Uncommon Benign Neoplasms and Pseudotumors of the Liver Open Access

Segmental atrophy (SA) of the liver is a rare and underrecognized benign entity with only a few reported series. SA can present as a mass lesion, posing a diagnostic challenge for radiologists and pathologists alike. Clinicopathologic characteristics remain poorly described, and radiologists, hepatologists, and surgeons are often unaware and ill-prepared to deal with this clinical entity. The etiology of SA is not precisely known, and it is not entirely clear why these lesions develop. Some speculate that they result from a form of vascular injury, such as local thrombosis of a vessel feeding a smaller subsegment of the liver, leading to ischemic parenchymal extinction and loss of hepatocytes. SA was originally described by Singhi et al,¹  wherein they described the clinicopathologic features of 18 cases. SA predominantly arises in middle-aged adults, with a slight female predominance. Although exceedingly rare, SA has been reported in children.²  Data from an unpublished study showed that SA has a strong association with longstanding cardiovascular disease and is rarely associated with connective tissue disorders.³  The lesions are often subcapsular and can range in size from 1.7 to 10 cm.^1,3  Histologically, depending on the stage of the lesion, SA displays a morphologic spectrum. In the early stages, there are occasional entrapped hepatocytes, a brisk bile ductular proliferation, and focal elastotic changes. As the lesions age, the bile ductular proliferation decreases, and elastosis increases. In the final stages, SA demonstrates nodules of dense fibrosis (Figure 1).

The most striking histologic feature in SA is the presence of abnormally thick-walled blood vessels throughout the lesion (Figure 2). Other salient features include dilated bile ducts and biliary cysts. The biliary cysts, if large, can sometimes be clinically concerning for mucinous cystic neoplasm or intraductal papillary neoplasm of bile ducts (Figure 3). A simple hepatic cyst or a solitary bile duct cyst secondary to a limited form of ductal plate malformation is another potential differential diagnosis because of their morphologic similarity to the biliary retention cyst in SA. Regenerative hepatic pseudotumor is another recently described pseudotumor caused by vascular flow changes, but it differs from segmental atrophy morphologically. The vascular changes in regenerative hepatic pseudotumor are associated with reactive parenchymal changes, including sinusoidal dilation, patchy bile ductular proliferation, and portal vein abnormalities, but, unlike SA, elastosis is absent or only focally present.⁴  In Table 2, we have listed the potential differential diagnosis of segmental atrophy based on the suggestion of the contributing pathologists at the time of consultation. However, in practice, the noted entities are often easily distinguishable from SA, except perhaps in limited samples.

Awareness of multiple stages of SA and recognizing its various morphologies allow for accurate diagnosis.

IgG4-RSD is a chronic fibroinflammatory disease affecting various organs, including salivary glands, thyroid, pancreas, bile ducts, and, less commonly, liver. Previously, the manifestations in each organ system were classified as unrelated diseases (eg, type 1 autoimmune pancreatitis, Riedel thyroiditis, Küttner tumor [submandibular gland], and Mikulicz disease [salivary and lacrimal glands]). However, affected patients often had lesions in multiple organs and expressed high levels of serum IgG4, which led to the unification of these diseases under the IgG4-RSD umbrella.⁵  Although there are clinical diagnostic criteria for IgG4-RSD (such as serum IgG4 levels >135 mg/dL), histologic evaluation remains the gold standard for the diagnosis. Normal IgG4 levels do not exclude the diagnosis of IgG4-related disease because serum IgG4 concentrations are normal in approximately 10% to 40% of patients with IgG4-RSD.^6,7  Histologically, hepatic IgG4-RSD can range from mild nonspecific portal inflammation to sclerosing cholangitis and inflammatory pseudotumor. Classic histologic appearance based on Boston consensus criteria includes storiform fibrosis, obliterative phlebitis, and IgG4-enriched lymphoplasmacytic infiltrate.⁷  Immunohistochemistry can support the diagnosis when there are increased IgG4⁺ cells for which the cut points vary in different organs (Figure 4). For the liver or bile ducts, the suggested cut points are greater than 50 IgG4⁺ cells per high-power field (HPF) for surgical resection specimens and greater than 10 IgG4⁺ cells per HPF for biopsies.⁷  Another supporting immunohistochemistry finding is an IgG4/IgG ratio of greater than 40%. This can be problematic in practice because the IgG immunostain typically shows high background staining. The current recommendations are to count 3 HPFs with the highest density of IgG4⁺ plasma cells and use these same 3 fields for IgG⁺ counts to generate the IgG4/IgG ratio.⁸  Although immunohistochemistry can support the diagnosis, one should not be overly reliant on IgG immunohistochemistry for the diagnosis. Multiple studies have shown that elevated serum IgG4 and increased numbers of IgG4⁺ plasma cells can be seen in the setting of biliary tract carcinomas, primary sclerosing cholangitis, and RDD.^9,10  Thus, an undersampled bile duct carcinoma or primary sclerosing cholangitis may be misdiagnosed as IgG4-RSD if a pathologist is overly reliant on the IgG4⁺ cell count. While steroid-responsive, IgG4-RSD conveys risk for progressive fibrosis and eventually cirrhosis. RDD is a key differential diagnosis of IgG4-RSD because of the presence of vasculopathy and increased IgG4⁺ plasma cells. RDD is a rare non–Langerhans cell histiocytic proliferation that can manifest in nodal and extranodal sites. Involvement of the gastrointestinal tract and especially liver is exceedingly rare. Emperipolesis, although nonspecific, is a helpful diagnostic feature. In general, arteries are more likely to be affected in RDD in contrast to obliterative phlebitis of IgG4-RSD, and immunostaining with S100 protein is a useful tool for confirming the diagnosis (Figure 5).¹¹ 

Inflammatory myofibroblastic tumor displays overlapping features with those of IgG4-RSD and is often replete with IgG4⁺ plasma cells. Most cases, but not all, can be separated with the use of immunohistochemistry for ALK1 and ROS1 and searching for obliterative phlebitis. A subset of cases requires application of a next-generation sequencing–based assay that covers known inflammatory myofibroblastic tumor fusions to confirm the diagnosis.¹² 

A rare subset of inflammatory Epstein-Barr virus–driven lesions has been reported in the liver and spleen as “inflammatory pseudotumor-like follicular/fibroblastic dendritic cell sarcoma (IPT-like FDCS).” Such tumors arise in young to middle-aged adults and are characterized by spindle cells in an inflammatory background. The blood vessels in the tumors frequently have fibrinoid material deposited in their walls (Figure 6). It is not clear whether these lesions are in fact follicular dendritic cell neoplasms because CD23 can be absent. These tumors can recur, sometimes multiple times, but are overall believed to be indolent.¹³ 

A variety of infections can present as hepatic pseudotumors. Although rare, syphilis is an important infectious cause of inflammatory pseudotumor and should always be considered in the differential diagnosis, especially when evaluating biopsies from high-risk populations, such as human immunodeficiency virus (HIV) patients and men who have sex with men.¹⁴  The presumed mechanism of hepatic infection in HIV patients is from portal invasion of organisms after anorectal infection as a result of portal venous drainage of the rectum.¹¹  The liver can be involved in all stages of syphilis. Late syphilis can present with mass lesions formed by gummas or inflammatory pseudotumors mimicking neoplasms, particularly metastases.^15,16  Gummas are rarely encountered but are characterized by a central zone of coagulative necrosis and a surrounding rim of fibroinflammatory tissue. When hepatic syphilis presents as an inflammatory pseudotumor, histologic clues include the presence of a plasma cell–rich fibroblastic proliferation with abscesses, granulomas, Kupffer cell hyperplasia, and portal edema with pericholangitis or cholangitis in the surrounding liver (Figure 7). The differential diagnosis in such cases revolves around the entities discussed in the section above concerning IgG4-related disease.

Immunohistochemistry for Treponema pallidum can be a powerful tool in the diagnosis of syphilis. However, a negative stain does not exclude the diagnosis when the morphology and clinical circumstances support it. Typically, when the immunostain is positive, the organisms are concentrated in the areas of the mass lesion and not the background liver. Therefore, a negative immunostain may represent an undersampled mass lesion.¹⁴  Congenital syphilis can present with diffuse sinusoidal fibrosis or a giant cell hepatitis pattern.

Hydatid disease is the most common cause of hepatic cysts worldwide and is caused by infection with the larval stage of the tapeworm Echinococcus. It is a zoonotic infection in which humans are infected by exposure to contaminated feces of primary or intermediate hosts. Although not endemic in the United States, cases are occasionally encountered in the United States and central Europe.^17,18  The cysts are slow-growing and therefore are often asymptomatic for years.¹⁹  Hepatic echinococcosis involves the liver in 2 basic patterns. Echinococcus granulosus is the most common and causes slow-growing cystic lesions that can attain sizes of up to 30 cm in diameter and is most commonly encountered in individuals raising sheep. The cysts often contain several daughter cysts. Echinococcus multilocularis is the alveolar form, which is transmitted by contact with wild animals and has a more aggressive clinical course; it can invade and destroy infected liver, induce a tumorlike growth, and mimic malignancy.²⁰  The cysts are often multilocular, and the cystic cavities contain thick, pasty material. The cysts of E granulosus, if well preserved, are composed of 3 structural components: innermost germinal membrane, a middle hyalinized laminated layer, and an outer layer of hyalinized fibrosis. Echinococcus multilocularis, on the other hand, can show a range of findings, from small cysts to necrotizing granulomatous inflammation without well-formed cyst walls. Trichrome stains, periodic acid–Schiff stain, or Grocott methenamine silver stains can highlight the degenerating parasite forms (Figure 8). Relatively recently, Reinehr et al¹⁸  developed an algorithm for not only diagnosing echinococcosis but also using a combination of morphologic and immunohistochemical criteria to discriminate between cystic echinococcosis (CE) and alveolar echinococcosis (AE). Six morphologic criteria that discriminated between cystic and alveolar echinococcosis were: size of smallest (CE/AE, >2/≤2 mm) and largest cyst (CE/AE, >25/≤25 mm), thickness of laminated layer (CE/AE, >0.15/≤0.15 mm) and pericystic fibrosis (CE/AE, >0.6/≤0.6 mm), striation of laminated layer (CE/AE, moderate-strong/weak), and number of cysts (CE/AE, ≤9/>9). Immunostaining with either of 2 novel antibodies (mAbEm2G11 [E multilocularis specific] and mAbEmG3 [reactive in AE and CE]) showed specificity equal to the authors' routine morphologic criteria.¹⁸ 

Hepatic angiomyolipoma (AML) is a rare benign neoplasm, and liver is the second most frequent site of involvement after the kidney. AML has a strong predilection for adult females.²¹  In contrast to renal examples, most hepatic AMLs are sporadic and only rarely associated with tuberous sclerosis (TS).²²  However, tested hepatic AMLs nearly invariably harbor TSC2 mutations as the driver mutation.²³  AMLs show differentiation along the lines of perivascular epithelioid cells and are considered part of the perivascular epithelioid cell family.²⁴  Grossly, they often present as nonencapsulated, well-circumscribed solitary lesions in a background of noncirrhotic liver. As the name implies, they are composed of varying amounts of smooth muscle–type cells, adipose tissue (can be fat poor or fat predominant), and blood vessels. The myoid component is the most specific for diagnosis. About 40% of cases show extramedullary hematopoiesis (Figure 9).²⁴  The presence of clusters of foamy macrophages can be a useful diagnostic clue in difficult cases.²³  AMLs are easy to recognize when all 3 components are present but can be confused with many entities when only 1 component is present. For example, myoid cells, either epithelioid or spindled, can be the only cell type, which can cause confusion with hepatic adenoma, hepatocellular carcinoma, malignant melanoma, smooth muscle tumors, and metastatic gastrointestinal stromal tumor. Almost half of the cases in a study by Tsui et al²⁵  were initially misdiagnosed as carcinomas or sarcomas. Fortunately, the mimics can be reliably excluded when histology is combined with immunohistochemistry. HMB-45 and Melan-A are positive in AMLs, whereas cytokeratin, HepPar1, and other hepatocellular markers are negative. However, there are important pitfalls of which to be aware. When hepatic epithelioid AML resembles hepatocellular adenoma and hepatocellular carcinoma, immunohistochemistry can be deceptive. AML can show an absence of liver fatty acid–binding protein, and the presence of fat can mimic the appearance for HNF1α-inactivated hepatocellular adenoma. Diffuse glutamine synthetase (unrelated to CTNNB1 mutation) staining can be seen in epithelioid AML and can be mistaken for the pattern of staining characteristic of β-catenin–activated hepatocellular adenoma or hepatocellular carcinoma.²³  Another important pitfall is the expression of CD117 in AML, mimicking metastatic gastrointestinal stromal tumor.²⁶  Most AMLs are considered benign and are associated with an excellent prognosis with infrequently reported malignant behavior. The criteria for malignancy in hepatic AML are not well established. Size >5 cm and mitoses ≥1 in 50 HPFs were the only features that predicted malignant behavior in 1 large study.²⁷  Folpe et al²⁸  advocated a 3-tiered system of benign, malignant, and uncertain malignant potential based on 7 high-risk features, including size >5 cm, high nuclear grade, hypercellularity, mitotic rate of >1 per 50 HPFs, necrosis, infiltration into surrounding normal parenchyma, and vascular invasion.²⁸  The reliability of these criteria is uncertain because many AMLs show similar features and behave indolently.

Occasionally, AML can be richly inflammatory^29,30  and mimic inflammatory myofibroblastic tumor or an inflammatory pseudotumor. However, the core feature of plump eosinophilic cells remains.

Mesenchymal hamartoma (MH) is rare (5% of pediatric liver tumors) but is the second most common pediatric hepatic tumor after hepatoblastoma. Although itself benign, on rare occasions it can progress to embryonal sarcoma and shares molecular alterations with those of embryonal sarcoma.³¹  MH is associated with Beckwith-Wiedemann syndrome and shows frequent genetic alterations of chromosome 19 involving a region called MHLB1 (evidence for its neoplastic nature).^32.33 In addition, recently identified germ-line and somatic mutations in DICER1 in the absence of chromosomal translocations involving 19q13.4 suggest that MH is a component of the DICER1 syndrome phenotype.³⁴  Like hepatoblastoma and germ cell tumors, MH can result in elevated serum α-fetoprotein levels, causing diagnostic confusion.³²  Grossly, MH can present as a solid or cystic lesion. Histologically, MH is a biphasic lesion composed of epithelial and mesenchymal components characterized by numerous dilated bile ducts in a loose mesenchymal stroma somewhat resembling fibroadenoma of the breast. Interspersed islands of normal-appearing hepatocytes are also seen. Extramedullary hematopoiesis is commonly present. Cytologic atypia and mitoses are absent in both components (Figure 10). The prognosis of MH is excellent after complete excision. Incomplete excision may be associated with malignant transformation to embryonal sarcoma.³⁵  Surgery is often curative, but there are rare reports of symptomatic unresectable examples requiring liver transplantation.³⁶ 

Benign vascular neoplasms of the liver are common; cavernous hemangioma is the most common benign hepatic tumor overall.³⁷  Vascular hepatic neoplasms often present with characteristic enhancement patterns radiologically.³⁸  The 2 hemangioma variants that can occasionally present diagnostic challenges because of their rarity and their unusual features are sclerosed hemangioma and anastomosing hemangioma, discussed here.

Hepatic sclerosed hemangioma is a rare benign vascular lesion. It is a hemangioma that has undergone degeneration and scarring. Despite recent radiologic advances, when the scarring is extensive, hepatic sclerosed hemangioma can mimic malignancy radiographically.³⁹  Histologically, scattered small vascular channels in a sclerotic background are seen. In later stages, the lesions become fully sclerotic, and the vascular channels undergo near-complete obliteration, leaving only ghostly remnants (Figure 11).⁴⁰  Focal scars (eg, healed granulomatous lesions) and segmental atrophy can be included in the differential diagnosis, but even when the involutional changes of hepatic sclerosed hemangioma are extensive, an underlying vascular architecture can still be identified. Focal scars are typically avascular and may contain residual foreign body–type giant cells or fungal spores. Segmental atrophy can be distinguished by an elastin stain, which is negative in sclerosed hemangioma.

Anastomosing hemangioma, also called hepatic small vessel neoplasm, is a rare distinctive benign hepatic vascular tumor that may be mistaken for angiosarcoma. These lesions are grossly well demarcated but histologically can have an infiltrative pattern mimicking angiosarcoma. Despite the infiltrative pattern, they lack the high-grade cytologic atypia of angiosarcoma. Anastomosing hemangioma is thought to be a benign neoplasm rather than reactive because it harbors GNAQ/GNA14 mutations.^41,42  Although there are limited available follow-up data, there are no reports of metastasis or recurrence to date. Grossly the tumor appears well circumscribed, with a gray-brown focally spongy appearance. Histologically, the tumor shows an infiltrative pattern with interconnecting vascular channels. Cytologically, anastomosing hemangioma may demonstrate mild cytologic atypia, usually in the supporting stroma rather than in the endothelial cells themselves, hobnailed endothelial cells, extramedullary hematopoiesis, and hyaline globules, but endothelial cell mitoses are absent. Immunohistochemistry for vascular markers is often useful because it highlights the anastomosing pattern by featuring blank spaces in between the labeled cells (Figure 12).⁴³  Awareness of this rare entity is essential to avoid overdiagnosis as angiosarcoma and unnecessary aggressive treatment.

The more common hepatic lesions often display specific imaging characteristics. The less familiar, rare benign tumors may pose diagnostic challenges. Here we discussed a selection of unusual benign liver lesions, focusing on nonepithelial tumors. When appropriate, pseudotumors and other rare benign lesions should be considered in the differential diagnosis to avoid misdiagnosis and overtreatment.