J Neurooncol (2010) 97:301–304 DOI 10.1007/s11060-009-0026-y
CASE REPORT
Central nervous system involvement in CD4+/CD56+ hematodermic neoplasm: a report of two cases No´ra Er} os • Ma´rta Marschalko´ • Katalin Balassa • Bernadett Hı´dve´gi Jo´zsef Szakonyi • Sa´ndor Ilniczky • Katalin Borka • Attila Kova´cs • ´ gota Szepesi • Gyula Bottlik • Judit Ha´rsing • Judit Csomor • A Andra´s Matolcsy • Sarolta Ka´rpa´ti • Judit Demeter
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Received: 5 July 2009 / Accepted: 21 September 2009 / Published online: 2 October 2009 Ó Springer Science+Business Media, LLC. 2009
Abstract CD4?/CD56? hematodermic neoplasm, formerly known as blastic NK-cell lymphoma, is an uncommon, aggressive non-Hodgkin’s lymphoma with cutaneous, lymph node, and bone marrow involvement at presentation. The disease is characterized by early leukemic phase; however, central nervous system involvement is rarely reported. Herein we describe two cases of CD4?/CD56? hematodermic neoplasm with meningeal manifestation. Microscopic analysis and flow cytometry of cerebrospinal fluid proved to be diagnostic; however, imaging studies were not informative. These observations call attention to the possibility of central nervous system involvement, which could be more common than expected previously. Authors recommend routine cerebrospinal fluid analysis
N. Er}os (&) M. Marschalko´ B. Hı´dve´gi J. Szakonyi G. Bottlik J. Ha´rsing S. Ka´rpa´ti Department of Dermatology, Venerology and Dermatooncology, Faculty of Medicine, Semmelweis University, Ma´ria str. 41, 1085 Budapest, Hungary e-mail:
[email protected] K. Balassa J. Demeter 1st Department of Internal Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary S. Ilniczky Department of Neurology, Faculty of Medicine, Semmelweis University, Budapest, Hungary K. Borka A. Kova´cs 2nd Department of Pathology, Faculty of Medicine, Semmelweis University, Budapest, Hungary ´ . Szepesi A. Matolcsy J. Csomor A 1st Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University, Budapest, Hungary
and prophylactic intrathecal chemotherapy in patients with this highly aggressive disease. Keywords CD4?/CD56? hematodermic neoplasm Blastic NK-cell lymphoma Central nervous system involvement Cerebrospinal fluid analysis Prophylactic intrathecal chemotherapy Abbreviations ALK Anaplastic lymphoma kinase TdT Terminal deoxynucleotidyl transferase LMP-1 Latent membrane protein-1 TCL1 T-cell leukemia antigen-1 BDCA-2 Blood-derived dendritic cell antigen-2 TIA-1 T-cell intracytoplasmic antigen-1 MPO Myeloperoxidase ESR Erythrocyte sedimentation rate PCR Polymerase chain reaction CT Computed tomography LDH Lactate dehydrogenase
Introduction CD4?/CD56? hematodermic neoplasm is an uncommon, highly aggressive non-Hodgkin’s lymphoma characterized by cutaneous, lymph node, and bone marrow involvement at presentation followed by rapid leukemic dissemination and fatal outcome. The disease has poor prognosis with median survival of 14 months [1]. Histopathology of the skin is characterized by diffuse dermal and subcutaneous lymphoid infiltrate without epidermal involvement. The tumor cells are characterized by: round, slightly irregular
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nuclei with fine chromatin pattern; one or more small eosinophilic nucleoli; scant cytoplasm without azurophilic cytoplasmic granules; and CD4?, CD56?, CD43?, CD45RA?, in some cases CD68? and TdT? phenotype; but expression of CD3, CD8, cytotoxic granules or LMP-1 are absent [2]. T-cell receptor genes are in a germline configuration and recurrent chromosomal abnormalities have not been detected in this entity. Based on the lymphoblastic morphology, CD56 expression, and lack of CD3 and other T-, B-, and myeloid cell markers the disease was supposed to be a NK-cell neoplasm; however, recent studies demonstrated its plasmacytoid dendritic cell origin by the strong expression of the typical cell markers CD123, TCL1, and BDCA-2 [3, 4]. Most patients have extracutaneous manifestation during the course of the disease; however, data on central nervous system (CNS) involvement are rare. We report two cases of CD4?/CD56? hematodermic neoplasm with CNS involvement.
Case reports Case 1 A 75-year-old man presented with a 3-month history of generalized erythematous-brown papules, plaques, and tumors on the trunk. Physical examination revealed hepatosplenomegaly, left supraclavicular, both axillary and right inguinal lymphadenopathy. No sign of CNS involvement was detected. Complete blood cell count showed white blood cells of 4.8 G/l, 35% neutrophils, 2% eosinophils, 1% basophils, 32% monocytes, 30% lymphocytes, red blood cells of 4.36 T/l, hemoglobin 121 g/l, platelet count 104 G/l, and erythrocyte sedimentation rate (ESR) of 42 mm/h. Other laboratory results were within normal limits. Histopathology of skin biopsy revealed monomorphic blast cell infiltrate in the dermis and subcutis without epidermotropism. The atypical lymphoblast-like cells had a CD45?, CD4?, CD56?, CD68?, CD2-, CD3-, CD7-, CD8-, TIA-1-, MPO-, CD34-, TdT-, CD30-, ALK-, CD20- phenotype. Polymerase chain reaction (PCR) analysis did not detect clonal T-cell receptor gamma gene rearrangement. Flow cytometric analysis showed 5% atypical CD4?/CD56? cells in peripheral blood, and 40% blasts in bone marrow. Cytogenetic analysis failed to detect any chromosomal aberrations. Computed tomography (CT) scans showed hepatosplenomegaly and mediastinal lymphadenopathy. Based on these findings CD4?/CD56? hematodermic neoplasm with skin, blood, bone marrow, hepatosplenic, and lymph node involvement was diagnosed. The patient was treated with modified CHOP chemotherapy (cyclophosphamide, idarubicin instead of doxorubicin
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because of cardiac impairment, vincristine, and methylprednisone). Six courses of chemotherapy resulted in complete response of the cutaneous symptoms and peripheral blood involvement. Two months later (7 months after initial diagnosis) headache, weakness, vertigo, neck stiffness, and singultation developed. Neurological status included ataxy of the trunk and lower extremities, symmetric deep tendon reflexes on the upper limbs, absent Achilles’ reflexes, left central facial palsy, and positive Romberg’s sign, while consciousness was not altered. Cranial CT scan with contrast medium did not show any abnormalities. Pleocytosis (816/3), elevated total protein level (4.03 g/l), and blast cells in cerebrospinal fluid indicated CNS involvement. Six courses of intrathecal methotrexate, cytarabine, and dexamethasone combination therapy resulted in remission of the neurologic symptoms and cerebrospinal fluid became cytologically normal. Systemic chemotherapy was continued with cytarabine and etoposide. Two weeks later visual hallucinations, disorientation, dizziness, and neck stiffness developed, without pathognomonic cranial CT findings. Intrathecal triple-combination therapy completed with intravenous cytosine arabinoside and vepesid chemotherapy eliminated the CNS symptoms for 1 month. This was followed by four cycles of biweekly intrathecal liposomal cytarabine (DepoCyteÒ) and low-dose dexamethasone therapy. The treatment was well tolerated, the CNS symptoms were in remission, and the control cerebrospinal fluid was clear. At the same time the cutaneous lesions relapsed and rapidly progressed. Follow-up did not prove meningeal relapse. In the following 2 weeks cutaneous progression, splenomegaly, generalized lymphadenopathy, urinary and stool incontinence, bone marrow involvement with pancytopenia, and sepsis led to death of the patient 13 months after initial diagnosis. At autopsy generalized cutaneous lesions and multiple (cervical, axillary, inguinal, para-aortic, and mesenterial)
Fig. 1 Lymphoid involvement of the cortex (case 1)
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Fig. 2 Blastic infiltration in the brain (HE, 920) (case 1)
lymphadenopathy was observed. Macroscopically the liver, the spleen, the kidneys, the suprarenal glands, the bone marrow, and the brain were infiltrated. Microscopic infiltration was detected in the wall of the stomach, the urinary bladder, the rectum, in the parenchyma of the lungs, and the prostate. The subendocardial and intermuscular infiltrate of the heart was an uncommon finding. A 1- to 2-cmwide cortical, mainly perivascular and subarachnoidal, infiltration was detected in the left temporal, the right frontal, the parietal, and the occipito-temporal lobe of the brain (Figs. 1, 2). Case 2 A 69-year-old woman presented with rapidly growing brownish-red, 2–7 cm large cutaneous plaques and tumors on the face and trunk (Fig. 3). Physical examination revealed a large, painless lymph node enlargement in the right inguinal region with edema of the lower extremity and pubical region, and cervical lymphadenopathy on the left side. Laboratory investigations demonstrated white blood cells of 26.5 G/l, 3% stabs, 68% segments, 1% eosinophils, 3% monocytes, 25% lymphocytes, red blood cells of 4.82 T/l, hemoglobin 146 g/l, platelet count 183 G/ l, ESR 70 mm/h, and lactate dehydrogenase (LDH) of 1,112 U/l. Other laboratory results were normal. Histopathology of skin revealed a confluent and nodular blast cell infiltrate in the dermis and subcutis without epidermal involvement. The blasts had narrow cytoplasm, ovoid, convoluted nuclei, fine chromatin pattern, and one or more nucleoli. The immunohistochemical analysis showed CD45?, CD2-, CD3-, CD4?, CD7?/-, CD8-, CD56?, TIA-1?, granzyme-B-, CD138-, CD20-, CD30-, ALK-, CD34-, TdT-, and MPO- cells. No clonal T-cell receptor gamma gene rearrangement or chromosomal aberrations was detected. Atypical CD4?/ CD56? cells were absent in peripheral blood, while 50%
Fig. 3 Brownish-red plaques and tumors of the trunk (case 2)
blasts were present in bone marrow. CT scans revealed involvement of the left mesopharyngeal region, multiple retroperitoneal and pelvic lymphadenopathy. All these findings were diagnostic for a CD4?/CD56? hematodermic neoplasm with skin, bone marrow, lymph node, and mesopharyngeal involvement. No CT signs of CNS infiltration were detected. Hyper-CVAD chemotherapy (cyclophosphamide, vincristine, adriablastin, dexamethasone) and prophylactic intrathecal methotrexate treatment were introduced. After the first cycle the cutaneous lesions and lymphadenopathy regressed; however, pancytopenia and serious tumor lysis syndrome with complex electrolyte imbalance complicated the course of the disease. Furthermore, despite the aggressive chemotherapy, widespread cutaneous relapse and a leukemic phase with 52% blasts developed 5 months after diagnosis. The new combination therapy (vincristine, etoposide, and dexamethasone) repeatedly induced a tumor lysis syndrome. Eight months after initial diagnosis new complications, severe CNS symptoms developed: numbness of the extremities, weakness, vertigo, aphagia, right peripheral facial paresis, dysarthria, dysphagia, generalized areflexia, right upper extremity palsy, and right hemihypesthesia. Flow cytometric analysis of cerebrospinal fluid indicated a meningeal manifestation with 63% CD4?/CD56? blasts (Fig. 4). Intrathecal methotrexate, cytarabine, and dexamethasone therapy was introduced, but despite this treatment the patient died due to disease progression 9 months after initial diagnosis.
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transplantation. Despite aggressive combined chemotherapy we observed rapidly progressive clinical course in our patients, with survival of 9 and 13 months. Both patients presented with skin, generalized lymph node, and bone marrow involvement followed by a leukemic phase and meningeal propagation at 7 and 8 months after onset. Microscopic analysis and flow cytometry of cerebrospinal fluid proved to be diagnostic, but cranial CT was not informative. Our observations indicate routine cerebrospinal fluid analysis and prophylactic intrathecal chemotherapy in patients with this highly aggressive lymphoma/leukemia.
References
Fig. 4 Flow cytometry of the cerebrospinal fluid revealed 63% CD4?/CD56? blasts
At autopsy skin involvement, generalized (pharyngeal, tonsillar, cervical, inguinal, mediastinal) lymphadenopathy, hepatosplenomegaly, esophageal, bone marrow, and kidney infiltration were detected. A subarachnoidal abscess was found in the right parietal region of the brain. Histology confirmed cutaneous, lymph node, hepatosplenic, renal, esophageal, and bone marrow infiltration; only the brain and the meninges proved to be finally tumor free.
Discussion CD4?/CD56? hematodermic neoplasm is an uncommon malignancy with about 150 patients reported previously [5]. Only a few cases with CNS involvement (brain or meninges) have been published [4, 6–11]. Kato et al. reviewed 18 previously published cases of CD4?/CD56? hematodermic neoplasm and found that 67% of the patients had multiple organ involvement [2]. Bekkenk et al. found that the following markers are associated with better outcome: age under 40 years, skin lesions exclusively, aggressive initial treatment with acute leukemia protocols, and [50% TdT expression of the malignant cells [1]. No case reports with detailed description of CNS symptoms and findings have been published previously, and only a few have reported the administration of intrathecal chemoprophylaxis with methotrexate or cytarabine [10, 12–14]. Curative treatment modalities of CD4?/CD56? hematodermic neoplasm have not been established; however, the best outcome was obtained by aggressive chemotherapy combined with radiotherapy and followed by bone marrow
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