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) TME trial MRC07 trial CRM positivity by randomisation arm
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 • 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
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 obvious 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: �� �� �� ypT �������� �������� pT �� � � � � � �� T1 T2 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 ������ � ��������� ���� ������ ����� ����� ����� ����������� ��� ��� ���� ������� ����������� ��� ��� �� �������������������� ��� ���� ��� ��� �� ����������� �� !" ���� �� ������������������ ��#� !"� ��� !$�������������� �� !%" � �&�# '�����( ����������� ��� !%" ) �&#� *�� ����������� ��� !%" ���� �&�� ��� ��� ����������� �� !%" ��� *�(�+,������������ ��� !%" ���� ,���(��� ����������� �� !%"� �#�� -�.�&'�(� ����������� ��� !%" )�� � /��� ������������ �)� !%" )�� !����������������� �� !%"� ��� ,�������$������������� �� !%" ��� 0��1������������� ��� !%"� ���� ����������������� ��# !%"�� ��� /���������������������� �#� !%" )�� -�2��������������� ��� !%" � 0���� ����������� #� !%" ���# ���1��3��� �# !%" ���) ���&���1��3��� ����3������������� �� !%" ���� �&#� ���1��3��� #� !%" ���� �&#� ���&���1��3��� ��"��"����#�$���%���&�����
Number of lymph nodes �!�����������&�����������'���� �������������(� �����������������
Number of lymph nodes
Number of lymph nodes ����� ��� ��� ��� ���� !" ��� ���� !%" ���� �����)�*�������'��������������� � �����������"���+����, � �!���������"����)�(� � !�+����������*�)��*������� ,-�.���������&�/0(1-2����� ��"��"����#�$���%���&�����
No lymph nodes
Tumor regression grading
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