pathology of neoadjuvant therapy neoadjuvant therapy
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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


  1. Pathology of neoadjuvant therapy

  2. 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

  3. Indications for neoadjuvant therapy • Reduction of local recurrences • Downstaging • Facilitating sphincter saving procedures

  4. Effects of neoadjuvant therapy • Downstaging • Decreased frequency of positive margins • Tumor regression

  5. Short term radiotherapy (5 x 5 Gy) TME trial MRC07 trial CRM positivity by randomisation arm

  6. Long interval and 5x5 Gy Rombouts et al, in preparation

  7. Interval and response

  8. 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

  9. 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

  10. TNM and neoadjuvant therapy • ypTNM should consider • ypTNM should consider not only viable tumour only viable tumour cells cells but also signs of and not signs of regressed tumour tissue regressed tumour tissue such as scars, fibrotic such as scars, fibrotic areas, fibrotic nodules, areas, fibrotic tissue, granulation tissue, mucin granulation tissue, mucin lakes, etc. lakes, etc. • TNM supplement 2001 • TNM supplement 2003

  11. 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

  12. 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

  13. pTNM is different from ypTNM ! • Often reported as one group • Difficult to prove, since there is an obvious selection bias • Surgery only group includes smaller tumors and more comorbidity • No clinical trials available • Main comparison with 5x Bosch et al, submitted

  14. 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

  15. Lymph nodes after neoadjuvant therapy

  16. TNM and neoadjuvant therapy • the relation between T and N will be different: �� �� �� ypT �������� �������� pT �� � � � � � �� T1 T2 From Nagtegaal and Marijnen, 2008

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

  18. 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

  19. Lymph node risk in ypT1-2 tumors • N = 135 (multicenter study) • Residual tumor area diameter • Histological grade

  20. Staging problems � Mucinous lakes � Complete response � Ex-positive lymph nodes � Number of lymph nodes

  21. Inclusion in T stage?

  22. Mucinous lakes

  23. 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 ?

  24. Staging problems � Mucinous lakes � Complete response � Ex-positive lymph nodes � Number of lymph nodes

  25. Complete response ?

  26. 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

  27. 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

  28. Staging problems � Mucinous lakes � Complete response � Ex-positive lymph nodes � Number of lymph nodes

  29. 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?

  30. Ex-positive lymph nodes ���������������������������������������� �������������������������������������� � �!��������������������������������� �

  31. Staging problems � Mucinous lakes � Complete response � Ex-positive lymph nodes � Number of lymph nodes

  32. Number of lymph nodes ������ � ��������� ���� ������ ����� ����� ����� ����������� ��� ��� ���� ������� ����������� ��� ��� �� �������������������� ��� ���� ��� ��� �� ����������� �� !" ���� �� ������������������ ��#� !"� ��� !$�������������� �� !%" � �&�# '�����( ����������� ��� !%" ) �&#� *�� ����������� ��� !%" ���� �&�� ��� ��� ����������� �� !%" ��� *�(�+,������������ ��� !%" ���� ,���(��� ����������� �� !%"� �#�� -�.�&'�(� ����������� ��� !%" )�� � /��� ������������ �)� !%" )�� !����������������� �� !%"� ��� ,�������$������������� �� !%" ��� 0��1������������� ��� !%"� ���� ����������������� ��# !%"�� ��� /���������������������� �#� !%" )�� -�2��������������� ��� !%" � 0���� ����������� #� !%" ���# ���1��3��� �# !%" ���) ���&���1��3��� ����3������������� �� !%" ���� �&#� ���1��3��� #� !%" ���� �&#� ���&���1��3��� ��"��"����#�$���%���&�����

  33. Number of lymph nodes �!�����������&�����������'���� �������������(� �����������������

  34. Number of lymph nodes

  35. Number of lymph nodes ����� ��� ��� ��� ���� !" ��� ���� !%" ���� �����)�*�������'��������������� � �����������"���+����, � �!���������"����)�(� � !�+����������*�)��*������� ,-�.���������&�/0(1-2����� ��"��"����#�$���%���&�����

  36. No lymph nodes

  37. Tumor regression grading

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