Case 3 -

Nodular Elastosis of the Liver Michael S. Torbenson Johns Hopkins University School of Medicine Baltimore, MD

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Introduction: Brief clinical history: A 62 year old female with a high CA125 underwent exploratory laparotomy to rule out ovarian cancer. The surgeon found no evidence for cancer but did see a pedunculated lesion of the liver that was near but not connected to the falciform ligament. The liver was otherwise grossly unremarkable. The lesion was biopsied. Case 3 - Figure 1 H&E, original magnification 20X. A low power view of the mass lesion shows scattered small islands of hepatocytes surrounded by abundant extracellar material. Case 3 - Figure 2 H&E, original magnification 40X. A medium power view shows the extracellular material involves the portal tracts. The hepatic artery and bile duct can be seen in the remnant of a portal tract. Case 3 - Figure 3 H&E, original magnification 40X. A medium power view shows the extracellular material involves the central veins. This central vein is nearly obliterated. Case 3 - Figure 4 H&E, original magnification 100X. A high power view shows the extracellular material as it abuts the islands of hepatocytes. The hepatocytes show no atypia. Case 3 - Figure 5 original magnification 100X. H&E. A high power view shows the extracellular material. There are scattered cells throughout the extracellular material but these cells show no atypia. No mitotic figures were observed. Case 3 - Figure 6 H&E, original magnification 16X. A high power view shows the extracellular material has a basophilic and somewhat fibrillar appearance. Case 3 - Figure 7 original magnification 100X. Miller's Elastic stain. An elastic stain shows the extracellular material is primarily composed of elastic fibers. Both VVG and Movat stains will also work equally well to highlight the elastic fibers in these cases. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Gross findings: Three unoriented fragments of pale tan tissue measuring from 0.5 to 0.8 cm in greatest dimensions. H&E findings: The biopsy specimens showed extensive deposition of extracellular material that surrounded nodules of benign hepatocytes. The extracellular material was finely granular and gray in color. There were scattered benign appearing mesenchymal cells throughout the extracellular material. Enmeshed in this material were residual portal tracts and central veins. A biliary cyst was also present on one edge of the lesion. A thrombosed vessel could also be seen at one edge of the specimen. Special Stains: The following special stains were performed. Histochemical Trichrome: negative Verhoeff-van Gieson Stain: The extracellular material turned black. Reticulin stain: Numerous reticulin fibers were evident in the extracellular material. Movat stain: The extracellular material turned yellowish-black. As a reminder, in the Movat stain, elastic fibers stain black while collagen and reticulin fibers stain yellow. Immunohistochemistry Positive stains: vimentin (cells embedded within the extracellular material) Negative stains: Congo red Kappa/lambda CD31 CD34 AE1/3 S100 HMB45 smooth muscle actin Differential Diagnoses: The differential includes the following, each of which are discussed in detail below. Cystic disease of the liver. Amyloid . Epithelioid hemangioendothelioma. Cancer associated elastosis. Systemic conditions. Final Diagnosis: Nodular Elastosis of the liver. Case Discussion: Nodular elastosis of the liver is a pseudotumor of the liver that can be challenging to diagnose. Nodular elastosis represents the end stage of a series of changes that are associated with segmental atrophy of the liver. An entire lobe of the liver can also undergo atrophy, but overall such cases are more commonly diagnosed by imaging studies and are only rarely seen as surgical specimens. Segmental atrophy, however, can present as a mass lesion that undergoes biopsy or resection. Based on our recent experience of 16 cases collected from several institutions, of resected or biopsied lesions, there appears to be a modest female predominance (70%) and a wide age range at presentation, from 14 to 91 years (median 65 years). The most common clinical presentation is right upper quadrant abdominal pain (75%). The mass lesions can be identified either at the time of surgery (as in our case) or by imaging studies. The majority of lesions are subcapsular (80%) and range in size from 2 to 10.0 cm. A striking feature in almost all cases is the presence of abnormally thick-walled vessels that may be thrombosed, fibrosed, and re-cannulized. They can be found throughout the lesion and both arteries and veins may be affected. Biliary cysts are also a common finding (35%). Although I am without direct experimental evidence to support this, I believe most of the cysts are "retention cysts" caused by duct obstruction and subsequent dilatation and cyst formation within the areas of blocked biliary drainage. In many cases, smaller cysts are clearly within portal tracts and represent dilatation of the native bile duct. At times, the larger cysts can rupture and develop a thick rind of inflammed fibrotic tissue. The cyst epithelium maybe denuded from large sections of these inflammed fibrotic cysts, but can almost always be seen with sufficient sectioning of the cyst wall. On follow-up, no recurrence has been reported. Based on seriating a set of 16 cases, there appears to be a defined set of morphological appearances through which these lesions progress. Early lesions appear to be composed principally of collapsed hepatic parenchyma with occasional islands of residual hepatocytes and brisk bile ductular proliferation. These early cases may show no elastosis or only focal elastotic changes. Over time the ductular reaction diminishes and the elastotic changes increase. The later lesions can be composed almost solely of elastosis with small scattered islands of unremarkable hepatocytes, as seen in our case, and diagnosed as "nodular elastosis". How common in this lesion? It is hard to say with any numerical certainty. Between our combined in-house and consult services, we see on average a case of segmental atrophy perhaps every year or two. Nodular elastosis is much less common: we have 2 cases in our files from 1984 to 2009. The histological findings tend to fairly distinctive for these cases and after seeing and perhaps struggling with the first case, subsequent cases tend to be fairly easily identified. Elastic fibers in the normal and diseased liver Elastic fibers provide flexibility and recoil-to-stretch in normal tissues and are particularly prominent in the skin, lungs, and walls of large vessels. Elastic fibers are composed principally of elastin and microfibrils. [1] Elastin is encoded by a single gene, ELN, but microfibrils are composed of a variety of proteins including fibulins and microfibril associated glycoproteins. [1] The elastic component of tissues is created during organogenesis and subsequent organ maturation and forms a complicated 3-diminsional network. Injured tissues in the adult can produce elastic fibers, but injured tissues have difficulty creating the normal fiber organizational patterns, often leading to deposition of disorganized and excessive amounts of elastic fibers. [1] In response to injury, elastic fibers can be synthesized by fibroblasts as well as smooth muscle cells [2] and endothelial cells. [3] In the normal liver, elastic fibers are found within the portal tracts, the walls of larger vessels, and in the connective tissue of the central veins. [4] In the setting of liver injury, elastic fibers are synthesized by portal myofibroblasts but not activated stellate cells. [5] Increased elastic fiber deposition can be seen in a variety of conditions and overall tends to parallel the amount of fibrosis. For example, in one study of non-alcoholic steatohepatitis, increased elastic fiber deposition was seen in all cases of advanced fibrosis but only rarely in cases with milder stages of fibrosis. [6] Of note, the elastic deposition in such cases do not form discrete lesions and in general are not seen on H&E stains. Etiological considerations The possibility that a vascular injury leads to the segmental atrophy and subsequent development of elastosis was outlined above. While this explanation fits well with our histological findings, there have been clinical reports that have linked segmental atrophy to bile duct injury, [7] suggesting there may be more than one pathway of injury that can lead to the same result of segmental atrophy and eventually to nodular elastosis. Elastotic polyps of the colon provide some interesting parallels. They can be found throughout the gastrointestinal tract and are composed of aggregates of elastic fibers found principally in the submucosal. [8] The H&E and histochemical staining qualities are essentially identical to that found in the nodular elastosis of the liver. Of particular relevance, 4/13 cases of elastotic polyps of the gastrointestinal tract were associated with elastotic submucosal blood vessels, [8] suggesting a shared vascular etiology with liver cases. Differential Cystic disease of the liver. In some cases, multiple small cysts may be present and this can raise the question of multicystic diseases of the liver. Proper classification can be assisted by knowing the radiological findings: diffuse cystic change in the liver or cysts within the kidneys would suggest cystic liver disease. On histological examination, a diagnosis of segmental atrophy and cystic changes could be based on identifying areas of parenchymal collapse, finding the thrombosed vessels, or finding the ductular reactions typical of early lesions. The presence of elastotic changes also will favor a diagnosis of lobar atrophy. Amyloid . Amyloid deposition can be in the differential in those cases containing abundant elastosis. A Congo red stain will be negative in elastosis but positive in amyloidosis. Epithelioid hemangioendothelioma. Epitheliod hemanagioendotheliomas often have a distinctive amphophilic tumor matrix that can resemble nodular elastosis. The neoplastic cells within this glycoprotein rich tumor matrix are typically more cellular than nodular elastosis, but in some cases there can be areas that have many fewer cells, leading to an overall cellular density that resembles nodular elastosis. However, the neoplastic cells of epitheliod hemanagioendotheliomas will have nuclear pleomorhpism and frequently have cytoplasmic vacuoles that can mimic signet ring cells. Mitotic figures, which can be seen in many epithelioid hemangioendotheliomas, are lacking in nodular elastosis. Immunostains for vascular markers factor VIII, CD34, and CD31 are negative in nodular elastosis but positive in 99%, 70% and 66% of epithelioid hemangioendotheliomas respectively. [9] Cancer associated elastosis. Irregular dense aggregates of elastic fibers can also be seen within the stroma of certain types of cancers in other organ systems. For example, in one study 66% of papillary thyroid carcinomas had stromal elastosis, as did 76% of lung adenocarcinomas, 50% of lung squamous cell carcinomas, 57% of breast carcinomas, and 22% of gastric carcinomas. [10] This same study found no evidence of stromal elastosis with hepatocellular carcinomas, an observation that fits well with our general experience. Thus, in the liver, nodular elastosis does not appear to be associated with carcinoma. However, a caveat is that atrophy of the entire right or left lobe (but typically not segmental atrophy) has been reported in individuals with hepatocellular or cholangiocarcinomas. [11] Systemic conditions. While data is limited, there has been no clinical evidence of extrahepatic manifestations of lobar atrophy/nodular elastosis changes to-date. Elastotic polyps of the gastrointestinal tract have rarely been reported to be associated with other elastotic conditions including elastrofibroma dorsi. [12] Review of the Literature/Treatment Options: Segmental atrophy/nodular elastosis is a benign lesion that does not require intervention, but since it often presents as a mass lesion, it often undergoes surgical resection. Once resected, there have been no reports of recurrence. Conclusion(s): Nodular elastosis is a histologically distinctive psuedototumor of the liver that is associated with vascular injury and segmental atrophy of the liver. References: Wagenseil JE, Mecham RP. New insights into elastic fiber assembly. Birth Defects Res C Embryo Today 2007; 81:229-40. Narayanan AS, Sandberg LB, Ross R, et al. The smooth muscle cell. III. Elastin synthesis in arterial smooth muscle cell culture. J Cell Biol 1976; 68:411-9. Carnes WH, Abraham PA, Buonassisi V. Biosynthesis of elastin by an endothelial cell culture. Biochem Biophys Res Commun 1979; 90:1393-9. Lamireau T, Dubuisson L, Lepreux S, et al. Abnormal hepatic expression of fibrillin-1 in children with cholestasis. Am J Surg Pathol 2002; 26:637-46. Ramadori G, Saile B. Portal tract fibrogenesis in the liver. Lab Invest 2004; 84:153-9. Nakayama H, Itoh H, Kunita S, et al. Presence of perivenular elastic fibers in nonalcoholic steatohepatitis Fibrosis Stage III. Histol Histopathol 2008; 23:407-9. Kaushik S, Fulcher AS, Turner MA. Segmental hepatic atrophy: a sequela of blunt intrahepatic bile duct injury. J Trauma 2003; 54:1225-7. Hobbs CM, Burch DM, Sobin LH. Elastosis and elastofibromatous change in the gastrointestinal tract: a clinicopathologic study of 13 cases and a review of the literature. Am J Clin Pathol 2004; 122:232-7. Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 1999; 85:562-82. Kondo T, Nakazawa T, Murata S, et al. Stromal elastosis in papillary thyroid carcinomas. Hum Pathol 2005; 36:474-9. Ham JM. Lobar and segmental atrophy of the liver. World J Surg 1990; 14:457-62. Enjoji M, Sumiyoshi K, Sueyoshi K. Elastofibromatous lesion of the stomach in a patient with elastofibroma dorsi. Am J Surg Pathol 1985; 9:233-7.