A 25-Year-Old Man with a Large Hepatic Tumor and Multiple Nodular Lesions

• ABSTRACT
• CASE REPORT
• DIFFERENTIAL DIAGNOSIS
• PATHOLOGIC FINDINGS
• COMMENT
• CLINICAL COURSE
• DIAGNOSES
• ABBREVIATIONS
• REFERENCES

ABSTRACT

A 25-year-old man without a prior history of liver disease presented with an 18-cm tumor of the right hepatic lobe, which was associated with multiple nodular lesions in the remaining parenchyma. The histologic and immunohistochemical features of the neoplasm were those of a poorly differentiated leiomyosarcoma with epithelioid features. The nodular lesions measured up to 4 cm in greatest dimension and had gross and microscopic features of focal nodular hyperplasia. This case suggests that multiple focal nodular hyperplasia may occasionally represent a parenchymal reaction to abnormal blood supply developing within the liver as a consequence of an enlarging malignant tumor.

CASE REPORT

A 25-year-old man without previous history of liver disease was admitted to a prefectural hospital in northern Greece because of abdominal pain and progressive jaundice. On physical examination the liver was palpable. Blood examination revealed hematocrit 34%, hemoglobin 10.5 g/dL, white blood cell count 10 × 10⁹/L, platelet count 278 × 10⁹/L, glucose 91 mg/dL, urea 15 mg/dL, creatinine 0.7 mg/dL, bilirubin 5.4 mg/dL, sodium 136 mEq/L, potassium 4.4 mEq/L, aspartate aminotransferase 100 U/L (normal range, 10-30 U/L), alanine aminotransferase 65 U/L (normal range, 7-27 U/L), alkaline phosphatase 460 U/L (normal range, 39-133 U/L), total protein 5.5 g/dL, and albumin 3.6 g/dL. The patient was hepatitis B surface antigen negative, anti-hepatitis C virus negative, and anti-human immunodeficiency virus negative. Ultrasonography and computed tomography (CT) scan revealed a tumor in the right hepatic lobe measuring 18 cm in greatest dimension, which contained a necrotic area with a central hemorrhagic focus; multiple nodules were present in the remaining hepatic parenchyma. The patient was transferred to the University Hospital of Thessaloniki for further imaging procedures and possible surgical resection of the tumor. Magnetic resonance imaging (MRI) confirmed the presence of the mass and provided better delineation of the necrotic and hemorrhagic area (Fig. [1]A). There was absence of flow void signals within the right portal vein associated with the presence of collateral vessels in the hepatic hilum, indicating right portal vein thrombosis. In addition, multiple focal nodular lesions up to 4 cm in diameter were detected that caused the liver to have an irregular contour (Fig. [1]A and B). Complete physical examination and CT of the chest did not reveal any other tumors.

On laparotomy, the presence of a large tumor in the right hepatic lobe was confirmed. Many subcapsular nodular lesions were also noted. No other tumor was found in the abdominal cavity. Multiple fragments of tumor and a wedge-shaped portion of the right lobe containing a nodular lesion were sent for frozen section examination. Further surgery was deferred on the basis of the operative and histologic findings.

DIFFERENTIAL DIAGNOSIS

This young man without a prior history of liver disease presented with an 18-cm tumor of the right hepatic lobe. On blood examination, he had hyperbilirubinemia and mild elevation of liver enzymes. Serologic markers for hepatitis B and C were negative. Radiologic examination of the liver with ultrasonography, CT, and MRI showed features of a malignant neoplasm with heterogeneity, necrosis, and right portal vein occlusion. The tumor was accompanied by a number of nodular lesions with subcapsular location and a hypointense center on MRI.

The most common primary malignant tumor of the liver is hepatocellular carcinoma (HCC). Although ordinary HCC is rare in young patients without chronic liver disease, a specific subtype, namely fibrolamellar carcinoma, has been shown to have a predilection for this patient population.[1] [2] [3] Patients with fibrolamellar carcinoma often present with abdominal pain, but jaundice is rare. Cholangiocarcinoma and hepatoblastoma also may occur in young adults, but they are very unusual among individuals in this age group.

In addition to neoplasms of epithelial origin, the differential diagnosis in this patient includes primary hepatic sarcomas and malignant lymphoma, which are tumors that may occasionally originate in the liver.[1] [2] Whereas the more common primary sarcomas (i.e., angiosarcoma and malignant epithelioid hemangioendothelioma) tend to form multiple masses, others, such as leiomyosarcoma, are often solitary. The differential diagnosis also includes metastatic neoplasms, which are much more common than primary ones in patients without chronic liver disease. However, as a rule, metastatic tumors form multiple masses rather than one large one. In our patient, extensive workup failed to reveal any tumor outside of the liver.

The puzzling issue in this case is the association of the large malignant tumor with multiple distinct nodules in the remaining hepatic parenchyma. The terminology of hepatic nodular lesions recently has been reevaluated.[4] Regenerative nodules represent the most common hepatic nodular lesions, which can be monoacinar or multiacinar. Although the majority of regenerative nodules are small, occasional multiacinar nodules may reach a diameter of several centimeters. Large regenerative nodules arise most often in cirrhosis and submassive hepatic necrosis, both of which are very unlikely in this patient.

The size of the nodules, their subcapsular location, and the presence of a hypointense center on MRI are more suggestive of a different type of nodular lesion, namely focal nodular hyperplasia (FNH).[4] [5] [6] This entity shows a distinct predilection for women of reproductive age; however, a number of cases occurring in men are now on record. FNH is solitary in approximately two thirds of patients, and multiple in one third. On rare occasions, FNH is found in livers containing malignant tumors, such as hepatocellular carcinoma and malignant epithelioid hemangioendothelioma.[6] [7] [8] [9]

PATHOLOGIC FINDINGS

On gross examination, the fragments of tumor were gray-white and soft, with areas of necrosis. The nodular lesion measured 4 × 3 cm and had a green, soft, cut surface with a central stellate scar (Fig. [1]C).

On microscopic examination, the tumor cells showed marked pleiomorphism of size and shape; they were mostly spindle or ovoid (epithelioid), and contained hyperchromatic nuclei with prominent nucleoli (Fig. [2]A and B). The mitotic rate was high. Atypical mitotic figures were easily identified. Rare multinucleated tumor cells were noted. In most areas, the neoplastic cells grew diffusely, without any discernible pattern; however, in some spindle cell areas, fascicle formation was seen. Extensive tumor cell necrosis was also present.

On special stains, reticulin fibers were seen around groups of neoplastic cells; in some areas, the tumor cells were enveloped by reticulin fibers individually. Immunohistochemical stains revealed diffuse positive staining of the tumor cells for vimentin (Fig. [2]C). The majority of tumor cells were also positive for smooth muscle actin (Fig. [2]D) and cytokeratin cam5.2 (Fig. [2]E). The tumor cells were negative for desmin, myoglobin, S-100 protein, CD-34 antigen, Factor VIII-related antigen, Ulex europaeus lectin, cytokeratin AE1, epithelial membrane antigen, carcinoembryonic antigen, α-fetoprotein, and human hepatocyte antigen (HepPar1).

Sections of the nodular lesion demonstrated multiple arteries and veins, unaccompanied by bile ducts, within the central scar region (Fig. [3]A and B). The scar was surrounded by regenerative parenchymal nodules, which were bordered by fibrous septa with areas of hyalinization. Steatosis and cholestasis with marked cholate stasis (feathery degeneration) were evident in the nodules (Fig. [3]C). In some areas, prominent Mallory bodies were present (Fig. [3]D). Mild chronic inflammatory infiltrates and focal bile ductular proliferation were also noted in the central scar and fibrous septa. Isolated arteries were often seen in the septa. The hepatic parenchyma surrounding the nodular lesion showed compression changes and mild steatosis.

COMMENT

We reported on a patient with a high-grade malignant hepatic tumor and multiple nodular lesions with radiologic, gross, and microscopic features of FNH. The neoplasm consisted of spindle and epithelioid cells in a diffuse and fascicular arrangement. On the basis of the histologic features, our differential diagnosis included sarcomatoid hepatic carcinoma; various sarcomas that may exhibit epithelioid features; and malignant melanoma without melanin production (amelanotic malignant melanoma). The immunohistochemical findings were of assistance in narrowing the differential diagnosis between leiomyosarcoma and sarcomatoid carcinoma. The positive immunostaining for vimentin and smooth muscle actin, and the lack of staining for epithelial markers (with the exception of cytokeratin cam5.2) suggested a diagnosis of leiomyosarcoma.[10] In this context, it must be taken into account that cytokeratin cam5.2 may often be expressed in a variety of sarcomas, including leiomyosarcoma.[11] [12]

However, what makes this case interesting is not the exact nature of the malignant tumor, but the presence of multiple hepatic nodular lesions with features of FNH. Only one of the lesions was available for histologic examination; however, the radiologic and gross features of the remaining lesions were similar to those of the one removed. The lesion consisted of parenchymal nodules surrounding a central stellate scar, which contained multiple vessels unaccompanied by bile ducts. Both arteries and veins were present in the scar. A prominent artery, larger than expected for the location, as is often seen in FNH,[5] was not found in this lesion.

The nodules surrounding the scar showed marked cholestasis with feathery degeneration of hepatocytes and presence of Mallory bodies. These changes were apparently due to the lack of bile ducts within the lesion, as suggested previously by Butron Vila et al.[13]

Patients with multiple FNH may have additional lesions, often vascular in nature.[14] Hepatic hemangioma, arterial structural defects, vascular malformations of the central nervous system, meningioma, and astrocytoma have been considered to represent components of a syndrome that has been termed multiple FNH syndrome.[4] [14] [15] [16] The possibility that the leiomyosarcoma of our patient developed as a component, or within a component, of the multiple FNH syndrome cannot be ruled out, taking into account that leiomyosarcomas often arise in vessels. However, the absence of other characteristic lesions of the syndrome argues against this possibility.

A more plausible explanation is that the FNH lesions of this patient represented a parenchymal reaction to an abnormal blood supply developing within the liver as a consequence of the enlarging malignant tumor. Such a mechanism has been previously suggested to account for FNH associated with fibrolamellar carcinoma[7] [9] and malignant epithelioid hemangioendothelioma,[8] as well as for FNH-like changes occurring in the hepatic parenchyma adjacent to fibrolamellar carcinoma.[17] At this point, a distinction should be made between FNH and FNH-like lesions occurring in close proximity to hepatic tumors, as opposed to those located at more distant locations. Whereas neoplastic angiogenesis with increased arterial perfusion of the peritumoral parenchyma may be directly responsible for the former, systemic elevation of tumor-derived growth factors or hormones, in association with an additional local stimulus (such as a hepatic vein thrombus), are more likely to cause the latter.[9]

In conclusion, this case supports the view that FNH represents a nonspecific response of the hepatic parenchyma to increased local arterial perfusion.[9] Whereas an abnormal artery in the setting of increased estrogenic stimulation may be the most common causative factor of such a response,[5] FNH occasionally may be associated with infiltration of the hepatic parenchyma by a malignant tumor, as suggested by our case and those of others.[6] [7] [8] [9]

CLINICAL COURSE

The patient had an uneventful postoperative course. However, his clinical status deteriorated rapidly following discharge, and he died 3 months after surgery. No autopsy was performed.

DIAGNOSES

1. High-grade hepatic leiomyosarcoma

2. Multiple focal nodular hyperplasia

ABBREVIATIONS

FNH focal nodular hyperplasia

HCC hepatocellular carcinoma

REFERENCES

• 1 Anthony P P. Tumours and tumour-like lesions of the liver and biliary tract. In: MacSween RNM, Anthony PP, Scheuer PJ, et al, eds. Pathology of the Liver, 3rd ed Edinburgh: Churchill Livingston, 1994: 635-711
  Search in Google Scholar
• 2 Craig J R, Peters R L, Edmondson H A. Tumors of the liver and intrahepatic bile ducts. In: Atlas of Tumor Pathology 2nd series. Fascicle 26. Washington, DC: Armed Forces Institute of Pathology 1989
  Search in Google Scholar
• 3 Hytiroglou P, Theise N D. Differential diagnosis of hepatocellular nodular lesions.  Semin Diagn Pathol . 1998;  15 285-299
  PubMedSearch in Google Scholar
• 4 International Working Party. Terminology of nodular hepatocellular lesions.  Hepatology . 1995;  22 983-993
  CrossrefPubMedSearch in Google Scholar
• 5 Wanless I R, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver.  Hepatology . 1985;  5 1194-1200
  CrossrefPubMedSearch in Google Scholar
• 6 Nguyen B N, Flejou J-F, Terris B. Focal nodular hyperplasia of the liver. A comprehensive pathologic study of 305 lesions and recognition of new histologic forms.  Am J Surg Pathol . 1999;  23 1441-1454
  CrossrefPubMedSearch in Google Scholar
• 7 Saul S H, Titelbaum D S, Gansler T S. The fibrolamellar variant of hepatocellular carcinoma. Its association with focal nodular hyperplasia.  Cancer . 1987;  60 3049-3055
  PubMedSearch in Google Scholar
• 8 Bralet M-P, Terris B, Vilgrain V. Epithelioid hemangioendothelioma, multiple focal nodular hyperplasias, and cavernous hemangiomas of the liver. An unusual association.  Arch Pathol Lab Med . 1999;  123 846-849
  PubMedSearch in Google Scholar
• 9 Wanless I R. Epithelioid hemangioendothelioma, multiple focal nodular hyperplasias, and cavernous hemangiomas of the liver.  Arch Pathol Lab Med . 2000;  124 1105-1107
  PubMedSearch in Google Scholar
• 10 Watanabe K, Saito A, Wakabayashi H. Two autopsy cases of primary leiomyosarcoma of the liver.  Superiority of muscle-specific actin immunoreactivity in diagnosis. Acta Pathol Jpn . 1991;  41 461-465
  PubMedSearch in Google Scholar
• 11 Enzinger F M, Weiss S W. Soft Tissue Tumors, 3rd ed. St.  Louis: CV Mosby, 1995: 511-522
  Search in Google Scholar
• 12 Norton A J, Thomas J A, Isaacson P G. Cytokeratin-specific monoclonal antibodies are reactive with tumours of smooth muscle derivation. An immunocytochemical and biochemical study using antibodies to intermediate filament cytoskeletal proteins.  Histopathology . 1987;  11 487-499
  PubMedSearch in Google Scholar
• 13 Butron Vila M M, Haot J, Desmet V J. Cholestatic features in focal nodular hyperplasia of the liver.  Liver . 1984;  4 385-395
  PubMedSearch in Google Scholar
• 14 Wanless I R, Albrecht S, Bilbao J. Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome.  Mod Pathol . 1989;  2 456-462
  PubMedSearch in Google Scholar
• 15 Goldin R D, Rose D S. Focal nodular hyperplasia of the liver associated with intracranial vascular malformations.  Gut . 1990;  31 554-555
  PubMedSearch in Google Scholar
• 16 Mathieu D, Zafrani E S, Anglade M C. Association of focal nodular hyperplasia and hepatic hemangioma.  Gastroenterology . 1989;  97 154-157
  PubMedSearch in Google Scholar
• 17 Saxena R, Humphreys S, Williams R. Nodular hyperplasia surrounding fibrolamellar carcinoma: a zone of arterialized liver parenchyma.  Histopathology . 1994;  25 275-278
  PubMedSearch in Google Scholar

REFERENCES

• 1 Anthony P P. Tumours and tumour-like lesions of the liver and biliary tract. In: MacSween RNM, Anthony PP, Scheuer PJ, et al, eds. Pathology of the Liver, 3rd ed Edinburgh: Churchill Livingston, 1994: 635-711
  Search in Google Scholar
• 2 Craig J R, Peters R L, Edmondson H A. Tumors of the liver and intrahepatic bile ducts. In: Atlas of Tumor Pathology 2nd series. Fascicle 26. Washington, DC: Armed Forces Institute of Pathology 1989
  Search in Google Scholar
• 3 Hytiroglou P, Theise N D. Differential diagnosis of hepatocellular nodular lesions.  Semin Diagn Pathol . 1998;  15 285-299
  PubMedSearch in Google Scholar
• 4 International Working Party. Terminology of nodular hepatocellular lesions.  Hepatology . 1995;  22 983-993
  CrossrefPubMedSearch in Google Scholar
• 5 Wanless I R, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver.  Hepatology . 1985;  5 1194-1200
  CrossrefPubMedSearch in Google Scholar
• 6 Nguyen B N, Flejou J-F, Terris B. Focal nodular hyperplasia of the liver. A comprehensive pathologic study of 305 lesions and recognition of new histologic forms.  Am J Surg Pathol . 1999;  23 1441-1454
  CrossrefPubMedSearch in Google Scholar
• 7 Saul S H, Titelbaum D S, Gansler T S. The fibrolamellar variant of hepatocellular carcinoma. Its association with focal nodular hyperplasia.  Cancer . 1987;  60 3049-3055
  PubMedSearch in Google Scholar
• 8 Bralet M-P, Terris B, Vilgrain V. Epithelioid hemangioendothelioma, multiple focal nodular hyperplasias, and cavernous hemangiomas of the liver. An unusual association.  Arch Pathol Lab Med . 1999;  123 846-849
  PubMedSearch in Google Scholar
• 9 Wanless I R. Epithelioid hemangioendothelioma, multiple focal nodular hyperplasias, and cavernous hemangiomas of the liver.  Arch Pathol Lab Med . 2000;  124 1105-1107
  PubMedSearch in Google Scholar
• 10 Watanabe K, Saito A, Wakabayashi H. Two autopsy cases of primary leiomyosarcoma of the liver.  Superiority of muscle-specific actin immunoreactivity in diagnosis. Acta Pathol Jpn . 1991;  41 461-465
  PubMedSearch in Google Scholar
• 11 Enzinger F M, Weiss S W. Soft Tissue Tumors, 3rd ed. St.  Louis: CV Mosby, 1995: 511-522
  Search in Google Scholar
• 12 Norton A J, Thomas J A, Isaacson P G. Cytokeratin-specific monoclonal antibodies are reactive with tumours of smooth muscle derivation. An immunocytochemical and biochemical study using antibodies to intermediate filament cytoskeletal proteins.  Histopathology . 1987;  11 487-499
  PubMedSearch in Google Scholar
• 13 Butron Vila M M, Haot J, Desmet V J. Cholestatic features in focal nodular hyperplasia of the liver.  Liver . 1984;  4 385-395
  PubMedSearch in Google Scholar
• 14 Wanless I R, Albrecht S, Bilbao J. Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome.  Mod Pathol . 1989;  2 456-462
  PubMedSearch in Google Scholar
• 15 Goldin R D, Rose D S. Focal nodular hyperplasia of the liver associated with intracranial vascular malformations.  Gut . 1990;  31 554-555
  PubMedSearch in Google Scholar
• 16 Mathieu D, Zafrani E S, Anglade M C. Association of focal nodular hyperplasia and hepatic hemangioma.  Gastroenterology . 1989;  97 154-157
  PubMedSearch in Google Scholar
• 17 Saxena R, Humphreys S, Williams R. Nodular hyperplasia surrounding fibrolamellar carcinoma: a zone of arterialized liver parenchyma.  Histopathology . 1994;  25 275-278
  PubMedSearch in Google Scholar