Granulocytic sarcoma of the small intestine preceding acute myelomonocytic leukemia with abnormal eosinophils and inv(16)

Granulocytic Sarcoma of the Small Intestine Preceding Acute Myelomonocytic Leukemia with Abnormal Eosinophils and inv(16) S. J. Russell, F. J. Giles, D. S. Thompson, D. J. Scanlon, Helen Walker, and J. D. M. Richards

ABSTRACT: We report a case of preleukemic granulocytic sarcoma of the small intestine preceding the development of acute myelomonocytic leukemia with abnormal eosinophils and inversion of chromosome 16, inv(16)(p13q22). A literature review suggests that this is a recurring cytogenetic-clinicopathologic association and carries a favorable prognosis, especially if treated aggressively with antileukemic therapy at the time of diagnosis.

INTRODUCTION

G r a n u l o c y t i c s a r c o m a is a l o c a l i z e d t u m o r mass c o m p o s e d of i m m a t u r e cells of the g r a n u l o c y t i c series [1]. It o c c u r s in the setting of acute n o n l y m p h o c y t i c l e u k e m i a (ANLL) or blast crisis of c h r o n i c g r a n u l o c y t i c l e u k e m i a (CGL), and, less frequently, as a h a r b i n g e r of A N L L in n o n l e u k e m i c patients. T h e histologic diagnosis is facilitated by p r e s e n c e of e o s i n o p h i l m y e l o c y t e s and p o s i t i v e c h l o r o a c e t a t e esterase and l y s o z y m e stains. A b n o r m a l i t i e s of c h r o m o s o m e 16 i n v o l v i n g band q22 are strongly associated w i t h a u n i q u e category of A N L L d e s i g n a t e d M4Eo in the FAB classification [2-5]. The m o r p h o l o g i c h a l l m a r k of the disease is the p r e s e n c e in b o n e m a r r o w aspirates of a b n o r m a l e o s i n o p h i l s c o n t a i n i n g large, strongly b a s o p h i l i c g r a n u l e s [6]. Clinically, M4Eo is the best p r o g n o s t i c category of A N L L i d e n t i f i e d to date, w i t h a median s u r v i v a l in excess of 2 years [7, 8]. Intracerebral g r a n u l o c y t i c s a r c o m a has b e e n i d e n t i f i e d in a high p e r c e n t a g e of patients at the t i m e of relapse, and " p r o p h y l a c t i c " central n e r v o u s system (CNS) t h e r a p y has therefore b e e n r e c o m m e n d e d [9]. We report a case of p r e l e u k e m i c g r a n u l o c y t i c s a r c o m a of the small i n t e s t i n e (PGSSI) in a patient w h o s u b s e q u e n t l y d e v e l o p e d acute m y e l o m o n o c y t i c l e u k e m i a (AMMoL) M 4 E o w i t h inv(16). A literature r e v i e w r e v e a l e d that this m a y r e p r e s e n t a r e c u r r i n g c y t o g e n e t i c - c l i n i c o p a t h o l o g i c association.

From the Department of Cell and Molecular Biology, Institute of Cancer Research: Royal Cancer Hospital, Chester Beatty Laboratories, London, England (S. J. R.), the Department of Haematology, University College Hospital Gower Street. London, England (F. J. G., D. J. S., H. W., J. 1. M. R.] and the Department of Haematology, Luton & Dunstable Hospital, Luton, Bedfordshire, England (D. S. T.). Address reprint requests to Dr. S. J. Russell, Department of Cell and Molecular Biology, Institute of Cancer Research: Royal Cancer Hospital, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, England. Received April 13, 1988; accepted July 5, 1988.

231 ~c:~1988 Elsevier Science Publishing Co.. Inc. 655 Avenue of tile Americas, New York, NY 19010

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CASE REPORT

A 49-year-old man presented in February 1986 with a small intestinal obstruction and an enlarged inguinal lymph node. He had a 6-week history of colicky central abdominal pain, vomiting, and weight loss of 13 kg. A blood count at that time was normal, with hemoglobin 142 g/L, platelets 316 x 109/L and white blood cell count 6.4 x 109/L with a normal differential count. Laparotomy revealed an obstructing tumor of the small intestine with infiltration of the adjacent mesentery. There was extensive lymph node involvement in the pelvis, but the liver and spleen felt normal. The tumor was locally resected, and the histologic appearance was initially reported as large cell non-Hodgkin's lymphoma. Following an uneventful postoperative recovery, a bone marrow aspirate and trephine biopsy were performed, and chemotherapy was commenced using the cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen. There was rapid resolution of the inguinal lymphadenopathy, and the patient's general condition improved. The bone marrow showed normal architecture with reduced cellularity. Twelve percent of the nucleated cells were monocytoid blasts. Maturing myeloid cells appeared normal, but there was a relative excess of morphologically normal eosinophils (7%). Erythropoiesis appeared normal, and megakaryocytes appeared numerically and morphologically normal. Cytogenetic analysis of the bone marrow was not performed. Histology of the original tumor was reviewed and, because of the preponderance of eosinophil myelocytes and positive chloroacetate esterase and lysozyme stains, the diagnosis was changed to granulocytic sarcoma. In view of the good initial response to CHOP, this therapy was continued for five courses, following which computed tomography (CT) scans of abdomen and pelvis showed no evidence of residual disease, and the patient refused further therapy. Three months later he developed widespread lymphadenopathy, periumbilical skin infiltration, hepatosplenomegaly, bruising, purpura, and mouth ulceration. A Figure 1 Bone marrow aspirate showing abnormal eosinophil granulation. (Mag x 1000).

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Preleukemic Granulocytic Sarcoma and inv(16)

blood count revealed hemoglobin 98 g/L, platelets 31 × 109/L, and white blood cell count 97 × 109/L, of which 98% were blasts. Bone marrow aspirate was hypercellular with a heavy diffuse infiltrate (75%) of pleomorphic large blast cells, many with nuclear folding characteristic of monoblasts. These cells were Sudan black (SB) positive, periodic acid-Schiff (PAS) negative, and weakly positive for nonspecific esterase (NSE). Maturing myeloid cells showed predominantly eosinophilic differentiation (20% of nucleated cells) with distinct morphologic and cytochemical abnormalities. The majority of eosinophil myelocytes contained large basophilic granules (Fig. 1), and their eosinophilic granules stained positively with PAS. Karyotypic analysis of trypsin-Giemsa-banded bone marrow metaphase spreads showed pericentric inversion of chromosome 16 [inv(16)(p13q22)] with clonal evolution of a hyperdiploid line starting with addition of chromosome 22, followed by + 6, ÷ 9, and + 14 (Fig. 2). Twenty-three metaphases were examined in detail, and no normal karyotypes were identified. A diagnosis of AMMoL (M4Eo) was made and the patient rapidly achieved a complete remission with daunorubicin, cytarabine, and 6-thioquanine (DAT) therapy. After two courses of consolidation therapy he received high-dose chemotherapy with autologous bone marrow rescue [10] and is currently well and off all therapy 25 months from initial presentation.

DISCUSSION Preleukemic granulocytic sarcoma of the small intestine is rare, with only seven cases having been described in the literature since 1965, including the case reported here [3, 11-14; see Table 1). Of these seven cases, only five have progressed to

Figure 2 G-banded metaphase spread showing inv(16)(p13q22), trisomy 6, trisomy 14, and trisomy 22.

1

[ 9

8

6

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11

% 12

i 14

16

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Table 1.

Reported cases of PGSS1

Ref. [11] [12] [3] [13] [14] Current report

Age/sex 38/M 41/F

30/M 30/M 16/F 31/M 49/M

Progression to ANLL/time after initial diagnosis Yes/34 mo Yes/9 mo Yes/1 mo No No Yes/9 mo Yes/10 mo

Karyotype of ANLL

Survival from initial diagnosis

--46,XY,inv(16) --47,XY, + G 50,XY, + 6, + 9, + 14, + 22,inv(16)

39 mo 21 mo 34 mo 69 mo + 72 mo + 104 mo + 25 mo +

ANLL. It is significant that two patients received aggressive antileukemic therapy soon after diagnosis and were the only two who did not subsequently develop ANLL. Aggressive antileukemic therapy at the time of diagnosis therefore seems to be the most sensible therapeutic strategy. The overall prognosis has been relatively favorable, with a median survival of 39 months, and four patients still alive at the time of reporting. Cytogenetic data is available for only two previously reported cases of PGSSI progressing to ANLL, and one of these cases was clearly associated with inv(16) [3]. The patient, a 30-year-old male, presented with bowel obstruction by a granulocytic sarcoma 1 m o n t h before AMMoL became evident in the bone marrow. The associated chromosomal abnormality was inv(16)(p13q22), and there were no additional abnormalities initially, but the patient gained a chromosome 8 at the time of relapse. The other case of PGSSI for which cytogenetic data is available [14] had an extra G-group chromosome as the only reported clonal abnormality. It is quite possible that the abnormality in this case was trisomy of chromosome 22, which is the most frequently additional cytogenetic finding in M4Eo with inv(16) [8]. The cytogenetic study was performed in 1977, 6 years before inv(16) and its association with M4Eo was described. Of the two cases of PGSSI progressing to ANLL for whom no cytogenetic data is available, one patient died with extensive leukemic infiltration of his CNS, which suggests that this case may also have been M4Eo. Given that PGSSI progressing to ANLL is very u n c o m m o n , it will be a long time before this cytogenetic-clinicopathologic association can be better defined. Moreover, if progression to ANLL is prevented by aggressive antileukemic chemotherapy, the accrual of cytogenetic data will be even slower. It is therefore important that cytogenetic studies of the small bowel tumor be undertaken at the time of initial resection. The association between PGSSI and inv(16) raises an interesting etiologic issue. Does the malignant cell in this disease arise in the bone marrow and migrate to the bowel wall, or does a circulating bone marrow precursor cell become transformed in the bowel wall as a result of exposure to a gut carcinogen? The breakpoint on the long arm of chromosome 16 in inv(16) is k n o w n to split the metallothionein gene cluster [15] and is also the location of a heritable fragile site that appears to occur more c o m m o n l y in patients with M4Eo and their families than in the general population [16]. Perhaps exposure of a bone marrow precursor in the gut wall to an ingested heavy metal induces the metallothionein genes, thus increasing the chance

P r e l e u k e m i c G r a n u l o c y t i c S a r c o m a and inv(16)

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of this c h r o m o s o m a l r e a r r a n g e m e n t , e s p e c i a l l y in the p r e s e n c e of the fragile site. Inv(16)(p13q22) has also b e e n i d e n t i f i e d as a r e c u r r i n g c l o n a l c y t o g e n e t i c abnorm a l i t y in a d e n o c a r c i n o m a of the s i g m o i d c o l o n [17], w h i c h s u p p o r t s the idea of a gut c a r c i n o g e n capable of c a u s i n g the c h r o m o s o m a l r e a r r a n g e m e n t . T h e literature r e v i e w suggests that PGSSI progressing to M4Eo is a r e c u r r i n g c y t o g e n e t i c - c l i n i c o p a t h o l o g i c association and carries a favorable prognosis, especially if treated aggressively w i t h a n t i l e u k e m i c t h e r a p y at the t i m e of diagnosis.

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