ELSEVIER
Contents lists available at ScienceDirect
Seminars in Diagnostic Pathology
journal homepage: www.elsevier.com/locate/serndb
-
Seminars in Diagnostic Pathology
MARK R. WICK, MD
A Festschrift for Dr. Juan Rosal
Differential diagnosis of epithelioid and clear cell tumors in the liver
Steven Alexander Mann, Romil Saxena *
Indiana University School of Medicine, United States
CrossMark
ARTICLE INFO
Keywords: Epitheliod tumors Clear cell tumors Angiomyolipoma Epithelioid hemangioendothelioma Clear cell hepatocellular carcinoma
ABSTRACT
A tumor composed of large eosinophilic cells in the liver raises concern for hepatocellular carcinoma, which is typically composed of such cells. However, there are other tumors, both primary and metastatic, that may be composed predominantly of large epithelioid cells. Distinction of these tumors from he- patocellular carcinoma and from each other is of obvious importance for patient management. Similarly, a clear cell tumor anywhere in the body triggers suspicion for renal cell carcinoma. However, other tumors, including hepatocellular carcinoma can rarely be composed entirely of cell cells and the dis- tinction of these from one another, and of primary from metastatic disease is vital. As with the latter, accurate diagnosis is essential for patient management. Using illustrative examples, this article discusses differential diagnosis of liver tumors comprised predominantly of epithelioid cells or clear cells. @ 2017 Elsevier Inc. All rights reserved.
A needle biopsy of a liver mass is likely to show hepatocellular carcinoma (HCC), cholangiocarcinoma, a metastatic lesion or an- other primary liver tumor. The likelihood of each depends on the epidemiological context of the patient and state of the underlying liver. In Western countries, metastatic lesions are more common than primary liver tumors in a non-cirrhotic liver. The presence of underlying cirrhosis or advanced fibrosis tips the scales towards hepatocellular carcinoma; however, the latter may arise in non- cirrhotic and non-fibrotic liver in areas where vertical transmis- sion of hepatitis B is endemic. Similarly, the likelihood of a cho- langiocarcinoma is high in countries where infection with liver flukes is endemic, although the incidence of cholangiocarcinoma is reported to be increasing in Western countries as well.1,2
A tumor composed of large eosinophilic cells in the liver raises concern for hepatocellular carcinoma, which is typically composed of such cells. However, there are other tumors, both primary and metastatic, that may be composed predominantly of large epi- thelioid cells. Distinction of these tumors from hepatocellular carcinoma and from each other is of obvious importance for pa- tient management. Similarly, a clear cell tumor anywhere in the body triggers suspicion for renal cell carcinoma. However, other tumors, including hepatocellular carcinoma can rarely be com- posed entirely of cell cells and the distinction of these from one another, and of primary from metastatic disease is vital3,4 As with the latter, accurate diagnosis is essential for patient management. Using illustrative examples, this article discusses differential di- agnosis of liver tumors comprised predominantly of epithelioid cells or clear cells.
Case 1
A 41-year-old female with no significant past medical history presented with left flank pain, myalgia, and fatigue for one month. Computed tomography (CT) revealed left lower lung nodules (largest 1.5 cm) and a right hepatic mass up to measuring 8 cm. Fine needle aspiration (FNA) of the lung nodules was non-diag- nostic. A biopsy of the right liver mass was reported as hepato- cellular carcinoma. The patient was referred to our institution for a second opinion and another liver biopsy was performed.
Pathologic findings
The biopsy of the right liver mass showed nests and cords of large cells with abundant eosinophilic cytoplasm, large nuclei, prominent nucleoli, and open chromatin. Interspersed among the tumor was a hypocellular matrix including adipocytes and thick-walled vessels (Fig. 1A and B). The adjacent liver parenchyma was normal in ap- pearance. Immumohistochemical stain for HMB45 was positive in the tumor cells (Fig. 1C). Hepatocyte specific antigen (Fig. 1D) and glypi- can-3 were positive only in adjacent benign hepatocytes.
Diagnosis: Angiomyolipoma
Discussion
Angiomyolipoma is currently considered to be a member of the PEComa (tumor of perivascular epithelioid cells) family.5,6 More commonly found in the kidney, angiomyolipoma may rarely occur in the liver, where the epithelioid variant is more common. Composed predominantly of large eosinophilic cells, these tumors may be mistaken for a hepatocellular neoplasm.
* Corresponding author. E-mail address: rsaxena@iupui.edu (R. Saxena).
A
B
C
D
Hepatic angiomyolipoma occurs in middle-aged individuals and may present with abdominal pain or generalized symptoms such as fever, malaise, and anorexia. Rarely, the tumor may rup- ture and present with hemorrhage.2,6 Some cases are discovered incidentally during imaging for an unrelated condition. Despite the association with tuberous sclerosis, most cases are sporadic.
Grossly, angiomyolipoma appears well circumscribed but not encapsulated. The cut surface is heterogeneous and often var- iegated, usually with prominent hemorrhage and necrosis. The coloration is usually tan to yellow, depending on the composition of the cellular components, especially the amount of fat. Histologically, as its name implies, angiomyolipoma is composed of variable combination of three cell types: a smooth muscle-like component, vascular component, and fat cell component. The myoid cells may be either epithelioid or spindle in shape. The epithelioid variant, composed predominantly of epithelioid myoid cells may display a trabecular growth pattern, thus closely mimicking a hepatocellular neoplasm. Their cytoplasm sometimes demonstrates perinuclear condensation (classically described as a “spider-web” appearance), mimicking glycogenated hepatocytes or clear cells. Myoid cells are seen intimately associated with and surrounding blood vessels. The vascular component consists of thick-walled arterial or venous channels that lack elastic tissue lamina and thin-walled venous spaces. The fat component may be scant or absent in liver tumors, but when present, it may simulate simple steatosis.7 Despite its well-circumscribed appearance, angiomyolipoma demonstrates in- filtrative borders on microscopy. Using immunohistochemical stains, HMB-45 stains stronger in epithelioid myoid cells, while smooth muscle actin is stronger in spindle shaped myoid cells.
Angiomyolipoma may mimic metastatic melanoma, a problem compounded by immunohistochemical positivity of epithelioid myoid cells and fat cells for S100.2
Hepatic angiomyolipoma is a benign tumor; rare examples of malignant cases have been reported.8 Microscopic features that are associated with worse outcomes are predominant epithelioid morphology, nuclear atypia, high proliferation rate, and necrosis.6
Case 2
A 33-year-old female with a history of treated tuberculosis presented with worsening left pelvic pain for six months. CT showed multiple non-enhancing, hypodense lesions throughout the liver (largest 6 cm), right adrenal gland enlargement up to 5 cm, and a 2.5 cm sclerotic lucency in the left ilium. Two of the lesions in the right hepatic lobe were biopsied under ultrasound guidance.
Pathologic findings
The liver biopsy revealed a tumor composed of cords and single cells within a fibromyxoid background (Fig. 2A). These cells in- filtrated hepatic sinusoids and appeared to occlude large vascular structures (Fig. 2B). Signet ring-like cells were identified, some of which contained red blood cells within intracytoplasmic lumina (Fig. 2B and C). Immunohistochemical stain for CD34 was positive with a membranous pattern in the tumor cells (Fig. 2D).
A
B
C
D
E
F
Diagnosis: Epithelioid hemangioendothelioma
Discussion
Epithelioid hemangioendothelioma is a rare low-grade me- senchymal neoplasm that preferentially affects the liver. It typically presents in adults, usually in the sixth decade of life, and in contrast to similar tumors that occur in soft tissue, is more common in women9 Epithelioid hemangioendothelioma may be asymptomatic and discovered incidentally or it may present with abdominal pain, abdominal mass, jaundice or ascites. Most tumors are multifocal and involve both hepatic lobes at diagnosis. Serum alkaline
phosphatase may be elevated.2 Epithelioid hemangioendothelioma has a characteristic multilayered targetoid appearance on magnetic resonance imaging (MRI) that demonstrates a prominent peripheral rim with high T1-weighted signal intensity and very low T2- weighted signal intensity (bright-dark ring sign).10
Grossly, epithelioid hemangioendothelioma appears as multi- ple, firm, white to yellow tumor nodules which are well circum- scribed but not encapsulated. These masses often demonstrate central calcification and/or ossification. Microscopically, the tumor cells appear as variably dendritic or epithelioid in shape and are arranged as single cells or cords of cells within a fibromyxoid
stroma. Tumor cells often contain cytoplasmic vacuoles, some of which may contain red blood cells. The stroma is more dense in the center of tumor nodules, where it may be calcified or ossified. The periphery of the tumor nodules is more cellular, where tumor cells creep along the sinusoids of the adjacent liver and cause atrophy of the hepatocytes. The tumor also grows into vascular structures such as the portal or central veins where it may form “glomeruloid” tufts. This vascular invasion is thought to cause the MRI findings mentioned above, and may also account for symp- toms of veno-occlusive disease in some patients. The mitotic rate of epithelioid hemangioendothelioma is variable.6
When numerous, intracytoplasmic vacuoles in the tumor cells may be mistaken for steatosis on low power or for signet-ring cells on high power (Fig. 2E, F). Presence of a fibromyxoid stroma fur- ther heightens the resemblance to an adenocarcinoma. The pre- sence of red blood cells within the intracytoplasmic lumina assists in establishing a diagnosis of epithelioid hemangioendothelioma. Tumor cells are immunohistochemically positive for CD31, CD34, factor VIII, and FLI1 are positive. Stains for mucin are negative but may be positive in a poorly differentiated adenocarcinoma.
Epithelioid hemangioendothelioma demonstrates an indolent clinical course; the prognosis is better than angiosarcoma, even after incomplete resection or the presence of metastases. However, outcomes are variable and cases appear to be resistant to chemotherapy2,6 Liver transplantation has been carried out in patients with disease limited to the liver. The post-transplantation course is variable; late recurrences and occurrence of angiosarco- ma in the allograft have been described.11,12
Case 3
A 67-year-old female with history of breast cancer and multi- visceral transplantation (not including liver) presented with leu- kocytosis and two weeks of progressive fatigue. Positron emission tomography-computed tomography (PET-CT) revealed multiple variably hyperactive masses in the liver (largest 7 cm), a hy- permetabolic 11 cm mass in the central abdomen near the head of the pancreas, and mesenteric lymphadenopathy. A biopsy of the abdominal mass was reported at an outside institution as an un- differentiated malignant neoplasm. Because of clinical suspicion of post transplantation lymphoproliferative disease, a biopsy of one of the liver lesions was performed.
Pathologic findings
The biopsy revealed a high-grade tumor with a variegated ap- pearance and abundant necrosis. The tumor cells were pleo- morphic, variably spindled and epithelioid in shape with abundant eosinophilic cytoplasm and a few giant tumor cells (Fig. 3A). Si- nusoidal pattern of infiltration was seen and there were tumor nodules lined by hobnailed cells. The tumor nuclei were pleo- morphic with irregular nuclear membranes and prominent nu- cleoli. Immunohistochemical stains revealed the tumor cells to be diffusely positive for CD31 (Fig. 3B) and focally positive for CD34. The tumor cells were negative for cytokeratins, CD20, CD117, GATA-3, and DOG1.
A
B
C
D
Diagnosis: Angiosarcoma
Discussion
Angiosarcoma rarely presents as a primary tumor in the liver. When this occurs, it is usually in a middle-aged to elderly patient, with a preponderance for males, though it can also present in young adults and children. Historically, Thorotrast, a no longer used radiologic contrast medium, was associated with the devel- opment of angiosarcoma at various locations. Other risk factors for angiosarcoma include exposure to vinyl chloride monomer, ar- senic, and androgenic-anabolic steroids. Most primary hepatic angiosarcomas however have no clearly identifiable risk factor. Patients may present with hepatomegaly, signs of liver failure such as jaundice and ascites, thrombocytopenia, and hemoperitoneum. The prognosis is dismal with mean survival of six months. There is currently no effective therapy.2,6
Angiosarcoma typically appears dark red or brown in color, with a soft spongy or cystic consistency, and has indistinct in- filtrative borders. The microscopic architecture may be solid, pa- pillary, or cavernous. At the periphery of the tumor, the infiltrating cells spread along the hepatic sinusoids. This is usually accom- panied by sinusoidal dilatation and congestion. The tumor cells are more numerous and larger than normal sinusoidal lining cells and show variable degrees of pleomorphism and hyperchromasia. Mitosis, crowding, multilayering and solid areas are seen. The tu- mor cells can be spindled or epithelioid. A characteristic finding is the presence of of small tufts of stroma lined by tumor cells that bulge into cavernous spaces within the tumor. Angiosarcoma is positive for the common vascular markers, CD31, CD34, factor VIII, ERG and FLI1. Staining for FLI1 may be focal or patchy. Factor VIII is the most sensitive and specific stain for angiosarcoma.2,6 Tumor cells may also be positive for p53 and Ki67 demonstrates an ac- tively proliferating tumor.
Case 4
A 54-year-old male with a history of a low grade B-cell lym- phoproliferative neoplasm presented five years later with multiple visceral masses. PET-CT revealed numerous hypermetabolic mas- ses in the liver and lymphadenopathy. A lobectomy specimen from the lung was reported as poorly differentiated carcinoma of un- known origin. A gastric biopsy was reported as poorly differ- entiated adenocarcinoma with no in situ lesions present. A liver biopsy of one of the hepatic masses was received from the outside institution for second opinion.
Pathologic findings
The biopsy showed diffuse involvement by solid nodules and thickened cords of poorly differentiated epithelioid cells (Fig. 3C). The tumor cells were pleomorphic with high-grade nuclear atypia, varying amounts of cytoplasm, and numerous mitoses. Foci of dirty necrosis were present. The uninvolved liver parenchyma appeared normal. The tumor was morphologically compatible with the prior gastric biopsy and the description of the prior lung resection. Immunohistochemistry staining of the tumor cells in the current case was positive for synptophysin (Fig. 3D) and CK7 and negative for chromogranin, TTF-1, CK5/6, and CK20. Staining for CDX-2 was equivocal.
Diagnosis: Metastatic neuroendocrine carcinoma
Discussion
Neuroendocrine tumors (NETs) arise from individual or groups of cells from the diffuse neuroendocrine system, which is found
throughout the gastrointestinal tract, bronchopulmonary system, and urinary tract. Manifestations as primary tumors of the liver are very rare.13 These tumors can be functional and induce symptoms related to hormone product secretion. Otherwise, they are usually asymptomatic until they metastasize to the liver. This scenario places particular significance and burden on the interpretation of the liver biopsy. The classification of NETs has undergone great evolution and a recent emphasis has been on the inclusion of site specific grading and staging criteria.14
Both the architectural and cellular morphology of NETs can mimick hepatocellular neoplasms. The wide variety of patterns seen in NETs includes trabecular, acinar, and solid nodules. Lower grade tumor cells may be epithelioid with eosinophilic cytoplasm.3,4 The nuclei may not exhibit the characteristic (salt and pepper” chromatin pattern. Aside from the usual neuroendo- crine markers neuron-specific enolase, CD56, synaptophysin, and chromogranin, NETs may express confusing immunohistochemical profiles. NETs may show diffuse membranous MOC-31 staining, imitating metastatic adenocarcinomas in the liver. Focal glypican- 3 staining has been reported in NETs. Conversely, some HCCs ex- hibit neuroendocrine differentiation. Lastly, expression of the more specific neuroendocrine stains, chromogranin and synapto- physin, becomes lost in some poorly differentiated NETs.2
Staining patterns can provide evidence for localizing the site of the primary tumor, but lack of positivity for a stain cannot be used to rule out possible locations as these tumors lose their differ- entiation at higher grades. The use of TTF1, CDX2, and the com- bination of PAX-8 and GATA3 may localize the tumor to pulmon- ary, gastrointestinal, and kidney or urothelium origin, respectively. Positive staining for specific hormonal and enzymatic products can be seen in functional tumors and should be appropriately docu- mented, but attachment of these characteristics to the mainline final diagnosis is discouraged and best left up to clinical correla- tion. Normally NETs are slower growing than adenocarcinomas, but this is again variable. Current grading requires both mitotic counts and the use of Ki67 to measure proliferation, with the greater result being used to apply a grade to the tumor.15
Case 5
A 71-year-old female with symptomatic cholelithiasis pre- sented with a liver lesion that was incidentally discovered during an elective laparoscopic cholecystectomy. The hepatic mass was subcapsular and heterogeneous. A biopsy of the lesion was per- formed at the time of this procedure. Subsequent CT revealed a solitary hepatic tumor within an otherwise normal appearing liver.
Pathologic features
The biopsy revealed solid areas of clear tumor cells forming thick ill-defined trabeculae lined by endothelial cells (Fig. 4A). The clear cells had well defined cellular membranes and mild to moderate nuclear atypia (Fig. 4B). The tumor cells were strongly positive for hepatocyte specific antigen (Fig. 4C), weakly and fo- cally for glypican-3, and negative for PAX-8 (Fig. 4D). The diagnosis of hepatocellular carcinoma with clear cell features was rendered. The patient underwent resection of the mass and was living with a hepatic recurrence, complicated by portal vein thrombosis, two years later.
Diagnosis: Hepatocellular carcinoma, clear cell type
Discussion
Normal hepatocytes may display a variety of nonspecific nu- clear and cytoplasmic inclusions. The range of cytoplasmic
A
B
C
D
coloration from eosinophilic to clear depends upon the storage contents of individual hepatocytes and can vary with numerous interconnected metabolic processes. An abundance glycogen, fat, or water within the cytoplasm of hepatocytes causes a clear cell appearance.2 This clear cell change can predominate in HCC and is a recognized cytological variant in the current WHO classification of liver tumors.1 The appearance of this form of HCC is often dis- tinguishable from metastatic clear cell tumors. Metastatic clear cell renal cell carcinoma and adrenal cortical carcinoma in the liver should be considered in possible cases of HCC with clear cell fea- tures. These two metastatic carcinomas also represent potential hepatocellular mimickers due to their occasional epithelioid morphology.
Case 6
A 69-year-old female with a history of chronic kidney disease and smoking presented with profound weakness and weight loss over a few weeks. On physical exam, hepatomegaly was noted. CT without contrast revealed multiple right lung nodules up to 2 cm, left pleural deposits and hydrothorax, a 12 cm heterogeneous ag- gregate in the right lobe of the liver, a 12 cm left kidney mass, and a left adrenal mass up to 5 cm. Under ultrasound guidance, a biopsy of one of the lesions in the liver was achieved.
Pathologic findings
The liver biopsy showed diffuse infiltration of the liver par- enchyma by solid areas of clear cells within a loose stroma with
numerous vascular spaces. The clear cells had discrete cellular borders and mild to moderate nuclear atypia (Fig. 5A). Im- munochemical stains were strongly positive for PAX-8 (Fig. 5B) and membranous CD10 with patchy RCC positivity for the tumor cells. These cells were negative for hepatic specific antigen, argi- nase-1, and inhibin. The diagnosis of metastatic renal cell carci- noma was rendered. The patient rapidly declined and passed away two days after the biopsy was performed.
Diagnosis: Metastatic clear cell renal cell carcinoma
Discussion
Clear cell renal cell carcinoma (ccRCC) is a heterogeneous group of malignant kidney neoplasms and is the most common type of renal cancer. Cases of primary ccRCC can be sporadic, rarely fa- milial, or related to risk factors including obesity, hypertension, smoking, acquired cystic kidney disease related to long-term dia- lysis, or occupational exposure to trichloroethylene. About 70% of ccRCCs are incidentally found on imaging. Cases may present with hematuria or flank pain. Renal cell carcinoma may metastasize to the liver by way of renal vein invasion.16 In a large autopsy study, liver and bony involvement tied for the second most frequent lo- cation of renal cell carcinoma metastases (present in 40% of cases) after pulmonary metastases (75% of cases).17
The gross appearance in ccRCC specimens is typically a golden yellow tumor (due to high intracellular lipid content), with grossly apparent areas of necrosis and hemorrhage. The most common histologic arrangements are alveolar or acinar nodules with cyst formation. The characteristic tumor cell morphology is clear or eosinophilic cytoplasm with distinct cell membranes and varying
A
B
C
D
degrees of nuclear atypia and nucleolar prominence. Tumor cell eosinophilic cytoplasm is more common in high-grade tumors and next to areas of necrosis and hemorrhage. A network of small thin- walled blood vessels is seen in the background. PAX-8 im- munostaining is positive in renal cell carcinomas and membranous carbonic anhydrase IX and CD10 staining is characteristic of ccRCC. Though canalicular CD10 staining is more definitive, membranous CD10 staining can be seen in HCC as well. Both HCC and ccRCC are positive for CAM5.2, but EMA is positive only in ccRCC and membranous pCEA positivity is seen in only HCC. The im- munohistochemical stain RCC marker is relatively sensitive for ccRCC, but it should be mentioned that this stain is also positive in some non-renal tumors.18 Vimentin is also positive in ccRCC.2-4,16
Case 7
A 54-year-old male with a history of adrenal cortical carcinoma with a retroperitoneal recurrence and subsequent resection pre- sented with two new hepatic masses discovered by surveillance CT. Both liver tumors measured approximately 6 cm. An imaging- guided biopsy was performed to evaluate for adrenal cancer re- currence versus a new malignancy. See.
Pathologic findings
The biopsy showed hemorrhagic fragments of liver par- enchyma with associated inflammation and fibrosis. Minute foci of tumor nests were identified. These tumor cells were polygonal with high nuclear to cytoplasmic ratios and moderately abundant
clear to eosinophilic and finely granular cytoplasm (Fig. 5C). The tumor was morphologically compatible with the patient’s prior retroperitoneal recurrence. Immunohistochemical stains for sy- naptophysin and inhibin (Fig. 5D) were positive in the tumor cells. A diagnosis of metastatic adrenal cortical carcinoma was rendered. The patient was treated with carboplatin and etoposide and was living with residual disease two years later.
Diagnosis: Metastatic adrenal cortical carcinoma
Discussion
Adrenal cortical neoplasms represent a spectrum of tumors including adenomas, carcinomas, and borderline tumors con- troversially designated as the former or the later. Adrenal cortical neoplasms are usually incidentally discovered by imaging studies and the average age of diagnosis for adrenal cortical carcinoma (ACC) is around 50 years old. Adrenal cortical carcinomas may present later as a mass, with fever after becoming necrotic, or with symptoms related to the production of a functional hormonal product. About half of ACCs are functional. While not as common as clear cell renal cell carcinoma by incidence, ACC was found to metastasize more frequently to the liver than kidney primaries when present.19 About half of ACCs are metastatic at the time of diagnosis and the liver is the most common site of metastasis (60% of cases).20
Adrenal cortical carcinomas are soft and friable with a var- iegated cut surface. There are frequently associated areas of ne- crosis and hemorrhage. The microscopic architecture may re- semble the clusters and cords of cells of the adrenal cortex or be completely undifferentiated. Likewise, the tumor cell appearance
| Tumor Markers expressed | |
|---|---|
| Hepatocellular carcinoma | Arginase-1 (most sensitive and specific), glypican-3 (more sensitive for poorly differentiated tumors), Hep Par 1 (more sensitive for well differentiated tumors), AFP (insensitive), canalicular pCEA, canalicular CD10, CAM5.2 |
| Angiomyolipoma | HMB-45 (stronger in epithelioid variant), melan A, smooth muscle actin (stronger in spindled variant), focal S100 |
| Angiosarcoma | Factor VIII, CD31, CD34, FLI1 (patchy or focal) |
| Epithelioid hemangioendothelioma | Factor VIII, CD31, CD34, FLI1, occasional cytokeratin positivity |
| Neuroendocrine carcinoma | Synaptophysin (sensitive), chromogranin (specific) |
| Melanoma | Melan A, HMB-45, S100, SOX10, CAM 5.2, CD56 |
| Clear cell renal cell carcinoma | PAX-8, carbonic anhydrase IX, RCC, CD10, EMA, vimentin |
| Adrenal cortical carcinoma | Inhibin, melan A, synaptophysin, calretinin (focal), vimentin (strong), cytokeratins (weak) |
| Metastatic adenocarcinoma | MOC-31, diffuse mCEA, membranous or cytoplasmic pCEA, cytokeratins; (also mucin by mucicarmine histochemical stain) |
AFP, alpha-fetoprotein; HSA, hepatocyte-specific antigen; mCEA, monoclonal carcinoembryonic antigen; pCEA, polyclonal carcinoembryonic antigen; RCC, renal cell carcinoma marker.
ranges from bland clear cells to giant eosinophilic cells with bi- zarre, hyperchromatic nuclei. The presence of glands containing red blood cells favors the diagnosis of ccRCC over ACC. Adrenal cortical carcinomas are positive for inhibin, melan A, synapto- physin (but not chromogranin), calretinin focally, cytokeratins, and vimentin. More practical for the current discussion, ACC is weakly positive for cytokeratins and strongly positive for vimentin. As mentioned above, ACC shares immunohistochemical positivity for vimentin and melan A with ccRCC and melanoma, respectively. Additional markers can be used to avoid misdiagnosis related to these similarities. Also, unlike HCC with clear cell features, ACC is negative for CEA.2-4,20
Summary
Many primary hepatic and metastatic tumors are capable of displaying trabecular or hepatoid morphologies. Cytologically these tumors can all exhibit eosinophilic and epithelioid features, mimicking hepatocellular carcinoma. Typical examples of such tumors adrenal cortical carcinoma, epithelioid angiomyolipoma, epithelioid gastrointestinal tumor, melanoma, neuroendocrine carcinoma and renal cell carcinoma. In addition, almost any ade- nocarcinoma and mesenchymal tumor can be composed pre- dominantly of epithelioid cells.2-4 CD34 positivity in an epithelioid tumor should raise suspicion for epithelioid variant of gastro- intestinal stromal tumors (GISTs) in addition to vascular tumors. This is especially true for cases that include a gastric mass on imaging; the use of CD117 and DOG1 stains (both positive in GISTs) will help with this distinction.
Metastatic melanoma is an example of an epithelioid mimicker with an immunohistochemical profile that has the potential to be misinterpreted. Application of melanoma-specific markers will lead to proper diagnosis, but other malignancies that share posi- tivity for these markers (namely adrenal cortical carcinoma and angiomyolipoma) must also be kept in mind. Patchy pigmentation suggestive of melanin is helpful but not always present. For cases without a history of skin lesions or another primary tumor, clinical suspicion must remain high for epithelioid hepatic lesions. Such cases require correlation with the physical exam and perhaps imaging and endoscopy to identify the primary site of the lesion.
Hepatocellular carcinoma, the most common primary malig- nancy of the liver, is included in the differential of all hepatic masses. In Western societies these occur most commonly in the setting of a cirrhotic liver, although this is not a prerequisite. HCC may present radiographically as a single mass with satellite lesions or as multiple nodules. Histologically, HCC entity is known to form a wide variety of architectural patterns including trabecular, aci- nar, solid, scirrhous, or a combination of these patterns.1,2 It is common to find pseudoglandular formation; however, true gland
formation or the presence of a duct-forming component signals a lesion that is not hepatocellular, or a combined hepatocellular- cholangiocarcinoma. Presence of bile formation provided definitive evidence of hepatocellular differentiation, whereas mucin production is indicative of metastatic adenocarcinoma, intrahepatic cholangiocarcinoma or a combined hepatocellular- cholangiocarcinoma.3,4 Mucicarmine is preferred over PAS-dia- stase for evaluation of mucin production as the latter may highlight cytoplasmic glycoproteins within hepatocytes.
The sensitivity and specificity of hepatocyte specific antigens such as Hep Par 1 and arginase-1 vary, particularly with the level of tumor differentiation. Arginase-1 is the most sensitive and specific marker for HCC regardless of differentiation.21,22 The sensitivity of Hep Par 1 is 70-90%, but this decreases significantly with higher-grade tumors. Hep Par 1 has also been reported to be positive in a variety of tumors such as gastric, pulmonary, ovarian, and pancreaticobiliary carcinomas.21,23-25 Alpha-fetoprotein is less sensitive for HCC than Hep Par 1. Contrary to most hepatocyte specific markers, glycipan-3 is more specific for poorly differ- entiated HCC than for well-differentiated tumors. The downside is that glycipan-3 is not specific and it has been reported to be po- sitive in many other malignancies. Due to patchy staining patterns observed with arginase-1 and glycipan-3, as well as the relative nonspecificity of glycipan-3, a combination of the two is re- commended to identify poorly differentiated neoplasms in liver biopsies.
A canalicular-staining pattern for polyclonal carcinoembryonic antigen (pCEA) and CD10 is also specific for HCC, but membranous staining for CD10 may also be seen 3. Membranous staining for pCEA is evidence for adenocarcinoma rather than HCC, as is po- sitivity for monoclonal CEA. While MOC-31 is known as a marker for adenocarcinoma, normal hepatocytes in the setting of cirrhosis and up to 20% of HCCs are positive for membranous MOC-31 2. Some HCCs, most frequently the scirrhous variant, can be positive for other markers seen in adenocarcinoma such as CK7, CK19, CK20, and EPCAM22,26 complicating characterization of some tu- mors. Table 1 provides a summary of immunohistochemical mar- kers typically employed for characterization of liver tumors.
References
1. Theise ND, et al. Hepatocellular carcinoma, in WHO classification of tumours of the digestive system. [Editors]. In: Bosman FT, ed. World Health Organization., and International Agency for Research on Cancer. Lyon: International Agency for Research on Cancer; 2010:417.
2. Ferrell LD. Benign and malignant tumors of the liver. In: Odze RD and Goldblum JR, eds. Odze and Goldblum surgical pathology of the GI tract, liver, biliary tract, and pancreas; 2015:1, online resource.
3. Theise ND, Saxena R. Algorithmic approach to diagnosis of liver disorders. In: Odze RD and Goldblum JR, eds. Odze and Goldblum surgical pathology of the GI tract, liver, biliary tract, and pancreas; 2015:1, online resource.
4. Saxena R, et al. Diagnostic algorithms for tumours of the liver, in WHO classi- fication of tumours of the digestive system. In: Bosman FT, ed. World Health Organization., and International Agency for Research on Cancer. Lyon: Interna- tional Agency for Research on Cancer; 2010:417.
5. Ordonez NG, Rosai J. Urinary tract: Kidney, renal pelvis, and ureter; Bladder, in Rosai and Ackerman’s surgical pathology, Rosai J and Ackerman LV, eds. Edin- burgh; Mosby: New York; 2011.
6. Miettinen M, et al. Mesenchymal tumours of the liver, in WHO classification of tumours of the digestive system. In: Bosman FT, ed. World Health Organization., and International Agency for Research on Cancer. Lyon: International Agency for Research on Cancer; 2010:417 [p].
7. Tsui WM, et al. Hepatic angiomyolipoma: a clinicopathologic study of 30 cases and delineation of unusual morphologic variants. Am J Surg Pathol 1999;23 (1):34-48.
8. Nguyen TT, et al. Malignant hepatic angiomyolipoma: report of a case and re- view of literature. Am J Surg Pathol 2008;32(5):793-798.
9. Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 1999;85(3):562-582.
10. Economopoulos N, et al. Bright-dark ring sign in MR imaging of hepatic epi- thelioid hemangioendothelioma. J Magn Reson Imaging 2008;27(4):908-912.
11. Ben-Haim M, et al. Hepatic epithelioid hemangioendothelioma: resection or transplantation, which and when? Liver Transplant Surg 1999;5(6):526-531.
12. Lerut JP, et al. Hepatic haemangioendothelioma in adults: excellent outcome following liver transplantation. Transpl Int 2004;17(4):202-207.
13. Craig JR, Peters RL, Edmondson HA. Tumors of the Liver and Intrahepatic Bile Ducts.Atlas of tumor pathology. Washington, D.C: Armed Forces Institute of Pathology; 1989:280.
14. Rindi G, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system, in WHO classification of tumours of the digestive system. In: Bosman FT, ed. World Health Organization., and International Agency for Research on Cancer. Lyon: International Agency for Research on Cancer; 2010: 417.
15. Edge SB, American Joint Committee on Cancer. In: Edge SB, American Joint
Committee on Cancer., eds. Neuroendocrine Tumors, in AJCC Cancer Staging Manual. New York; London: Springer; 2010:181-189.
16. Moch H, et al. Clear cell renal cell carcinoma, in WHO classification of tumours of the urinary system and male genital organs, International Agency for Research on Cancer (IARC), et al., Editors; 2016:18-21.
17. Wyler L, et al. Brain metastasis in renal cancer patients: metastatic pattern, tumour-associated macrophages and chemokine/chemoreceptor expression. Br J Cancer 2014;110(3):686-694.
18. McGregor DK, et al. Diagnosing primary and metastatic renal cell carcinoma: the use of the monoclonal antibody ‘renal cell carcinoma marker’. Am J Surg Pathol 2001;25(12):1485-1492.
19. Disibio G, French SW. Metastatic patterns of cancers: results from a large au- topsy study. Arch Pathol Lab Med 2008;132(6):931-939.
20. Rosai J. Adrenal gland and other paraganglia. In: Rosai J, Ackerman LV, eds. Rosai and Ackerman’s Surgical Pathology. New York: Edinburgh; Mosby; 2011.
21. Nguyen T, et al. Comparison of 5 immunohistochemical markers of hepato- cellular differentiation for the diagnosis of hepatocellular carcinoma. Arch Pa- thol Lab Med 2015; 139(8): 1028-1034.
22. Krings G, et al. Immunohistochemical pitfalls and the importance of glypican 3 and arginase in the diagnosis of scirrhous hepatocellular carcinoma. Mod Pathol 2013;26(6):782-791.
23. Chu PG, Weiss LM. Immunohistochemical characterization of signet-ring cell carcinomas of the stomach, breast, and colon. Am J Clin Pathol 2004; 121 (6):884-892.
24. Fan Z, et al. Hep par 1 antibody stain for the differential diagnosis of hepa- tocellular carcinoma: 676 tumors tested using tissue microarrays and con- ventional tissue sections. Mod Pathol 2003;16(2):137-144.
25. Lau SK, et al. Comparative immunohistochemical profile of hepatocellular carcinoma, cholangiocarcinoma, and metastatic adenocarcinoma. Hum Pathol 2002;33(12):1175-1181.
26. Chu P, Wu E, Weiss LM. Cytokeratin 7 and cytokeratin 20 expression in epi- thelial neoplasms: a survey of 435 cases. Mod Pathol 2000; 13(9):962-972.