Pathology of neoadjuvant therapy Neoadjuvant therapy Types of - - PowerPoint PPT Presentation

Pathology of neoadjuvant therapy

Neoadjuvant therapy

• Types of neoadjuvant therapy and their implications
• Short-term versus long-term
• Interval issues
• Staging after neoadjuvant therapy
• ypTNM issues
• Lymph node issues
• Complete pathological response
• Tumor regression grading

Indications for neoadjuvant therapy

• Reduction of local recurrences
• Downstaging
• Facilitating sphincter saving procedures

Effects of neoadjuvant therapy

• Downstaging
• Decreased frequency of positive margins
• Tumor regression

Short term radiotherapy (5 x 5 Gy)

CRM positivity by randomisation arm

TME trial MRC07 trial

Long interval and 5x5 Gy

Rombouts et al, in preparation

Interval and response

Staging and downstaging

Downstaging is dependent on the time interval between radiotherapy and surgery Downstaging does not always leads to better prognosis TNM (or Dukes) has been developed for previously untreated patients

TNM and neoadjuvant therapy

• Prefix “y” or “yp” to indicate neoadjuvant therapy
• To indicate that the gold standard for staging (pathology) might not

correspond to pre-treatment staging

• To indicate possible regression/downstaging
• To indicate that the relation between T and N will / might be different

TNM and neoadjuvant therapy

• ypTNM should consider

not only viable tumour cells but also signs of regressed tumour tissue such as scars, fibrotic areas, fibrotic nodules, granulation tissue, mucin lakes, etc.

• TNM supplement 2001
• ypTNM should consider
• nly viable tumour cells

and not signs of regressed tumour tissue such as scars, fibrotic areas, fibrotic tissue, granulation tissue, mucin lakes, etc.

• TNM supplement 2003

TNM and neoadjuvant therapy

• Prefix “y” or “yp” to indicate neoadjuvant therapy
• To indicate that the gold standard for staging (pathology) might not

correspond to pre-treatment staging

• To indicate possible regression/downstaging
• To indicate that the relation between T and N will / might be different

TNM and neoadjuvant therapy

• Prefix “y” or “yp” to indicate neoadjuvant therapy
• To indicate that the gold standard for staging (pathology) might not

correspond to pre-treatment staging

• To indicate possible regression/downstaging
• To indicate that the relation between T and N will / might be different

pTNM is different from ypTNM !

• Often reported as one group
• Difficult to prove, since there is an
• bvious selection bias
• Surgery only group includes smaller

tumors and more comorbidity

• No clinical trials available
• Main comparison with 5x

Bosch et al, submitted

TNM and neoadjuvant therapy

• Prefix “y” or “yp” to indicate neoadjuvant therapy
• To indicate that the gold standard for staging (pathology) might not

correspond to pre-treatment staging

• To indicate possible regression/downstaging
• To indicate that the relation between T and N will / might be different

Lymph nodes after neoadjuvant therapy

TNM and neoadjuvant therapy

• the relation between T and N will be different:
• pT

T1 T2 ypT

From Nagtegaal and Marijnen, 2008

TEM and neoadjuvant therapy

• If the relation between T and N changed…
• What happens to the traditional TEM parameters ?
• Differentiation
• Lymphatic and vascular invasion

Lymph node risk in ypT1-2 tumors

• N = 135 (multicenter study)

No difference between ypN0 and ypN+

• Invasion depth
• TRG
• IMVI (was not present at all)
• PNI (was not present at all)
• Budding
• Necrosis
• Peritumoral infiltrate
• Mucinous lakes
• Calcifications

Lymph node risk in ypT1-2 tumors

• N = 135 (multicenter study)
• Residual tumor area diameter
• Histological grade

Staging problems

Mucinous lakes Complete response Ex-positive lymph nodes Number of lymph nodes

Inclusion in T stage?

Mucinous lakes

TNM and neoadjuvant therapy

• Acellular mucin/mucinous lakes
• Present in 27% of patients with a pCR
• No prognostic significance
• Justification to ignore it in staging ?

Staging problems

Mucinous lakes Complete response Ex-positive lymph nodes Number of lymph nodes

Complete response ?

Complete response ?

How to define? Clinical complete reponse (cCR) results in a pathological complete response (pCR) in only 30% Is ypT0 sufficient or ypT0N0 ? Local excision versus resection

TNM and neoadjuvant therapy

• Pathological complete response: ypT0N0
• But… 7% positive nodes when ypT0
• Clinical complete reponse (cCR) results in a pathological complete

response (pCR) in only 30%

• Standardisation and sufficient sampling is necessary
• 5 blocks at site of tumour
• If still no tumour block entire area
• If still no tumour 3 levels of each block
• If still no tumour – complete response

Staging problems

Mucinous lakes Complete response Ex-positive lymph nodes Number of lymph nodes

Ex-positive lymph nodes

Is ypN better than cN ? Small series describing ex-positive lymph nodes in a number of nodes (fibrosis, mucinous lakes) Indication of early metastatic disease? Good response indicated good prognosis? How good is clinical staging?

Ex-positive lymph nodes

• !

Staging problems

Mucinous lakes Complete response Ex-positive lymph nodes Number of lymph nodes

Number of lymph nodes

• !"
• #

!"

• !$
• !%"
• &#

'(

• !%"

) &# *

• !%"
• &
• !%"
• *(+,
• !%"
• ,(
• !%"

#

• .&'(
• !%"

)

• /

) !%" ) !

• !%"
• ,$
• !%"
• 01
• !%"
• #

!%"

• /

# !%" )

• 2
• !%"
• #

!%" # 13 # !%" ) &13 3

• !%"
• &#

13 # !%"

• &#

&13 ""#$%&

Number of lymph nodes

!&' (

Number of lymph nodes

Number of lymph nodes

• !"
• !%"
• )*'

"+, !")( !+*)*

,-.&/0(1-2

""#$%&

No lymph nodes

Tumor regression grading

Why do we want to know?

• Prognostic relevance: better response is better outcome
• Alternative endpoint for clinical trials
• Potential for local excision / watchfull waiting
• Indicative of downstaging
• Risk of lymph node metastases
• Predictive marker for adjuvant therapy

But we cannot do it!

1. Different classification schemes 2. Different stage grouping methods 3. Poor interobserver variability 4. Also present in patients not treated with neoadjuvant therapy

$& 3 4 5'6& 7

)7 ) 77 7 14748*

The origin of TRG systems

Different classification schemes

Different classification

No regression 5 4 1 No regression Dominant tumor mass with obvious fibrosis 4 3 2 < 25% regression Tumor cells easy to find 3 2 3 25% - 50% regression Tumor cells difficult to find 2 1 4 > 50% regression No residual tumor cells 1 5 Complete regression Mandard Rodel modification

• f Dworak

AJCC

Different stage grouping

name year n type Mace 2015 538 AJCC Losi 2006 112 Dworak Berho 2009 86 Dworak Kim 2010 420 Dworak Park 2010 108 Dworak Roy 2012 75 Dworak Huebner 2012 237 Dworak Lim 2012 581 Dworak Hermanek 2013 225 Dworak Santos 2014 139 Dworak Yoon 2015 261 Dworak McCoy 2015 205 Dworak Vecchio 2005 114 Mandard Suarez 2008 119 Mandard Lindebjerg 2008 135 Mandard Salmo 2011 75 Mandard Dhadda 2011 158 Mandard Min 2011 178 Mandard Santos 2013 139 Mandard Peng 2015 190 Mandard Beddy 2008 126

• wn

Arredondo 2013 228

• wn

1 2 3 4 5 1 2 3 4

Interobserver variability is high ….

Up to 32% regression without radiotherapy

But there is a clear difference

And a correlation with outcome

The situation is more complex

• a biological explanation -

What actually happens:

• In case of shrinkage:

less LNM

• Presence of “TD” is

associated with poor prognosis

• Dworak is not

predictive

Tumor fragmentation as response mechanism

1. Remaining tumor cells are present in the deeper layers of the bowel 2. Downstaging and tumor regression are different 3. Posttreatment biopsies do not present an adequate picture 4. Patients with a near complete pCR can have a poor prognosis 5. Tumor deposits after neoadjuvant therapy are something else….

Downstaging versus tumor regression

Downstaging has more prognostic impact

Value of posttreatment biopsies

Value of posttreatment biopsies

In 42 patients: “false” negative submucosa !!!! 38% of this population

• 2/7 of benign lesions

(clinically and on initial biopsy) turned out to be cancer

This explains the near-pCR prognosis

This explains the near-pCR prognosis

Tumor deposits after neoadjuvant therapy

factor No therapy Neoadjuvant setting Lymph node metastases RR 4.2 (95% CI 3.2 -5.6) RR 1.7 (95% CI 1.1-2.8) Lymphatic invasion RR 3.8 (95% CI 2.2-6.4) RR 1.5 (95% CI 0.6-3.9) Vascular invasion RR 2.6 (95% CI 1.8-3.7) RR 0.2 (95% CI 0.0-3.1) Perineural invasion RR 1.7 (95% CI 1.4 -2.2) RR 2.5 (95% CI 0.6 -10.8) The biological background is different! in preparation

Conclusions

• Many problems with TRG: need for standardisation and consensus
• Digital pathology
• Comparisons with MRI
• More insights in biology of tumor response
• Many studies suggest that TRG on itself is not independent prognostic
• TD after neoadjuvant therapy are different