Nodal staging of colorectal cancer, TNM and practical issues

Gábor Cserni1. Bács-Kiskun County Teaching Hospital, Kecskemét2. University of Szeged, Szeged

Different staging systems: A,B,C,(D)Same letters – sometimes different meaning

Cserni G. J Clin Pathol 2003;56:327

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

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, 2018.

https://cancerstaging.org/About/news/Pages/Implementation-of-AJCC-8th-Edition-Cancer-Staging-System.aspx

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)

pT3: pT3a (≤ 5 mm from the muscularis propria) & pT3b (> 5 mm from the muscularis propria)

pT3a tumors have a better prognostic profile than pT3b.

These are not TNM categories recognized in the AJCC staging books, but are mentioned in theTNM Supplement (since 1993).

Bori R et al. Pathol Oncol Res 2009;15:527-32.

Merkel S et al. Int J Colorectal Dis 2001;16:298–304.

pT4a – peritoneal involvement (TNM8)

• Direct tumor extension• With perforation in which the tumor cells

are continuous with the serosal surfacethrough inflammation

• No pT4a category for non peritonealizedareas (e.g. posterior ascending colon)

• <1mm from serosal surface and accompanied by serosal reaction; if multiple levels exclude serosal surface involvement → pT3

pT4a – peritoneal involvement

1. Lack of peritoneal involvement2. 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 surface4. Ulceration and apparently free tumor cells floating on the peritoneal surface (especially in crevices)

Shepherd N et al. Gastroenterology 1997 (Gloucester)

Category 3 & 4 had worsesurvival

Shepherd N et al. Gastroenterology 1997

Assessment of peritoneal involvementHigher pT4 ratio as a result of more precise pathological work-up

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

(y)pT1 (y)pT2 (y)pT3 pT4

1997

2006

2016

n =77111159

Percentage of pT1-4 categories

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)

LNs (TNM8)

• At least 12• Number of nodes correlates with survival• Micrometastasis (may be designated as

pN1mi, but it is better to consider themstandard positive nodes)

• pN0(i+) (<0.2 mm) worse prognosis thanpN0

Theory and practice

https://www.slideshare.net/optimaltransformation/a-collection-of-quotes-from-albert-einstein

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

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

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

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

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

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

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

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

Is this a lymph node metastasis? (2)x 25

Smooth muscle, elastic fibers

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

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

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

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

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

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

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

Is this a LN metastasis? (3)X4 x20X40 x20

Primary vs MetastasisRectosigmoid colonpT1 here, butpT2 elsewherepN1b (2/10)

Primary vs MetastasisRectosigmoid colonpT1 here, butpT2 elsewherepN1b (?)

CDX2

Primary vs MetastasisRectosigmoid colonpT1 here, butpT2 elsewherepN1 (?) – NOpT2 pN0 &Occult prostaticcancer M1

PSAP

CDX2

Is this a LN metastasis? (4)

Is this a LN metastasis? (4)

No cells, just mucin (negative) –ypN0

Halving / Slicing larger LNs

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

Tumor deposits

• Of 400 pts with pT3 N+M0 colon ca 18% had tumor deposits (TD)(TNM5, 1998)

• TD: adenocarcinomawithin adipose or fibrous tissue but not associated with a LN

• Grossly palpatedlesions, generally submitted as LN

Goldstein NS, Turner JR. Cancer 2000

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 perineuraltumor foci

Goldstein NS, Turner JR. Cancer 2000

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

Lymph node metastasis vs TD

V1

V1 – orcein stain

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: → pNcategory

– 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

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

The suggested number of LNs to be assessed for a reliable pN0

• 6 Hernanz F et al. Dis Colon Rectum 1994;37:373-6.

• 7 Caplin S et al. Cancer 1998;83:666-72. - Mainprize KS et al. J Clin Pathol 1998;51:165-6. - Cserni G. J Clin Pathol 2002;55:386-90.

• 8 Maurel J et al. Cancer 1998;82:1482-6.

• 9 Cianchi F et al. World J Surg 2002;26:384-9.

• 12 TNM Supplement 3rd Ed

• 13 Scott KWM et al. Br J Surg 1989;76:1165-7.

• 14 Wong JH et al. J Clin Oncol 1999;17:2896-900. - Tepper JE et al. J Clin Oncol 2001;19:157-63.

• 16 Cserni G et al. Pathol Oncol Res 1999;5:291-6.

• 17 Goldstein NS. Am J Surg Pathol 2002;26:179-89.

• 20 Greco P et al. Virchows Arch 2006;449:647-651.

How many LNs? As many as possible!

0 10 20 30 400.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

surv

ival

est

imat

e

number of nodes examined

5-year OS

10-year OS

a

bc

8574 T3N0M0 CRC from the SEER database

Cserni G, et al. Is there a minimum number of lymph nodes that should be histologicallyassessed for a reliable nodal staging of T3N0M0 colorectal carcinomas?

J Surg Oncol 2002; 81:63-69.

Distribution of pN categories at BKMK

1997• Mean (SD): 9 (6)• Median: 8• Range: 0-31

2006 (2016)• 19 (11) 13 (6)• 17 13• 3-57 0-48

1997

(y)pN0

(y)pN1

(y)pN2

pNx

2006

(y)pN0

(y)pN1

(y)pN2

pNx

Number of LNs assessed

More

Distance from the tumour as qualitative feature

Cserni G, et al. Distance of lymph nodes from the tumor, an important feature in colorectal cancer specimens. Arch Pathol Lab Med 2001; 125:246-249.

Tumour+ 1-1 cm

2 cm 2 cm

3 cm3 cm

D C B A B C D

100 cases of CRC Mean: 17 LN / case

An example

A

B

A

B

B

C

C

C

No fraction D in this specific case

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; 125:246-249.

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

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 - 10.3 % 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.

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 Rectum2001;44:410-7.

• 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 Surg2000;135:926-32.

Bilchik AJ, et al. J Clin Oncol2001;19:1128-36.

The only positive (only CK+) / 18 LN

Same case reported in 2 papers

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;88:37-40.

• 1/3 (33%) & 2/13 (15%) Tsoulias GJ et al. Am Surg 2002;68:561-5.

• 5/13 (38%) & NA Cserni G et al. Pathol Oncol Res 1999; 5:291-6.

• 3/7 (43%) & 2/16 (13%) Merrie AE et al. Dis Colon Rectum 2001;44:410-7.

• 2/7 (29%) & 2/20 (10%) Fitzgerald TL et al. J Surg Oncol 2002;80:27-33.

• 1/3 (33%) & NA Esser S et al. Dis Colon Rectum 2001;44:850-6

• 2/8 (25%) & NA Kitagawa Y et al. Surg Clin North Am 2000;80:1799-809.

• 12/20 (60%) & 2/15 (13%) Joosten JJA et al. Br J Surg 1999;86:482-6.

Lymphatic mapping in CRCMeta-analysis van der PAS MH et al, Lancet Oncol 2011

• 3767 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?

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 theperitoneum

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 sitepM1c Metastasis to the peritoneum +/- other

organ involvement

Final recapitulating case(TNM8)

- 81-year-old female with bowel obstruction- emergency operation: coecal dilation and

necrosis, tumor of descending colon, totalcolectomy specimen

Primary tumour x0.8 pT…

Ulcerated luminal surface

Serosal surface

Primary tumour x5 pT…

Primary tumour x40 pT…

X40

Primary tumour

– pTx– pT0– pTis– pT1– pT2– pT3– pT4a– pT4b

Primary tumour

– pTx– pT0– pTis– pT1– pT2– pT3– pT4a– pT4b

Primary tumour x1 pT

Ulcerated luminal surface

Serosal surface

Primary tumour: pT… (x4)

Serosal crevice

Primary tumour: pT… (x10)

Primary tumour: pT… (x20)

Primary tumour: pT… (x40)

Final recapitulating casePrimary tumour

– pTx– pT0– pTis– pT1– pT2– pT3– pT4a– pT4b

Final recapitulating casePrimary tumour

– pTx– pT0– pTis– pT1– pT2– pT3– pT4a– pT4b

Primary tumour: (histological type)

x1

Primary tumour: (histological type)

x1

Primary tumour: (histological type)

x1ca 3-4:1

Lymph nodes(gross n=13 from the 3 cm periT region)

10 negativeLNs + 3

Lymph nodes(gross n=13 from the 3 cm periT region)

10 negative LNs + 2 TDs+ 1 LN met:1/11 LN + 2TDs

Final recapitulating caseTumour + Nodes

– pTx - pNx– pT0 - pN0– pTis - pN1a– pT1 - pN1b– pT2 - pN1c– pT3 - pN2a– pT4a - pN2b– pT4b

Final recapitulating caseTumour + Nodes

– pTx - pNx– pT0 - pN0– pTis - pN1a– pT1 - pN1b– pT2 - pN1c– pT3 - pN2a– pT4a - pN2b– pT4bBecause TDs do not count, if you have an LN met.

Omentum (x0.8)

Omentum

x5

Omentum

x5

x20 (micropapillary component)

Final recapitulating caseTumour + 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

Final recapitulating caseTumour + 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.

Final recapitulating caseT + 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

CK7 CDX2CA125

CK20 (not shown):– in both areas

CK7 CDX2

CK7 CDX2

Final recapitulating caseT + 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

Id. Markó Károly: Visegrád 1826