Case 2 -
Chemotherapy Related Sinusoidal Obstruction Syndrome (SOS) and Nodular Regenerative Hyperplasia (NRH) of the Non-tumoral Liver / Fibrotic Nodules with No or Few Residual Tumoral Glands
University of Geneva
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A 65 year old man, with a rectal carcinoma since 3 years, was referred to our center for evaluation
of surgical resection of metachronous liver metastases. Preoperative assessment showed absence of
underlying chronic hepatic disease serologically confirmed. A CT scan revealed four hepatic metastases
measuring from 3 to 7 cm in the right liver, and one metastasis of 2 cm in the left liver. Because of
their number, size and location, they were initially estimated unresectable. Therefore preoperative
oxaliplatin based-chemotherapy was performed. After six cycle of chemotherapy, a new CT scan showed only
three metastases measuring now from 2 to 4 cm, corresponding to a radiologic response with shrinkage of
three metastases and radiological disappearance of two others. Hepatic metastases were now surgically
resectable. A major right hepatectomy associated to left hepatic tumorectomy was scheduled. Three weeks
prior to this major liver resection, a percutaneous right portal vein embolisation was done in order to
hypertrophy the left remaining liver and avoid the risk of postoperative liver insufficiency. At
operation the liver was macroscopically blue and with a firm consistence. Hepatic bleeding during
parenchymectomy necessitated peroperative blood transfusion. Postoperatively despite adequate remaining
hepatic volume, the patient showed transitory increase in transaminases and decrease in prothrombin time
of less than 50% of normal in addition to serum bilirubin more than 50 m mol/L on postoperative till day
9 . The liver function tests normalized, except for GGT. He clinically did well but could be discharged
only on postoperative day 14. The patient is alive 2 years after operation without tumoral recurrence.
Case 2 - Figure 1
Low power view showing areas of sinusoidal congestion involving centrilobular and mediolobular lobular surface
Case 2 - Figure 2
Medium power view showing, sinusoidal congestion is severe, outlined by atrophic hepatocyte trabeculae. The perisinusoidal space of Disse is extensively dilated and contains several erythrocytes in close contact with hepatocytes
Case 2 - Figure 3
high power field showing sinusoidal congestion and extravasation of erythrocytes
- Chemotherapy related sinusoidal obstruction syndrome (SOS) and nodular regenerative hyperplasia
(NRH) of the non-tumoral liver.
- Fibrotic nodules with no or few residual tumoral glands
Pathologic Findings :
Liver resections received for examination were a right hepatic lobe measuring 15 x10x 7.5 cm and
weighing 950 gm and two left tumorectomy measuring 4 and 4.5 cm respectively. At surface and on cut
surface, the non tumoral liver showed a bluish-red marbled feature . Five well-circumscribed
polylobulated white tumoral masses, measuring 3.9, 3.5, 2.2, 1.1 and 0.9 cm respectively were found.
Resection margins were at distance of >0.1 cm of the tumors.
Histologically the non tumoral liver shows zones of sinusoidal congestion
that predominates in centrilobular zones. There are characterized by
sinusoidal vasodilatation filled with erythrocytes. Occasionally, along the
dilated sinusoid, there is focal or diffuse erythrocytes extravasation in the perisinusoidal space
and focally venular inlets are easily discernible.
Areas of SOS are variably accompanied by atrophy of hepatocellular plates or by hepatocytic
dissociation. Hepatocellular necroses are rare. On Trichrome's Masson,
centrilobular fibrosis is observed. Depending on the zones, it concerns mainly the centrilobular veins
and/ or the sinusoids. Centrilobular vein fibrosis resulted in variable degrees of luminal occlusion,
only rarely complete. Mild fibrosis was occasionally localized to venular inlets. Centrilobular
sinusoid fibrosis was often segmental focal centrilobular. On reticulin
staining, nodular transformation is discernable characterized by small bulging nodules composed of
enlarged hepatocytic plates occasionally centered by portal tracts and delineated at the periphery by
atrophic hepatocytes or by dilated sinusoids. All tumoral masses mainly consisted of large zone of
fibrosis with mild mononuclear inflammation. At periphery, few residual adenocarcinomatous glands were
The commentary will discuss the three main points illustrated by this case, namely that:
- The efficacy of new chemotherapies against
colorectal cancer combined to hepatic surgery has drastically modified survival in stage IV colorectal
cancer and are increasingly been used as preoperative chemotherapy.
- Several drawbacks with new chemotherapies may
have clinical impact, amongst which liver toxicity, one target being the hepatic sinusoids..
- The role of the pathologist has considerably
changed when evaluating a hepatic resection for colorectal metastases. Today besides looking at the safe
margins, he should give information to the surgeon and oncologist on the histologic tumoral response to
neoadjuvant chemotherapy and on the nontumoral liver associated lesions, both having gained importance
for the treatment strategies after the liver surgery.
1. Preoperative chemotherapy combined to liver surgery increases the potential for cure in patients with hepatic metastatic colorectal cancer
Colorectal cancer is the third most frequent cancer in the western world . It is early a systemic
disease. More than 50% of patients will develop hepatic colorectal metastases (HCRM) and without
treatment, the 5-year survival rate range from 0% to 8%.
Surgical resection of HCRM represents the curative treatment, with 30-65 % 5-year survival rate
according to disease severity, radicality of surgery and response to chemotherapy as main prognostic
factors. However, more than 75% of patients have at time of diagnosis unresectable HCRM due to the
number of nodules, their size or location.
Over the last decade, major advances in chemotherapeutic agents improved substantially the chances of
treatment of patients with HCRM. While the traditional treatment using 5-fluororouracil (5-FU) and LV
(leucovorin) had low response rates (< 25%), new agents like irinotecan, an inhibitor of topoisomerase
I, or oxaliplatin (OX), a non-nephrotoxic platinum complex added to 5FU-LV (Folfiri or Folfox
combinations) obtained a tumour response in up to 40-50% of the patients. The use of triple associations
with irinotecan, OX and 5-FU-LV increased further the efficacy of systemic chemotherapy. An objective
clinical response can be obtained in 70-80% of cases. The use of preoperative chemotherapy has today
largely i ncrease hepatic resectability rates and improved the overall median survival of patients with
HCRM. The more recent development of 2 monoclonal antibodies, cetuximab (Erbitux®), a monoclonal
antibody against the epidermal growth factor receptor (EGFR) and bevacizumab (Avastin®), a humanized
antibody against the vascular endothelial growth factor (VEGF) has improved the response rates even
Thus the growing efficacy of chemotherapy, accompanied by advances in liver surgery techniques and
interventional radiology (hemi-portal embolisation, radiofrequency thermal ablation), led to develop new
strategies to increase the number of patients with HCRM who may benefit from a curative approach, and to
improve long-term survival.
2. Hepatic sinusoids as target of oxaliplatin based chemotherapy toxicity
The hepatic sinusoid is a unique exchange vessel made of highly specialized cells. It is lined by
fenestrated endothelial cells, has no basement membrane and is surrounded by minimum collagen in the
space of Disse. This minimises any barriers to substrate diffusion and allow direct communication
between the sinusoidal lumen and the space of Disse. Sinusoidal endothelial cells (SECs) have an
important role in filtration and endocytic function. The sinusoid lumen contains phagocytic Kupffer
cells, T lymphocytes and NK cells which are important for host defense and immunity. It is encircled by
hepatic stellate cells located extraluminally in the space of Disse. Physiologically, quiescent hepatic
stellate cells are specialized pericytes containing fat droplets that store vitamin A and, with SECs,
play a major role in regulating the diameters of sinusoids and the distribution of blood flow as well as
in individual sinusoids, lobules, or segments of lobules. Sinusoid is thus the principle site for
regulation of hepatic blood flow.
Injury to the hepatic sinusoids manifests in several ways. Concerning SECs, they may loose their
fenestrations resulting in a decrease sinusoid porosity (known as capillarization phenomena observed i.e.
in cirrhosis and aging liver). They may round up because of loosen of their adherence to the space of
Disse or even detach resulting in a completely denuded space of Disse; the SECs then embolize and
obstruct the sinusoid (i.e. in ischemia-reperfusion injury, early sinusoidal obstruction syndrome,
peliosis hepatits, several drug toxicity); finally the sinusoid may be obstructed by fibrosis (hepatic
sinusoidal fibrosis, late sinusoidal obstruction syndrome). In many of these microvascular injuries, the
change to the sinusoid is a primary event that may lead to hepatocyte hypoxia with liver dysfunction and
disruption of the portal circulation.
One drawback of chemotherapies used for treatment of colorectal cancer is liver toxicity. As
illustrated by this case, OX based chemotherapy is associated to sinusoidal lesions in non-tumorous
liver. S inusoidal dilatation corresponds to one of OX related vascular lesions. It is often
accompanied in addition by erythrocytes extravasation in the perisinusoidal space, and hepatocytic plate
disruption, both representing an alteration in sinusoidal wall integrity .
OX related sinusoidal lesions are morphologically similar to those seen in veno-occlusive disease (VOD),
a condition that occurs mainly as a complication of high-dose chemotherapy in the setting of stem cell
transplantation and recently renamed by DeLeve et al as "sinusoidal obstruction syndrome"
(SOS). In fact, VOD animal model demonstrated that centrilobular vein involvement is not essential to
the development of SOS and that major injury occurs in the hepatic sinusoids. Occlusion of the
centrilobular veins occurs only in 50 to 75% of patients with SOS after hematopoietic stem cell
The more severe the OX related sinusoidal injuries the more often they are coupled to NRH, peliosis
and centrilobular venular as well as sinusoidal centrilobular fibrosis. NRH is important to diagnosed,
because it was described in portal hypertension cases developing at end of OX based chemotherapy. NRH is
characterized by the diffuse transformation of normal hepatic parenchyma into small, regenerative nodules
with little to no fibrosis, compressing the surrounding parenchyma that exhibit atrophic plates or
dilated sinusoids. Although, it may have a prolonged silent clinical course, when symptomatic, patients
develop cholestasis with elevated alkaline phosphatase or signs of portal hypertension which may dominate
the clinical presentation and course of disease. Despite today's sensitive imaging modalities, histology
is the only way to diagnose NRH with confidence. From a pathologist's perspective, the diagnosis of NRH
can be challenging and reticulin staining is mandatory. The pathogenesis of NRH has not yet been
conclusively established. It is believed to be related to modifications of intrahepatic blood flow,
leading to atrophic hypoperfused areas intermingled with hyperperfused regenerative areas. The original
hypothesis related heterogeneous intrahepatic perfusion to obstructive portal vein injury. Today, the
circulatory impairment has been extended also to sinusoidal level. Drugs associated NRH are often devoid
of portal vein lesion, as illustrated herein.
From a clinician's perspective, the importance of OX-related hepatic injury is increasingly
recognized essentially with regard to the preoperative, operative or short post-operative period.
Chemotherapy related sinusoidal injury is significantly associated with longer hospital stay and poor
liver function reserve after major hepatectomy, increase risk of operative bleeding,
development of portal hypertension and ascites , and possibly increased mortality.
However, long term prognosis and outcome of patients with SOS and NRH is largely unknown. Yet, it is of
importance since modern multimodality treatment of HCRM had lead to a significant increase in the
survival patients that potentially develop long-term chemotherapy related liver complications. An
unresolved question is whether hepatectomy should be delayed in patients with OX related hepatic lesions.
It is not known if SOS and NRH are reversible once the cause is stopped . In fact, we observed
persistence and even progression of SOS and NRH in the setting of two stage hepatectomies, and even
fibrosis several months after chemotherapy had been discontinued in secondary hepatectomy for
recurrence of HCRM. The risk of evolution may be significant, particularly for those patients who
receive adjuvant or multiple chemotherapy cycles, and in whom despite an apparent
indolent course, may develop delayed complication.
Nonalcoholic steatohepatitis, can occur after treatment with irinotecan, especially in obese
patients. Irinotecan-associated steatohepatitis can affect hepatic reserve and increase morbidity and
mortality after hepatectomy.
3. Importance of HCRM histologic tumor response to chemotherapy for predicting outcome
About 10 years ago, the role of the pathologist in hepatic colorectal metastases (HCRM) resection
consisted only in looking for the safe margins of the resection and when synchronous to establish the TNM
grade of the disease. However, chemotherapy of colorectal liver metastases has dramatically improved
over the last decade, with tumoral response rates increasing from 25% with 5-fluorouracil, to up to 80%
with different combinations of new agents such as oxaliplatin, irinotecan, bevacizumab and cetuximab.
Such effective chemotherapies are used before surgery to render unresectable HCRM resectable and
increasingly as neoadjuvant treatment, in the hope to improve the long-term outcome by operating on
patients with controlled disease, even with the primary tumor in place. Recently, it was observed and
confirmed that the histological response to the chemotherapy was a new clinical outcome endpoint after
resection of CRLM.
The use of preoperative chemotherapies has changed the strategies for the treatment of HCRM. At the
present time, surgery is essential but only a part of the treatment. OX, because of its efficacy on
colorectal cancer is likely to continue to have a crucial role in adjuvant and neoadjuvant chemotherapy
of patients with HCRM. However pathologists should have a high index of suspicion that non tumorous
liver of these patients may display distinctive vascular lesions and fibrosis, and sampling of non
tumorous liver and performing special stains is highly advisable. Awareness of potential clinical
consequences and recognition of lesions on preoperative liver biopsy is also highly desirable since it
could modify surgical strategy and have a significant impact of liver surgical safety. Delayed
complication should also be kept in mind. Finally, understanding the pathogenesis of SOS and NRH might
help identify diagnostic markers, prevent these changes and develop novel treatment. Histological
response to chemotherapy is correlated with long term survival.
From a practical point of view , a pathological report for surgical
resection for HCRM should today mention:
- Status of resection margin
- Degree of tumoral response if preoperative chemotherapy as been performed
- Type and degree of lesions in the surrounding non tumoral liver; performing a reticulin staining
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