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Journal of Clinical Oncology, Vol 25, No 36 (December 20), 2007: pp. 5825-5826 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.4908
Primary Cutaneous Large B-Cell Lymphoma of the Leg and Acute HypercalcemiaNanticoke Memorial Hospital, Seaford, DE A 90-year-old woman presented with altered mental status 2 months after developing deep vein thrombosis of the right lower extremity. She had history of Alzheimer's disease, but she required minimal family assistance. Emergency head computed tomography (CT) did not reveal any acute changes, and her admission laboratory tests were remarkable for serum calcium of 14.6 mg/dL (reference range, 8.5 to 10.5 mg/dL) up from 10.1 mg/dL just a week earlier. There was no history of calcium or vitamin D ingestion or recent use of any new medication. Her physical examination was remarkable for right lower extremity edema up to the thigh and 3 x 2-cm superficial skin ulceration over the lateral aspect of the right knee. This asymptomatic skin ulceration was initially noticed a month earlier as a small skin breakdown that continued to increase in size, despite the use of different oral antibiotics for presumed infectious etiology. Further laboratory testing showed normal serum protein electrophoresis without any M spike, and both intact parathyroid hormone and parathyroid hormone–related peptide were undetectable. 25-Hydroxyvitamin D was low at 19 ng/mL (reference range, > 30 ng/mL) while 1,25-dihydroxyvitamin D was elevated at 116 pg/mL (reference range, 15 to 60 pg/mL). Twenty-four–hour urine calcium was also increased at 454 mg in 24 hours (reference range, < 250 mg). Intravenous normal saline infusion, prednisone, and calcitonin normalized serum calcium temporarily, and the patient returned to her baseline functional status. CT imaging of the neck, chest, abdomen and pelvis did not reveal any abnormal mass or lymphadenopathy. During a 2-week period of conservative therapy, the skin ulcer increased in size to a 6 x 4 cm ulcer with necrotic center and raised border (Fig 1). The presence of the rapidly eroding skin ulcer and the absence of other source of 1,25-dihydroxyvitamin D raised the possibility of locally aggressive squamous cell carcinoma with extrarenal 1,25-dihydroxyvitamin D production. An excisional biopsy was attempted, but there was deep infiltration into the fascia preventing complete resection. Microscopic examination revealed a diffuse dermal and subcutaneous infiltrate of pleomorphic cells (Fig 2; hematoxylin and eosin; 40x). At high power, prominent nucleoli and frequent mitoses were seen (Fig 3; hematoxylin and eosin; 400x). Immunohistochemical studies showed positive staining with an antibody to CD20 (Fig 4; CD20 immunostain; 40x), confirming the diagnosis of primary cutaneous large B-cell lymphoma, leg type (PCLBCL-LT). Positron emission tomography did not reveal any areas of abnormal uptake. Bone marrow biopsy as well as local radiation and chemotherapy options were discussed in detail with the family but were declined, and the patient died within 4 weeks of her diagnosis.
Primary cutaneous B-cell lymphoma is a relatively uncommon form of extranodal non-Hodgkin's lymphoma that originates in the skin at the time of initial diagnosis, without any evidence of extra cutaneous involvement within 6 months of diagnosis.1 It is currently classified into three main entities including primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center lymphoma, and PCLBCL-LT.2 PCLBCL-LT is more common in women older than age 70 years.3 Though genetic translocation t(14;18) is not found in PCLBCL-LT, a strong bcl-2 expression is common in PCLBCL-LT in contrast to cutaneous large B-cell lymphomas found on the head and the trunk.4 bcl-2 protein expression has been reported as a poor prognostic factor in patients with primary cutaneous large B-cell lymphomas, though other reports did not confirm the value of bcl-2 expression as an independent prognostic factor.5,6 The presence of multiple skin lesions has been associated with poor prognosis in patients with PCLBCL-LT.7 Other factors, including age and round-cell morphology, were also proposed as independent prognostic factors.7 Different treatment modalities, including chemotherapy, radiotherapy, and anti-CD20 antibody (rituximab), have been used to treat cutaneous B-cell lymphomas with occasional good response,8-10 but in general, PCLBCL-LT carries a worse prognosis compared with other cutaneous B-cell lymphomas with a 5-year survival rate of 58%.3
Hypercalcemia is an occasional paraneoplastic event seen in some patients with aggressive lymphomas. The reported mechanisms include the secretion of parathyroid hormone-related protein,11,12 interleukin-6, and tumor necrosis factor13 as well as the overexpression of extrarenal 1 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Pandolfino TL, Siegel RS, Kuzel TM, et al: Primary cutaneous B-cell lymphoma: Review and current concepts. J Clin Oncol 18:2152-2168, 2000 2. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768-3785, 2005 3. Vermeer MH, Geelen FA, van Haselen CW, et al: Primary cutaneous large B-cell lymphomas of the legs: A distinct type of cutaneous B-cell lymphoma with an intermediate prognosis—Dutch Cutaneous Lymphoma Working Group. Arch Dermatol 132:1304-1308, 1996 4. Geelen FA, Vermeer MH, Meijer CJ, et al: Bcl-2 protein expression in primary cutaneous large B-cell lymphoma is site-related. J Clin Oncol 16:2080-2085, 1998[Abstract] 5. Grange F, Petrella T, Beylot-Barry M, et al: Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas. Blood 103:3662-3668, 2004 6. Senff NJ, Hoefnagel JJ, Jansen PM, et al: Reclassification of 300 primary cutaneous B-Cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: Comparison with previous classifications and identification of prognostic markers. J Clin Oncol 25:1581-1587, 2007 7. Grange F, Bekkenk MW, Wechsler J, et al: Prognostic factors in primary cutaneous large B-cell lymphomas: A European multicenter study. J Clin Oncol 19:3602-3610, 2001 8. Sabroe RA, Child FJ, Woolford AJ, et al: Rituximab in cutaneous B-cell lymphoma: A report of two cases. Br J Dermatol 143:157-161, 2000[CrossRef][Medline] 9. Zinzani PL, Quaglino P, Pimpinelli N, et al: Prognostic factors in primary cutaneous B-cell lymphoma: The Italian Study Group for Cutaneous Lymphomas. J Clin Oncol 24:1376-1382, 2006 10. Moore MM, Kovich OI, Brown LH: Primary cutaneous B-cell lymphoma (low-grade, non large cell). Dermatol Online J 13:8, 2007[Medline] 11. Ota H, Azuma K, Horiuchi T, et al: [An elderly case of non-Hodgkin's lymphoma (NHL) with hypercalcemia]. Nippon Ronen Igakkai Zasshi 40:167-171, 2003[CrossRef][Medline] 12. Schottker B, Heinz W, Weissinger F, et al: Parathyroid hormone-related protein-associated hypercalcemia in a patient with CLL type low grade leukemic B-cell lymphoma. Haematologica 91:ECR45, 2006 13. Daroszewska A, Bucknall RC, Chu P, et al: Severe hypercalcaemia in B-cell lymphoma: Combined effects of PTH-rP, IL-6 and TNF. Postgrad Med J 75:672-674, 1999 14. Moore JJ, Isbister JP, Clifton-Bligh P, et al: Calcitriol mediated hypercalcaemia in a T cell rich B cell lymphoma. Aust N Z J Med 28:479-480, 1998[Medline] 15. Matsuhashi Y, Tasaka T, Uehara E, et al: Diffuse large B-cell lymphoma presenting with hypercalcemia and multiple osteolysis. Leuk Lymphoma 45:397-400, 2004[CrossRef][Medline] 16. Narimatsu H, Morishita Y, Shimada K, et al: Primary cutaneous diffuse large B cell lymphoma: A clinically aggressive case. Intern Med 42:354-357, 2003[Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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hydroxylase leading to increased production of 1,25-dihydroxy vitamin D.
