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Journal of Clinical Oncology, Vol 23, No 24 (August 20), 2005: pp. 5837-5839 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.07.005
Unusual Leukemia PresentationsCASE 1. Pulmonary Chloroma Preceded by Leukemia Cutis 7 Years Earlier
Department of Hematology/Oncology, University of Tuebingen Medical Center, Tuebingen, Germany A 31-year-old white man presented with a 3-month history of pronounced night sweats, high fevers, weight loss, and more recently, persistent nonproductive cough, and chest pain. Seven years earlier, the patient had multiple indolent skin nodules, 2 to 5 mm in size, dispersed irregularly on the trunk and extremities (Fig 1). Clinical and histologic findings with skin biopsy were most consistent with eruptive xanthomatosis. The nodules were refractory to treatment and showed spontaneous resolution after a period of approximately 6 months. Current physical examination revealed no abnormalities. CBC and chemistry profile were normal except for mild leukocytosis (13.410/µL) showing a normal differential count, normochromic anemia (hemoglobin 12.4 g/dL), and an elevated C-reactive protein (7.56 mg/dL). The chest radiograph showed a right-sided pulmonary infiltrate (Fig 2A). Presuming pneumonia, antibiotic treatment was started. As the patient's condition worsened, a computed tomography (CT) scan was performed. Pulmonary consolidation in the right middle and upper lobe, accompanied by partial atelectasis and right-sided pleural effusion, as well as nodular infiltrates in both lungs, and enlargement of mediastinal lymph nodes were noted (Fig 2B). Analysis of pleural effusion aspirate and a small transbronchial biopsy performed in a local hospital were not conclusive for diagnosis. A few cells were positive for CD34+. The patient was referred to our clinic. General assessment, including CT scans of head, neck, abdomen, and pelvis, as well as cytology and flow cytometry of peripheral blood, bone marrow, and cerebral fluid did not display any additional abnormalities. An open lung biopsy revealed a diagnosis of acute extramedullary monocytic leukemia. The lung specimen showed diffuse mononuclear infiltration with a peribronchial, interstitial, and intraalveolar distribution (Fig 3A and 3B). Immunochemistry revealed expression of CD45 (LCA), and partly, of CD68 (KP1, PGM1), lysozyme, and CD34 (QBEND10; Fig 3C). Reactions were negative for naphthol chloroacetate esterase, myeloperoxidase, as well as for c-kit, TdT, CD20, CD5, CD10, CD23, CD3, CD56, CD1a, CD30, CD15, S100-protein, LMP-1, desmin, and actin. MiB1 stained approximately 20% of tumor cells. After double induction therapy with cytarabin and idarubicin, the patient's condition improved, "B" symptoms disappeared, and partial tumor regression was documented by CT scan. His clinical course was complicated by progressive pulmonary infiltrates, and subsequent leukemia relapse occurred in the mesenteric lymph nodes. Further chemotherapy was utilized, along with an allogenic stem-cell transplantation from a matched unrelated donor, but unfortunately, he died on day 49 as a result of post-transplantation complications. Reanalysis of the skin biopsy taken 7 years earlier showed perivascular infiltration of the corium by cells consistent with monocytic leukemic blasts (Fig 4A), staining positive for CD34 (QBEND10) and CD68 (KP1; Fig 4B). CD20 and CD3 were not expressed. MiB1 stained 10% of these cells. To our knowledge, besides leukemic blasts, only fibroblast-like cells, found in prechronic lymphedema, may coexpress CD34 and CD68.1 However, the cells infiltrating the corium showed a completely different morphology and pattern of distribution in comparison to fibroblasts. Unfortunately, because of scarcity of skin biopsy specimens, no further analysis could be done, for example, to rule out myelomonocytic differentiation of the leukemic blasts.
Extramedullary manifestation of acute leukemia usually occurs with, or follows the onset of, systemic disease.2–4 While manifestations at many different sites have been demonstrated, most commonly, skin, lymph nodes, liver, spleen, gingiva, CNS, and bone are involved.4,5 In patients treated for leukemia, there are several reports on isolated extramedullary relapse, usually heralding marrow relapse. This condition, also called myeloid sarcoma, granulocytic sarcoma, or chloroma, is thought to be related to a poorer efficacy of chemotherapy or graft-versus-leukemia response in extramedullary sites, as well as to specific biologic properties of leukemic blasts like increased tissue invasion (eg, CD87) and adherence abilities (eg, CD138 and CD56).6,7 Isolated presentation of extramedullary leukemia without any signs of systemic disease is a rare condition. To our knowledge, lung and/or pleural involvement in this setting has only been described in six patients previously.4,8–11 There is a high rate of initially misdiagnosed patients (47%), mostly taken and treated for malignant lymphoproliferative disorders, particularly aggressive non-Hodgkin's lymphoma.4,8 Therapy restricted to local procedures like surgery/radiation is highly effective in local disease control but does not affect survival, which strongly suggests the presence of systemic disease with undetected marrow involvement.3 If left untreated, in most cases (88%), extramedullary leukemia progresses to systemic disease with confirmed bone marrow involvement within 11 months, while 58% of the patients who receive systemic chemotherapy are free of detectable marrow affection at this time or later.8 Spontaneous regression of acute leukemia in the adult is a rare, but well-documented event. First described by Eisenlohr in 1878,12 with approximately 100 cases up to 1955, it became less common after patients underwent effective antileukemic therapies.13 The mechanisms of spontaneous regression in acute leukemia are unknown. Activation of the immune system in the context of severe systemic infections, which have been reported to precede spontaneous leukemia remission often, is thought to be one of the mechanisms.13,14 Transfusion of blood components,14 hormonal changes like termination of pregnancy,15 and administration of G-CSF16 have been linked to spontaneous remissions in adult acute leukemia. In some cases, such as that of our patient, none of the above listed conditions could be documented.17,18 Most remissions last only a few months, but long-term remissions and even complete cytogenetic remissions have been reported.13 In our patient, we presume the unusual case of spontaneous regression of leukemia cutis, with a rare form of late isolated extramedullary relapse of a biologically more aggressive disease in the lungs and the mediastinal lymph nodes 7 years later. Interestingly, bone marrow involvement could never be shown. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. Kaiserling E: Cellular reactions in prechronic and chronic lymphedema: Morphological and immmunohistochemical findings. Lymphology 37:39–47 (suppl) 2. Neiman RS, Barcos M, Berard C, et al: Isolated granulocytic sarcoma: A clinicopathologic study of 61 biopsed cases. Cancer 48:1426–1437, 1981[CrossRef][Medline]
3. Imrie KR, Kovacs MJ, Selby D, et al: Isolated chloroma: The effect of early antileukemic therapy. Ann Intern Med 123:351–353, 1995 4. Byrd JC, Edenfield WJ, Shields DJ, et al: Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: A clinical review. J Clin Oncol 13:1800–1816, 1995
5. Raja V, Bryant B, Bessman DJ, et al: Soft tissue sarcomas, Case 1: Granulocytic sarcoma: Presentation with nodal and skin involvement. J Clin Oncol 22:2026–2027, 2004
6. Baer MR, Stewart CC, Lawrence D, et al: Expression of the neural cell adhesion molecule CD56 is associated with short remission duration and survival in acute myeloid leukemia with t(8;21)(q22;q22). Blood 90:1643–1648, 1997 7. Bene MC, Castoldi G, Knapp W, et al: CD87 (urokinase-type plasminogen activator receptor), function and pathology in hematological disorders: A review. Leukemia 18:394–400, 2004[CrossRef][Medline] 8. Yamauchi K, Yasuda M: Comparison in treatments of nonleukemic granulocytic sarcoma. Cancer 94:1739–1746, 2002[CrossRef][Medline] 9. Florschutz A, Schumann HJ, et al: Primary pulmonary manifestation of extramedullary acute myelocytic leukemia. Pneumologie 55:302–305, 2001[CrossRef][Medline] 10. Wong KF, Chan JKC, Chan JCW: Acute myeloid leukemia presenting as granulocytic sarcoma of the lung. Am J Hematol 43:78–79, 1993[Medline] 11. Meis JM, Butler JJ, Osborne BM, et al: Granulocytic sarcoma in nonleukemic patients. Cancer 58:2697–2709, 1986[CrossRef][Medline] 12. Eisenlohr C: Leucaemia lienalis, lymphatica et medullaris mit multiplen Gehirnnervenlähmungen. Archiv f ür Pathologie, Anatomie und Physiologie und für Klinische Medizin (Virchows Arch) 73:56–73, 1878[CrossRef] 13. Maywald O, Buchheidt D, Bergmann J, et al: Spontaneous remission in adult acute myeloid leukemia associated with systemic bacterial infection: Case report and review of the literature. Ann Hematol 83:189–194, 2004[CrossRef][Medline] 14. Mitterbauer M, Fritzer-Szekeres M, Mitterbauer G, et al: Spontaneous remission of acute myeloid leukemia after infection and blood transfusion associated with hypergammaglobulinaemia. Ann Hematol 73:189–193, 1996[CrossRef][Medline] 15. Antunez DM, Ahn YS, Temple JD, et al: Spontaneous remission of acute leukemia after termination of pregnyncy. Cancer 63:1621–1623, 1989[CrossRef][Medline] 16. Takahashi M, Koike T, Aizawa Y, et al: Complete remission in three patients with acute myeloblastic leukemia by administration of G-CSF without antileukemic agents. Am J Hematol 56:42–44, 1997[CrossRef][Medline] 17. Spadea A, Latagliata R, Martinelli E, et al: Transient spontaneous remission in a case of adult acute myelogenous leukemia. Br J Haematol 76:154, 1990[Medline] 18. Paul R, Remes K, Lakkala T, et al: Spontaneous remission in acute myeloid leukemia. Br J Haematol 86:210–212, 1994[Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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