Benign cystic mesotheliomas are relatively rare benign tumors that occur mainly in young women, but they can occur in both genders and any age [12–14]. Synonyms include inflammatory inclusion cyst of the peritoneum, multilocular peritoneal inclusion cyst, and multicystic mesothelial proliferation. They most often arise in the pelvic peritoneum, usually in the tubo-ovarian region, but secondary serosal involvement of other organs has been reported (uterus, kidney, bladder, liver, and colon) [13, 15, 16]. Involvement of the liver is very rare [13–16].

While some authors regard this lesion as a true neoplasm, most authorities consider cystic mesothelioma to represent a reactive mesothelial proliferation [15–17]; this is supported by the presence in most cases of identifiable inciting agents, such as previous surgery, pelvic inflammation, endometriosis, or other forms of mesothelial irritation [15, 16]. A hormonal association is suggested by the female predominance and only rare occurrence after menopause [14]. The prognosis of benign cystic mesothelioma is excellent [15, 16], but there can be local recurrence [14].

Benign cystic mesothelioma can range from a small and localized lesion to a diffuse multifocal process [15, 16]. It is typically asymptomatic, but can sometimes present as a palpable mass, with ascites, or constipation [13, 15]. Radiologically, the lesion can be highly vascular and mimic focal nodular hyperplasia or hepatocellular carcinomas [14]. Liver involvement can be accompanied by involvement of other organs such as the pelvic or inguinal region, or rarely the pericardium [18, 19].

Grossly, the tumors are located in the liver immediately beneath the Glisson capsule (Fig. 1.5) and can measure up to 10 cm. They are typically encapsulated and have a soft glistening surface and a cystic (microcystic and macrocystic) configuration [14]. The cysts often contain a gelatinous fluid [14, 18].

Microscopically, the lesion is partially cystic, encapsulated, and features high vascularity. The cysts are lined by flattened cells (Fig. 1.6) with bland, oval to spindled nuclei, sometimes with a hobnail appearance. In addition to the cysts, the lesion contains tubular and gland-like spaces, anastomosing loose cords, as well as areas with solid, reticulated nests of epithelioid cells (Fig. 1.7). The tubular and glandular structures are lined by epithelioid cells with clear, vacuolated cytoplasm. The tumor cells have indented/cleaved nuclei that are moderately pleomorphic and have small rims of cytoplasm. A fibrous stroma featuring a rich vascular proliferation (medium-to large-sized vessels) is interspersed between the cystic spaces (Fig. 1.8). Hemorrhage is often widespread in the lesion. This, along with the overall high tumor vascularity, can mimic a vascular neoplasm [14, 18].

By immunohistochemistry, the lesional cells are positive for keratin, CAM 5.2, HBME-1, D2-40, calretinin, WT-1 (Fig. 1.9), EMA, and CK5/6. Approximately 30 % of tumors show nuclear positivity for estrogen receptor. The proliferative index is less than 1 %. Ultrastructural analysis confirms mesothelial differentiation, characterized by the presence of microvilli and desmosomes [14, 18].

The differential diagnosis includes lymphangioma, which develops in younger individuals and usually spares the pelvis. Furthermore, lymphangiomas are richer in smooth muscle bundles and often contain follicular lymphoid aggregates. By immunostains, lymphangiomas express D2-40, CD31, and CD34 and lack mesothelial marker expression. Hemangiomas have a similar immunostain profile to lymphangiomas, which can distinguish them from benign cystic mesothelioma in challenging cases. Another possibility to consider in the differential diagnosis is metastatic cystic variant of clear cell renal cell carcinoma; this is differentiated from benign cystic mesothelioma by a history of a renal mass, the presence of clusters of clear cells within the cyst wall, immunostain expression of keratin, RCC, and PAX-8, and the lack of expression of mesothelial markers. Benign cystic mesotheliomas can be distinguished from malignant mesothelioma by the lack of cytologic atypia and the lack of complex and/or infiltrative growth, low cellularity, and lack of mitotic activity [14, 18].

Echinococcosis is an infectious disease caused by larva of Taeniid cestodes (tapeworms) belonging to the Echinococcus species [20]. The cystic form is also known as “hydatid cyst.” Humans are infected by ingesting Echinococcus eggs, which are excreted by infected animals [20–22].

Echinococcosis has two main forms, a cystic form characterized by large cystic lesions and an alveolar form featuring alveolar structures (1 mm to 3 cm) [23]. Cystic Echinococcosis is most common in temperate zones such as the Mediterranean, Australia, Central Asia, and some parts of America [24], whereas alveolar Echinococcosis is endemic in the northern hemisphere (North America, Asia, China, Japan, and Europe) [21, 25]. The hepatic lesions grow very slowly in the liver (1–5 mm/year). Therefore, the disease remains asymptomatic for long periods of time [23]. Symptoms eventually result from the mass effect exerted by the cyst/alveolar lesions or by cyst rupture, which can lead to anaphylactic shock (intraperitoneal rupture) or secondary cholangitis (rupture into biliary system) [20, 23]. The alveolar form can also lead to liver failure due to infiltrative growth and potential spread to other organs (through rupture into the abdominal cavity or biliary tree) [26, 27].

The diagnosis is typically made by ultrasound findings and positive serology [23, 28–30]. Because of this, Echinococcosis-related liver lesions rarely get evaluated by the surgical pathologist. However, there can be atypical imaging findings that lead to biopsies or to resections. In resection specimens, the typical cystic form is characterized by a spherical cyst (Fig. 1.10), measuring up to 30 cm, and has a fibrous rim. The cyst can be unilocular but more frequently contains several daughter cysts, developed by growth and invagination of the germinal membrane.

The cyst wall consists of four layers, though in any given histological section some of the layers may not be apparent.

The alveolar form, on the other hand, features multilocular, necrotic, cystic cavities, containing thick pasty material and lacking a fibrous wall. Histologically, the cysts have a laminated membrane, but no germinal membrane or protoscolices. Hooklets can be found. The laminated membrane is often fragmented; a PAS stain may be necessary to highlight it. The cysts in the alveolar form invade necrotic liver tissue in a manner similar to malignant neoplasms. The host response is variable and may contain a granulomatous reaction with neutrophils and eosinophils, or feature a peripheral rim of extensive necrosis, fibrosis, and calcification.

Mortality from Echinococcosis is uncommon in developed countries, but death rate from Echinococcosis is as high as 5 % worldwide [23, 28, 31]. The treatment of choice for the cystic form is puncture aspiration, injection, and re-aspiration (PAIR), which results in parasitological clearance in 96 % of cases [32]. In this form of treatment, the cysts are aspirated and then re-injected with ethanol or hypertonic saline, which is left in the cyst for a short time before removal by re-aspiration. Treatment of the alveolar form, on the other hand, is similar to treatment for malignancies and consists of radical surgery followed by chemotherapy [20].

Endometriosis is a common condition that most frequently involves the pelvis [33]. Endometriosis is rarely found in extra-pelvic locations; and when this occurs, it is termed “atypical endometriosis” [34]. Atypical endometriosis can involve virtually any organ, and intrahepatic endometriosis is one rare form [35]. When there is hepatic involvement, a previous history of endometriosis is present in 67 % of cases [35]. Hepatic endometriosis is not limited to women of reproductive age; 33 % of lesions are described in post-menopausal women [35].

Patients typically present with abdominal pain, but only a small minority of patients (5.5 %) presents with cyclical abdominal pain accompanying the menstrual cycle [35]; this makes the clinical diagnosis extremely difficult. Therefore, diagnosis is almost always dependent on histologic examination. The diagnosis can be very difficult to make on needle biopsy and the diagnosis is not made until the lesion is excised in most cases. Despite its rarity, this entity should be considered in women with recurrent hepatic cysts, regardless of age.

Grossly, hepatic endometriosis is typically cystic and shows hemorrhage, sometimes resembling ovarian chocolate cysts. Histologically (Figs. 1.17 and 1.18), hepatic endometriosis features endometrial glands (or cysts lined by endometrial glandular epithelium), endometrial stroma, and hemorrhage (Fig. 1.19); identifying two of these features is sufficient to render the diagnosis of endometriosis.

The epithelium has a variable appearance, ranging from flattened to elongated and pseudostratified cells. The endometrial stroma consists of stromal cells with “naked nuclei” surrounded by reticulin fibers and spiral arterioles. The immunohistochemical profile is characterized by positive staining for keratin stains (including CK7) in the epithelium, positive staining for CD10 in the endometrial stroma, and positive staining for ER and PR in both components (Fig. 1.20).

The main entity to be considered in the differential diagnosis is mucinous cystic neoplasm of the liver [36]. Both stromal and epithelial elements are distinct; the stroma in mucinous cystic neoplasm is more cellular and resembles ovarian stroma (cellular fibroblast like cells in whirling and storiform patterns) rather than endometrial stroma. The stroma in both lesions is positive for ER and PR, but only the epithelium of endometriosis will be positive for ER and PR, whereas the epithelium of mucinous cystic neoplasms is not. In addition, the epithelial lining is almost always mucinous in mucinous cystic neoplasms and does not resemble endometrial epithelium. In difficult cases, immunostains for CD10 and inhibin can be helpful; the former is positive in the stroma of endometriosis, whereas the latter is positive in the stroma of mucinous cystic neoplasms [36].

Focal fatty nodules are defined as localized macrovesicular steatosis involving a number of contiguous hepatic lobules, but with otherwise normal liver architecture. This lesion is also known as focal fat infiltration. Focal fatty nodules are usually seen in adults (age range 20–80 years) with a female predominance [37]. They can be large, with some reported cases as large as 12 cm [38]. While most are recognized by radiology, some cases can be challenging [39], leading to targeted biopsies. On fine-needle aspirates, the fat-laden hepatocytes can sometimes resemble signet ring cells, suggesting a diagnosis of metastatic signet ring cell carcinoma [38].

Although this condition can be seen in otherwise normal livers, it has been associated with a variety of conditions including diabetes mellitus, alcoholic liver disease, congestive heart failure, porphyria cutanea tarda, and viral hepatitis. Rarely, it can be associated with acute bleeding [38]. The pathogenesis remains unknown.

Grossly, focal fatty nodules may be single or multiple and may involve one or both hepatic lobes. They appear as well-demarcated, pale-yellow or yellow-white nodules within the liver parenchyma, ranging in size from less than 1 cm to up to 10 cm. Microscopically, macrovesicular steatosis involves multiple contiguous hepatic acini, which still have recognizable portal tracts and central veins (Fig. 1.21). Occasionally, Mallory bodies may also be seen, especially in subscapular lesions. Primary tumors of the liver need to be carefully excluded, before making the diagnosis of focal fatty nodule, including angiomyolipoma, focal nodular hyperplasia, hepatic adenoma, and hepatocellular carcinoma.

Inflammatory pseudotumor is a benign mass-forming lesion that is histologically composed of fibrous tissue, proliferating myofibroblasts, and a prominent inflammatory infiltrate which is composed mostly of plasma cells. Inflammatory pseudotumor has also been described in the literature as plasma cell granuloma, xanthogranuloma, post-inflammatory tumor, inflammatory myofibroblastic lesion, fibroxanthoma, pseudolymphoma, and histiocytoma. Serum CA19-9 levels are elevated in some cases [40, 41].

Inflammatory pseudotumors usually have a good prognosis. Conservative treatment can include steroids, other anti-inflammatory drugs, and/or antibiotics, which can result in complete regression. Initial uncertainty about the diagnosis or local complications may lead to surgical excision.

Inflammatory pseudotumors in the liver are rare and account for less than 1 % of focal liver lesions [42–44]. They usually occur in adults between fourth and seven decades of life with a male predominance [45–47]. Common presenting symptoms include fever, abdominal pain, weight loss, and jaundice. The exact pathogenesis is not known, but an exaggerated inflammatory response to some infectious agent, autoimmune phenomenon, or systemic inflammation has been suggested as possible etiologies.

Inflammatory pseudotumors within the liver are usually solitary, but can sometimes be multiple (about 20 %). Single inflammatory pseudotumors tend to be larger than multifocal lesions. Their size can vary from less than 1 cm to lesions to greater than 10 cm. More than half of the tumors are seen in the right hepatic lobe.

Grossly, they appear as well-circumscribed, firm, yellow or tan white lesions. Microscopically, the lesions have a prominent inflammatory infiltrate with a predominance of mature polyclonal plasma cells in a background of fibrous tissue and spindled myofibroblastic proliferation (Figs. 1.22 and 1.23). There should be no atypia in the spindled myofibroblastic cells and mitoses are absent to very rare. The collagen can be dense or loose. Storiform areas, while not diagnostic, suggest the possibility of IgG4-related disease (see below). Lymphocytes, neutrophils, macrophages, and eosinophils are also variably present and can sometimes be focally prominent. Inflammatory pseudotumors may also show xanthogranulomatous inflammation with multinucleated giant cells (Fig. 1.24). Occasionally, lymphoid aggregates including follicles may also be seen (Fig. 1.25).

The hepatic-vein tributaries and portal-vein branches may show obliterative phlebitis, similar to the phlebitis seen in type 1 autoimmune pancreatitis. The phlebitis tends to involve medium- to larger-sized portal veins and is more common in single lesions than in multifocal disease. In other cases, the occluded vessels may have little inflammation, probably reflecting older lesions. Bile ducts can also be identified within inflammatory pseudotumors, showing periductal lymphoplasmacytic infiltration with or without concentric periductal fibrosis (Fig. 1.26).

Immunohistochemically, the spindled cells in inflammatory pseudotumors are often vimentin and smooth muscle actin-positive, while immunostains for anaplastic lymphoma kinase (ALK) are negative. Patchy cytokeratin staining may be seen in some inflammatory pseudotumors [43].

The differential diagnosis includes a number of entities and a diagnosis of inflammatory pseudotumors is always one of exclusion. The edge of an abscess can look essentially identical on biopsy and should be included in the differential diagnosis of biopsy specimens. In addition, syphilis can cause lesions that are essentially identical to idiopathic inflammatory pseudotumors (Fig. 1.27) [48]. Silver stains are often not sensitive enough to detect the organisms, but immunohistochemistry works very well (Fig. 1.28).

Studies have also suggested a relationship between IgG4 and some inflammatory pseudotumors [49–51]. In fact, a subset of hepatic inflammatory pseudotumors have numerous IgG4-positive plasma cells (Fig. 1.29) and they may be part of the IgG4-related disease complex. For this reason, IgG4 stains are helpful in many cases. A cut off of at least ten IgG4-positive plasma cells per high power field is often used for the diagnosis of IgG4-related disease complex. However, even cases with increased IgG4-positive plasma cells need to be correlated with clinical and serological findings, as increased numbers of IgG4-positive plasma cells only suggest the diagnosis and do not establish it.

There are a number of other less common tumors to consider in the differential. Some angiomyolipomas can have striking inflammation and mimic inflammatory pseudotumors, but tumor positivity for HMB-45 and Melan-A will help make the correct diagnosis [52]. Some liposarcomas can also have areas that closely resemble inflammatory pseudotumors [53]. Epstein-Barr virus-related follicular dendritic cell tumor is also in the differential, but this rare tumor will be positive for CD21 and CD35 by immunohistochemistry [54]. Finally, inflammatory pseudotumors can be associated with carcinomas that obstruct the common bile duct, with subsequent infectious cholangitis and inflammatory pseudotumor formation [40]. Thus, a diagnosis of an inflammatory pseudotumor should be followed by further studies to rule out other disease processes, including neoplasms and biliary tract obstruction. Overall, multifocal lesions are more commonly associated with chronic biliary tract disease than single lesions.

Heterotopic tissues are usually found incidentally in the liver, either during surgery or at the time of autopsy. Exceptions do occur, however, in which they present with a mass lesion.

Juvenile xanthogranuloma (also called nevoxanthendothelioma) is a histiocytic disorder that primarily affects young individuals in the first two decades of life and most often presents with a solitary cutaneous lesion. The typical skin lesions are small yellowish to erythematous nodules (most ≤1 cm) that are located in the head and neck region. Microscopically (Fig. 1.40), they have a pushing border and consist of a mixture of mononuclear cells, multinucleated cells (with or without Touton features), and spindle cells (interspersed or aggregated, but not always present). The mononuclear cells and giant cells occasionally have a xanthomatous appearance and sometimes feature nuclear grooves reminiscent of Langerhans cells. In approximately 10 % of cases, the mononuclear cells demonstrate nuclear atypia and mitotic activity. The classical Touton giant cells are present in 85 % of cases, but can be sparse or common in any given case. Touton giant cells have a central wreath of nuclei and a peripheral rim of cytoplasm (with or without vacuoles). Eosinophils, and less often lymphocytes and plasma cells, can also be seen. The lesional mononuclear cells are positive for CD68, factor XIIIa, S100 (weak), and are negative for CD1a.