Medical and Pediatric Oncology 12:255-257 (1984)

Extramedullary Recurrence of Acute Lymphoblastic Leukemia 15 Years After Initial Diagnosis

Gary V. Burton, MD, J. Brice Weinberg, MD, and Michael J. Borowitz, MD, PhD

We describe a 19-yeardd man with recur- rence of a lymphoid malignancy involving the ethrnoid sinus 15 years following diagnosis and 10 years after discontinuation of therapy for childhood acute lymphoblastic leukemia (ALL). The cytologic appearance and immu- nologic phenotype of the tumor cells suggest

that this malignancy represents a recurrence of his original tumor. Initial relapse of ALL is unusual after 4 years of continuous remission off therapy. This case illustrates that late re- lapse can occur and may present with unu- sual sites of involvement.

Key words: acute lymphoblastic leukemia, lymphoblastic lymphoma, late relapse, infancy and adulthood

INTRODUCTION

Therapy of childhood acute lymphoblastic leukemia (ALL) has provided successful long-term survival, with 50% of those entering remission expected to survive 5 years or longer [ 11. It has been suggested that an opera- tional definition of “cure” be made if the patient remains in remission 4 years after completion of therapy [2]. Although the risk of relapse is considered extremely low after 7-8 years of continuous remission, there are several reports of late relapse occurring in the central nervous systen (CNS), testes, and bone marrow either after dis- continuation of therapy, or while on long-term (3-11 years) maintenance therapy [3-81. We describe a patient with extramedullary recurrence of a lymphocytic malig- nancy 10 years after discontinuation of therapy, and 15 years after initial diagnosis of acute ALL.

CASE REPORT

In June of 1963, L.C. presented at age 4 to a commu- nity hospital with pallor and a syncopal episode. There was no lymphadenopathy and splenomegaly . Laboratory examination revealed a hemoglobin of 4.0 g/100 ml and white blood cell (WBC) count of 6,300/mm3 with 84% blasts with convoluted nuclei. The bone marrow was hypercellular with 99 % blasts and was interpreted as ALL (Fig. la). He was treated with prednisone and 6- mercaptopurine (6-MP), 50 mg daily, and he achieved subsequent remission. Daily 6-MP was continued until August of 1968, when a bone marrow and spinal fluid

0 1984 Alan R. Liss, Inc.

analysis were interpreted as normal, and the 6-MP was discontinued. The patient was first seen at Duke Univer- sity Medical Center in September 1969. The physical examination, complete blood count (CBC), and bone marrow were normal. He did well with no treatment until January 1978, when he presented to the Durham VA Medical Center with facial pain and a left supraorbital and paranasal mass. He underwent a left lateral rhinot- omy and external ethmoidectomy . Pathologic examination revealed lymphoblasts suggestive of lymphoblastic lymphoma (Fig. 2). Intravenous pyelography, lymph- angiography, head computed tomography (CT), and bone marrow were normal. He received 1,000 rads of radiation to the lesion and then refused further treatment or follow-up. In November 1978 he presented to a com- munity hospital with acute abdominal pain; laparotomy revealed an intussusception of the jejunum with bowel infarction around a polypoid mass that on microscopic examination revealed lymphoma. He was referred back to the Durham VA Medical Center where head CT, upper GI, barium enema, and bone marrow were again found to be normal. He refused further cranial irradiation, but agreed to systemic chemotherapy with vincristine, meth- otrexate, and 6-MP, which he received intermittently for

From the Department of Medicine, Division of Hematology/Oncol- ogy (J.B. W.), Veterans Administration, and Departments of Medicine (G.V.B.) and Pathology (M.J.B.), Duke University Medical Centers, Durham, North Carolina.

Address reprint requests to Gary V. Burton, MD, Division of Hema- tology Oncology, Duke University Medical Center, Durham, NC 27710.

256 Burton, Weinberg, and Borowitz

a lymphoblast count of 606/mm3. Bone marrow and abdominal CT were normal. He received 1,250 rads spinal radiotherapy (Tll-L3). An Ommaya reservoir was placed, and intrathecal methotrexate, hydrocortisone, and cytosine arabinoside therapy was given. The patient re- fused further cranial irradiation or systemic chemother- apy. He returned in November 1982, complaining of global headache. Spinal fluid revealed a protein of 29 mg/100 ml with 145 lymphoblasts/mm3 (Fig. lb). Cell surface marker studies [9,10] showed that the tumor cells were common ALL antigen and Ia antigen positive and lacked all T-cell markers, indicating that the phenotype was that of the most common form of childhood ALL. He received 2,000 rads cranial irradiation, followed by weekly intrathecal methotrexate and cytosine arabino- side. He is currently receiving systemic therapy with vincristine, prednisone, doxombicin, bleomycin, and L- asparaginase.

Fig. 1. a. Photomicrograph of peripheral blood film at presentation, showing variably sized lymphoblasts with high nuclear/cytoplasmic ratios and fine chromatin. Wright stain. X 1000. b. Photomicrograph of cerebrospinal fluid filter preparation at relapse, again showing blasts with very high nuclear/cytoplasmic ratios and fine chromatin. One cell has a prominent nucleolus. Papanicolaou stain, x 1000.

Fig. 2. Section of the ethmoid lesion showing a dense infiltrate of lymphoid cells with irregular nuclear shapes and scant cytoplasm. Most cells are much larger than normal small lymphocytes, and have finer nuclear chromatin. Hematoxylin and eosin. X 525.

13 months. In October 1980, a normal ENT examination, barium enema, upper GI with small-bowel follow- through, bone marrow test, and abdominal CT were obtained, and the patient refused further chemotherapy.

He returned to the Durham VA Medical Center in February 1982 with left lower extremity weakness. Mye- logram revealed cord compression at T11, with cerebro- spinal fluid (CSF) protein content of 180 mg/100 ml and

DISCUSS I0 N

This patient had recurrence of a malignant lympho- cytic disorder 15 years from initial diagnosis and 10 years after discontinuation of therapy. Although this may rep- resent a second malignancy, available data suggest that this is more likely a recurrence of his original tumor. The histologic and cytologic appearances of his recurrence were similar to that of the original tumor, and surface marker studies showed a phenotype of the typical child- hood ALL. The sites of extramedullary recurrences were very unusual. These included the ethmoid sinus, followed by the GI tract (resulting in an intussusception), and finally two separate recurrences involving the CNS. There was no evidence of bone marrow involvement at the times of these recurrences. Extramedullary relapse of ALL in the gastrointestinal tract has been reported but clinically apparent small-bowel involvement in ALL is extremely rare [ 11,121. Most extramedullary sites of re- lapse are in the CNS, testis, and ovary [12-161, and occasionally in the eye [ 171 or bone [3]. Other extrame- dullary sites of involvement during peripheral blood re- mission are well documented but these are rarely clinically evident, and usually occur with concomitant “silent” bone marrow involvement [ 18,191.

This patient readily entered remission at initial presen- tation at age 4 with minimal treatment, which, by current standards, would be considered inadequate therapy. He also entered remission after all subsequent recurrences, indicating that his tumor is very sensitive to treatment. Although the prognosis of a patient with recurrence of ALL is considered poor, others have noted that it is better in those with “late” relapse [20]. This case illustrates that late relapse is possible in the “cured” patient with ALL, and that the recurrence may involve atypical sites.

Late Relapse in ALL 257

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ADDENDUM:

The patient completed six months of intrathecal and systemic therapy in May, 1983. As of June, 1984, he had maintained complete clinical remission off all therapy.