Metastatic Tumors in the Liver

Lizhi Zhang, MD

31.1 INTRODUCTION

The liver is one of the most common organs involved by metastases. In fact, metastatic tumors are the most common malignant neoplasms of the liver. Distinguishing metastatic tumors from primary hepatic tumors and determining their origins are of importance for clinical management. Liver biopsies play two main roles. First, in patients with known primaries, liver biopsies can confirm metastatic disease. Second, in metastatic disease of unknown primary, histological and immunostain findings can help identify the likely site of origin, always being interpreted in the context of clinical, serological, and imaging findings.

31.3 CLINICAL FEATURES

Most patients with liver metastases present with symptoms and signs related to their primary disease. Most individuals present with nonspecific findings, such as abdominal pain, jaundice, ascites, or weight loss. Metastatic functioning neuroendocrine tumors can present with carcinoid syndrome, which typically develops only after there are liver metastases. In other cases of metastatic disease, patients are completely asymptomatic and liver metastasis is an incidental finding.

Overall, approximately 60% of all primary tumors that metastasize will eventually involve the liver.¹ Carcinomas and melanomas are more likely than sarcomas to metastasize to the liver in adults. Autopsy studies show that the most common carcinomas metastatic to the liver are as follows: colorectal, breast, lung, pancreas, neuroendocrine tumor, stomach, and cervix.² By contrast, the liver metastases in children are most likely to be from neuroblastoma, Wilms tumor, or sarcomas.³ However, these patterns are largely autopsy based and may not be the same as seen in surgical pathology biopsy specimens because most surgical pathology specimens are from cases where the primary tumor is unknown or uncertain based on clinical and imaging evaluations.

31.4 LABORATORY FINDINGS

Liver transaminases and alkaline phosphatase levels are often nonspecifically elevated in patients with liver metastases. However, serum tumor markers can provide some guidance for the possible sites of origin (Table 31.1), though none has sufficient sensitivity or specificity to replace imaging and histological studies. Of note, additional useful markers are likely to be discovered as molecular-based studies mature.

31.5 GENERAL APPROACH TO WORK UP

Working up a liver tumor of unknown origin is the art of pathology. A pathologist must use a logical approach that combines clinical information, morphological features, immunophenotype, and other special stains or techniques to reach a correct diagnosis. Good communication with clinicians and radiologists can obtain useful information regarding the nature of the liver tumor. Although immunohistochemistry has become essential and is readily available, a pathologist must follow a step-by-step approach to avoid underusing or overusing immunohistochemistry.

Primary versus metastatic tumor

The first step is to determine if a liver malignancy is primary or metastatic. The most common primary malignant tumors of the liver are hepatocellular carcinoma and cholangiocarcinoma. When clinical history of known cancer in other organs is available, an accurate diagnosis can be reached with no or very few immunostains. For example, when a liver biopsy from a patient with a known history of colorectal adenocarcinoma reveals an adenocarcinoma with columnar cells and dirty necrosis, then the diagnosis can be achieved based on hematoxylin and eosin (H&E) with few (e.g., CDX2) or no stains.

Other helpful clues come from imaging studies. The presence of numerous hepatic lesions, for example, greater than five, favors metastatic disease. In contrast, the presence of a single hepatic tumor without identifiable lesions elsewhere in the body is more common in primary liver carcinoma. The presence of advanced fibrosis or cirrhosis also favors a primary liver neoplasm, although metastatic tumors can rarely be seen in cirrhotic livers.

Carcinoma versus nonepithelial lineage tumor

Immunostains are key tools for determining epithelial versus nonepithelial differentiation, but morphological examination on the H&E sections is still essential. In addition, morphology needs be taken into account when interpreting immunostaining results because tumors can aberrantly express epithelial markers. For example, epithelioid hemangioendothelioma can be positive for CK7 and can be misdiagnosed as a poorly differentiated adenocarcinoma if morphology and other immunostain findings are not taken into account.

If a tumor is poorly differentiated or undifferentiated, and no useful clinical information is available, then immunostains play a central role in working up the tumor. Immunostains are first used to determine the basic lineage of the neoplasm. Examples of useful stains include stains for carcinoma (EMA, pancytokerin, Oscar keratin, cytokeratin AE1/AE3,
and Cam5.2), sarcoma (desmin, smooth muscle actin, CD34, and KIT), melanoma (S100, Melan-A, HMB-45, SOX 10, MiTF, and tyrosinase), and lymphoma (CD3, CD20, and CD45). Other stains for rare entities include germ cell tumor markers (PLAP, Oct4, α-fetoprotein [AFP], SALL4, and human chorionic gonadotropin [hCG]), plasmacytoma (CD138 and MUM1), and rhabdoid tumor or epithelioid sarcoma (INI1). Of note, it is often important to use multiple markers because poorly differentiated malignancies may have focal expression or lose expression of some lineage markers. Once the broad lineage of the tumor has
been determined, more specific immunostains can be performed for further tumor subclassification. Commonly used immunostain markers are listed in Table 31.2; however, none of immunostaining markers is perfect for a specific entity and there are many pitfalls when interpreting immunostaining results.

Table 31.1 Commonly used serum tumor markers

Serum tumor markers	Primary associated tumors	Additional associated tumors
α-Fetoprotein (AFP)	Hepatocellular carcinoma, embryonal cell carcinoma, and yolk sac tumor	Cholangiocarcinoma, hepatoid carcinoma, some acinar cell carcinomas
Beta unit of human chorionic gonadotropin (β-hCG)	Choriocarcinoma, embryonal cell carcinoma, and gestational trophoblastic disease	Rare GI carcinomas
Calcitonin	Medullary thyroid carcinoma;	Carcinomas of lung, liver, and kidneys
CA15-3	Breast carcinoma	Other carcinomas
CA19-9	Pancreatobiliary adenocarcinoma	Colorectal, gastric, and esophageal adenocarcinoma
CA125	Ovarian carcinoma	Carcinomas of endometrium, fallopian tube, breast, lung, esophagus, stomach, liver, and pancreas
Carcinoembryonic antigen (CEA)	Colorectal carcinoma	Carcinomas of breast, lung, stomach, pancreas, bladder, medullary thyroid, head and neck, cervix, and liver
Chromogranin A (CgA)	Pheochromocytoma, neuroblastoma	Small cell carcinoma and neuroendocrine tumors
Des-gamma-carboxyprothrombin (DCP)	Hepatocellular carcinoma
Gastrin	Gastrin producing neuroendocrine tumor (gastrinoma), most arising in the duodenum or pancreas
Glucagon	Glucagonoma
Insulin	Insulinoma
Metanephrines	Pheochromocytoma	Neuroblastoma and ganglioneuromas
Neuron-specific enolase (NSE)	Small cell carcinoma	Neuroblastoma, pheochromocytoma, and neuroendocrine tumors
Pancreatic polypeptide	Pancreatic polypeptide producing neuroendocrine tumor, most arising in the pancreas
Prostate-specific antigen (PSA)	Prostate carcinoma
Serotonin	Neuroendocrine tumor
Squamous cell carcinoma antigen	Squamous cell carcinoma of the cervix, lung, and head and neck
Vasoactive intestinal polypeptide (VIP)	VIP producing neuroendocrine tumor, most arising in the pancreas

Adenocarcinoma versus other types of carcinoma

Once a carcinoma has been identified, the specific type of carcinoma needs to be determined based on both morphology and immunophenotype. If gland formation and/or mucin production are identified, a diagnosis of adenocarcinoma can be established. If a carcinoma shows other morphological features typical for a neoplasm, such as keratinization for squamous cell carcinoma or organoid growth pattern and neuroendocrine nuclear features for neuroendocrine tumor, then specific immunostains can be used to confirm the diagnosis. Otherwise, if the tumor is poorly differentiated or the morphological features are nonspecific, a broad immunostain panel for different types of carcinoma should be considered. Commonly used markers include the following: hepatocellular carcinoma (HepPar-1, arginase, glypican-3, polyclonal CEA, CD10,
and albumin in situ hybridization); squamous cell or urothelial carcinoma (CK5/6, CK903, p40, GATA-3, and p63); neuroendocrine tumors including small cell carcinoma (synaptophysin and chromogranin); mesothelioma (calretinin, WT-1, and D2-40); acinar cell carcinoma (trypsin and Periodic acid-Schiff [PAS]). After a diagnosis of adenocarcinoma is established, a combination of CK7/CK20 can be used with other organ specific markers for lung, gastrointestinal, breast, prostate, or other origins. Different CK7/CK20 staining
patterns can provide useful clues for determining tumor origin and deciding second round of immunostain work up (Table 31.3). Of note, there are no organ specific markers for squamous cell carcinoma. In addition, adenocarcinoma arising in upper gastrointestinal tract or pancreatobiliary tract can have similar morphology and immunophenotype.

Table 31.2 Commonly used tumor origin markers and some pitfalls for primary and metastatic tumors of the liver

Tumors	Tumor lineage markers	Aberrantly expressed markers and pitfalls
Adrenal cortical neoplasm	Melan-A, inhibin, calretinin
Angiomyolipoma	HMB-45, SMA
Angiosarcoma	ERG, CD31, CD34, Fli-1, factor VIII	Synaptophysin, cytokeratin
Breast carcinoma	GATA3, ER, GCDFP-15, mammoglobin	S100
Cholangiocarcinoma	CK7, CK20 (variable), CDX2 (variable), VHL	CK20 and CDX2 positivity is more common in hilar and extrahepatic tumors; TTF-1 positive in 50% extrahepatic tumors
Choriocarcinoma	β-hCG, CD10
Colorectal and appendiceal carcinoma	CDX2, CK20, SATB2, villin	MSI-high tumors with reduced staining for CK20 and CK7 positivity
Embryonal carcinoma	SALL4, OCT4, CD30, SOX2
Endocervical adenocarcinoma	PAX8, p16, CEA, loss of PAX2
Endometrial adenocarcinoma	PAX8/PAX2, ER
Epithelioid hemangioendothelioma	ERG, CD31, CD34, Fli-1, factor VIII	Keratin
Epithelioid sarcoma	Loss INI-1, keratin, CD34
Gastrointestinal stromal tumor	KIT, DOG1	CD34 (60%), SMA (30%)
Hepatocellular carcinoma	Arginase, glypican-3, HepPar-1, Albumin-ISH, CD10 or polyclonal CEA (canalicular pattern)	MOC31 (35%), CDX2 (5%), CK19 (15%)
Leiomyosarcoma	SMA, MSA, caldesmon
Lung adenocarcinoma	TTF1, Napsin
Melanoma	S100, Melan-A, HMB-45, MiTF, SOX10, tyrosinase	KIT, cytokeratin, synaptophysin
Mesothelioma	Calretinin, WT1, D2-40, CK5/6,	GATA-3 (50%)
Neuroendocrine tumor	Chromogranin, synaptophysin, CD56, NSE
Ovarian clear cell carcinoma	PAX8, VHL, CEA
Ovarian serous carcinoma	PAX8, ER, WT1, p53
Pancreatic acinar cell carcinoma	Trypsin, α₁-antitrypsin	Glypican-3 (60%); if >30% positive for NET markers, classified as mixed acinar-neuroendocrine carcinoma
Pancreatic ductal adenocarcinoma	MUC5AC, S100P, CDX2 (variable)	Loss of SMAD4 (50%), but also in some cholangiocarcinomas and ampullary carcinoma; monomorphic anaplastic carcinoma loss INI-1
Pancreatic neuroendocrine tumor	Islet-1, PAX8, PDX1	Trypsin (focal), CK19 and KIT positivity indicating aggressive behavior
Prostate adenocarcinoma	PSA, PSAP, ERG, NKX3.1	Chromogranin and synaptophysin after hormone therapy
Renal cell carcinoma, clear cell type	PAX8/PAX2, RCC, VHL, CD10	Napsin (75%)
Renal cell carcinoma, chromophobe type	PAX8, KIT	GATA-3 (50%)
Renal cell carcinoma, papillary type	PAX8/PAX2, RCC	Napsin (30%)
Small intestinal adenocarcinoma	CK7, CK20 (variable), CDX2 (variable)	HepPar-1 (60%)
Solid pseudopapillary tumor	Nuclear β-catenin, PR, CD10
Solitary fibrous tumor	CD34, Stat6
Squamous cell carcinoma	p40, CK5/6, p63, desmocollin-3	HPV positivity suggests cervical or oropharynx primary; GATA3 is positive 80% of skin squamous cell carcinomas, 30% of cervical, and 20% of lung/larynx; glypican 3 (20%)
Thyroid papillary or follicular neoplasm	TTF1, PAX8, thyroglobulin
Thymoma	PAX8, p63, CD5
Thyroid medullary carcinoma	Calcitonin, TTF1, CEA
Translocational RCC	TFE3
Urothelial carcinoma	GATA3, Uroplakin, p40, CK5/6, CK903, p63
Yolk sac tumor	SALL4, glypican-3, AFP

31.6 GROSS FINDINGS

Most liver metastases are multifocal and involve both lobes of the liver. Scattered nodules with varying sizes are present throughout the hepatic parenchyma. Metastasis less commonly presents as a solitary hepatic lesion. Metastatic tumors are typically seen in noncirrhotic livers, although metastases can occur in cirrhotic livers with a low frequency. Gross features are generally nonspecific, but some findings may suggest certain types of tumors. For instance, melanomas may be black or brown in color. Mucinous adenocarcinomas may have abundant mucin with a gelatinous glistening appearance. Squamous cell carcinomas may be white and granular. Colorectal carcinoma may have an umbilicated appearance. Fibrous capsules are rarely seen in metastases, except for a few colorectal carcinomas. Most liver metastases are solid masses, but cystic changes may occur due to necrosis. Besides forming masses or nodules, poorly differentiated adenocarcinomas can also diffusely involve the liver sinusoids, causing hepatomegaly with no grossly visible lesion.

Table 31.3 General CK7 and CK20 staining patterns

Staining patterns

Tumors predominantly with this pattern

Variable tumors with this pattern

CK7⁺/CK20⁺

Urothelial carcinoma

Ovarian mucinous carcinoma

Endocervical adenocarcinoma

Small intestinal adenocarcinoma

Pancreatic adenocarcinoma

Cholangiocarcinoma

Gastric adenocarcinoma

CK7⁺/CK20^–

Ductal and lobular breast carcinoma

Malignant mesothelioma

Endometrial adenocarcinoma

Ovarian serous and endometrioid carcinoma

Pulmonary adenocarcinoma

Salivary gland neoplasm

Thyroid neoplasm

Squamous cell carcinoma

Pancreatic adenocarcinoma

Cholangiocarcinoma

Gastric adenocarcinoma

Small intestinal adenocarcinoma

CK7^–/CK20⁺

Colorectal adenocarcinoma

Appendiceal adenocarcinoma

Appendiceal goblet cell carcinoid

Merkel cell carcinoma

Gastric adenocarcinoma

Cholangiocarcinoma

CK7^–/CK20^–

Hepatocellular carcinoma

Prostatic adenocarcinoma

Renal cell carcinoma

Small cell carcinoma

Neuroendocrine tumor

Germ cell tumor

Adrenal cortical tumor

Squamous cell carcinoma

Epithelioid sarcoma

Malignant mesothelioma

Thyroid neoplasm

Thymoma

31.7 MICROSCOPIC FINDINGS

Morphological clues to determine tumor differentiation lineage

Careful H&E examination is a key step that has not been replaced by immunostains. Often, features identified on H&E sections can provide strong evidence suggesting tumor differentiation and can direct the use of immunostains. For instance, bile production is essentially diagnostic of hepatocelluar differentiation and in most cases, although hepatoid carcinoma from other organs can also produce bile.⁴ Glandular differentiation or mucin production indicates an adenocarcinoma. A mucicarmine stain can help to identify mucin production when it is focal or not evident on H&E. True glandular differentiation must be separated from psuedoglands, which are commonly present in hepatocellular carcinoma, fibrolamellar
carcinoma, neuroendocrine tumors, and acinar cell carcinomas (Figs. 31.1 and 31.2). Squamous differentiation is characterized by keratinization with squamous pearl formation, large cells with glassy eosinophilic cytoplasm, distinct cell borders, and intercellular bridge (Fig. 31.3). If a glandular component is identified in addition to squamous differentiation, a diagnosis of adenosquamous carcinoma is made.

Tumor growth patterns are also important clues to the differential diagnosis. Neuroendocrine tumors often have an organoid pattern similar to that seen in primary tumors (Fig. 31.4). A prominent trabecular growth pattern is also common in neuroendocrine tumors. Acinar structures suggest acinar cell carcinoma or neuroendocrine tumors. When tumor cells form anastomosing channels, a vascular neoplasm should be considered.

Figure 31.1 Hepatocellular carcinoma. Pseudoglands and bile production in hepatocellular carcinoma.

Figure 31.2 Neuroendocrine tumor. Pseudoacinar formation in neuroendocrine tumor.

Nuclear features can also provide clues for the tumor origin. Uniform nuclei with finely stippled chromatin without conspicuous nucleoli typically suggest a neuroendocrine tumor (Fig. 31.4). Small cell carcinoma is characterized by nuclear molding, smudgy chromatin, and inconspicuous nucleoli, often with crush artifact (Fig. 31.5). Unusually large eosinophilic nucleoli can be seen in melanoma and prostate carcinoma. Nuclear grooves suggest a solid pseudopapillary tumor, papillary thyroid carcinoma, or granulosa cell tumor. Irregular and elongated nuclei with prominent nuclear grooves and folds are suggestive of Langerhans cell histiocytosis.

Figure 31.3 Squamous cell carcinoma. Single cell keratinization in squamous cell carcinoma.

Figure 31.4 Neuroendocrine tumor. Organoid growth pattern with “salt-and-pepper” chromatin pattern without conspicuous nucleoli typically seen in neuroendocrine tumor.

Figure 31.5 Small cell carcinoma. Nuclear features of small cell carcinoma.

Eosinophilic hyaline inclusions can be seen in a group of tumors, including solid pseudopapillary tumors (Fig. 31.6), embryonal sarcomas, and rare angiosarcomas. Steatosis is most commonly seen in hepatocellular carcinoma, but other carcinomas can also show fatty change, usually with a microvesicular pattern of steatosis, including adrenal cortical carcinomas (Fig. 31.7) and solid pseudopapillary tumors of the pancreas. The differential for metastatic clear cell carcinoma includes renal cell carcinoma, clear cell neuroendocrine tumor, clear cell acinar cell carcinoma, and adrenal cortical carcinoma. A rhabdoid or plasmacytoid morphology can be seen with tumors of several different lineages, including carcinoma, melanoma, gastrointestinal stromal tumor, plasmacytoma, and anaplastic large cell lymphoma. As part of this, SMARCB1/INI-1 immunostains are important to rule out poorly differentiated rhabdoid tumors, which can be either primary to the liver or metastatic. Spindle cell tumors suggest sarcoma, but sarcomatoid carcinomas have to be excluded by immunostains. The differential for nonepithelial spindle cell tumors includes solitary fibrous tumors (Fig. 31.8), gastrointestinal stromal tumor (Fig. 31.9), leiomyosarcoma (Fig. 31.10), inflammatory myofibroblastic tumor, angiosarcoma, Kaposi sarcoma, follicular dendritic cell sarcoma, or melanoma.

Figure 31.6 Pancreatic solid pseudopapillary tumor. Eosinophilic globules in metastatic pancreatic solid pseudopapillary tumor.

Figure 31.7 Metastatic adrenal cortical carcinoma. Lipid-rich tumor cells.

Distinguishing hepatocellular carcinoma from its mimickers

Metastatic tumors that can most closely mimic hepatocellular carcinoma include neuroendocrine tumors,
renal cell carcinomas, acinar cell carcinoma, adrenal cortical carcinomas, melanoma, and epithelioid angiomyolipomas. Hepatocellular carcinoma is usually excluded by a panel of multiple hepatocellular markers, such as HepPar-1, arginase, glypican-3, and albumin in situ hybridization. Polyclonal carcinoembryonic antigen (CEA) and CD10 are older markers of hepatic differentiation that depend on identifying a canalicular staining pattern but are not widely used anymore because newer stains have better performance characteristics. In our practice, we typically start with HepPar-1 and/or arginase if the morphological impression is a well to moderately differentiated hepatocellular carcinoma. Positive staining for one of them can usually confirm the diagnosis in morphologically consistent well or moderately differentiated hepatocellular carcinomas. If the immunostains are negative, then tests for other markers including glypican-3 and albumin in situ hybridization are used. Additional stains are used to exclude other tumors depending on the morphology and the clinical findings.

Figure 31.8 Metastatic solid fibrous tumor. Bland spindle cells and “staghorn” vascular pattern.

Figure 31.9 Metastatic gastrointestinal stromal tumor. Spindle cell type.

Figure 31.10 Metastatic leiomyosarcoma.

A rare dilemma can be to distinguish primary hepatocellular carcinoma from metastatic hepatoid carcinoma. The most common sites of origin for metastatic hepatoid carcinomas are the stomach, pancreas, and lung. Patients can have elevated serum AFP levels and the tumor can morphological be consistent with hepatocellular carcinoma. Metastatic hepatoid carcinomas can be positive for any of the hepatic markers (HepPar-1, glypican 3, arginase, or albumin in situ hybridization), so none of these will distinguish metastatic from primary disease (Figs. 31.11 and 31.12). Likewise, other proposed markers to separate these two entities (SALL4, MOC31, CK19) have not stood the test of time and are not clinically helpful. Clues
to the possibility of metastatic hepatoid carcinoma include tumors showing only focal areas of hepatic differentiation on H&E, histories of mass lesions in other organs such as the upper gastrointestinal tract, pancreas, or lung, and atypical immunophenotypes. Examples of immunophenotypes that are atypical for hepatocellular carcinoma include strong and diffuse TTF1 nuclear staining or strong and diffuse CDX2 staining. Of note, other nonhepatoid carcinomas may also be positive for hepatic markers (HepPar-1, glypican 3, arginase, or albumin in situ hybridization), but if they do not have hepatoid morphology, then they are not classified as hepatoid carcinomas.

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