Pathologic quiz case: Hepatic mass in a patient with renal cell carcinoma.

Abstract

A 69-year-old white woman had a radical right nephrectomy for stage I renal cell carcinoma of clear cell type. She had yearly computed tomographic scans that showed no evidence of tumor. Seven years postnephrectomy, however, an abdominal computed tomographic scan identified a new 2.0-cm, hypodense, nonenhancing peripheral mass present in the posterior right lobe of her liver (Figure 1). There was no associated biliary dilatation or lymphadenopathy, and no recurrent mass was identified in the right renal surgical bed. Physical examination was unremarkable. Blood tests revealed a white blood cell count of 5.5 × 109/L; hemoglobin, 140 mmol/L; platelets, 146 × 109/L; and normal liver function tests with a prothrombin time of 13.1 seconds and international normalized ratio of 1.0. The patient's carcinoembryonic antigen value was less than 1.0 μg/L, and CA19-9 was within the normal range. Viral hepatitis serology, α-fetoprotein levels, and antimitochondrial antibodies were unavailable. A chest radiograph and whole body bone scan showed no evidence of metastases. Fine-needle aspiration of the liver mass revealed polymorphous lymphoid cells, normal hepatocytes, and rare atypical spindle cells. A computed tomography–guided needle core biopsy revealed a chronic inflammatory infiltrate.The hepatic lesion was surgically resected, as metastatic renal cell carcinoma could not be definitively excluded. The patient's postoperative course was uneventful. Grossly, the resected liver segment contained a well-circumscribed, tan, nonencapsulated, solitary nodule of rubbery consistency, measuring 1.7 × 1.0 × 0.9 cm (Figure 2). Microscopically, the hepatic mass was composed of polymorphic small lymphocytes forming prominent lymphoid follicles with germinal centers of varying size, containing tingible-body macrophages. There was mild circumferential hemorrhage and a dense infiltrate of lymphocytes associated with small central blood vessels in several portal areas immediately around the nodule (Figure 3); only rare necrotic liver cells were documented. The interfollicular spaces within the mass contained aggregates of plasma cells and numerous hyalinized trabeculated structures (Figure 4). Cytologic atypia was not a feature. Mitoses were infrequent. No bile ducts were involved in the nodular lesion. The remainder of the resected liver parenchyma was unremarkable.Immunostaining demonstrated the germinal centers to be composed predominantly of CD20 (L26)-positive and Bcl-2–negative lymphocytes, whereas lymphocytes surrounding germinal centers and present within the interfollicular areas were mainly positive for CD3 and Bcl-2. The interfollicular hyalinized structures stained positive for factor VIII. A stain for dendritic reticulum cells demonstrated a typical pattern within germinal centers. There was an equal frequency of plasma cells that stained positive for κ and λ light-chain immunoglobulins. Flow cytometry revealed a reactive profile. Polymerase chain reaction for immunoglobulin heavy-chain gene rearrangement amplified polyclonal DNA.Very few cases of reactive lymphoid hyperplasia (RLH) forming benign hepatic tumor–like masses have been reported.1–4 There are usually no associated systemic manifestations. These lesions are generally discovered incidentally and are radiologically present as hypoechoic hypervascular masses. They are well demarcated and characterized by hyperplastic lymphoid follicles with reactive germinal centers, which consist of polymorphic and polyclonal cell populations and aggregations of mature lymphocytes, plasma cells, other types of inflammatory cells, and occasionally stromal fibrosis. Small vessel proliferation and hyalinization in the interfollicular areas and within angiofollicular structures in adjacent portal areas may be a prominent finding, which may mimic the hyaline-vascular type of Castleman disease.5 However, the characteristic regressive germinal centers with “onion skin” morphology are absent. The surrounding liver tissue usually exhibits portal chronic inflammation. Reactive lymphoid hyperplasia is thought to represent an immune-mediated reactive phenomenon,3,4 which in some cases may arise in association with chronic viral hepatitis.6 The prognosis of this entity is good, as most patients treated by resection of the lesion have shown no ill effects, recurrence, or progression to lymphoma.Advances in diagnostic imaging modalities have allowed the detection of increasing numbers of small novel hepatic tumors. The incidental discovery of a macroscopic lymphoproliferative lesion in the liver is an uncommon occurrence, which evokes diagnostic difficulties for the pathologist. Differentiating RLH from low-grade lymphomas may not always be possible on histologic evaluation alone. The term pseudolymphoma was formerly used as a synonym for RLH presenting as macroscopic tumorlike nodular infiltrates in anatomic sites such as the tubular gastrointestinal tract, skin, lung, thyroid, breast, ocular adnexae, kidney, pancreas, and spleen. Although the pathogenesis remains unknown, RLH may develop with autoimmune diseases, after anticonvulsant therapy, and following mechanical stimulation. The term pseudolymphoma has fallen out of favor because many studies subsequently showed that most of these benign-appearing lesions harbor a clonal cell proliferation.7Reactive lymphoid hyperplasia should not be confused with intrahepatic lymphoid follicles, sometimes seen with well-formed active germinal centers, that can occur in autoimmune hepatitis, primary biliary cirrhosis, and chronic hepatitis B and C infection. Such follicles are usually much smaller and confined to portal areas. Furthermore, one should look for destructive cholangitis associated with primary biliary cirrhosis or interface hepatitis (piecemeal necrosis) around lymphoid nodules with varying degrees of portal fibrosis in cases of chronic hepatitis B or C infection. It is incumbent on the pathologist also to exclude rare entities, such as ectopic spleen, solitary plasmacytoma, or unicentric Castleman disease (angiofollicular hyperplasia) involving the liver.8 On microscopic examination, the nodular lesion of Castleman disease appears to be composed of a stellate fibrous scar delimiting smaller nodules of disorganized large and clear hepatocytes.8 Present in the fibrous septa are numerous hyperplastic lymphoid follicles with germinal centers, separated by sheets of plasma cells and increased vascularity. In addition to the characteristic concentric (onion-skin) arrangement of small lymphocytes seen around follicles, an increase of dendritic reticulum cells, often dysplastic, in germinal centers and the marginal zone may help further distinguish true Castleman disease from RLH with Castleman-like features.Inflammatory myofibroblastic tumors, or inflammatory pseudotumors or plasma cell granulomas, may manifest morphologic features similar to RLH, particularly when prominent lymphoid follicles with well-formed germinal centers are observed.2 Grossly, however, inflammatory myofibroblastic tumors tend to show a variegated appearance with areas of hemorrhage and necrosis. Microscopically, the proliferation of myofibroblasts, prominent xanthogranulomatous component, presence of whorled or hyaline fibrosis, and occasional occlusive portal phlebitis should help distinguish inflammatory myofibroblastic tumors from RLH.Hepatic involvement by lymphoma is considered to represent stage IV disease, unless the liver represents the primary and only site of disease. Primary lymphomas may present as a solitary mass in 60% of cases or as multiple masses in 35% of cases.9 These numbers have increased since the emergence of the acquired immunodeficiency syndrome (AIDS) epidemic. Most primary hepatic lymphomas have been shown to be large B-cell non-Hodgkin lymphomas, although occasional T-cell lymphomas have also been described.9 As a rule, low-grade non-Hodgkin lymphoma tends to produce multiple portal-based infiltrates, compared to the large irregular tumor masses seen in the higher grade types. Cases of primary hepatic mucosa-associated lymphoid tissue lymphomas presenting as solitary or multiple nodules have been described as well.10 In these cases, centrocyte-like cells surrounding reactive B-cell follicles tend to form lymphoepithelial lesions within bile ducts.Hepatic involvement in Hodgkin disease can also manifest as large irregular masses or as smaller, more diffusely distributed nodules. It is essential in such cases to identify Reed-Sternberg cells. The presence of granulomas (without Reed-Sternberg cells) is not always helpful, as they may only be encountered in about 15% of cases with Hodgkin disease and in 10% of patients with non-Hodgkin lymphoma. Infrequently, clusters of epithelioid cells with a giant cell reaction may also be encountered within RLH lesions.In contrast to RLH, primary lymphomas of the liver, if untreated, are associated with a poor prognosis, particularly if there is related cirrhosis. Therefore, it is important to recognize the occurrence of these benign hyperplastic lymphoid lesions so as not to erroneously diagnose them as low-grade lymphomas. For a definitive diagnosis, careful histologic analysis integrated with immunohistochemical and flow cytometric analysis, as well as molecular genetic methods, should prove helpful in making the correct diagnosis.