Benign and Malignant Mesenchymal Tumors of the Liver



Benign and Malignant Mesenchymal Tumors of the Liver


Rondell P. Graham, MBBS

Andrew L. Folpe, MD



26.1 INTRODUCTION

Mesenchymal tumors of the liver can be challenging because they are not common in clinical practice. In this chapter, we will provide our general approach to the diagnosis of mesenchymal tumors of the liver. Then, we will delve into the characteristics of the most frequent primary neoplasms, describe how to distinguish them from mimics, and highlight ancillary tests which allow confirmation of specific diagnoses.


26.2 THE DIAGNOSTIC APPROACH

As in other anatomic sites, mesenchymal tumors of the liver are much less common than epithelial tumors. Therefore, it is prudent to exclude a nonmesenchymal tumor (e.g., carcinoma, melanoma, and lymphoma) before making the diagnosis of a mesenchymal tumor. The liver provides an added layer of challenge in that metastases significantly outnumber primary tumors. These considerations should be borne in mind when faced with a liver mass, particularly in a liver without cirrhosis. It is useful to note the patient’s age and gender, an antecedent history of carcinoma, melanoma, or other tumors, and their primary site, histologic grade or type and the temporal relationship to the current liver mass(es). Where applicable, review of the slides from the original tumor may be helpful in confirming or excluding a metastasis. The presence of multiple liver masses favors metastasis, but there are many exceptions. Correlation with radiologic imaging may be of value, especially for small biopsies.

As always, a systematic approach to the histology is best. We recommend initial review of the liver mass to determine the growth pattern, circumscription and cellular composition of the tumor, and the presence or absence of a matrix. When immunostains are performed, they are often best done in panels, which not only support the primary diagnosis under consideration but also exclude other entities in the differential diagnosis. Table 26.1 presents an initial panel of immunostains which the authors find helpful in a number of common scenarios where mesenchymal tumors come in to consideration.









Table 26.1
Initial immunostain panels for select morphologic scenarios and the differential diagnoses for which they provide support























Morphologic scenario


Select differential diagnoses


Initial immunostain panel


Spindle cell neoplasm without specific features


Sarcomatoid carcinoma, malignant melanoma, GIST, smooth muscle tumor, myofibroblastic tumor


OSCAR cytokeratin, KIT, DOG1, S100, HMB45, SMA


Epithelioid neoplasm negative for cytokeratins


Malignant melanoma, GIST, rhabdomyosarcoma, angiosarcoma, histiocytic neoplasm


S100, HMB45, SOX10, KIT, ERG/FLI1, CD163, Desmin


Plasmacytoid neoplasm


Carcinoma, GIST, neuro-endocrine tumor, acinar cell carcinoma, malignant melanoma, rhabdomyosarcoma, plasma cell neoplasm


OSCAR cytokeratin, trypsin, chromogranin, synaptophysin, S100, SOX10, Desmin, MUM1


Poorly differentiated neoplasm or small round blue cell tumor


High-grade carcinoma, malignant melanoma, hematopoietic neoplasm, rhabdomyosarcoma, high-grade sarcoma


OSCAR cytokeratin, AE1/AE3, S100, SOX10, Desmin, SMA, CD45 TLE1—screen for synovial sarcoma CD99—screen for Ewing sarcoma



26.3 VASCULAR TUMORS


Hepatic hemangioma



Etiology

The etiology of hemangiomas is unknown, although usage of steroids, female sex hormones, and pregnancy have been postulated to be related to the growth of hepatic hemangiomas.1, 2, 3


Clinical features

Hepatic hemangioma is the most common primary mesenchymal tumor of the liver.4 The reported incidence ranges from 0.4% to 7.4%.4,5 It occurs more often in women with a female-to-male ratio of about 3:1.6 Hemangiomas are often incidentally discovered on imaging, at surgery, or at autopsy.7 Occasional cases of massive hemangiomas or thrombosed hemangiomas can be associated with abdominal discomfort and thrombocytopenia.4 Hemangiomas arise sporadically as
solitary masses in most cases, but there can be multiple hemangiomas in rare conditions such as Von Hippel-Lindau syndrome or systemic hemangiomatosis syndromes.8,9


Gross findings

Hepatic hemangiomas are usually solitary, but rarely can be multiple. The sizes can range from a few millimeters to up to 30 cm. Grossly, hemangiomas appear as red-brown or red-blueish, well-demarcated lesions with a spongy cut surface (Fig. 26.1). Some long-standing cases may contain white fibrotic areas.


Microscopic findings and histological types

Hepatic hemangiomas are uniformly well-circumscribed lesions and may be of three types. The first and most common type is cavernous hemangioma. Much less common hepatic hemangiomas include capillary hemangiomas and anastomosing hemangiomas.

Cavernous hemangiomas. Cavernous hemangiomas are characterized by widely dilated vascular channels with fibrous walls lined by a single layer of flattened inconspicuous endothelial cells devoid of cytological atypia (Fig. 26.2). They are sharply demarked from the surrounding liver parenchyma on gross examination but often have an “infiltrative growth” at their edges on histology.10 Liver acini or portal tracts are absent within the lesion. Mitotic figures are absent. The lumens of vascular channels are usually filled with blood, but recently formed thrombi or organized thrombi are often seen as well. Some cavernous hemangiomas may undergo partial or complete sclerosis and thrombosis with calcification, and these lesions are known as sclerosed hemagiomas.

The term giant cavernous hemangioma is commonly used when tumors are >4 cm or 5 cm. The giant cavernous hemangiomas have similar histologic features to smaller cavernous hemangiomas. Some giant cavernous hemangiomas can have poorly defined
borders with a vascular proliferation composed of small aggregates of dilated vessels with smaller sizes compared with the main tumor. This finding has been named “hemangiomatosis.”10 However, this feature is not unique to large hemangiomas and can also be focally seen at the edges of small cavernous hemangiomas.






Figure 26.1 Cavernous hemangioma. The macroscopic appearance of a cavernous hemangioma. The mass displays a red-brown spongy appearance with tan branching septa corresponding to areas of sclerosis.






Figure 26.2 Cavernous hemangioma. This is a cavernous hemangioma composed of variably sized vascular spaces lined by attenuated endothelial cells.






Figure 26.3 Capillary hemangioma.






Figure 26.4 Anastomosing hemangioma. The tumor shows an interanastomosing proliferation of capillary-sized vessels. The neoplastic endothelial cells are characteristically devoid of hyperchromasia and significant nuclear atypia.

Capillary hemangioma. Capillary hemangioma is very rare in liver, with just a handful of case reports.11 The morphology of hepatic capillary hemangioma is the same as those arising in the soft tissues. The lesion may have a fibrous capsule and consists of capillary-sized proliferating vessels arranged in a lobular configuration (Fig. 26.3). The endothelial cells are plump without atypia. Sometimes the plump cells may be confluent and obscure the vascular channels. Immunostains can be used to confirm the vascular nature of the tumor.

Anastomosing hemangioma. Anastomosing hemangioma is a relatively rare and recently recognized variant of hepatic hemangioma, which is generally well circumscribed and is characterized by a nonlobular, interanastomosing, sinusoidal proliferation of capillary-sized vessels12 (Fig. 26.4). The interanastomosing pattern may raise concern for well-differentiated angiosarcoma, but mitotic figures and multilayering of the neoplastic endothelial cells are absent. The endothelial cells of anastomosing hemangioma may be slightly prominent with a “hobnail” appearance, but lack nuclear hyperchromatism and irregularity. Some cases have intermixed features of conventional cavernous hemangioma. Other useful clues to the diagnosis of anastomosing hemangioma are small thrombi, mature adipose tissue, and extramedullary hematopoiesis.12, 13, 14


Immunohistochemical findings

Immunostains are not routinely used for diagnosing typical cases, but they may be helpful to confirm the endothelial phenotype of the lesional cells in small biopsy specimens or sclerosed hemangiomas. The endothelial cells lining hemangiomas are positive for all vascular markers, including CD31, CD34, von Willebrand factor, ERG, and FLI1.





Lymphangioma

Hepatic lymphangiomas are rare tumors, which are commonly associated with systemic lymphangiomatosis.18,19 Grossly, the hepatic lymphangiomas typically present as multiple variable-sized cysts containing clear or chylous fluid. Single hepatic lymphangiomas are rare. Microscopically, the lesion is composed of variable-sized cystic spaces containing clear lymph fluid and lined by a single layer of flat endothelial cells (Fig. 26.6). The endothelial cells are bland and can have a papillary architecture in some cases. They are readily distinguished from cavernous hemangioma because of lack of red blood cells in the luminal space.


Kaposi sarcoma

Kaposi sarcoma is a low-grade malignant tumor that has a characteristic slit-like pattern of growth on histology. It is most commonly seen in AIDS patients and is uniformly associated with human herpes virus 8 (HHV-8) infection. Although Kaposi sarcoma most often affects skin and mucosal sites, liver involvement may occur in 34% of patients with Kaposi sarcoma.20 There are four different forms of Kaposi sarcoma and all can involve liver: (1) the “classic” form typically affects elderly individuals (>60 years), mainly in the Eastern Europe and the Mediterranean region; (2) the “African endemic” form affects young adults of equatorial Africa and is characterized by localized nodular lesions; (3) the
“epidemic” form occurs in patients with AIDS; and (4) the “iatrogenic” form is caused by immunosuppressive drugs administered after organ transplant and has aggressive behavior with a tendency to spread.

Microscopically, Kaposi sarcoma usually involves the portals tracts, but the tumor can infiltrate into the adjacent liver parenchyma. The lesion shows a characteristic slit-like pattern of proliferating vessels lined by spindle cells with large plump nuclei admixed with collagen fibers, extravasated red blood cells, and hemosiderin-laden macrophages. Mitotic figures are present but are low in number. Periodic acid-Schiff (PAS)-positive hyaline globules, which may represent destroyed red blood cells, are frequently found in neoplastic cells. The neoplastic cells are positive for endothelial markers including CD31, CD34, FLI-1, and ERG, but factor VIII immunostain is usually negative. In addition, lymphatic markers such as D2-40 and podoplanin are also positive. Almost all cases display strong nuclear staining of HHV-8, regardless of their subtypes.


Epithelioid hemangioendothelioma



Etiology

Epithelioid hemangioendothelioma is caused by WWTR1-CAMTA1 gene fusions in ˜90% of cases.21, 22, 23 An unusual vasoformative neoplasm containing the YAP1-TFE3 fusion gene has been reported as a variant of epithelioid hemangioendothelioma, but more likely represents a distinct entity.24


Clinical features

Epithelioid hemangioendothelioma is often incidentally discovered, and lung or other metastases may be present at the time of diagnosis.25,26 Some patients present with ascites and portal hypertension because of venous occlusion by tumor.27,28 There is a slight female predominance, with a female-to-male ratio of 3:2. The mean age at diagnosis is 41.7 years (range: 3 to 86 years).25,26


Gross findings

Epithelioid hemangioendothelioma is characteristically multifocal and forms ill-defined bilobar tan nodules (Fig. 26.7). The nodule sizes may range from a few millimeters to several centimeters. Some tumor nodules may appear white and firm, often mimicking metastatic carcinoma. Calcifications may also be present.






Figure 26.7 Epithelioid hemangioendothelioma. An ill-defined tan nodule of epithelioid hemangioendothelioma. Multiple nodules such as this are seen grossly in most cases.






Figure 26.8 Epithelioid hemangioendothelioma. The tumor is defined by a distinctive myxoid matrix as shown in this example. The neoplastic cells form linear arrays and show intracytoplasmic “blisters.”


Microscopic findings

Epithelioid hemangioendothelioma frequently encircles bile ducts and hepatocytes, and shows a propensity for portal vein and central vein invasion.25,29 Histologically, epithelioid hemangioendothelioma is characterized by cords, chains, and single file arrays of small, bland endothelial cells growing in a distinctive myxoid to fibrous stroma25,29,30 (Fig. 26.8). In the liver, the matrix in the center of the lesion often has
a “burnt out,” fibrotic appearance (Fig. 26.9). At the peripheral of the lesion, the tumor cells tend to grow along hepatic sinusoids. Although the underlying hepatic acinar architecture is preserved, the liver cell plates become gradually atrophic, and eventually disappear and are replaced by tumor. Careful inspection shows scattered tumor cells with intracytoplasmic “blisters” or “vacuoles,” containing red blood cells sometimes, representing primitive vascular lumen formation. In some cases, the neoplastic cells may be obscured by the accompanying inflammatory infiltrate.29






Figure 26.9 Epithelioid hemangioendothelioma. In the liver, tumors frequently show a “burnt out” center which is characterized by hyalinization of the stroma. Intracytoplasmic blister cells can be seen.






Figure 26.10 Epithelioid hemangioendothelioma. A CD31 highlights the neoplastic cells.


Immunohistochemical findings

The vascular markers CD31, CD34,29 von Willebrand factor, ERG, and FLI1 are positive in the neoplastic cells and in this morphological context confirms the diagnosis (Fig. 26.10). Anomalous cytokeratin expression may be present, leading to confusion with adenocarcinoma, in particular cholangiocarcinoma.30 Taking advantage of the identification of the genetic driver of epithelioid hemangioendothelioma, nuclear expression of carboxyl-terminus CAMTA1 can be used to support the diagnosis of epithelioid hemangioendothelioma.31,32


Molecular and special techniques

Approximately 90% of cases of epithelioid hemangioendothelioma are characterized by the recurrent fusion gene WWTR1-CAMTA1 which is the genetic driver of the tumor. Detection of this fusion transcript by RT-PCR confirms the diagnosis of epithelioid hemangioendothelioma.21,23





Angiosarcoma



Etiology

Most angiosarcomas develop without a clear etiology.35 A minor fraction of hepatic angiosarcomas arise in a background of occupational vinyl chloride exposure.35,36 Thorotrast exposure was historically a risk factor for hepatic angiosarcoma, but is no longer in use.37


Clinical features

Hepatic angiosarcoma is the third most common primary liver malignancy, after hepatocellular carcinoma and cholangiocarcinoma, but still only accounts for 2% to 3% of all primary liver malignancies.38 Angiosarcomas usually arise in middle-aged or elderly adults.39,40 The clinical presentation of hepatic angiosarcoma is nonspecific. Patients may present with abdominal pain, weight loss, hepatomegaly, liver failure, or thrombocytopenia.40 Catastrophic intra-abdominal bleeding occurs in about one-fourth of all cases.38


Gross findings

Angiosarcomas form large hemorrhagic tumor masses with solid and cystic blood containing areas and ill-defined borders (Fig. 26.11). Satellite masses may be present. It can involve either lobe or the entire liver.






Figure 26.11 Angiosarcoma. The tumor is cystic and hemorrhagic.






Figure 26.12 Angiosarcoma. A sinusoidal pattern of growth is seen. Note the hobnail appearance of the neoplastic cells and subtle multilayering.


Microscopic findings

Angiosarcoma is a remarkably protean tumor that shows a widely variable appearance from tumor to tumor, and even within a single tumor. Angiosarcoma may display sinusoidal, papillary, cavernous/peliotic, or solid architectural patterns. The cytology also varies widely, from minimal atypia, often with a “hobnail” appearance, to severely anaplastic. Growth along the sinusoids of the hepatic plate, the so-called “sinusoidal pattern” (Fig. 26.12), may be particularly subtle; in such cases, the endothelial cells often show minimal atypia and frequently have spindled morphology. The presence of endothelial cell multilayering is a valuable clue to the diagnosis of angiosarcoma in cases with sinusoidal growth. The cavernous or peliotic pattern of hepatic angiosarcoma may also be quite treacherous because these lesions consist of relatively well-formed, large blood filled spaces lined by malignant endothelial cells with minimal atypia. Angiosarcoma can also purely consist of spindle cells with abundant extracellular matrix that mimics other sarcomas. Occasionally, the solid areas of angiosarcomas can undergo necrosis and cavitation, leaving a cavity filled with blood, fibrin, and necrotic debris that has only small rim of viable malignant cells. Thankfully, many hepatic angiosarcomas are much more obvious, consisting of a proliferation of obviously malignant endothelial cells forming papillary (Fig. 26.13), sieve-like, spindled, or solid formations (Fig. 26.14). Some angiosarcomas may show almost exclusively epithelioid morphology, mimicking carcinoma, mesothelioma, or a high-grade lymphoma (Fig. 26.15). In such cases, the presence of occasional intracytoplasmic lumen formation and the presence of small, peripheral zones of more typical
vasoformative growth are valuable clues to the correct diagnosis. Mitotic figures, including atypical mitotic forms, are usually easily identified in hepatic angiosarcoma, but may on occasion be difficult to identify. Mitotic activity is not required for the diagnosis of angiosarcoma, particularly when infiltrative growth is present.4

Hepatic angiosarcoma in children may have Kaposiform areas consisting of spindle cells, sometimes containing PAS-positive intracytoplasmic globules. Thorotrast-associated angiosarcoma may have brown-gray Thorotrast granules, which can be present either free or within macrophages. A precursor lesion consisting of endothelial hypertrophy and hyperplasia has been described in cases related to Thorotrast, vinyl chloride, and arsenic exposure.41,42






Figure 26.13 Angiosarcoma. The neoplastic cells appear to line collagenous cores creating a papillary appearance.






Figure 26.14 Angiosarcoma. The obviously malignant spindle-shaped cells of angiosarcoma.






Figure 26.15 Epithelioid angiosarcoma. The tumor cells resemble a poorly differentiated carcinoma.






Figure 26.16 Angiosarcoma. An immunostain for ERG is positive.


Immunohistochemical findings

Angiosarcomas are variably positive for vascular markers (CD31, CD34, factor VIII, ERG, and FLI1) (Fig. 26.16). Overall, the frequency of positivity of vascular markers in angiosarcomas is as follows: 40% to 90% of cases are positive for factor VIII, 60% to 90% are positive for CD34, 30% to 100% are positive for CD31, and nearly 100% are positive for ERG and FLI1.43, 44, 45, 46 An important diagnostic pitfall is the expression of cytokeratins.47 Cytokeratin expression is seen in about 30% to 50% of cases (Fig. 26.17), in particular those showing epithelioid morphology, emphasizing the need to apply a panel of immunohistochemical stains in this differential diagnostic setting. Rare angiosarcomas also express synaptophysin and/or chromogranin, mimicking neuroendocrine tumors.48







Figure 26.17 Angiosarcoma. An immunostain for CAM 5.2 is positive.


Molecular and special techniques

Recent studies have described recurrent genetic abnormalities in skin and visceral angiosarcomas. Angiosarcomas of the liver have not been specifically studied but the findings of these studies deserve mention. CIC mutations or rearrangements have been found in approximately 10% of angiosarcomas,49 and PLCG1, PTPRB, and KDR mutations have each been noted in another 10%.49 These alterations are mutually exclusive. Recurrent NUP160-SLC43A3 fusion genes have been identified in approximately 35% of angiosarcomas.50 This fusion gene was mutually exclusive of KDR mutations. The relevance of these findings to primary hepatic angiosarcomas is unclear at this time.


Nov 24, 2019 | Posted by in GASTROENTEROLOGY | Comments Off on Benign and Malignant Mesenchymal Tumors of the Liver
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