—  SPECIALTY CONFERENCE  —

Liver Pathology

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

Laura Rubbia-Brandt
University of Geneva
Geneva, Switzerland




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Clinical History
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

Case 2 - Figure 4
Nodular regeneration limited by atrophic plates
Case 2 - Figure 5
fibrotic nodule


Final Diagnosis:
  1. Chemotherapy related sinusoidal obstruction syndrome (SOS) and nodular regenerative hyperplasia (NRH) of the non-tumoral liver.

  2. 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 present .

Commentary
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 further.

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 transplantation.

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.

In Conclusion:
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:
  1. Status of resection margin

  2. Degree of tumoral response if preoperative chemotherapy as been performed

  3. Type and degree of lesions in the surrounding non tumoral liver; performing a reticulin staining is advisable.

References
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