Hepatic Infiltration by Splenic Marginal Zone Lymphoma in a Patient With Cured Hepatitis C

Splenic marginal zone lymphoma (SMZL) accounts for only 1-2.7% of all lymphomas. Almost all patients have bone marrow (BM) involvement but only one-third has liver involvement. The higher prevalence of hepatitis C virus (HCV) infection in these patients has led to the hypothesis of viral involvement in lymphomagenesis. In this report, we present a case of a 48-year-old woman, with cured hepatitis C, presenting with fever, weight loss, nausea, abdominal pain, and jaundice. She had leucocytosis with lymphocytosis, a progressively worsening cytocholestasis, and hepatosplenomegaly. Liver biopsy, immunophenotyping, and BM biopsy were performed, resulting in the diagnosis of SMZL. The patient started chemotherapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone) with an initial good response, but later progression to high-grade lymphoma and was recommended to undergo salvage chemotherapy followed by auto-transplant. Despite the unusual liver involvement, we should consider hepatic infiltration by lymphomas, such as SMZL, especially in patients with a history of HCV infection.

We discuss a rare case of a 48-year-old woman, with cured hepatitis C, diagnosed with SMZL presenting with uncommon hepatic infiltration initially and later progression to high-grade lymphoma.

Case Presentation
A 48-year-old Caucasian woman presented with an eight-month history of anorexia, weight loss (25 Kg), nocturnal hypersudoresis, nausea, and food vomiting, which had exacerbated in the last two months. Three days before admission, she had developed intense abdominal pain on both flanks and afternoonpredominance fever (38.5 ºC); she was admitted to the ER.
Her medical history included untreated chronic hepatitis C (diagnosed 16 years ago) and cholecystectomy. She was medicated with alprazolam 1 mg and diazepam 10 mg once daily. She was a current smoker (4.5 pack-years), former drug addict (intravenous heroin usage between 20-28 years of age), and had discontinued her alcohol abuse (one year ago). She had had contact with a vaccinated cat. She denied any recent travel, transfusions, or risky sexual behavior.
In the ER, she appeared slightly jaundiced with abdominal pain on palpation of both flanks with spleen's inferior pole palpable on the left flank and palpable hepatic edge 3 cm from the costal margin. The remainder of the general examination was normal.

including admission and maximum values during inpatient investigation
Serum protein electrophoresis and immunoglobulin assay were normal and there was no complement consumption. Antinuclear antibodies presented a homogeneous pattern (titer: 1/160). Antineutrophil cytoplasmic, anti-hepatic, anti-mitochondrial, anti-double-stranded DNA, and anti-extractable nuclear antigens antibodies were negative.
Serologies showed a positive HCV antibody with undetectable viral load, previous hepatitis A and cytomegalovirus infection, and reactive varicella-zoster IgM antibody (non-reactive IgG antibody). HIV, hepatitis B virus (HBV), Epstein-Barr virus, Treponema pallidum, Leptospira, Borrelia, and mononucleosis serological tests were negative. Blood and urine cultures were also negative.
Cervical-thoracic-abdominal-pelvic CT scan ( Figure 1) confirmed the pathologic findings in abdominal ultrasound (Figure 2), revealing a ganglion formation (18 x 11 mm) anteriorly to the pericardium, suggestive features of chronic liver disease, splenomegaly (17.5 cm), and signs of portal hypertension, as well as discreetly prominent main bile duct (10 mm) secondary to cholecystectomy and several ganglia in the hepatic hilum (largest: 28 x 17 mm).  BM biopsy (Table 2; Figure 6) showed hypercellularity with atypical nodular small lymphocytes infiltration (60%) expressing CD20 and PAX-5, compatible with infiltration by SMZL.     [1,6]. Hairy cell leukemia was ruled out as CD103 and CD25 were negative [7]. Since serum protein electrophoresis and immunoglobulin were normal, associated with small lymphocytes with cytoplasmic extensions and atypical nodular lymphoid infiltration in BM, SMZL seemed the most likely diagnosis.
In the presence of a rapid clinical and analytical deterioration, the patient was started on prednisolone (60 mg/day for eight days) resulting in nausea and abdominal pain resolution with a slight improvement in cytocholestasis, despite maintaining fever. Due to the suspicion of transformation to diffuse large B-cell lymphoma (rapid clinical progression and high LDH and SUV), combined with splenic biopsy risks, she was also started on R-CVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone). After the first cycle, she developed anaemia (Hb: 6.3 g/dL), leukopenia (2.21 x 10 3 /uL), and thrombocytopenia (12 x 10 3 /uL). She was discharged from inpatient service, continuing treatment in a day hospital unit. Twenty-one days after R-CVP initiation, the patient underwent the first cycle of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisolone) with a 50% reduction in doxorubicin and vincristine. The second cycle of R-CHOP had 100% of the doxorubicin dose and 50% of the vincristine dose, while the third and fourth cycles were full doses. The fifth and sixth cycle, due to neuropathy, was performed with vincristine 1 g. The patient initially had a good response, being asymptomatic, without fever or pancytopenia with improved cytocholestasis [normal GOT, GPT, and bilirubin; high AP (117-173 U/L)] and normalization of inflammatory markers six months after discharge. HCV viral load remained negative three months after discharge.
Despite the initial good response, the disease progressed to high-grade lymphoma. Revaluation PET ( Figure  3B) showed a reduction of the affected areas but intensely avid FDG foci in the spleen (qSUVmax=12.2) and lateroaortic adenopathies, reflecting refractory disease.
Three months after the sixth R-CHOP cycle, the patient presented with stiff and painful subcutaneous nodules at occipital, abdominal, and infra-mammary regions. Subcutaneous nodule biopsy immunophenotyping ( Table 2) and cervical lymph node biopsy were performed, revealing a diffuse large Bcell lymphoma (Figure 7). In the presence of a high-grade lymphoma under first-line treatment, the patient accomplished two cycles with ifosfamide, etoposide, and carboplatin with persistent disease, and then underwent rituximab, dexamethasone, cytarabine, and cisplatin followed by chimeric antigen receptor T-cell therapy. Two months later, the PET showed complete remission ( Figure 4C).
The prevalence of HCV in patients with SMZL is higher than that in the general population, and patients with HCV presented with SMZL in 4.2% of cases [4,8]. Although the mechanism is not completely understood, lymphoma development may be related to HCV chronic antigenic stimulation [9]. The causal role of HCV in lymphomagenesis is supported by the phenomenon of lymphoma regression after HCV eradication [2].
Our patient, at diagnosis, had spontaneously cured hepatitis C. Although the exact date of cure is unknown, we speculate whether the risk of developing SMZL in such patients is similar to the general population or higher due to previous HCV infection. On the other hand, given that the disease is cured in some cases after hepatitis C treatment, we also wonder whether the mechanism behind the cure may be related to the pharmacological mechanisms as well as HCV eradication.
Differential diagnosis with respect to lymphoplasmacytic lymphoma is difficult as SMZL may present with plasmacytic differentiation and serum monoclonal paraproteinemia (28%) [1,3]. If lymphocytes are organized in marginal zone pattern or intrasinusoidal involvement, as observed in our patient's BM biopsy, SMZL should be suspected [3].
There is no consensus on the treatment of this condition: splenectomy, chemotherapy, rituximab, or antiretroviral treatment may be employed in HCV patients [2]. Due to the significant morbidity associated, risk of infection, and no impact on BM disease, splenectomy may be an unreasonable option [10][11][12][13]. Rituximab monotherapy has been associated with high response rates, higher five-year progression-free survival rates, and a favorable safety profile [10][11][12][13][14][15].

Conclusions
Although liver involvement in SMZL is uncommon, this diagnosis should be considered in patients with hepatic abnormalities, especially if associated with HCV infection. SMZL is usually indolent; however, sometimes, there is transformation into high-grade lymphomas, which are more aggressive and associated with shorter survival periods.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.