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Common Primaries of Liver Metastases

Introduction
Due to the complexity of Patient A’s presenting symptoms, doctors have yet to reach a consensus of a cause. As determining the source of her abnormal findings will dictate further treatment plans, the importance of arriving on an early diagnosis is stressed. This review will discuss common primaries that metastasize to the liver, as well as analyze the likelihood of a primary myeloma that has spread hepatically.
Cellular Basis of Metastasis
In his 1889 paper, Stephen Paget revolutionized pathophysiology by proposing the ‘seed and soil’ hypothesis of metastasis: vasculature of an organ does not solely determine the likelihood of developing a secondary tumour at the site; equally as important stems the “initiating cell” (the ‘seed’) with the compatibilityof the “organ microenvironment” (the ‘soil’)(4, 9). Among all primaries in both male and female populations, the commonest locations for secondary tumours to develop are liver, lung, and bone(3). The anatomy of the portal venous system allows both arterial and venous systems to deposit mutated cells into the liver(5). Furthermore, as all blood travels to the lungs for oxygenation, quite often carcinogenic cells will pass through and settle there(3). Likewise, nutritious, highly vascularized bone marrow creates a favourable microbiomes for cancerous cells to replicate in, explaining why many cancers will eventually metastasize to the axial skeleton(10).
Clinical Implications
Patient A’s previous diagnosis of breast cancer is clinically significant as investigated in Pan et al.’s meta-analysis for risks of recurrence twenty years after endocrine therapy. They determined that even with five years of adjuvant hormonal therapy, there remained a chance of recurrence and metastases for at least twenty years post-treatment(11). As Patient A did not receive hormonal therapy at the time, her chance of recurrence is further increased: multiple studies have shown that endocrine therapy significantly reduces the chance of relapse in both premenopausal and postmenopausal populations(12, 13). Conversely, the relationship of osteoarthritis and myeloma has yet to be studied, but reviews of rheumatoid arthritis and multiple myeloma have not yet uncovered any correlation between the two, and further epidemiological studies are required(14).
Alkaline phosphatase (ALP) is a membrane-bound glycoprotein expressed throughout the body(6). Because of its four isozyme forms and ubiquity, it acts as a non-specific marker of possible maladies, yet it remains standard investigation protocol(6). Elevated ALP, specifically the liver/bone/kidney isozyme, implicates a wide range of possibilities, with common causes including high osteoblast turnover (osteoporosis), damaged hepatocytes, and elderly population(6, 15).
Common Primaries of Liver Metastases
Rarely does myeloma metastasize to the liver; two of the common primaries of liver metastases are gastrointestinal (colorectal and gastric) and breast(5).
The most common source of liver metastases is from colorectal carcinomas, with 66-72% (female-male) of primary tumours spreading hepatically(3). Due to adenocarcinomas being the predominant molecular basis of colorectal carcinomas, differential diagnosis of a metastatic lesion in the liver of a known colorectal origin would likely be intrahepatic cholangiocarcinoma(5, 16). Genetically, caudal-type homeobox 2 (CDX2) presents in 90-100% of colorectal adenocarcinomas, functioning as a promotor of specific genes critical to the development of intestinal cells(17); despite its diagnostic potential, it presents in majority of gastrointestinal adenocarcinomas, making it unspecific as a stand-alone biomarker(17). However, if used along with Special AT-rich sequence-binding protein 2 (SATB2) in marker panels, there is evidence for CDX2 and SATB2 to be implemented as standard biomarkers for diagnosing primary colorectal carcinomas which have metastasized to the liver(18).
Secondary to colorectal carcinomas are metastatic breast carcinomas, specifically the invasive ductal carcinoma (IDC) population(5). Similar to the colorectal tumours, IDC histologically resembles an adenocarcinoma; hence, the main differential diagnosis of a liver metastasis remains an intrahepatic cholangiocarcinoma(5). To explain the proclivity of IDC to metastasize to the liver, claudin-2 is a key protein involved in the formation of tight junctions between adjacent cells(19). Tabariès et al. investigated the role of this protein in hepatic metastases and found there to be elevated levels specific to breast-liver metastases due to the “enhanced adhesion to resident hepatocytes”(20). Furthermore, CK7 and CK20 are immunohistochemical tumour markers expressed in a wide range of malignant neoplasms, and the pattern of positive/negative expression helps narrow down the origin of an unknown primary(17); in IDC, the most common phenotypes are CK7-positive/CK20-negative. By comparing ER/PR/HER-2 profiles of the hepatic lesions in addition to CK7/CK20 status, pathologists can determine whether the initial tumour was derivative of breast tissue(5).
Extramedullary Myeloma and Hepatic Involvement
Because of Patient A’s elevated ALP and its association with both hepatic and bone-related pathologies, her physicians are currently investigating the potential of a myeloma with hepatic involvement. However, the literature has indicated this progression is extremely uncommon and should be a diagnosis of exclusion(2, 21, 22). Multiple myeloma (MM) is an uncontrolled proliferation of plasma cells accumulating in the bone marrow; when it spreads to and begins to involve soft tissue, it is thereafter known as extramedullary myeloma (EM)(2, 23). To diagnose EM, PET scans are the preferred choice of imaging (sensitivity approximately 85%, specificity approximately 90%), with a biopsy to confirm the histological profile after all other investigations have remained inconclusive(2, 7, 23, 24). Pathological developmental patterns appear predominantly as diffuse hepatic infiltration rather than nodular(7). To determine a primary myeloma, immunohistochemical screen of serum protein electrophoresis and free light chains would be measured(25).
Due to the scarcity of EM to the liver, no standard treatment regimen has been established(2). The use of bortezomib, in combination with glucocorticoids, cyclophosphamide, and dexamethasone, has demonstrated some clinical potential in EM(7, 8). Reviews of anatomical resections for liver metastasis positively suggest further investigation into implementing surgery as standard procedure for metastatic hepatic involvement(26). The anatomy of Glisson’s capsule largely divides the liver to reduce probability of entire-organ spread, which is why anatomical resection is recommended over non-anatomical resection(26); non-anatomical resections would be appropriate in cases with few metastatic lesion and pathologically little risk of microscopic invasion(26).



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