EXTRAORDINARY CASE REPORT
Erythrodermic Leukemia Cutis in a Patient With Pre-B-Cell Acute Lymphoblastic Leukemia Roberto A. Novoa, MD,* Karolyn A. Wanat, MD,† Misha Rosenbach, MD,‡ Noelle Frey, MD,§ Dale M. Frank, MD,¶ and Rosalie Elenitsas, MD‡
Abstract: The clinical differential diagnosis of erythroderma is extensive and includes both benign and malignant causes. The authors present an exceptional case of erythroderma secondary to pre-B-cell lymphoblastic leukemia cutis, with diagnostic findings on biopsy. Key Words: erythroderma, leukemia cutis, lymphoblastic leukemia
oval nuclei, fine chromatin, and scant cytoplasm (Fig. 2). Immunohistochemical stains showed that neoplastic cells were positive for BCL-2, CD10, CD79a, and TdT, and negative for CD3, CD5, CD20, BCL-6, CD34, and kappa/lambda light chains (Fig. 3). Ki-67 staining demonstrated a markedly elevated proliferative index. These findings were diagnostic of leukemia cutis secondary to the patient’s lymphoblastic leukemia. The patient was subsequently transitioned to hospice care and passed away.
(Am J Dermatopathol 2015;37:650–652)
DISCUSSION INTRODUCTION The clinical differential diagnosis of erythroderma is extensive and includes both benign and malignant causes. Although the histology of erythrodermic exfoliative dermatitis is often nonspecific, we present an exceptional case of erythroderma secondary to leukemia cutis, with diagnostic findings on biopsy.
CASE A 65-year-old woman with a history of pre-B-cell acute lymphoblastic leukemia (pre-B ALL) presented to the dermatology department with a 6-week history of gradually worsening erythroderma. She was diagnosed with pre-B ALL in 2010 and had experienced a complete remission with the Linker protocol (daunorubicin, vincristine, prednisone, and asparaginase), followed by relapse and further treatments with hyper CVAD (cyclophosphamide, vincristine, doxorubicin dexamethasone, methotrexate and cytarabine) and blinatumomab without remission. During the most recent hospitalization, she noted erythematous plaques that began on her abdomen and gradually coalesced. The patient denied pain or pruritus. Examination revealed confluent, erythematous, exuberantly scaling thin plaques involving approximately 70% of the patient’s total body surface area (Fig. 1). She had massive bilateral lower extremity edema but no ectropion or lymphadenopathy. Two punch biopsies were performed and revealed a perivascular infiltrate composed of large atypical mononuclear cells with From the *Stanford Dermatopathology Service, Department of Pathology, Stanford Medical Center, Stanford, CA; †Department of Dermatology, University of Iowa, Iowa City, IA; ‡Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA; §Division of Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA; and ¶Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA. The authors declare no conflicts of interest. Reprints: Roberto A. Novoa, MD, Stanford Dermatopathology Service, Department of Pathology—H2110, Stanford Medical Center, 300 Pasteur Drive, Stanford, CA 94305 (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
650
| www.amjdermatopathology.com
Patients with lymphoblastic neoplasms of T-cell or B-cell origin may present with lymphoblastic lymphoma or with lymphoblastic leukemia.1 Pre-B ALL presents with cutaneous findings in 1.8% of cases, with the most common findings being infiltrated nodules and plaques on the head and neck.2 On histological examination, blasts are distributed in monotonous perivascular infiltrates and are characterized cytologically by a high nucleus to cytoplasmic ratio, oval or irregular nuclei, bland chromatin, and elevated mitotic activity. Stromal fibrosis may occasionally be seen.3 When presenting with nodules and tumors, neoplastic cells form dense dermal aggregates, often with a defined Grenz zone. Blasts express pan–B-lineage markers (CD19, CD79a, CD22, and PAX5) and markers of immaturity (CD34, TdT, and CD10).3,4 The morphologic differential diagnosis includes cutaneous involvement by pre-T-cell lymphoblastic leukemia, the blastoid variant of mantle cell lymphoma, and other small blue cell neoplasms, such as desmoplastic round cell tumors and Ewing family tumors.1,5 T-cell lymphoblastic lesions usually express pan– T-cell markers, most commonly the lineage-specific CD3,
FIGURE 1. Clinical examination revealed an exfoliative dermatitis, with thin erythematous scaling plaques. Am J Dermatopathol Volume 37, Number 8, August 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 8, August 2015
FIGURE 2. Histopathologic examination demonstrated a perivascular infiltrate composed of large atypical mononuclear cells with oval nuclei, fine chromatin, and scant cytoplasm (original magnification ·40, inset: original magnification ·400).
Erythrodermic Leukemia Cutis
lymphoblastic leukemia, including blinatumomab, a bispecific T-cell engager antibody with a CD3 receptor and a CD19 receptor, and CART19, a targeted T-cell therapy with a chimeric T cell targeting CD19.10,11 Unfortunately, blinatumomab was not effective in our patient. There have been reports of leukemia cutis as the first sign of relapse in pre-B ALL, including 1 case of leukemia cutis at a venous catheter site and another of recurrent aleukemic leukemia cutis.12,13 In pre-B ALL, circulating blasts, high leukocyte count, advanced age, elevated serum lactate dehydrogenase, organomegaly, poor performance status, and poor response to chemotherapy are negative prognostic factors.14 In general, leukemia cutis is a poor prognostic sign, but the exact survival rate of patients with leukemia cutis secondary to pre-B ALL is unknown. Erythroderma has not been previously reported in pre-B ALL, and our patient’s lesions may have reflected her extensive burden of disease. The histopathologic interpretation of erythroderma may be challenging, as the most common etiologies may resemble one another in their erythrodermic states, and even advanced Sézary syndrome may present with
FIGURE 3. Immunohistochemical stains showed that neoplastic cells were positive for BCL-2, TdT, CD10, and CD79a, and negative for CD3 and CD20. The Ki-67 proliferative index was markedly elevated (original magnification ·200).
CD7, and markers of immaturity CD1a (which is specific to T lymphoblasts), CD34, TdT, and CD10. Blastoid mantle cell lymphomas may be difficult to distinguish morphologically from true lymphoblastic lesions but are immunophenotypically distinct; these mature B-lineage neoplasms express CD5 and brightly express CD20, unlike most B lymphoblastic leukemias. Mantle cell lymphomas are also negative for markers of immaturity (CD34, TdT, and CD10) and are defined biologically by the aberrant overexpression of cyclin D1, which can be detected by immunohistochemistry and confirmed by FISH evidence of the characteristic (11;14) translocation.6,7 Small blue cell neoplasms may be distinguished by their lobulated arrangement and negative staining for TdT and CD79a.8 Of note, the characteristic CD99 positivity seen in Ewing family tumors has been reported in some precursor B-cell lymphoblastic lymphomas as well.4,9 In addition to standard chemotherapy regimens, there have been a number of recent advances in the treatment of Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
nonspecific spongiotic dermatitis. Although exceptionally rare, and with few reports in the literature,15,16 clinicians and pathologists should be aware of leukemia cutis as a rare cause of erythroderma. REFERENCES 1. Maitra A, McKenna RW, Weinberg AG, et al. Precursor B-cell lymphoblastic lymphoma: a study of nine cases lacking blood and bone marrow involvement and review of the literature. Am J Clin Pathol. 2001;115: 868–875. 2. Little AJ, Martinez-Diaz GJ, Gehris RP. Solitary, enlarging painful violaceous tumor on the cheek of a 10-year. Cutaneous precursor B-cell acute lymphoblastic leukemia (pre-B ALL). JAMA Dermatol. 2013; 149:609–614. 3. Cho-Vega JH, Medeiros LJ, Prieto VG, et al. Leukemia cutis. Am J Clin Pathol. 2008;129:130–142. 4. Borowitz MJ, Chan JK. B lymphoblastic leukaemia/lymphoma, not otherwise specified. In: Swerdlow S, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008:165–175.
www.amjdermatopathology.com |
651
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Novoa et al
Am J Dermatopathol Volume 37, Number 8, August 2015
5. Hsiao CH, Su IJ. Primary cutaneous pre-B lymphoblastic lymphoma immunohistologically mimics Ewing’s sarcoma/primitive neuroectodermal tumor. J Formos Med Assoc. 2003;102:193–197. 6. Cesinaro AM, Bettelli S, Maccio L, et al. Primary cutaneous mantle cell lymphoma of the leg with blastoid morphology and aberrant immunophenotype: a diagnostic challenge. Am J Dermatopathol. 2014;36:e16–e18. 7. Sriganeshan V, Blom TR, Weissmann DJ. A unique case of mantle cell lymphoma with an aberrant CD52/CD10+ immunophenotype and typical morphology. Arch Pathol Lab Med. 2008;132:1346–1349. 8. Goldblum JR, Folpe AL, Weiss SW. Malignant soft tissue tumors of uncertain type. In: Enzinger and Weiss’s Soft Tissue Tumors. 6th ed. Philadelphia, PA: Elsevier; 2014:1028–1044. 9. Kahwash SB, Qualman SJ. Cutaneous lymphoblastic lymphoma in children: report of six cases with precursor B-cell lineage. Pediatr Dev Pathol. 2002;5:45–53. 10. Portell CA, Advani AS. Novel targeted therapies in acute lymphoblastic leukemia. Leuk Lymphoma. 2014;55:737–748.
11. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptormodified T cells for acute lymphoid leukemia. N Engl J Med. 2013; 368:1509–1518. 12. Lee JI, Park HJ, Oh ST, et al. A case of leukemia cutis at the site of a prior catheter insertion. Ann Dermatol. 2009;21:193–196. 13. Ansell LH, Mehta J, Cotliar J. Recurrent aleukemic leukemia cutis in a patient with pre-B-cell acute lymphoblastic leukemia. J Clin Oncol. 2013;31:e353–e355. 14. Lin P, Jones D, Dorfman DM, et al. Precursor B-cell lymphoblastic lymphoma: a predominantly extranodal tumor with low propensity for leukemic involvement. Am J Surg Pathol. 2000;24:1480–1490. 15. Jeong KH, Lew BL, Sim WY. Generalized leukaemia cutis from a small cell variant of T-cell prolymphocytic leukaemia presenting with exfoliative dermatitis. Acta Derm Venereol. 2009;89:509–512. 16. Raj A, Rai R, Rangarajan B. Exfoliative dermatitis with leukemia cutis in a patient with chronic myeloid leukemia: a rare association. Indian J Dermatol Venereol Leprol. 2011;77:208–210.
652
Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
| www.amjdermatopathology.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Erythrodermic Leukemia Cutis in a Patient With Pre-B-Cell Acute Lymphoblastic Leukemia Roberto A. Novoa, MD,* Karolyn A. Wanat, MD,† Misha Rosenbach, MD,‡ Noelle Frey, MD,§ Dale M. Frank, MD,¶ and Rosalie Elenitsas, MD‡
Abstract: The clinical differential diagnosis of erythroderma is extensive and includes both benign and malignant causes. The authors present an exceptional case of erythroderma secondary to pre-B-cell lymphoblastic leukemia cutis, with diagnostic findings on biopsy. Key Words: erythroderma, leukemia cutis, lymphoblastic leukemia
oval nuclei, fine chromatin, and scant cytoplasm (Fig. 2). Immunohistochemical stains showed that neoplastic cells were positive for BCL-2, CD10, CD79a, and TdT, and negative for CD3, CD5, CD20, BCL-6, CD34, and kappa/lambda light chains (Fig. 3). Ki-67 staining demonstrated a markedly elevated proliferative index. These findings were diagnostic of leukemia cutis secondary to the patient’s lymphoblastic leukemia. The patient was subsequently transitioned to hospice care and passed away.
(Am J Dermatopathol 2015;37:650–652)
DISCUSSION INTRODUCTION The clinical differential diagnosis of erythroderma is extensive and includes both benign and malignant causes. Although the histology of erythrodermic exfoliative dermatitis is often nonspecific, we present an exceptional case of erythroderma secondary to leukemia cutis, with diagnostic findings on biopsy.
CASE A 65-year-old woman with a history of pre-B-cell acute lymphoblastic leukemia (pre-B ALL) presented to the dermatology department with a 6-week history of gradually worsening erythroderma. She was diagnosed with pre-B ALL in 2010 and had experienced a complete remission with the Linker protocol (daunorubicin, vincristine, prednisone, and asparaginase), followed by relapse and further treatments with hyper CVAD (cyclophosphamide, vincristine, doxorubicin dexamethasone, methotrexate and cytarabine) and blinatumomab without remission. During the most recent hospitalization, she noted erythematous plaques that began on her abdomen and gradually coalesced. The patient denied pain or pruritus. Examination revealed confluent, erythematous, exuberantly scaling thin plaques involving approximately 70% of the patient’s total body surface area (Fig. 1). She had massive bilateral lower extremity edema but no ectropion or lymphadenopathy. Two punch biopsies were performed and revealed a perivascular infiltrate composed of large atypical mononuclear cells with From the *Stanford Dermatopathology Service, Department of Pathology, Stanford Medical Center, Stanford, CA; †Department of Dermatology, University of Iowa, Iowa City, IA; ‡Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA; §Division of Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA; and ¶Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA. The authors declare no conflicts of interest. Reprints: Roberto A. Novoa, MD, Stanford Dermatopathology Service, Department of Pathology—H2110, Stanford Medical Center, 300 Pasteur Drive, Stanford, CA 94305 (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
650
| www.amjdermatopathology.com
Patients with lymphoblastic neoplasms of T-cell or B-cell origin may present with lymphoblastic lymphoma or with lymphoblastic leukemia.1 Pre-B ALL presents with cutaneous findings in 1.8% of cases, with the most common findings being infiltrated nodules and plaques on the head and neck.2 On histological examination, blasts are distributed in monotonous perivascular infiltrates and are characterized cytologically by a high nucleus to cytoplasmic ratio, oval or irregular nuclei, bland chromatin, and elevated mitotic activity. Stromal fibrosis may occasionally be seen.3 When presenting with nodules and tumors, neoplastic cells form dense dermal aggregates, often with a defined Grenz zone. Blasts express pan–B-lineage markers (CD19, CD79a, CD22, and PAX5) and markers of immaturity (CD34, TdT, and CD10).3,4 The morphologic differential diagnosis includes cutaneous involvement by pre-T-cell lymphoblastic leukemia, the blastoid variant of mantle cell lymphoma, and other small blue cell neoplasms, such as desmoplastic round cell tumors and Ewing family tumors.1,5 T-cell lymphoblastic lesions usually express pan– T-cell markers, most commonly the lineage-specific CD3,
FIGURE 1. Clinical examination revealed an exfoliative dermatitis, with thin erythematous scaling plaques. Am J Dermatopathol Volume 37, Number 8, August 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 8, August 2015
FIGURE 2. Histopathologic examination demonstrated a perivascular infiltrate composed of large atypical mononuclear cells with oval nuclei, fine chromatin, and scant cytoplasm (original magnification ·40, inset: original magnification ·400).
Erythrodermic Leukemia Cutis
lymphoblastic leukemia, including blinatumomab, a bispecific T-cell engager antibody with a CD3 receptor and a CD19 receptor, and CART19, a targeted T-cell therapy with a chimeric T cell targeting CD19.10,11 Unfortunately, blinatumomab was not effective in our patient. There have been reports of leukemia cutis as the first sign of relapse in pre-B ALL, including 1 case of leukemia cutis at a venous catheter site and another of recurrent aleukemic leukemia cutis.12,13 In pre-B ALL, circulating blasts, high leukocyte count, advanced age, elevated serum lactate dehydrogenase, organomegaly, poor performance status, and poor response to chemotherapy are negative prognostic factors.14 In general, leukemia cutis is a poor prognostic sign, but the exact survival rate of patients with leukemia cutis secondary to pre-B ALL is unknown. Erythroderma has not been previously reported in pre-B ALL, and our patient’s lesions may have reflected her extensive burden of disease. The histopathologic interpretation of erythroderma may be challenging, as the most common etiologies may resemble one another in their erythrodermic states, and even advanced Sézary syndrome may present with
FIGURE 3. Immunohistochemical stains showed that neoplastic cells were positive for BCL-2, TdT, CD10, and CD79a, and negative for CD3 and CD20. The Ki-67 proliferative index was markedly elevated (original magnification ·200).
CD7, and markers of immaturity CD1a (which is specific to T lymphoblasts), CD34, TdT, and CD10. Blastoid mantle cell lymphomas may be difficult to distinguish morphologically from true lymphoblastic lesions but are immunophenotypically distinct; these mature B-lineage neoplasms express CD5 and brightly express CD20, unlike most B lymphoblastic leukemias. Mantle cell lymphomas are also negative for markers of immaturity (CD34, TdT, and CD10) and are defined biologically by the aberrant overexpression of cyclin D1, which can be detected by immunohistochemistry and confirmed by FISH evidence of the characteristic (11;14) translocation.6,7 Small blue cell neoplasms may be distinguished by their lobulated arrangement and negative staining for TdT and CD79a.8 Of note, the characteristic CD99 positivity seen in Ewing family tumors has been reported in some precursor B-cell lymphoblastic lymphomas as well.4,9 In addition to standard chemotherapy regimens, there have been a number of recent advances in the treatment of Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
nonspecific spongiotic dermatitis. Although exceptionally rare, and with few reports in the literature,15,16 clinicians and pathologists should be aware of leukemia cutis as a rare cause of erythroderma. REFERENCES 1. Maitra A, McKenna RW, Weinberg AG, et al. Precursor B-cell lymphoblastic lymphoma: a study of nine cases lacking blood and bone marrow involvement and review of the literature. Am J Clin Pathol. 2001;115: 868–875. 2. Little AJ, Martinez-Diaz GJ, Gehris RP. Solitary, enlarging painful violaceous tumor on the cheek of a 10-year. Cutaneous precursor B-cell acute lymphoblastic leukemia (pre-B ALL). JAMA Dermatol. 2013; 149:609–614. 3. Cho-Vega JH, Medeiros LJ, Prieto VG, et al. Leukemia cutis. Am J Clin Pathol. 2008;129:130–142. 4. Borowitz MJ, Chan JK. B lymphoblastic leukaemia/lymphoma, not otherwise specified. In: Swerdlow S, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008:165–175.
www.amjdermatopathology.com |
651
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Novoa et al
Am J Dermatopathol Volume 37, Number 8, August 2015
5. Hsiao CH, Su IJ. Primary cutaneous pre-B lymphoblastic lymphoma immunohistologically mimics Ewing’s sarcoma/primitive neuroectodermal tumor. J Formos Med Assoc. 2003;102:193–197. 6. Cesinaro AM, Bettelli S, Maccio L, et al. Primary cutaneous mantle cell lymphoma of the leg with blastoid morphology and aberrant immunophenotype: a diagnostic challenge. Am J Dermatopathol. 2014;36:e16–e18. 7. Sriganeshan V, Blom TR, Weissmann DJ. A unique case of mantle cell lymphoma with an aberrant CD52/CD10+ immunophenotype and typical morphology. Arch Pathol Lab Med. 2008;132:1346–1349. 8. Goldblum JR, Folpe AL, Weiss SW. Malignant soft tissue tumors of uncertain type. In: Enzinger and Weiss’s Soft Tissue Tumors. 6th ed. Philadelphia, PA: Elsevier; 2014:1028–1044. 9. Kahwash SB, Qualman SJ. Cutaneous lymphoblastic lymphoma in children: report of six cases with precursor B-cell lineage. Pediatr Dev Pathol. 2002;5:45–53. 10. Portell CA, Advani AS. Novel targeted therapies in acute lymphoblastic leukemia. Leuk Lymphoma. 2014;55:737–748.
11. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptormodified T cells for acute lymphoid leukemia. N Engl J Med. 2013; 368:1509–1518. 12. Lee JI, Park HJ, Oh ST, et al. A case of leukemia cutis at the site of a prior catheter insertion. Ann Dermatol. 2009;21:193–196. 13. Ansell LH, Mehta J, Cotliar J. Recurrent aleukemic leukemia cutis in a patient with pre-B-cell acute lymphoblastic leukemia. J Clin Oncol. 2013;31:e353–e355. 14. Lin P, Jones D, Dorfman DM, et al. Precursor B-cell lymphoblastic lymphoma: a predominantly extranodal tumor with low propensity for leukemic involvement. Am J Surg Pathol. 2000;24:1480–1490. 15. Jeong KH, Lew BL, Sim WY. Generalized leukaemia cutis from a small cell variant of T-cell prolymphocytic leukaemia presenting with exfoliative dermatitis. Acta Derm Venereol. 2009;89:509–512. 16. Raj A, Rai R, Rangarajan B. Exfoliative dermatitis with leukemia cutis in a patient with chronic myeloid leukemia: a rare association. Indian J Dermatol Venereol Leprol. 2011;77:208–210.
652
Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
| www.amjdermatopathology.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
