Isolated Cutaneous Anaplastic Large Cell Lymphoma Progressing to Severe Systemic
Disease With Myocardial Involvement and Central Nervous System Infiltration
Yi Fan Rannan-Eliya,BM BCh,MRCPCH,1Karen Pulford,PhD,2Rob Johnson,BM,MRCP,3 Ian Peart,MB ChB,FRCP,3George Kokai,MD,DS,MRCPath,4Colin Baillie,MB ChB, FRCS(Paed),5
Kamel Ait-Tahar,PhD,2and Barry Pizer,MB ChB,FRCPCH,PhD1*
INTRODUCTION
Anaplastic large cell lymphoma (ALCL) is a rare pediatric tumor with a variety of manifestations ranging from isolated skin disease to a life-threatening systemic cancer. ALCL tumors frequently express ALK fusion proteins and constitute ALK-positive ALCL, a phenotype reported to be related to improved outcome [1].
We describe a female who initially presented with localized skin disease associated with an insect bite. However, she subsequently relapsed with widespread systemic ALK-positive ALCL that included lymphoma deposits in the myocardium. Her disease responded well to chemotherapy but she later developed a fatal relapse in the CNS. We also present data on an immune response to ALK in respect of a fluctuation in the levels of circulating antibodies to ALK corresponding to the different phases of her illness.
CASE REPORT
A 14-year-old female received an insect bite near her umbilicus, around which an area of inflammation persisted. Six months later, she presented with a fluctuant area, and incision and drainage revealed granulation tissue at the base, histology showing no evidence of malignancy. Induration persisted and further excision was performed. Unexpectedly, the histology returned as CD30-positive ALK-CD30-positive ALCL. Staging investigations were all clear. Complete excision was performed, confirmed histologically. No adjuvant treatment was given.
Ten months after surgery, she presented with lethargy, diarrhea, and vomiting. Examination revealed left iliac fossa (LIF) fullness. A CT scan showed a 9 8 cm LIF mass associated with pericardial and bilateral pleural effusions, mediastinal and axillary lympha-denopathy. ALK-positive ALCL was demonstrated on ultrasound-guided biopsy of the mass and on pleural fluid aspiration. Lumbar cerebrospinal fluid and bone marrow were negative.
She was treated according to the ALCL 99 study [2], with six courses of chemotherapy, each including high dose intravenous methotrexate, without intrathecal chemotherapy, planned to be followed by maintenance vinblastine.
Four days after starting chemotherapy, she suffered three cardiac arrests within 24 hr, warranting resuscitation, cardioversion, inotropic support, and anti-arrhythmic medications. Trans-thoracic
echocardiography showed poor biventricular function, abnormal left ventricle tissue density, and a possible mass in the right atrium. Complete heart block and marked prolongation of the QTc was associated with 20 further ventricular fibrillation arrests. An implant pacemaker and internal defibrillator were placed. Trans-esophageal echocardiogram showed findings consistent with extensive my-ocardial involvement, including the posterior left ventricle, septum, atrio-ventricular groove, and pedunculated lesions within the right atrium (Fig. 1A), right ventricle, and left ventricle (Fig. 1B).
She duly received six courses of chemotherapy with clinical improvement. Reassessment CT scan and echocardiography showed a complete response to treatment and improved fractional shortening. As she was about to commence vinblastine, she deteriorated with left pupil dilatation, and vomiting followed by flaccid areflexic paralysis, bulbar signs, and opthalmoplegia. A lumbar puncture demonstrated CNS relapse; 2,850 white cells, 92% lymphoma cells. It was decided against further treatment and she died peacefully.
An investigation into an immune response to ALK [3] demon-strated fluctuating titers of circulating antibodies to ALK correspond-ing to the different phases of her illness. The antibody titer at diagnosis was 1:750. This increased to 1:20,250 upon systemic relapse. Four months later following complete response to treatment, the antibody titer decreased to 1:750 and rose to 1:2,250 3 weeks before CNS relapse.
Anaplastic large cell lymphoma (ALCL) is a rare tumor compris-ing around 10–15% of childhood lymphomas. We describe the case of a female who initially presented with localized skin disease associated with an insect bite. However, she subsequently relapsed with widespread systemic ALK-positive ALCL that included lymphoma deposits in the myocardium, a very rare manifestation.
Her disease responded well to chemotherapy but she later developed a fatal relapse in the CNS. We also present data on an immune response to ALK, demonstrating a fluctuation in the levels of circulating antibodies to ALK corresponding to the different phases of her illness. Pediatr Blood Cancer 2008;50:879–881.
ß 2007 Wiley-Liss, Inc.
Key words: anaplastic large cell lymphoma; myocardium; heart; central nervous system; ALK
ß 2007 Wiley-Liss, Inc. DOI 10.1002/pbc.21357
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1Department of Paediatric Oncology, Royal Liverpool Children’s NHS Trust, Liverpool, UK; 2Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, UK; 3Department of Paediatric Cardiology, Royal Liverpool Children’s NHS Trust, Liverpool, UK; 4Department of Paediatric Pathology, Royal Liverpool Children’s NHS Trust, Liverpool, UK; 5Department of Paediatric Surgery, Royal Liverpool Children’s NHS Trust, Liverpool, UK
*Correspondence to: Barry Pizer, Department of Paediatric Oncology, Royal Liverpool Children’s Hospital, Eaton Road, Liverpool L12 2AP, UK. E-mail: barry.pizer@rlc.nhs.uk
Received 30 March 2007; Accepted 25 July 2007
DISCUSSION
ALCL has been defined as a tumor with anaplastic large cell morphology of T-cell immunophenotype with co-expression of CD30 and epithelial membrane antigen (EMA) [4].
Most pediatric cases present with advanced disease with extranodal involvement in around 60% of cases with soft tissue, bone, and skin being the most frequent sites. In certain series, 30% had bone marrow involvement on careful immunohistochemical staining while CNS involvement occurs in less than 5% at diagnosis [5].
Treatment of systemic ALCL has historically been with intensive multi-agent chemotherapy regimens for B-cell lymph-omas. In children, high complete remission rates of 82–95% are achieved, with 5-year survival rates of 65–83% [6,7].
ALCL (40–85%) are associated with chromosomal abnormal-ities affecting the ALK gene at 2p23 [8] resulting in tumor cell expression of ALK fusion proteins, constituting the specific tumor entity, ALK-positive ALCL. ALK expression is related to a favorable outcome, first described by Shiota [1] and confirmed by others [9].
Pulford et al. confirmed that the ALK protein is the target of an immune response [3], demonstrating circulating antibodies against NPM-ALK protein in ALK-positive ALCL patients. Subsequent studies have confirmed ALK as a tumor-associated antigen eliciting both T- and B-cell responses [10]. The variation in levels of circulating antibodies to ALK found in the present case and on the basis of preliminary evidence [3] suggests that measurement of antibody titers may have prognostic value in ALCL. The presence of an immune response to ALK also raises the possibility of new therapeutic techniques.
As for systemic ALCL, tumor cells in primary cutaneous ALCL are positive for CD30, EMA, and T-cell markers, have striking cellular pleomorphism and a high mitotic rate. However, the clinical course of isolated cutaneous ALCL is so different from systemic ALCL that it has a separate classification [4]. Of note is that cutaneous ALCL rarely exhibit the 2:5 translocation [11].
An association exists between cutaneous malignancy and diverse external antigens such as insect bites, tattoo, zoster, and trauma. These insults can cause a cutaneous benign hyperplastic lymphoid infiltrate or ‘‘pseudolymphoma’’ that simulates lymphoma and can harbor occult clonal populations that progress to overt cutaneous lymphoma. Piccaluga [12] reported a female who received a tick bite and then developed cutaneous ALCL.
Isolated skin ALCL is rare in childhood [13,14]. Lesions can show spontaneous regression, with rates of up to 42% [13,14]. Cutaneous
ALCL have received varying treatments, including observation, radiotherapy, surgical excision, and chemotherapy [14]. Complete remission is nearly always achieved [14,15], with chemotherapy offering ‘‘no advantages as compared with local radiation therapy or simple excision’’ [14]. It has been argued that ALK expression by isolated skin ALCL should be considered in respect to therapeutic decision making [16]. Currently, most would advocate conservative treatment with surgical complete resection as in this case.
Cardiac involvement by lymphoma [17] and ALCL in particular [18] is very rare. It occurs late in the illness and is difficult to diagnose. Case reports detail lymphomatous involvement of the heart presenting with severe contractile impairment, complete heart block, or pericardial tamponade [17,18]. A previous pediatric case report [19] describes a 6-year-old with a histologically confirmed ALCL mass in the anterior wall of the right ventricle. He received chemotherapy and was in remission 2 years after diagnosis at the time of reporting. Our case was more acute and severe in presentation, with arrhythmias, conduction defects, and rapidly progressive heart failure. The lymphomatous deposits responded fully to the chemotherapy, such that the pacing and defibrillating functions were no longer needed, although the pacemaker remained in situ. Recovery of pacing and contractile function has been recorded in other cases following treatment [20].
In our case, the extent of cardiac involvement was only demonstrated by trans-esophageal echocardiography, a technique supported by other authors [21].
In patients who are initially without CNS disease, relapse with CNS disease is very rare [22]. Treatment has varied in series from systemic methotrexate [7], high dose araC, intrathecal chemother-apy [6], and cranial irradiation. The ALCL 99 study [2] was based on the NHL-BFM 90 trial [23] and sought to compare the effectiveness of CNS prophylaxis provided by 1 g/m2 methotrexate with
intrathecal methotrexate with 3 g/m2 methotrexate without intrathecal therapy. Preliminary results suggest no difference in outcome between these two treatments [24].
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1. Shiota M, Mori S. Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: A distinct clinicopathologic entity. Leukemia 1997;11:538–540.
2. ALCL 99 protocol (NHL 2000 06) UKCCSG.
3. Pulford K, Falini B, Banham AH, et al. Immune response to the ALK oncogenic tyrosine kinase in patients with anaplastic large-cell lymphoma: Blood. 2000;96:1605–1607.
4. Delsol G, Ralfkaier E, Stein H, et al. Anaplastic large cell lymphoma. In: Jaffe ES, Harris NL, Stein H, et al., editors. Pathology and Genetics of tumors of haematopoietic and lymphoid tissues. World Health Organisation Classification of Tumors. Lyon: International Agency for Research on Cancer (IARC) Press; 2001: pp 230–235. 5. Stein H, Foss HD, Durkop H, et al. CD30þ ALCL: A review of
its histopathologic, genetic, and clinical features. Blood 2000;96: 3681–3695.
6. Williams DM, Hobson R, Imeson J, et al. Anaplastic large cell lymphoma in childhood: Analysis of 72 patients treated on The United Kingdom Children’s Cancer Study Group chemotherapy regimens. Br J Haematol 2002;117:812–820.
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Pediatr Blood Cancer DOI 10.1002/pbc
Fig. 1. Trans-esophageal echocardiography showing myocardial tumor involvement of right atrium (A) and left ventricle (B).
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12. Piccaluga PP, Ascani S, Fraternali Orcioni G, et al. Anaplastic lymphoma kinase expression as a marker of malignancy. Applica-tion to a case of anaplastic large cell lymphoma with huge granulomatous reaction. Haematologica 2000;85:978–981. 13. Bekkenk MW, Geelen FAMJ, van Voorst Vader PC, et al. Primary
and secondary cutaneous CD30þ lymphoproliferative disorders: A report form the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood 2000;95:3653–3661.
14. Beljaards RC, Kaudewitz P, Berti E, et al. Primary cutaneous CD30-positive large cell lymphoma: Definition of a new type of cutaneous lymphoma with a favorable prognosis. A European Multicenter Study of 47 patients. Cancer 1993;71:2097–2104. 15. De Bruin PC, Beljaards RC, van Heerde P, et al. Differences in
clinical behaviour and immunophenotype between primary cutaneous and primary nodal ALCL of T-cell or null cell phenotype: Histopathology. 1993;23:127–135.
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4 cases and review of the literature. Pediatr Dev Pathol 2005;8: 52–60.
17. Testolin L, Basso C, Pittarello D, et al. Cardiogenic shock due to metastatic cardiac lymphoma: Still a diagnostic and therapeutic challenge. Eur J Cardiothorac Surg 2001;19:365–368.
18. Lim ZY, Grace R, Salisbury JR, et al. Cardiac presentation of ALK positive anaplastic large cell lymphoma. Eur J Haematol 2005;75: 511–514.
19. Papadopoulou AL, Argiriou M, Bonoris M, et al. Ki-1 lymphoma with cardiac involvement at initial presentation. Pediatr Hematol Oncol 1998;15:265–269.
20. Takeuchi E, Yanagawa H, Nishikubo N, et al. Successful treatment of metastatic cardiac lymphoma with complete A-V block. Anticancer Res 1998;18:2815–2817.
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23. Seidemann K, Tiemann M, Schrappe M, et al. Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymohoma: A report of the Berlin-Frankfurt-Munster Group Trial NHL-BFM 90.
24. Brugieres L, Le Deley MC, Rosolen A, et al. Anaplastic large cell lymphoma (ALCL) in children: No difference of efficacy but more toxicity of chemotherapy including methotrexate (MTX) 1 g/m2in 24 hour infusion with intra-thecal injection (IT) than chemotherapy with MTX 3 g/m2in 3 hours infusion without IT. Results of the ALCL99-R1 randomised trial. Oral presentation at ASH, 2006; Abstract number 398.
False Positivity of FDG–PET/CT in a Child With Hodgkin Disease
Dildar Bahar Beker,MD,1Su Gulsun Berrak, MD,1* Cengiz Canpolat,MD,1Halil Tugtepe,MD,2Tunc Ones,MD,3and Tulay Tecimer,MD4
INTRODUCTION
Current treatment of Hodgkin lymphoma is mainly based on accurately assesing the stage of disease and individualizing the therapy accordingly to avoid longterm sequela [1]. FDG-PET/CT is increasingly used for staging, restaging and evaluation of recurrence in lymphoma patients [2–4]. It is generally performed after con-ventional measures, especially in the presence of conflicting results [5]. However, its routine application in pediatric cancer imaging has not been yet established with prospective, double blind, randomized studies. A child with Hodgkin lymphoma and false positive Gallium and FDG-PET/CT scans during follow-up is presented.
Role of Positron Emission Tomography (PET) with F-18-2-fluoro-2-deoxy-D-glucose (FDG) in staging of Hodgkin disease is well established despite several controversies. We report a Stage III Hodgkin lymphoma patient with false positive FDG–PET/CT results. Seven-year-old male with Hodgkin lymphoma was in remission at end of chemotherapy. At third and fourth months of postchemother-apy follow-up, increased gallium uptake and positive FDG–PET/CT
in right lower quadrant of abdomen was observed. Open biopsy revealed lymphoid hyperplasia. He has been followed for 21 months without any evidence of disease. Despite its documented benefit, we believe that results of FDG–PET/CT should be interpreted with great caution in order to avoid unnecessary interventions. Pediatr Blood Cancer 2008;50:881–883. ß 2007 Wiley-Liss, Inc.
Key words: false positivity; FDG–PET/CT; Hodgkin; lymphoma
ß 2007 Wiley-Liss, Inc. DOI 10.1002/pbc.21197
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1Pediatric Hematology-Oncology, Marmara University Medical Center, Altunizade, Istanbul, Turkey; 2Pediatric Surgery, Marmara University Medical Center, Altunizade, Istanbul, Turkey; 3Nuclear Medicine, Marmara University Medical Center, Altunizade, Istanbul, Turkey;4Pathology, Marmara University Medical Center Altunizade, Istanbul, Turkey
*Correspondence to: Berrak Su Gulsun, Hamidiye M, Ulubatlı Hasan C, Tiryaki A4/16,C¸ekmeko¨y, 34782, Istanbul, Turkey.
E-mail: sberrak@yahoo.com
Received 24 October 2006; Accepted 5 February 2007
