Segmental atrophy of the liver: Review of a rare pseudotumor

Abstract

Segmental atrophy (SA) of the liver is a rare, often underrecognized, benign condition that presents as a mass lesion, mimicking a neoplasm, which poses a significant diagnostic challenge. Given its rarity, only a limited number of case reports and series have been published, resulting in sparse literature on the entity. This review aims to summarize the clinicopathologic and diagnostic features of SA and thus improve its recognition.

Key Words: Segment atrophy; Liver; Hepatic; Pseudotumor; Elastotic

Core Tip: Segmental atrophy (SA) of the liver is a rare pseudotumor that typically presents as a liver mass mimicking a neoplasm. It is usually asymptomatic and most often discovered incidentally. SA is more commonly seen in female patients, with an average age of 59.6 years. The exact pathogenesis remains poorly understood, though it is strongly associated with vascular injury. Histopathologically, the lesion progresses through several stages, ranging from parenchymal collapse to nodular elastosis and eventually nodular fibrosis. Recognizing these distinct morphologic stages is essential for accurate diagnosis.

INTRODUCTION

Segmental atrophy (SA) of the liver is a rare and underrecognized pseudotumor. It was first described by Singhi et al[1] in 2011. SA typically presents as a mass-like lesion clinically and radiographically, leading to potential misinterpretation as a neoplastic process[1]. Diagnostic challenges are further complicated by its variable morphology and the limited literature available, resulting in a lack of comprehensive understanding of this entity.

Given the limited awareness of SA and its potential for misdiagnosis, accurate diagnosis requires careful clinicopathologic correlation. This review aims to consolidate our current knowledge of SA, including its proposed pathogenesis, clinical presentation, imaging characteristics, histopathologic features, differential diagnosis, and treatment strategies. Increasing awareness and understanding of this rare entity will enhance its recognition, which is essential for accurate diagnosis and appropriate management.

PATHOGENESIS

The precise pathogenesis of SA is not well understood but is postulated to develop as a response to vascular injury[1]. Abnormal blood vessels are consistently observed in this lesion, including thick-walled arterioles and venules that often show signs of prior vascular injury—such as luminal thrombosis, fibrosis of the vessel wall, and recanalization, indicating a reparative response to previous vascular occlusion[1]. The associated vascular findings suggest that underlying ischemic injury may play a role in hepatic SA by inducing the production of elastic fibers leading to the development of nodular elastosis[1]. In normal liver tissue, elastic fibers are found in the walls of the portal and centrilobular venous branches, as well as in the walls of the major vessels. Hepatic injury can trigger a sequence of reactions that lead to cell death, which in turn, causes portal myofibroblasts to produce an excess of elastic fibers that are deposited in a disorganized pattern, which is the characteristic finding in SA[2]. These findings are supported by similar results reported by Hobbs et al[3] in colonic elastotic polyps. The authors note that the elastotic lesions within the submucosa of the gastrointestinal tract appear to be centered around blood vessels, suggesting a possible shared vascular etiology with nodular elastosis in the liver. Furthermore, a recent retrospective study involving 45 patients found that 78% had a history of hypertension or cardiovascular disease. This demonstrates a potential link between SA and remote vascular injury due to chronic cardiovascular conditions, especially hypertension[4].

Although both fibrosis and elastosis represent stromal responses to tissue injury, they appear to separate from the very beginning stage due to their different underlying mechanisms. Classic hepatic fibrosis typically arises from hepatocellular injury and chronic inflammation, promoting collagen deposition via activation of hepatic stellate cells. In conditions such as nonalcoholic steatohepatitis, elastic fibers tend to accumulate only in advanced diseases, with a diffuse distribution generally proportional to the extent of fibrosis[5]. By contrast, elastosis in SA is a dominant and early feature with focally prominent, well-demarcated, and disproportionately abundant, especially in the nodular elastosis stage[1]. The accumulation of elastic fibers is always accompanied by a slower and more gradual increase in fibrotic septa.

While the precise signaling pathways underlying elastosis in SA have not been elucidated, several regulatory mechanisms involved in elastosis and remodeling, which have been previously described in chronic liver diseases, are likely relevant. Transforming growth factor-β plays a central role as a profibrotic cytokine and is stored in association with elastic fibers; upon release during tissue remodeling, it can modulate fibroblast activity and promote extracellular matrix deposition[6]. In addition, elastin-derived peptides generated through partial degradation have been shown to influence fibroblast activation, inflammation, and angiogenesis, suggesting a role beyond structural support[6]. Other potential contributors include hypoxia-induced signaling pathways [e.g., hypoxia-inducible factor-1alpha (HIF-1alpha)][7] and platelet-derived growth factor[8] may be mediated by ischemia-induced activation of portal myofibroblasts. These molecular events could contribute to early and nodular stage of elastosis observed in SA[1,5].

CLINICAL MANIFESTATIONS

Studies show that the lesion is usually asymptomatic[1]. However, when symptomatic, the most common presentation is right upper quadrant abdominal pain[1,9-11] (Table 1), followed by ascites. The lesion can also become apparent as an incidental finding on imaging[1,12-15].

Table 1 Clinical and pathologic features of reported segmental atrophy of the liver.

Ref.	Gender	Age	Presentation	Coexisting conditions	Radiology findings	Procedure/treatment	Pathology findings	Follow-up
Singhi et al[1], N = 18	F = 13; M = 5	Mean age: 60.5 years (14-91)	Right upper abdominal pain (78%), ascites (11%), incidental mass (11%)	NA	Subcapsular mass in 83% of cases; size 18-10.0 cm (mean 5.2 cm)	Segmental resection (n = 3), wedge resection (n = 12); needle biopsies (n = 3)	Ranges from parenchymal collapse with hepatocyte islets/ductular proliferation to nodular elastosis with dense fibrosis	NA
Thomas et al[9]	M	54	Right-sided abdominal pain, progressive abdominal distention, and lower extremity edema for 3 weeks. History of alcoholic cirrhosis	NA	CT (triple phase scan): 1.7 cm × 2 cm intensely enhancing lesion with arterial attenuation but no washout on delayed phase images	Ultrasound-guided biopsy	Active alcoholic hepatitis with cirrhosis and segmental atrophy	NA
BedadaI et al[10]	F	4	2-year history of abdominal pain and a palpable mass	None	CT: 9 cm × 10 cm liver lesion with central hypodense and peripheral isodense areas in the left lobe	Complete lesion excision	Areas of elastosis to fibrosis, small islets of hepatocytes, liver parenchyma with fibrous tracts and mild bile duct proliferation. Thin-walled veins were present in the fibrous septa, with a few prominent vessels	No recurrence at 6 months
Li et al[11]	M	3	2-month history of progressively worsening right upper abdominal pain	None	CT: A large (9.2 cm × 7.4 cm × 13.3 cm) heterogeneous hypodense mass in the right liver lobe with cystic and solid components; the solid parts mildly enhanced post-contrast	Right hemi-hepatectomy	Hepatocyte atrophy fibrous tissue proliferation with collagenization, visible vasculature, and occasional dilated bile ducts	No recurrence at 12 months
Spolverato et al[12]	M	73	Incidental mass during laparoscopy for gastric conduit revision after esophageal cancer	None	NA	Segmental resection	Loss of parenchyma, mild inflammation, ductular proliferation, biliary retention cysts, early fibrosis/elastosis	NA
Spolverato et al[12]	M	74	Suspected cholangiocarcinoma	None	Left liver atrophy; possible mass in left hemi-liver	Left hemi-hepatectomy	Atrophic liver with marked inflammation, large bile ducts, and rare reactive epithelium (consistent with segmental atrophy)	NA
Spolverato et al[12]	M	73	Questionable lesion in pancreatic adenocarcinoma context	Pancreatic adenocarcinoma	NA	Wedge resection	Dense chronic inflammation with scarring and bile duct proliferation	NA
Ishizaki et al[13]	F	45	Asymptomatic, lesion found on routine ultrasound	None	CT: Low-density mass (10.5 cm × 7.5 cm) in anterior/medial segments, no enhancement	Central hepatectomy	Parenchyma replaced by fibrous tissue with elastic fibers, anomalous vessels, intimal thickening, thrombi, and recanalization	No recurrence at 5 years
Garg et al[14], N = 6	F = 6	Mean age: 58.3 years (37-80)	Incidental findings were noted in 5 cases during workup or surgery for nodules or tumors elsewhere in the body. One additional case presented with right upper abdominal pain	4/6: Lung adenocarcinoma (n = 1); pancreatic neuroendocrine tumor (n = 1); colorectal adenocarcinoma (n = 1); ovarian granulosa cell tumor (n = 1)	Single lesion in each patient; mean size 18 mm (range 3-36 mm)	NA	NA	NA
Findeis-Hosey et al[15], N = 10	F = 6; M = 4	Median age: 68 years (44-80)	All asymptomatic. Identified incidentally during whole-body imaging, surgery for carcinoma history, or autopsy	6/10: Colorectal adenocarcinoma (n = 2), breast carcinoma (n = 1), hepatocellular carcinoma (n = 1), pancreatic carcinoma (n = 1), and carcinoma of unknown primary (n = 1)	56% of cases had a single liver lesion, mean tumor size 16 mm	12 cases from 10 patients; segmental resections (n = 7); needle core biopsies (n = 5)	92% of cases showed elastic material and thick-walled vessels; 50% of cases have ductular proliferation; 17% of cases have biliary cysts and residual hepatocytes	NA

CT: Computed tomography; NA: Not available.

An analysis of underlying conditions (Table 1) in 41 reported cases reveals that 11 (26.8%) have a coexisting malignancy, including colorectal adenocarcinoma (n = 3), pancreatic adenocarcinoma (n = 2), lung adenocarcinoma (n = 1), pancreatic neuroendocrine tumor (n = 1), ovarian granulosa cell tumor (n=1), breast carcinoma (n = 1), hepatocellular carcinoma (n = 1), and carcinoma of unknown primary (n = 1) (Table 1). Other common conditions, such as coagulopathy, infections, rheumatologic diseases, or generalized inflammatory conditions (e.g., alcoholism, obesity), are not described in the reported cases.

There is no specific laboratory test or biomarker for SA. Abnormal laboratory values may be present though and can include elevated cholestatic markers, such as alkaline phosphatase and gamma-glutamyl transferase, as well as increased liver transaminases, including alanine aminotransferase and aspartate aminotransferase[2]. Total and direct bilirubin levels are within normal ranges in the limited cases reported[10], as SA does not appear to impair biliary drainage in a clinically significant manner unless associated with liver malignancy or other underlying hepatic conditions.

EPIDEMIOLOGY

Most studies indicate that SA is more common in females, with a female to male ratio of 2:1 (Table 1). The average age at diagnosis is 59.6 with a range of 3-91 years. It is rare in children, with only a few cases reported[10,11].

Although SA is considered a rare condition, its true prevalence may be underestimated due to asymptomatic cases, misdiagnosis, or underreporting in medical literature. Most published studies are case reports or small case series (Table 1), making it difficult to establish definitive epidemiological patterns.

IMAGING FINDINGS

SA is an uncommon benign lesion and can mimic primary malignancy or metastases due to variable imaging features. Most lesions are subcapsular, and their size ranges from 0.3 to 13.3 cm with a mean of 4.9 cm (Table 1). Garg et al[14] summarized the imaging features of SA. On ultrasound, the atrophied liver can appear hypoechoic or isoechoic compared to uninvolved hepatic parenchyma with ill-define margins and no Doppler flow signal, suggesting reduced vascularity[2]. On contrast-enhanced single-phase (portal venous) computed tomography (CT), most lesions are well-circumscribed and hypodense with occasional focal calcifications. However, in cases with background fatty liver, the lesion may appear hyperdense. In magnetic resonance imaging, the lesion appears hypointense on T1-weighted images, iso- to hyperintense on T2-weighted images, and hyperintense on diffusion-weighted images. The lesion remains hypointense on arterial, portal venous, and delayed phases, except in cases with background fatty liver where it may appear hyperintense in all phases. In a fluorodeoxyglucose-positron emission tomography, atrophic areas are isometabolic compared to the background hepatic parenchyma with no fluorodeoxyglucose uptake, which serves as a useful clue to its benign nature.

A well-defined intrahepatic atrophic area with a distinct transition between healthy and affected liver tissue should raise suspicion for SA. Given its imaging variability and potential to mimic malignant conditions, radiologic correlation with clinical and histopathological findings is essential for accurate diagnosis.

HISTOPATHOLOGIC FINDINGS

Singhi et al[1] and Spolverato et al[12] describe a stepwise progression of histopathologic changes in SA, with lesions transitioning from parenchymal collapse and minimal elastosis to nodular elastosis and dense fibrosis. Microscopically, progressive elastosis is a defining feature present in all stages except in the final stage, in which the parenchyma is completely replaced by dense fibrosis. The sequential nature of this histologic progression suggests an evolution from early parenchymal collapse to advanced fibrosis with elastosis playing a central role.

Early stage

Early lesions are composed of collapsed hepatic parenchyma with occasional trapped islands of residual hepatocytes, chronic inflammation, and brisk bile duct proliferation[1]. This bile duct proliferation is typically observed at the interface between the atrophic parenchyma and surrounding liver tissue, with small, irregular bile ducts[10]. This pattern is consistent with a type 1 ductular reaction, commonly associated with parenchymal loss and stromal remodeling. A finely granular, gray-tinged amphophilic extracellular matrix is present and stains positive with Verhoeff-van Gieson elastic stain. The extent of elastosis is mild (1%-10%).

Second stage

As the lesion progresses to the second stage, chronic inflammation decreases along with the degree of ductular proliferation such that it may no longer be evident. Whereas elastosis significantly increases to involve 11%-80% of the affected tissue.

Third/nodular elastosis stage

At this stage, the lesion forms a nodule that is well-delineated from the background parenchyma and is composed almost entirely of elastotic fibers (> 90%). The entity is more distinct at this point with an abrupt interface between lesional tissue and background liver (Figure 1A). The lesional tissue consists of an elastic-rich matrix with rare, scattered islands of hepatocytes (Figure 2A) and occasional entrapped portal tracts and central veins. An abrupt transition is also observed between the elastic-rich matrix and the residual hepatocyte islands. The matrix demonstrates mild cellularity with small, bland-appearing spindle cells that are devoid of atypia or mitoses.

Figure 1 Segmental atrophy of liver: Identified in a 79-year-old male who presented with abdominal bloating. A: An abrupt interface exists between the lesion and the background liver. The lesion, in its elastotic stage, is composed almost entirely of elastic-rich matrix (hematoxylin-eosin, ×40); B: Elastin staining highlights the elastic fibers (Elastin, ×40).

Figure 2 Segmental atrophy of liver: An incidental finding in the autopsy of an 87-year-old female died of cardiopulmonary arrest. A: The lesion consists of an elastic-rich matrix with entrapped islands of hepatocytes. The abnormally thick-walled vessels with fibrosis are striking (hematoxylin-eosin, ×100); B: Elastin staining highlights the extensive elastosis as well as blood vessels (Elastin, ×100).

Final/ nodular fibrosis stage

In the final stage, referred to as nodular fibrosis, the lesion exhibits dense fibrosis with small, scattered islands of hepatocytes. Residual portal tracts, small biliary cysts, and abnormal vascular structures are also present, but fibrosis is the key element as it replaces most of the hepatic parenchyma.

A striking histologic feature that is common to all reported cases is the presence of abnormally thick-walled vessels (Figure 2A). This wall thickening occurs in both arteries and veins, many of which show thrombosis, fibrosis, and recanalization. Notably, the vascular change is limited to the lesional tissue as thick-walled vessels are not observed in the surrounding uninvolved hepatic tissue.

Another feature of SA are biliary cysts of variable size that tend to be located at the periphery of the lesion. They range from large, grossly evident cysts to small cysts that are only microscopically evident as dilated preexisting ducts within portal tracts. The presence of large biliary cysts can increase clinical concern for a neoplastic process, such as mucinous cystic neoplasm or intraductal papillary neoplasm[16]. Some large biliary cysts may show rupture, epithelial denudation, fibrosis, and granulomatous inflammation. Of note, background liver cirrhosis has been reported in one case[12].

Special and immunohistochemical staining

Singhi et al[1] were the first and, to date, the only researchers to describe the role of immunohistochemistry in SA. They describe several special histochemical stains useful for confirming the diagnosis and distinguishing SA from other hepatic conditions.

Verhoeff-van Gieson elastic stain highlights elastic fibers and reveals the extensive elastotic deposition characteristic of SA (Figure 1B and 2B). Reticulin staining shows numerous reticulin fibers within the matrix, while Masson trichrome stain helps differentiate collagen deposition, which is notably absent in nodular elastosis. Movat pentachrome stain further supports the diagnosis, showing diffuse black staining of elastic fibers with fine yellow strands of reticulin dissecting through the matrix, and reinforces the presence of significant elastosis. Additionally, vimentin immunohistochemical staining shows positivity in the benign spindle cells within the matrix, which exhibit a dendritic appearance that is not easily visible on standard hematoxylin and eosin staining.

DIFFERENTIAL DIAGNOSIS

Although SA demonstrates a well-defined histological evolution, it is important to consider a broad differential diagnosis, as various other diseases can present with similar findings.

Hepatic sclerosing cavernous hemangioma

Sclerosing cavernous hemangiomas (SCH) are benign tumors that can mimic the nodular elastosis stage of SA[15] with similar residual entrapped hepatocytes and at least mild elastic fibrosis. However, thick-walled blood vessels and ductular reaction are significantly more common in SA than in SCH. Additionally, elastic staining is more diffuse in SA[15].

Cancer-associated atrophy

SA needs to be differentiated from secondary types of atrophy. Areas of focal liver atrophy are associated with various intrahepatic neoplastic lesions, most commonly cholangiocarcinoma and metastatic adenocarcinoma[2,17,18]. Takayasu et al[17] report hepatic atrophy in six patients with bile duct obstruction caused by cholangiocarcinoma, all of whom had portal vein occlusion. Similar findings are reported by Han et al., noting that both primary and metastatic liver malignancies can lead to hepatic atrophy in the setting of combined biliary obstruction and portal vein occlusion[19]. In cases of cancer-associated atrophy, the malignant tumor is typically apparent and conversely is absent in cases of SA[1]. Thus, the differentiation of these entities relies on comprehensive evaluation of laboratory tests, radiologic imaging, and histology.

Amyloid

Amyloid refers to the extracellular deposition of misfolded, insoluble proteins in tissues. Histologically, it shows amorphous eosinophilic/pale, glassy, hyaline material. In contrast, the elastosis of SA appears as finely granular and/or fibrillar pale, eosinophilic to gray-tinged amphophilic material, and occasionally with a fibrous component. Distinguishing elastosis in SA from amyloid on hematoxylin and eosin staining can be challenging due to overlapping features. However, Congo red staining is positive in amyloid but negative in elastosis, while elastin stain can confirm the presence of elastosis.

Cystic disease of the liver

Multiple small cysts can occur in SA and may mimic multi-cystic diseases of the liver. However, these entities can be distinguished by imaging characteristics and histology examination. Radiologically, diffuse cystic changes in the liver or cysts within the kidneys support cystic liver disease. Whereas, SA is diagnosed histologically by identifying areas of parenchymal collapse, thrombosed vessels, or the ductular reactions that are typical of early lesions[1,16].

A simple hepatic cyst or a solitary bile duct cyst, potentially resulting from a limited form of ductal plate malformation, is also a consideration in the differential diagnosis due to their morphologic similarity to the retention-type biliary cyst seen in SA[16]. The presence of thick-walled vessels with elastosis adjacent to the cyst supports the diagnosis of SA.

Regenerative hepatic pseudotumor

A recently described pseudotumor in association with localized vascular thrombi can be differentiated from SA based on their distinct histology findings[20]. In regenerative hepatic pseudotumor, the vascular changes, such as central vein thrombi and portal vein thrombi, are associated with reactive parenchymal changes, including sinusoidal dilation, patchy bile ductular proliferation, and portal vein abnormalities, but elastosis is absent or only focally present[16]. This is notable given that progressive elastosis is a defining feature of SA.

Atrophy-hypertrophy complex

SA shares some features with the atrophy-hypertrophy complex but differs in its localized involvement[14]. The atrophy-hypertrophy complex is a compensatory process where part of the liver atrophies while another part hypertrophies, usually in response to biliary obstruction or vascular injury[21,22]. In contrast to SA, which is typically subsegmental or segmental and subcapsular, the atrophy-hypertrophy complex usually affects entire lobes. The underlying causes of hepatic atrophy-hypertrophy are broad, and include cirrhosis, malignancies (hilar cholangiocarcinoma, hepatocellular carcinoma, hepatic metastases), iatrogenic factors (post-cholecystectomy changes, portal vein embolization), parasitic biliary infections, and trauma[22-24]. Additional distinguishing features are that the atrophic region in SA shows elastosis and fibrosis, and the atrophy-hypertrophy complex is characterized by hyperplasia of the unaffected liver[25].

TREATMENT AND PROGNOSIS

To date, only a few cases of SA have been reported in the literature, all confirmed through histological examination of needle core biopsies or surgical specimens (wedge or segmental resections) (Table 1). Surgical resection is reserved for when the atrophy is suspected to be secondary to another condition[2]. There are no standardized treatment protocols for SA, and there is no evidence to support routine follow-up given that no studies to date suggest an association between SA and the transformation of malignancy.

CONCLUSION

SA is a benign pseudotumor that presents diagnostic challenges due to its diverse histologic presentation and limited characterization in the literature. When diagnosing SA, it is crucial to rule out other potentially serious underlying diseases, such as carcinomas, which can cause atrophy. SA lesions exhibit a sequential histologic progression, with elastotic changes playing a key role. Treatment is typically limited to surgical resection, and further research is needed to improve diagnostic accuracy and management strategies for this underrecognized entity.