CLINICAL

AND

LABORATORY OBSERVATIONS

Testicular Myeloid Sarcoma: An Unusual Presentation of Infant Acute Myeloid Leukemia Adriana Fonseca, MD,*w Katrin Scheinemann, MD,*w Jan Jansen, MD,z and Ronald Barr, MB, ChB, MD*wzy

Summary: Testicular myeloid sarcoma (MS) is a rare disorder; even more so during infancy. There are only 3 cases described previously. We report a 3-month-old baby boy with MS who presented with a testicular mass. This case also features cerebrospinal fluid involvement at diagnosis and bone marrow pathology only detectable by genetic analysis. After completion of the initial treatment, the child relapsed with an MS in the brain and succumbed despite further therapy. Key Words: testicular, myeloid, sarcoma, infant, leukemia

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M

yeloid sarcoma (MS) is an accumulation of myeloblasts in an extramedullary location. MS is also known as extramedullary myeloid cell tumor, chloroma, granulocytic sarcoma, myelosarcoma, or myeloblastoma. It can present at multiple sites including skin, bone, central nervous system (CNS), and testis,1–3 skin being the most common site.3 Testicular presentation of MS in infants is decidedly rare; to date, only 3 cases have been reported.4–6

CASE PRESENTATION A previously healthy 3-month-old baby boy presented in June 2011 for evaluation of a testicular mass that his mother had noticed just 2 weeks earlier. Physical examination revealed a well-developed baby boy. A bluish discoloration was observed in the right hemiscrotum as well as a noticeably larger right testis. A solid, smooth, nontender mass measuring approximately 2.53.0 cm was defined. It was not separable from adjacent normal structures but the spermatic cord was normal. No lymphadenopathy or organomegaly was observed. Ultrasonography showed a right testicular hypoechoic, complex mass with increased blood flow, measuring 3.8 2.92.1 cm, suggestive of malignancy. The cord and the contralateral testis were apparently normal (Fig. 1). A right orchidectomy was performed urgently (Fig. 2A) and histopathologic analysis revealed a small, round, blue cell tumor with necrosis. Immunohistochemical analysis revealed positivity for vimentin, myeloperoxidase (Fig. 2B), CD1a, CD15, CD43, CD68, and CD117, suggestive of MS. Genetic analysis of the primary tumor showed MLL rearrangement in 72.5% of the cells examined. Bilateral bone marrow aspiration and biopsies were performed. Histopathologic analysis showed a normal bone marrow Received for publication February 28, 2013; accepted November 25, 2013. From the *McMaster Children’s Hospital, Hamilton Health Sciences; Departments of wPediatrics; zPathology and Molecular Medicine; and yMedicine, McMaster University, Hamilton, ON, Canada. The authors declare no conflict of interest. Reprints: Ronald Barr, MB, ChB, MD, Room 3N27, Health Sciences Centre, McMaster University, 1200 Main St. West, Hamilton, ON L8S 4J9, Canada (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins

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without features of malignancy. Flow cytometry revealed 15% cells in the blast/hematogone region and 1% myeloblasts. Cytogenetic analysis (G banding) detected multiple rearrangements involving chromosome 11 (11q23) implying involvement of MLL, correlating with the findings in the testicular lesion. A cerebrospinal fluid (CSF) sample had a cell count of 104/mm3 with 20% blasts. Systemic therapy was started according to the COG AAML 0531 protocol that included a total of 5 cycles, (2 inductions and 3 intensifications) using cytarabine, etoposide, daunorubicin, and L-asparaginase. CNS-directed therapy was started promptly with intrathecal cytarabine twice weekly. The CSF pleocytosis cleared quickly by the time of the second lumbar puncture. He received a total of 5 intrathecal doses during induction 1. Remission was confirmed in the bone marrow and CSF after induction chemotherapy. During treatment the child experienced several complications, including multiple infections, which were treated successfully with antibiotics. Otherwise, he tolerated it fairly well and completed the protocol in December 2011. The child did not have a matched sibling and, therefore, hematopoietic stem cell transplantation was not considered. In February 2012, he presented to the emergency room with a 2-day history of nausea, projectile vomiting, decreased oral intake, irritability, and posturing. Physical examination revealed a very irritable child with rigid back arching, neck hyperextension, and a bulging fontanel. Computed tomography of the head demonstrated a large cerebellar mass and hydrocephalus. Magnetic resonance imaging showed a heterogeneous enhancing mass in the left cerebellar hemisphere measuring 3.7 3.5 cm (Fig. 3). The mass was causing upward and downward brain herniation with effacement of the cerebral aqueduct and moderate supratentorial hydrocephalus. Evidence of abnormal pachymeningeal enhancement at the region of the petrous bone extending into the internal auditory canal on the left side was also observed. There was additional pachymeningeal enhancement in the cervical spinal canal. Bone marrow analysis was normal, and fluorescence in situ hybridization was inconclusive. An urgent craniotomy was performed for evacuation of the tumor and insertion of an external ventricular drain. Histopathologic analysis

FIGURE 1. Ultrasonogram of testis showing a solid, hypoechoic complex mass.

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FIGURE 3. Magnetic resonance image (MRI) demonstrating a mass in the left cerebellar hemisphere (Axial 3D MPRage with gadolinium contrast).

FIGURE 2. A, Surgical specimen from orchidectomy. B, Immunohistochemical analysis for myeloperoxidase in testicular mass. of the lesion showed a very cellular tumor with a starry-sky appearance and frequent mitoses. Immunohistochemical analysis demonstrated positivity for vimentin, myeloperoxidase, and CD99, with 50% of the cells being Ki-67 positive, confirming the diagnosis of MS. Intrathecal and intraventricular chemotherapy was administered with methotrexate, cytarabine, and hydrocortisone and a 5-day course of IV fludarabine was administered. On the last day of chemotherapy the child spiked a fever and his condition deteriorated rapidly. G-CSF as well as broad-spectrum antibiotics were started but he remained febrile, showing evidence of septic shock refractory to fluid boluses. At that point the family decided to continue only with supportive measures, and he died a few hours after.

DISCUSSION Testicular MS during infancy is a rare entity; only 3 previous cases have been reported in the literature (Table 1). The clinical presentation was similar in all with scrotal bluish discoloration and a palpable testicular mass. The first case was a 3-month-old infant with isolated MS of the testis who was treated with intensive systemic chemotherapy and was disease-free 18 months after diagnosis.4 The second case was a 2-month-old infant with a mass involving the testis and spermatic cord. Bone marrow examination confirmed acute myeloid leukemia (AML). That patient received intensive systemic chemotherapy and bone marrow transplantation and was disease-free 1 year after the transplant.5 The third case was an 8-month-old

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infant with bilateral testicular MS and CSF involvement. There was no information about his treatment or outcome.6 The patient reported here seems to be unique in several ways. He was diagnosed with MS after orchidectomy; unlike the other cases, the results of his bone marrow histopathologic analysis and flow cytometry were normal, although genetic analysis revealed a subset of cells with multiple rearrangements of chromosome 11, suggestive of early bone marrow involvement. By contrast, bone marrow involvement is detectable in almost all patients with initially isolated MS.7 The present case also had CNS involvement at diagnosis and, despite a good initial response to treatment, he relapsed with a florid MS in the brain. MS appears to be more common in the pediatric population, with an incidence of up to 30% in children with AML compared with 2% to 5% in adults.7 It is most common with the M5 subtype. Douet-Guilbert and colleagues retrieved from the literature 19 cases of children with MS. Rearrangement of 11q23; t (9; 11)(p21-22;23) was present in 9 of the patients and was identified as the most frequent abnormality.8 The incidence of MLL rearrangements in infants with AML is as high as 50% to 60%,6 and these rearrangements have been identified as predictors of poor outcomes.6 This case speaks to the unpredictable nature of MS, which can precede, follow, or occur during or in the absence of AML.6 MS is an uncommon presentation of a not uncommon malignancy in children. According to Park et al,6 “The presence of granulocytic sarcoma is associated with generally a poorer outcome and shorter overall survival” and Hereema-McKenney et al9 “cases of congenital leukemia with 11q23 translocations tend to have a more consistently aggressive clinical course.” However, other authors10,11 have reported that the presence of MS may r

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Testicular Myeloid Sarcoma

TABLE 1. Characteristics of Infants With Myeloid Sarcoma

Age (mo)

References Armstrong et

al4

Testicular Involvement

Bone Marrow

Cytogenetics

CNS

Treatment

3

Left

Normal

NM

Negative

Chemotherapy

Walker et al5

2

Right

AML

NM

NM

Chemotherapy + BMT

Park et al6

8

Bilateral

NM

Positive

NM

This study

3

Right

Positive

Chemotherapy

Early involvement

50,XY t(2,11)(p21;q23) 46,XY t(10,11,15) (p13;q13;q15)

Outcome Disease-free at 12 months f/u Disease-free 12 months after transplant NM Died after CNS relapse

AML indicates acute myeloid leukemia; BMT, bone marrow transplant; CNS, central nervous system; f/u, follow-up; NM, not mentioned.

indicate a better prognosis. MS should always be part of the differential diagnosis in the evaluation of unusual masses. Genetic analysis must be undertaken to clarify the diagnosis and allow the determination of appropriate treatment strategies. REFERENCES 1. Vardiman JW. The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues: an overview with emphasis on the myeloid neoplasms. Chem Biol Interact. 2010;184:16–20. 2. Bain EE, Rothman I, Lin L. De novo myeloid sarcoma in a 4-month-old infant: a case report and review of the literature. J Cutan Pathol. 2013;40:321–325. 3. Johnston DL, Alonzo TA, Gerbing RB, et al. Superior outcome of pediatric acute myeloid leukemia patients with orbital and CNS myeloid sarcoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2012;58:519–524. 4. Armstrong MB, Nafiu OO, Valdez R, et al. Testicular chloroma in a nonleukemic infant. J Pediatr Hematol Oncol. 2005;27:393–396. 5. Walker BR, Cartwright PC. Granulocytic sarcoma presenting as testicular and paratesticular masses in infancy. J Urol. 2001; 165:224.

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6. Park KU, Lee DS, Lee HS, et al. Granulocytic sarcoma in MLL-positive infant acute myelogenous leukemia: fluorescence in situ hybridization study of childhood acute myelogenous leukemia for detecting MLL rearrangement. Am J Pathol. 2001;159:2011–2016. 7. Klco JM, Welch JS, Nguyen TT, et al. State of the art in myeloid sarcoma. Int J Lab Hematol. 2011;33:555–565. 8. Douet-Guilbert N, Morel F, Le Bris MJ, et al. Rearrangement of MLL in a patient with congenital acute monoblastic leukemia and granulocytic sarcoma associated with a t(1;11)(p36;q23) translocation. Leuk Lymphoma. 2005;46: 143–146. 9. Heerema-McKenney A, Cleary M, Arber D. Pathology and molecular diagnosis of leukemias and lymphomas. In: Pizzo P, Poplack D, eds. Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2011: 138–163. 10. Dusenbery KE, Howells WB, Arthur DC, et al. Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia. A report from the Children’s Cancer Group. J Pediatr Hematol Oncol. 2003;25:760–768. 11. Tsimberidou A, Kantarjian H, Wen S, et al. Myeloid sarcoma is associated with superior event-free survival and overall survival compared with acute myeloid myeloid leukemia. Cancer. 2008;113:1370–1378.

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Testicular myeloid sarcoma: an unusual presentation of infant acute myeloid leukemia.

Testicular myeloid sarcoma (MS) is a rare disorder; even more so during infancy. There are only 3 cases described previously. We report a 3-month-old ...
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