lymph vessels (LVI) or lymph nodes precludes posttreatment classification as a complete pathological response (pcr). no stage group assigned, under preparation

30 Post Neoadjuvant Therapy ypt0 yn1mi cm0

31 Biologic Markers Histologic Grade

32 Biomarker Categories Modified Nottingham (Bloom Scarf Richardson) tumor grade should be documented All invasive carcinomas should have the following determined by appropriate assays whenever possible ER status PR status HER2 status Marker of proliferatio if also recommended Ki67

33 Histologic Grade All invasive carcinoma of breast should be assigned histologic grade Nottingham modification of SBR grading system recommended Nottingham modification of the Bloom Richardson system Tubule formation 1 point: Tubular formations in >75% of the tumor 2 points: Tubular formations in 10 75% of the tumor 3 points: Tubular formations in <10% of the tumor Note: For scoring tubule formations, the overall appearance of the tumor has to be taken into consideration. Nuclear pleomorphism 1 point: Nuclei with minimal variation in size and shape 2 points: Nuclei with moderate variation in size and shape 3 points: Nuclei with marked variation in size and shape Note: The tumor areas having cells with greatest atypia should be evaluated. Mitotic count 1, 2, or 3 points, according to Table 20.5

34 Histologic Grade Tubule Formation Score 1 Tubule formations in >75% Score 2 in10-75% Nuclear Grade Score 3 In <10% Score 1 Score 2 Score 3

35 Histologic Grade Mitotic Count Number of mitotic figures in most active area, counting 10 high power fields: (a) (b) (c) 1 point: points: points: (a) Nikon or Labophot 40x objective or comparable with field diameter of 0.44 mm (b) Leitz or Ortholux 25x objective or comparable with field diameter of 0.59 mm (c) Leitz or Diaplan 40x objective or comparable with field diameter of 0.63 mm Notes: Count mitotic figures at periphery of tumor in most mitotically active area; count 10 high power fields in the same area, but not necessarily contiguous; select fields with as much tumor as possible; avoid poorly preserved areas; ignore cells with hyperchromatic and pyknotic nuclei, which may be undergoing apoptosis Quick scan mitotic impression is less accurate (Hum Pathol 2008;39:584) Calibration of microscopc magnification: NHSBSP No 58, Jan 2005:80,

36 Calibration of microscopc magnification: NHSBSP No 58, Jan 2005:80,

37 Histologic Grade Nottingham s combined histologic grade G1. Well Differentiated: - score 5 G2. Moderately Differentiated: score 6,7 G3. Poorly Differentiated: score 8,9 Sum of the scores of tubule formation + nuclear grade+ mitosis

38 Nuclear grade of DCIS Features Pleomorphism Size Chromatin Grade I (Low) Monotonous (monomorphic) 1.5X to 2X the size of a normal RBC or a normal duct epithelial cell nucleus Usually diffuse, finely dispersed chromatin Grade II (Intermediate) Intermediate Intermediate Intermediate Grade III (High) Markedly pleomorphic > 2X the size of a normal RBC or a normal duct epithelial cell nucleus Usually vesicular with irregular chromatin distribution Nucleoli Only occasional Intermediate Prominent, often multiple Mitoses Only occasional Intermediate May be frequent Orientation Polarized toward luminal spaces Intermediate Usually not polarized toward the luminal space Schwartz GF, Lagios MD, Carter D, et al. Cancer 1997;80:

39 Biologic Markers ER, PR and HER2

40 ER and PR ER & PR expression measured primarily by IHC 1% of cells stained considered positive for ER & PR Multiple results always use positive results If biopsy and resection specimens are tested, and One is positive, while the other is negative, then Use the positive results to assign the stage group ER PR

41 American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer Reporting elements for ER and PR IHC assay Percentage of invasive tumor cells exhibiting nuclear staining Intensity of staining: strong, medium, or weak Interpretation: Positive, negative, or uninterpretable Internal and external contrils (positive, negative, or not present) Standard assay conditions met/not met (including cold ischemic time and fixation parameters) Positive for ER or PR if finding of 1% of tumor cell nuclei are immunoreactive Negative for ER or PR if finding of <1% of tumor cell nuclei are immunoreactive in the presence of evidence that the sample can express ER or PR (positive internal control) Uninterpretable for ER, or PR if finding that no tumor nuclei are immunoreactive and that internal controls lack any nuclear staining Hammond et al. J Clin Oncol Jun 1; 28(16):

42 ER and PR Allred score= PS + IS (range 0~8)

43 Evaluation of HER2 Proteon Expression by IHC (2013 ASCO/CAP Guideline) Wolff et al. J Clin Oncol. 2013; 31:

44 Evaluation of HER2 Gene Amplification by ISH (2013 ASCO/CAP Guideline) Wolff et al. J Clin Oncol. 2013; 31:

45 Evaluation of HER2 Gene Amplification by ISH (2013 ASCO/CAP Guideline) Wolff et al. J Clin Oncol. 2013; 31:

46 Her2 IHC Negative Equivocale Positive Her2 SISH Not Amplified Amplified NA NA A A

47 Multigene Panels

48 Inclusion of Multigene Panels (when available) as Stage Modifiers T1 and T2 HR-positive, HER-2 negative and LN negative tumors ==== T1aT1bN0M0 21 Gene Recurrence Score (Oncotype Dx) : RS < 11 Breast Cancer Index: Low risk range EndoPredict: low risk score Mammaprint: low risk score PAM 50 (Prosigna): low range ROR

49 Two Stage Groups Anatomic Pathologic

50 Pathologic Prognostic Groups Based on pathologic findings at definitive surgery and biomarkers (grade, ER, PR, and HER2, multigene prognostic panels) Relavant to all patients treated with definitive surgery as initial treatment Not appropriate for patients reveiving neoadjuvant systemic or radiation treatment It is the recommended staiging system for use in the USA by all tumor registries

51 Cases

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53 ER PR pt2(m) pn0 cm0 Anatomic Stage Group IIA Moderately differentiated, score 7 (2+3+2) Pathologic Prognostic Stage ER(+), PR (+), HER2 (-), Ki67 50% Group IA

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55 Lymph node metastasis pt2 (m) pn1 cm0 Anatomic Stage Group IIB Histologic grade: poorly differentiated by Nottingham's combined histologic grade (total score = 9; tubule formation=3, nuclear grade=3, mitosis=3) Pathologic Prognostic Stage Group IIIA ER(-), PR (-), HER2(-) Ki67 50%

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57 Medial Slice #1 pt2 (m) pn0 cm0 Lateral Slice #21 Mass #1 0.9x0.4cm x 0.5cm(slice 8) Mass #6 Histologic grade: moderately differentiated 0.3x0.3cm by X0.5cm (slice 12) Nottingham's Anatomic combined Stage histologic Group grade IIA Mass #2 2.0x1.2cm x 2.0cm(slice 8 to 11) (total score = 7; tubule formation= 2, nuclear grade= 3, mitosis= 2)) Pathologic Prognostic Stage Group IA Mass #3 0.6x0.6cm X 0.5cm (slice 8) Mass #4 0.8x0.4cm X0.5cm (slice 8) ER(+), PR (+), HER2(-) Ki67 10% Mass #7 3.4x1.0cm X3.0cm(slice 13 to 18) Mass #5 0.7x0.7cm X1.5cm (slice 10 to 12)

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59 Mass #1 3.0x1.3x0.7cm (slice 6 to 11) Mass #2 0.7x0.5X0.5cm (slice 8) Mass #3 0.5x0.2x0.2cm (slice 10) pt2 (m) pn0 (sn) cm0 Anatomic Stage Group IIA Histologic grade: well differentiated by Nottingham's combined histologic grade (total score = 4; tubule formation=1, nuclear grade=2, mitosis=1) Pathologic Prognostic Stage Group IA Mass #4 0.5x0.1x0.1cm (slice 10) ER(+), PR (+), HER2(2+) FISH NA Ki67 1%

60 Summary Changes and clarification for T, N, M changes Clarifications for post-neoadjuvant therapy classification Inclusion of grade, HER2, ER, PR Inclusion of multigene panels Two stage group options: Anatomic for use where biomarker (grade, ER, PR, HER2) not available Prognostic for use on all USA pts

61 Thank you for your attention!