Int J Hematol (2012) 95:320–323 DOI 10.1007/s12185-012-1025-x
CASE REPORT
Primary hepatic lymphoma in a patient with previous rectal adenocarcinoma: a case report and discussion of etiopathogenesis and diagnostic tools Lucia Raimondo • Idalucia Ferrara • Alfonso De Stefano • Chiara Alessandra Cella Francesco Paolo D’Armiento • Giuseppe Ciancia • Roberto Moretto • Amalia De Renzo • Chiara Carlomagno
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Received: 12 July 2011 / Revised: 31 January 2012 / Accepted: 31 January 2012 / Published online: 21 February 2012 Ó The Japanese Society of Hematology 2012
Abstract Primary hepatic lymphoma is an extremely rare malignancy accounting for 0.016% of all cases of nonHodgkin lymphomas. Approximately 1–4% of histologies described show a follicular pattern. We report a case of primary hepatic non-Hodgkin lymphoma that developed in a middle-aged woman 3 years after radical treatment (neoadjuvant chemoradiotherapy and surgery) for a rectal adenocarcinoma. Abdomen ultrasound showed a single nodule in the liver, which raised the issue of differential diagnosis with a metastasis from rectal cancer. After surgical removal of the nodule, histology revealed a primary B cell, stage IE follicular non-Hodgkin lymphoma, confined to the liver; indeed, no foci of lymphoma were found elsewhere in the body. Keywords Hepatic non-Hodgkin lymphoma Rectal cancer Second tumour Introduction Primary hepatic lymphoma (PHL) is a rare malignancy representing about 0.4% of cases of extranodal non-Hodgkin
lymphoma (NHL) and only 0.016% of all NHL cases [1]. The most common histological type of PHL is diffuse large B cell lymphoma; other histological types account for\5% of cases [1, 2]. Despite its association with several viral infections (HIV, HBV, HCV and EBV), inflammatory diseases (liver cirrhosis and primary biliary cirrhosis), and immunological disorders (autoimmune diseases and immunosuppressive therapy), the pathogenesis of PHL is not yet well established [3, 4]. In fact, although the liver contains lymphoid tissue, host-related factors could render the liver a poor environment for the development of malignant lymphomas [4]. Second malignancies occur in about 6.4–13.7% of patients treated for solid tumours in 20 years of follow-up, and are correlated with the administration of specific drugs (for example, alkylating agents and topoisomerase II inhibitors) and radiation (for example, in Hodgkin lymphoma treatment) [5–10]. To our knowledge, ours is the first report of PHL in a patient previously treated with chemoradiotherapy for rectal cancer.
Case report L. Raimondo A. De Stefano C. A. Cella R. Moretto C. Carlomagno (&) Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Universita` di Napoli Federico II, Via Sergio Pansini 5, 80131 Naples, Italy e-mail:
[email protected] I. Ferrara A. De Renzo Dipartimento di Medicina Clinica e Sperimentale, Area di Ematologia, Universita` di Napoli Federico II, Naples, Italy F. P. D’Armiento G. Ciancia Dipartimento di Scienze Biomorfologiche e Funzionali, Universita` di Napoli Federico II, Naples, Italy
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A 52-year-old non-smoker woman referred to our Institution in April 2007 with a 7-month history of diarrhoea and a diagnosis of rectal tumour. Colonoscopy with biopsy and histological examination (Fig. 1a) revealed a well-differentiated adenocarcinoma (EGFR?). Staging procedures with endorectal ultrasound, whole body computed tomography, and positron emission tomography with FDG and iodinated contrast showed a uT3N? primary tumour, without distant metastases. Serum tumour markers (CEA, CA 19.9) were within normal value. Anamnesis included bronchiectasie, nasal polypectomy, right radial fracture and
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Fig. 1 Rectal adenocarcinoma. a Rectal biopsy showing adenocarcinoma (H&E 9106). b Rectal specimen post neoadjuvant chemoradiotherapy; mucinous aspects with lakes of mucus largely acellular and only partly composed of neoplastic cells (Tumour Regression Grade 2)
right ear anvil removal several years before. Physical examination revealed no abnormal findings. All laboratory tests were within normal range. The patient received two cycles of neoadjuvant chemotherapy (capecitabine: 1650 mg/m2, days 1–14 and oxaliplatin: 50 mg/m2, days 1 and 8, every 21 days) concomitantly with pelvic conformal radiotherapy (1.8 Gy daily up to 45 Gy in 5 weeks). In July 2007, she underwent rectal resection with colon–rectal anastomosis. Histology showed rare residual rectal cancer cells in the bowel wall (Tumour Regression Grade 2 as measured by the Mandard Scale); pathological stage was pT1 N0 (Fig. 1b). From September 2007 to January 2008, she received 6 cycles of adjuvant chemotherapy with capecitabine. Thereafter, follow-up visits were scheduled every 6 months with tumour markers, biochemistry, and whole body computed tomography that was negative for local and distant recurrence (hepatic and renal cystis and fibrocalcific lung sequelae were the only abnormal findings). In May 2010, abdomen ultrasound showed a hypoechoic area at the left hepatic lobe (about 28 mm in diameter), with high perinodular and low intranodular vascularization at Doppler sonography, suggestive of an angioma (Fig. 2). The patient then underwent abdominal magnetic resonance imaging with contrast medium, which showed an area of 33 mm at the fourth hepatic segment with contrastographic characteristics of metastatic disease (Fig. 3). The early enhancement and faster wash out after intravenous contrast administration at contrast-enhanced ultrasonography confirmed the diagnosis of metastasis. Carcinoembryonic antigen and alpha fetoprotein serum levels were negative. In September 2010, the patient underwent a subsegmentectomy of the III–IV hepatic segments, and intraoperative liver ultrasound confirmed the absence of other lesions. Histology indicated a diagnosis of non-Hodgkin B cell lymphoma with a follicular and diffuse growth pattern in the proportion of 80 and 20%, respectively (according to WHO 2008) (Fig. 4a). At additional immunophenotyping, immunohistochemistry was positive for CD20 (Fig. 4b),
Fig. 2 Abdomen Doppler ultrasound hypoechoic area (about 28 mm diameter) at left hepatic lobe with high perinodular and low intranodular vascularization suggesting an angioma
CD10, Bcl2, Bcl6, CD45 RO, CD3 and CD5, and negative for D1 cyclin, CD23 and CD43, thereby confirming the presence of follicular cells with some interfollicular T lymphocytes. The patient was referred to the Division of Hematology where staging procedures were performed: bone marrow biopsy plus aspirate were negative; whole body computed tomography and positron emission tomography with FDG and iodinated contrast showed a solid area (13 9 16 mm diameter, standardized uptake value [SUV max] 5.7) at the IVb hepatic segment, which liver ultrasound showed to be a residual postoperatory phlogistic area; (EBV) VCA IgG was positive, whereas EBV IgM, HIV Ab-p24, HCVAb and HBsAg were negative. The TNM stage of the NHL was definitely IE, with no residual disease after hepatic resection. Thus, the patient started adjuvant treatment with rituximab (375 mg/m2, day 1), fludarabine (25 mg/m2 days 1–3) and mitoxantrone (10 mg/m2, day 1) every 21 days, for 6 cycles. Restaging after completion of chemotherapy
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Fig. 3 Hepatic MRI. a Hypointensity on T1 weighted image. b Hyperintensity on T2 weighted image
Fig. 4 Hepatic tissue showing non-Hodgkin B cell lymphoma. a H&E 920, b CD20 immunohistochemistry showing positivity
with whole body computed tomography and positron emission tomography with FDG and iodinated contrast showed no lesion in the liver or in lymph nodes.
Discussion Primary hepatic lymphoma is defined as a lymphoma that is localized in the liver, without evidence of extrahepatic involvement in the spleen, lymph nodes, bone marrow or other lymphoid structures [1]. The usual age at presentation is 50 years, with a male-to-female ratio of 2.3:1 [1–4, 11]. The aetiology of PHL is unknown, although several factors might be implicated in its development. There is evidence that HCV infection is linked to NHL through different mechanisms of malignant transformation; namely, chronic B cell stimulation leading to polyclonal, and eventual monoclonal B cell expansion, and induction of t(14-18) translocation leading to the overexpression of the antiapoptotic factor bcl2 and monoclonal IgH rearrangement [1–4, 11, 13]. Also HBV, by causing chronic antigenic stimulation, is frequently associated with NHL [1–4, 11–13]. Other viruses that have been implicated in the pathogenesis of PHL are EBV and HIV. EBV is important in the posttransplant setting and in immunocompromised patients because it results in loss of T cell surveillance and consequent polyclonal B cell proliferation. The loss of T cell
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surveillance with uninhibited B cell proliferation could also be the mechanism of malignant transformation in patients with immunosuppression [1–4, 11, 13]. In fact, PHL is more frequent in patients with AIDS and in cyclosporinetreated transplant recipients than in general population [1–4, 11, 13]. We can exclude an infectious aetiology in our patient because of negative serology for HIV, HBV, HCV and EBV active infection. The treatment of tumours with chemotherapy and radiotherapy cause double-stranded-breaks and interstrand cross-links that may be implicated in the growth of a second NHL [6]. Among lymphoproliferative disorders, myelodysplasia and leukaemia are the most common second malignancies; the weighted average of second NHL is about 5% [6]. Alkylating agents and topoisomerase II inhibitors have been implicated in these kinds of lymphopropliferative disorders due to their high mutagenic property, whereas antimetabolites (including fluoropyrimidines) are considered to be relatively safe in terms of the risk for second neoplasms [6, 8]. Radiotherapy can induce neoplasms especially when total body irradiation is combined with high-dose chemotherapy before autologous stem cell transplantation. The risk of the development solid tumours within the field of exposure to radiation increases as a function of time elapsed from radiation and dosage. The longer the time from radiation, the higher the risk of a second neoplasm
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(median latency period 17–30 years) [7–10]. The risk of second malignancies away from the irradiated sites has been designated ‘‘bystander effect’’ (carcinogenesis at organs not directly exposed to radiation) due to mediators released from irradiated tissues and as a consequence of scattered radiation energy from the primary target [14]. In our case, we believe that chemotherapy (fluoropyrimidine plus low total dose of oxaliplatin) and pelvic radiotherapy were not directly linked with second hepatic NHL that developed 3 years after treatment. Moreover, the short latency between pelvic radiotherapy and second hepatic NHL excludes this linkage even if we were to consider the bystander effect. A challenge in the case reported herein was the radiological differential diagnosis of the single hepatic nodule. The most common presentation of PHL is a single welldefined liver lesion; less commonly, it presents as diffuse infiltration that portends a worse prognosis [1, 15–17]. The imaging appearance of hepatic lymphoma is non specific as it very often mimics a metastatic deposit [15]. On ultrasound, the lesions usually appear hypoechoic with no typical vascularization pattern [1, 15]. On computed tomography scans, PHL lesions appear as hypoattenuating, with no enhancement after the administration of intravenous contrast in half the cases and a ring of enhancement in about 25% of cases [1, 15, 16]. Classically, magnetic resonance findings in PHL are described as ‘‘hypointense’’ or ‘‘isointense’’ on T1-weighted images, and ‘‘hyperintense’’ on T2-weighted images [1, 18]. Positron emission tomography with FDG can help to rule out disease outside the liver [19]. In our patient, Doppler ultrasound was not informative because the vascularization pattern was similar to that of an angioma, while the magnetic resonance images were suggestive of a metastatic lesion. Moreover, the abdomen contrast-enhanced ultrasonography showed early enhancement of the lesion with a rapid wash out, which is typical of a secondary lesion. In summary, it is impossible to differentiate a single non-Hodgkin hepatic lesion from a metastatic nodule only by imaging techniques, especially in case of a history of colorectal neoplasm in a patient with unremarkable physical examination and no B symptoms. Biopsy (or surgical removal) should be performed whenever possible in case of an isolated hepatic nodule with radiological malignant aspects, especially when serum tumour markers or biochemistry is not informative, because only histology can ensure a true differential diagnosis. Acknowledgments We are grateful to Jean Ann Gilder (Scientific Communication srl) for revising and editing the text. Conflict of interest of interest.
The authors declare that they have no conflict
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