Nodal staging of colorectal cancer, TNM and practical issues

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1 Nodal staging of colorectal cancer, TNM and practical issues Gábor Cserni 1. Bács-Kiskun County Teaching Hospital, Kecskemét 2. University of Szeged, Szeged

2 Different staging systems: A,B,C,(D) Same letters sometimes different meaning Cserni G. J Clin Pathol 2003;56:327

3 Primary tumor: (c)t & pt (TNM7, 2010-) T & pt TX: Not assessable (to be minimized) T0: No tumor Tis: carcinoma in situ: intraepithelial tumor or involving the lamina propria (intramucosal) T1: Tumor invading into submucosa. T2: Tumor invading into muscularis propria. T3: Tumor invading through the muscularis propria into pericolorectal tissues. T4a: Tumor penetrating through visceral peritoneum.* T4b: Tumor invading into adjacent organs or structures* (through the peritoneum or over the m. propria for retro- or infraperitoneal localizations) (opposite meanings in TNM5) * Still reverted in RCPath reporting proforma using TNM5, accessed 1 May 2017

4 Implementation delayed In order to ensure that the cancer care community has the necessary infrastructure in place for documenting 8th Edition stage, the AJCC Executive Committee, in dialogue with the National Cancer Institute (NCI-SEER), Centers for Disease Control and Prevention (CDC), the College of American Pathologists (CAP), the National Comprehensive Cancer Network (NCCN, the National Cancer Data Base (NCDB), and the Commission on Cancer (CoC), made the decision to delay the implementation of the 8th Edition Cancer Staging System to January 1, Cancer-Staging-System.aspx

5 Primary tumor: (c)t & pt (TNM8, 2018-) T & pt TX: Not assessable (to be minimized) T0: No tumor Tis: carcinoma in situ tumor involving the lamina propria (intramucosal carcinoma) only. (Intraepithelial carcinoma = HG dysplasia ptis) T1: Tumor invading into submucosa. T2: Tumor invading into muscularis propria. T3: Tumor invading through the muscularis propria. T4a: Tumor demonstrating serosal involvement. T4b: Tumor invading into adjacent organs or structures (through the peritoneum or over the m. propria for retro- or infraperitoneal localizations)

6 pt3: pt3a ( 5 mm from the muscularis propria) & pt3b (> 5 mm from the muscularis propria) Bori R et al. Pathol Oncol Res 2009;15: pt3a tumors have a better prognostic profile than pt3b. These are not TNM categories recognized in the AJCC staging books, but are mentioned in the TNM Supplement (since 1993). Merkel S et al. Int J Colorectal Dis 2001;16:

7 pt4a peritoneal involvement (TNM8) Direct tumor extension With perforation in which the tumor cells are continuous with the serosal surface through inflammation No pt4a category for non peritonealized areas (e.g. posterior ascending colon) <1mm from serosal surface and accompanied by serosal reaction; if multiple levels exclude serosal surface involvement pt3

8 pt4a peritoneal involvement Shepherd N et al. Gastroenterology 1997 (Gloucester) 1. Lack of peritoneal involvement 2. Fibrin and inflammatory exsudate on the peritoneum with tumor cells beneath the peritoneum, but not on it (TNM: pt3) 3. Tumor propagation on the peritoneal surface 4. Ulceration and apparently free tumor cells floating on the peritoneal surface (especially in crevices)

9 Category 3 & 4 had worse survival Shepherd N et al. Gastroenterology 1997

10 Assessment of peritoneal involvement Higher pt4 ratio as a result of more precise pathological work-up Percentage of pt1-4 categories 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0, n = (y)pt1 (y)pt2 (y)pt3 pt4

11 Lymph nodes: pn (TNM7) pnx: Not assessable (eg: removed earlier / not removed / no LNs identified) pn0: No regional LN metastasis (including isolated tumor cell clusters) pn1: Metastasis to 1-3 regional LNs pn1mi Micrometastasis (>0.2 mm and/or >200 cells, but none > 2.0 mm) pn1a Metastasis to 1 LN (>2 mm) pn1b Metastasis to 2-3 LN (at least one metastasis >2 mm) pn1c Tumor deposit(s) (TD) in the subserosa, mesocolon, pericolic, perirectal tissues, without LN structure, if there is no LN metastasis pn2: Metastasis to 4 or more regional LNs pn2a Metastasis to 4-6 LNs (at least one metastasis >2 mm) pn2b Metastasis to 7 or more LNs (at least one metastasis >2 mm)

12 LNs (TNM8) At least 12 Number of nodes correlates with survival Micrometastasis (may be designated as pn1mi, but it is better to consider them standard positive nodes) pn0(i+) (<0.2 mm) worse prognosis than pn0

13 Theory and practice

14 Is this a lymph node? (1) (x10-x20)

15 Is this a lymph node? (2) (x10-x20)

16 Is this a lymph node metastasis? (1) x 2

17 Is this a lymph node metastasis? (1) x 2

18 Is this a lymph node metastasis? (1) x 35

19 Is this a lymph node metastasis? (2) x 2.5

20 Is this a lymph node metastasis? (2) x 10 (central part)

21 Is this a lymph node metastasis? (2) x 1.5

22 Is this a lymph node metastasis? (2) x 25 Smooth muscle, elastic fibers

23 Is this a lymph node? (3) (x 3)

24 Is this a lymph node? (3) (x 10)

25 Is this a lymph node? (4) (x 5)

26 Is this a lymph node? (4) (x 4.5) (Orcein-H)

27 Is this a lymph node? (4) (x 4 x 4.5) (SMA - H-caldesmon)

28 Is this a lymph node? (5) (x 10)

29 Is this a lymph node? (5) (x 10 x 40) Orcein

30 X4 X40 Is this a LN metastasis? (3) x20 x20

31 Primary vs Metastasis Rectosigmoid colon pt1 here, but pt2 elsewhere pn1b (2/10)

32 Primary vs Metastasis Rectosigmoid colon pt1 here, but pt2 elsewhere pn1b (?) CDX2

33 Primary vs Metastasis Rectosigmoid colon pt1 here, but pt2 elsewhere pn1 (?) NO pt2 pn0 & Occult prostatic cancer M1 PSAP CDX2

34 Is this a LN metastasis? (4)

35 Is this a LN metastasis? (4)

36 No cells, just mucin (negative) ypn0

37 Halving / Slicing larger LNs

38 LNs vs TDs (tumor deposits) Lymph nodes have the following features: capsule, subcapsular sinus, lymphoid tissue, often with follicles, sometimes perinodal lymphoid tissue as well; they may have smooth muscle in their capsule very rarely, it seems, they may have even elastic fibres in the capsule

39 Tumor deposits Of 400 pts with pt3 N+M0 colon ca 18% had tumor deposits (TD)(TNM5, 1998) TD: adenocarcinoma within adipose or fibrous tissue but not associated with a LN Grossly palpated lesions, generally submitted as LN Goldstein NS, Turner JR. Cancer 2000

40 Tumor deposits Independent factors associated with shorter DFS: Any TDs (independent of size) Increasing number of TDs Increasing number of involved LNs Grade TDs proved to be perivascular (large vessels), intravascular and/or perineural tumor foci Goldstein NS, Turner JR. Cancer 2000

41 Lymph node metastasis vs TD Tumor nodule lacking elements of a LN TNM5 >3 mm: LN metastasis pn 3 mm: discontinuous tumor spread pt TNM6 Regular outline: LN metastasis pn irregular outline: venous invasion: V1

42 Lymph node metastasis vs TD V1 orcein stain V1

43 Lymph node metastasis vs TD Tumor nodule lacking elements of a LN TNM7 Can be: discontinuous tumor spread, completely destroyed LN (N1/2), venous invasion (V1/2), If destroyed LN: pn category Discontinuous spread, venous invasion (V1/2) TD (pn1c, if no LN metastasis, for T1-2 tumors) TD and V1 on the basis of the orcein (elastica) stain

44 TD (TNM8) No elements of a LN Not venous invasion (V1, V2), not lymphovascular (small vessel) involvement (L1), not perineural involvement (Pn1) If there is no LN metastasis: pn1c If there is a LN metastasis: this should not be added to the number of metastatic nodes

45 The suggested number of LNs to be assessed for a reliable pn0 6 Hernanz F et al. Dis Colon Rectum 1994;37: Caplin S et al. Cancer 1998;83: Mainprize KS et al. J Clin Pathol 1998;51: Cserni G. J Clin Pathol 2002;55: Maurel J et al. Cancer 1998;82: Cianchi F et al. World J Surg 2002;26: TNM Supplement 3rd Ed 13 Scott KWM et al. Br J Surg 1989;76: Wong JH et al. J Clin Oncol 1999;17: Tepper JE et al. J Clin Oncol 2001;19: Cserni G et al. Pathol Oncol Res 1999;5: Goldstein NS. Am J Surg Pathol 2002;26: Greco P et al. Virchows Arch 2006;449:

46 How many LNs? As many as possible! T3N0M0 CRC from the SEER database year OS 0.8 a survival estimate b c 10-year OS number of nodes examined Cserni G, et al. Is there a minimum number of lymph nodes that should be histologically assessed for a reliable nodal staging of T3N0M0 colorectal carcinomas? J Surg Oncol 2002; 81:63-69.

47 Distribution of pn categories at BKMK (y)pn2 pnx More (y)pn2 pnx (y)pn0 (y)pn0 (y)pn1 (y)pn Mean (SD): 9 (6) Median: 8 Range: 0-31 Number of LNs assessed 2006 (2016) 19 (11) 13 (6)

48 Distance from the tumour as qualitative feature D C B A B C D Tumour cm 2 cm 2 cm 3 cm 3 cm 100 cases of CRC Mean: 17 LN / case Cserni G, et al. Distance of lymph nodes from the tumor, an important feature in colorectal cancer specimens. Arch Pathol Lab Med 2001; 125:

49 An example C A C A B B B C No fraction D in this specific case

50 Results 53 pn1 or pn2 All but 1 staged correctly as pn+ on the basis of LNs from fraction A All staged correctly on the basis of A and B (3 cms from the tumor in each direction SUGGESTION: LNs from below the tumor and its 3 cm-wide perimetry should be evaluated for reliable staging. Look for further LNs if <7, or if pn1 with 3 LNs +! Cserni G, et al. Arch Pathol Lab Med 2001; 125:

51 Further testing 762 further CRCs studied - sections A & B (3cm) vs C & D (>3cm) till end 2008 Only 4/369 N+ cases had metastasis in a LN from segment CD without having metastasis in the AB segment. 14 further cases would have been wrongly classified as pn1 instead of pn2 This error rate is LOWER than the FNR of lymphatic mapping Cserni G et al. J Clin Pathol 2011

52 Sentinel nodes and lymphatic mapping in CRCs 85/86 successfull SN identifications 29 N+ cases; 15 only SN+ (7 only micrometastatic; 2 only IHC) 3 false negative cases (3.6% FNR as reported % FNR as I understand it) The aim would be a more reliable and improved staging (detailed pathology of SLNs). Saha S et al. Ann Surg Oncol 2000;7:120-4.

53 Unexpected lymph drainage Lymphatic mapping studies have demonstrated that direct drainage may occur from a tumor site to apical or even paraaortic LNs. Merrie AE, et al. Dis Colon Rectum 2001;44: This LN proved to be the only positive LN resected with the colon, but was outside the margins of a standard right hemicolectomy, the operation usually performed for a primary carcinoma at the given location. Tsioulias GJ, et al. Arch Surg 2000;135: Same case reported in 2 papers Bilchik AJ, et al. J Clin Oncol 2001;19: The only positive (only CK+) / 18 LN

54 Less success in other series (11-50 pts, mean 24 pts / series) False negative rates (false negatives / all positives) & upstaging rates: 1/3 (33%) & NA Evangelista W et al. Tumori 2002;88: /3 (33%) & 2/13 (15%) Tsoulias GJ et al. Am Surg 2002;68: /13 (38%) & NA Cserni G et al. Pathol Oncol Res 1999; 5: /7 (43%) & 2/16 (13%) Merrie AE et al. Dis Colon Rectum 2001;44: /7 (29%) & 2/20 (10%) Fitzgerald TL et al. J Surg Oncol 2002;80: /3 (33%) & NA Esser S et al. Dis Colon Rectum 2001;44: /8 (25%) & NA Kitagawa Y et al. Surg Clin North Am 2000;80: /20 (60%) & 2/15 (13%) Joosten JJA et al. Br J Surg 1999;86:482-6.

55 Lymphatic mapping in CRC Meta-analysis van der PAS MH et al, Lancet Oncol mapping procedures (2961 colon, 806 rectum) Mean weighted identification rate: 94% (95%CI: 92-95%) Pooled sensitivity: 76% (95%CI: 72-80%) being independent of pt category and tumor localisation To be considered for cn0 M0 patients, as there is about 15% upstaging; prognostic importance?

56 Distant Metastasis: M (TNM7) Mx: Not defined pm0: There is no such category M0: No metastasis present M1(pM1): Metastasis present pm1a Metastasis in 1 organ or site (>0.2 mm) pm1b Metastasis in >1 organ or site or the peritoneum

57 Distant Metastasis: M (TNM8) Mx: Not defined pm0: There is no such category M0: No metastasis present M1(pM1): Metastasis present pm1a Metastasis in 1 organ or site e.g. liver, lung, ovary, non-regional lymh node(s) pm1b Metastasis in >1 organ or site pm1c Metastasis to the peritoneum +/- other organ involvement

58 Final recapitulating case (TNM8) - 81-year-old female with bowel obstruction - emergency operation: coecal dilation and necrosis, tumor of descending colon, total colectomy specimen

59 Primary tumour x0.8 pt Ulcerated luminal surface Serosal surface

60 Primary tumour x5 pt

61 Primary tumour x40 pt X40

62 Primary tumour ptx pt0 ptis pt1 pt2 pt3 pt4a pt4b

63 Primary tumour ptx pt0 ptis pt1 pt2 pt3 pt4a pt4b

64

65 Primary tumour x1 pt Ulcerated luminal surface Serosal surface

66 Primary tumour: pt (x4) Serosal crevice

67 Primary tumour: pt (x10)

68 Primary tumour: pt (x20)

69 Primary tumour: pt (x40)

70 Final recapitulating case Primary tumour ptx pt0 ptis pt1 pt2 pt3 pt4a pt4b

71 Final recapitulating case Primary tumour ptx pt0 ptis pt1 pt2 pt3 pt4a pt4b

72 Primary tumour: (histological type) x1

73 Primary tumour: (histological type) x1

74 Primary tumour: (histological type) x1 ca 3-4:1

75 Lymph nodes (gross n=13 from the 3 cm perit region) 10 negative LNs + 3

76 Lymph nodes (gross n=13 from the 3 cm perit region) 10 negative LNs + 2 TDs + 1 LN met: 1/11 LN + 2TDs

77 Final recapitulating case Tumour + Nodes ptx - pnx pt0 - pn0 ptis - pn1a pt1 - pn1b pt2 - pn1c pt3 - pn2a pt4a - pn2b pt4b

78 Final recapitulating case Tumour + Nodes ptx - pnx pt0 - pn0 ptis - pn1a pt1 - pn1b pt2 - pn1c pt3 - pn2a pt4a - pn2b pt4b Because TDs do not count, if you have an LN met.

79 Omentum (x0.8)

80 Omentum x5

81 Omentum x20 (micropapillary component) x5

82 Final recapitulating case Tumour + Nodes + Metastasis ptx - pnx - Mx pt0 - pn0 - M0 ptis - pn1a - pm0 pt1 - pn1b - (p)m1a pt2 - pn1c - (p)m1b pt3 - pn2a - (p)m1c pt4a - pn2b pt4b

83 Final recapitulating case Tumour + Nodes + Metastasis ptx - pnx - Mx pt0 - pn0 - M0 ptis - pn1a - pm0 pt1 - pn1b - pm1a pt2 - pn1c - pm1b pt3 - pn2a - pm1c pt4a - pn2b pt4b The omentum supports peritoneal carcinosis, this can be a pm category.

84 Final recapitulating case T + N + M ptx - pnx - Mx pt0 - pn0 - M0 ptis - pn1a - pm0 pt1 - pn1b - pm1a pt2 - pn1c - pm1b pt3 - pn2a - pm1c pt4a - pn2b pt4b STAGE IV.C

85

86 CK7 CDX2 CA125 CK20 (not shown): in both areas

87 CK7 CDX2

88 CK7 CDX2

89 Final recapitulating case T + N + M ptx - pnx - Mx pt0 - pn0 - M0 ptis - pn1a - pm0 pt1 - pn1b - (p)m1a pt2 - pn1c - (p)m1b pt3 - pn2a - (p)m1c pt4a - pn2b cannot be determined pt4b w/o additional means & rpt3a rpn1 ovarian serous carcinoma

90 Id. Markó Károly: Visegrád 1826