Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer.
BACKGROUND
In advanced metastatic colorectal adenocarcinoma, the addition of a neo-adjuvant systemic treatment to surgery might translate into a survival advantage, although this is yet to be confirmed by ongoing randomized trials. The objective of this study was to assess the effects of preoperative systemic chemotherapy on the morphology of non-tumoral liver.


METHODS
A large series of surgically resected liver metastases (n=153) was selected. Light microscopy, electron microscopy, and immunohistochemistry using antibodies against endothelial cells (CD31) and hepatic stellate cells (alpha-SM actin, CRBP-1) were performed to identify sinusoidal wall integrity.


RESULTS
We found that 44 (51%) of the 87 post-chemotherapic liver resection specimens had sinusoidal dilatation and hemorrhage, related to rupture of the sinusoidal barrier. In contrast, the 66 livers treated by surgery alone remained normal. In 21 out of the 44 post-chemotherapy patients (48%), perisinusoidal and veno-occlusive fibrosis also developed. Sinusoidal injury persisted several months after end of chemotherapy, and fibrosis may progress. Development of lesions was strongly correlated to the use of oxaliplatin; 34 out of 43 patients (78%) treated with this drug showed striking sinusoidal alterations.


CONCLUSIONS
Systemic neo-adjuvant chemotherapy in metastatic colorectal cancer frequently causes morphological lesions involving hepatic microvasculature. Sinusoidal obstruction, complicated by perisinusoidal fibrosis and veno-occlusive lesion of the non-tumoral liver revealed by this study, should be included in the list of the adverse side-effects of colorectal systemic chemotherapy, in particular related to the use of oxaliplatin.
Division of Clinical Pathology, University Hospital, Geneva, Switzerland. laura.rubbia-brandt@hcuge.ch
L
L
Rubbia-Brandt
V
V
Audard
P
P
Sartoretti
A D
AD
Roth
C
C
Brezault
M
M
Le Charpentier
B
B
Dousset
P
P
Morel
O
O
Soubrane
S
S
Chaussade
G
G
Mentha
B
B
Terris
D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D006498:Hepatectomy; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced* / Q000473:pathology / Q000601:surgery; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000601:surgery / Q000648:ultrastructure; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology / Q000601:surgery; D008113:Liver Neoplasms / Q000556:secondary* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D000077150:Oxaliplatin; D011379:Prognosis
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin