ASCR Journal

Introduction

Mixed-phenotype acute leukaemia (MPAL), also known as biphenotypic acute leukaemia (BAL) is a category, introduced in the World Health Organization (WHO) classification to describe cases with multilineage expression of surface markers on the blast cells or concomitant presence of two separate cell lineages in one malignant clone [1]. It is a rare entity in childhood, accounting for approximately 2-5% of the cases with acute leukaemia in some reported series [2]. There are no specific clinical presentations or chromosomal aberrations reported for BAL. On the other hand, acute leukaemia can present with a variety of life-threatening features: acute tumour lysis syndrome, cerebral and pulmonary leukostasis, superior mediastinal compression, disseminated intravascular coagulation or hypercoagulability state and an increased risk of thromboembolic events. The latter complication affects more frequently adults, predominantly involves the venous circulation and rarely the arteries [3]. Mesenteric arterial thrombosis is unusual as an initial manifestation of acute leukemia. We present a very rare case of a childhood BAL with an extramedullary intraabdominal infiltrate, presenting as a mesenteric thrombosis and intestinal infarction.

Case Report

Upon the admission to the Pediatric ICU the patient was in a severely impaired general condition, but alert and orientated, with moderate diffuse abdominal pain on palpation and abdominal distension, decreased peristalsis and unconvincing signs of peritoneal irritation. There was no peripheral lymph nodes’ enlargement or hepatosplenomegaly on palpation. The breathing sounds were clear bilaterally without tachypnea or dyspnoea. The arterial blood pressure was 100/60 mm Hg and the heart rate – 88 beats/minute. The complete blood count showed anaemia: haemoglobin – 75 g/l, leucocytosis – 46 x 10⁹/l and mild thrombocytopenia: 138 x 10⁹/l and the following differential blood count: neutrophils – 66%, monocytes – 23% and lymphocytes – 11%. The chemistry results were within reference range except for mildly elevated lactate dehydrogenase – 601 UI/l and C-reactive protein – 19 mg/l. The coagulation tests showed prolonged prothrombin time: 21.5”, elevated D-dimers: 35.7 mcg/ ml and normal activated partial thromboplastin time – 26.3”. The blood gas analysis showed normal pH, mild hypoxia and hypercapnia. As a part of the oncological work-up, we performed bone marrow aspiration biopsy. Morphologically the bone marrow was hypercellular, infiltrated by large-sized blast cells (50% of the cellular content) with abundant basophilic vacuolated cytoplasm, containing granules and irregularly shaped “monstrous” nucleus, consistent with acute monobasic leukaemia (AMoL, M5 FAB subtype). The flow cytometry of the bone marrow showed 25% monoblastic population positive for myeloperoxidase, CD13, CD33, CD64, CD14 (±), CD11b, CD36 (±), CD15 (±), CD16 (±) and negative for CD300e, HLA DR, CD34, CD117 and 30% monocytic population positive for CD64, CD14, CD36 and CD300e. The second review of the immunohistochemistry of the biopsied intraabdominal infiltrate detected biphenotypic malignant clone, compatible with T-cell lineage (positivity for CD3, CD5, CD7 and CD2) and myeloid lineage (positivity for CD11c, CD33, CD68, and lysozyme). The molecular genetic tests from the bone marrow sample were negative for AML1-ETO, CBFb-MYH11, M-BCR-ABL, m-BCR-ABL, FLT3-ITD and FLT3-TKD.

On the basis of the morphological and flow cytometry findings from the extramedullary abdominal infiltrate we made the diagnosis of BAL with prevailing monoblastic/monocytic malignant clone, which was the only present in the bone marrow of the patient. Chemotherapy was started according to AML BFM 2012 protocol with AIE induction (Cytarabine at a dose of 100 mg/m²/day as continuous infusion on days 1 and 2; Cytarabine at a dose of 100 mg/m² as a 30-minute infusion every 12 hours on days 3 to 8; Idarubicin 12 mg/m² on days 3, 4, and 5; Etoposide 150 mg/m² on days 6, 7, and 8) with omission of the lumbar puncture and intrathecal injection of Cytarabine to avoid the abdominal discomfort resulting from the recent surgery and the placed drainage. Dexamethasone was also added to the induction therapy because of the presence of a T-cell malignant clone in the abdominal leukemic infiltrate. The supportive therapy consisted of parenteral nutrition, antibiotics and antifungal drugs, anticoagulation with enoxaparin and continuous infusion of morphine. After the end of the chemotherapy block granulocyte colony-stimulating factor was also added. During the next weeks the marked abdominal distension, diffuse tenderness on palpation and decreased to absent peristalsis persisted and the patient was not passing stools except for several episodes of hematochezia. The daily discharge of biliary to feculent materials from the nasogastric tube reached 2500 to 3000 ml and the hemorrhagic secretion from the peritoneal drainage also persisted. Despite the conducted chemotherapy and the clearance of the blast cells from the peripheral blood, on the 20th post therapeutic day intestinal perforation occurred, which required relaparotomy. Intraoperatively diffuse necrotic changes on the thinned intestinal wall were detected and bowel resection with ileostomy was not feasible. Three days after the second surgery a fatal outcome due to multiple organ failure followed.

Discussion

Herein we report a very rare case of childhood BAL with extramedullary abdominal infiltrate, causing total mesenteric thrombosis and widespread intestinal infarction, thus turning out to be the life-limiting prognostic factor of the malignancy. The diagnosis is based on the WHO flow cytometry criteria, which are met by the immunohistochemistry findings in the biopsy specimen from the intraabdominal lesion [4]. In this case we have detected two separate populations of blast cells, thus meeting the criteria of T/myeloid MPAL. T/myeloid MPAL accounts for less than 1% of all acute leukemia cases and is probably more frequent in children than B/myeloid MPAL [1]. Generally, the frequency of BAL remains largely unknown, as well as the best standard of treatment. Myeloid-directed and lymphoid-directed therapies are explored without proven advantage on the treatment response [4,5]. Because of the monoblastic/monocytic lineage specificity of the malignant clone in the bone marrow we started AML-directed therapy combined with Dexamethasone and this resulted in peripheral blast clearance. The clinical presentation of the reported case is more consistent with a myeloid sarcoma concomitant with a bone marrow involvement from AMoL, but the surprising bilinear characteristic (T-cell and monoblastic) of the extramedullary abdominal infiltrate also poses therapeutic challenges. The myeloid sarcoma is defined as an extramedullary mass, which consists of myeloid blast cells and could occur concurrently with acute myeloid leukemia in the bone marrow or as an isolated lesion. The frequency in children is higher than in adults and the most frequently involved sites are the skin and the bones, especially the orbit [6,7]. The gastrointestinal tract is a rare localization of a myeloid sarcoma with few case reports in the literature [8-14]. The largest reported series describes 11 cases, of which only one is with full-thickness intestinal infiltrate, proven by a biopsy [15]. The authors find a strong association with CBFb-MYH11 positivity of the blast cells in this case series, confirmed also by other case reports [16]. Besides, mesenteric thrombosis especially with this severity is exceedingly rare in children and there are only few published case reports and small series [18,19]. Most commonly it is associated with hereditary thrombophilia, nephrotic syndrome or polyarteritis nodosa [20,21]. In a case series of 24 children with venous thromboembolism at uncommon sites, only 2 cases of mesenteric thrombosis were observed [22]. To our knowledge, this is the first reported case of total mesenteric artery occlusion associated with childhood leukemia. In conclusion, the surgeons should be aware of this rare and potentially fatal complication of childhood leukemia, which could occur without any alarming hematological signs, pointing out towards a malignancy. Although the most common cause for an intestinal obstruction by a tumor is Non-Hodgkin lymphoma, other causes should also be considered.

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References

1. Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, et al. (2017) Mixedphenotype acute leukaemia, T/myeloid, not otherwise specified. In: WHO classification of tumors of hematopoetic and lymphoid tissues. 4th edition: 185-186.
2. Al-Seraihy A, Owaidah T, Ayas M, El-Solh H, Al-Mahr M, et al. (2009) Clinical characteristics and outcome of children with biphenotypic acute leukemia. Hematologica, 94: 1682-1690.
3. Krill T, Baliss M, Zaibaq J, Abdulla HM, & Parupudi S. (2019) Acute lymphoblastic leukemia presenting with mesenteric ischemia. Gastroenterology and hepatology from bed to bench, 12: 370-373.
4. Charles N, Boyer D. (2017) Mixed-phenotype leukemia. Arch Pathol Lab Med, 141: 1462-1468.
5. Lee HG, Baek HJ, Kim HS, Park SM, Hwang TJ, et al. (2019) Biphenotypic acute leukemia or acute leukemia of ambiguous lineage in childhood: clinical characteristics and outcome. Blood Res, 54: 63
6. Samborska M, Derwich K, Skalska-Sadowska J, Kurzawa P, Wachowiak J. (2016) Myeloid sarcoma in children – diagnostic and therapeutic difficulties. Contemp Oncol (Pozn), 20: 444-448.
7. Dusenbery K, Howells W, Arthur D, Alonzo T, Lee JW, et al. (2003) Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia. A report from the Children’s Cancer Group. J Pediatr Hematol Oncol, 25: 760-768.
8. Antic D, Elezovic I, Bogdanovic A, Vukovic NS, Pavlovic A, et al. (2010) Isolated myeloid sarcoma of the gastrointestinal tract. Intern Med, 49: 853-856.
9. Choi EK, Ha HK, Park SH, Lee SJ, Jung SE, et al. (2007) Granulocytic sarcoma of bowel: CT findings. Radiology; 243: 752-759.
10. Kohl SK, Aoun P. (2006) Granulocytic sarcoma of the small intestine. Arch Pathol Lab Med, 130: 1570-1574.
11. Kumar B, Bommana V, Irani F, Kasmani R, Mian A, et al. (2009) An uncommon cause of small bowel obstruction: Isolated primary granulocytic sarcoma. QJM, 102: 491-493.
12. McCusker S, Trangucci J, Frederick W, Richi A, Abunnaja S. (2016) Primary Myeloid Sarcoma of the Small Intestine: Case Report and Literature Review. Conn Med, 80: 349-352.
13. Wang P, Li Q, Zhang L, Ji H, Zhang CZ, Wang B. (2017) A myeloid sarcoma involving the small intestine, kidneys, mesentery, and mesenteric lymph nodes: A case report and literature review. Medicine (Baltimore); 96: e7934.
14. Narayan P, Murthy V, Su M, Woel R, Grossman R, et al. (2012) Primary myeloid sarcoma masquerading as an obstructing duodenal carcinoma Case Rep Hematol: 490438.
15. Dalland J, Meyer R, Ketterling R, Reichard K. (2020) Myeloid sarcoma with CBFB-MYH 11 fusion (inv (16) or t (16;16)) prevails in the A clinicopathological analysis of 11 cases and review of the literature. Am J Clin Pathol, 153: 333-341.
16. Álvarez P, Navascués CA, Ordieres C. (2011) Granulocytic sarcoma of the small bowel, greater omentum and peritoneum associated with a CBFb/MYH11 fusion and inv(16) (p13q22): a case report. Int Arch Med, 4: 3.
17. Hayakawa T, Morimoto A, Nozaki Y, Kashii Y, Aihara T, et al. (2011) Mesenteric venous thrombosis in a child with type 2 protein S J Pediatr Hematol Oncol 33: 141-143.
18. Kumar R, Kerlin B. (2017) Thrombosis of the Abdominal Veins in Front Pediatr, 5: 188.
19. Oğuzkurt P, Senocak M, Ciftci A, Tanyel F, Büyükpamukçu N. (2000) Mesenteric vascular occlusion resulting in intestinal necrosis in J Pediatr Surg, 35: 1161-1164.
20. Shamekh A, Goldsworthy L, Pullattayil S, Mubarak W, Shabani A, et (2021) Superior mesenteric artery thrombosis in a child with chronic abdominal pain. J Pediatr Surg Case Reports, 64: 101724.
21. Ulinski T, Guigonis V, Baudet-Bonneville V, Auber F, Garcette K, et (2003) Mesenteric thrombosis causing short bowel syndrome in nephrotic syndrome. Pediatr Nephrol, 18: 1295-1297.
22. Pergantou H, Avgeri M, Komitopoulou A, Xafaki P, Kapsimali Z, et al. (2014) Venous thromboembolism at uncommon sites in neonates and J Pediatr Hematol Oncol; 36: 624-629.