Myeloid Sarcoma of the Testis and Skin With Osteolytic Bone Lesions in Blastic Transformation of Primary Myelofibrosis

Abstract

Myeloid sarcoma is a localized tumor composed of myeloblasts and other immature myeloid cells outside the bone marrow. It is usually associated with acute myeloid leukemia and rarely with chronic myeloproliferative disorders. We present a 43-year-old male who developed a solitary tumor in his left testis 6 years after an initial diagnosis of primary myelofibrosis. Four months later, another infiltrative tumor in the skin overlying his left wrist was discovered. After orchiectomy, the immunohistochemistry revealed tumor cells expressing LCA, CD34, CD117, MPO, CD15, lysozym, and CD43+, which confirmed diagnosis of myeloid sarcoma. The histologic and immunohistochemical findings were similar. The patient was treated with local radiotherapy to the skin tumor site, resulting in regression of the tumor and with chemotherapy when acute myeloblastic leukemia developed. The patient survived 21 months after initial presentation.

Myeloid sarcoma (MS) is a rare extramedullar tumor composed of immature myeloid cells. It may precede the onset of acute myeloid leukemia (AML), but more often it is secondary to acute or chronic leukemia or myelodysplastic syndrome. It has rarely been reported in myeloproliferative neoplasms. MS has been observed in 2% – 9.1% of AML patients. It is frequently observed in AML of monoblastic/myelomonocytic origin, but has been found in other subtypes of AML as well.^1–3 MS may occur in any tissue or organ but commonly affects skin, bone, and soft tissue in the head and neck, breasts, ovaries, brain, testis, and gastrointestinal tract.^4–5 Treatment of MS typically includes both radiotherapy and chemotherapy, depending on whether the bone marrow is involved. The morphological characteristics of MS can be confused with lymphoma; therefore a definitive diagnosis requires immunophenotyping.

Case Report

A 43-year-old male with splenomegaly presented in 2001 when a diagnosis of primary myelofibrosis (PMF) was established. The bone marrow trephine biopsy revealed a hypercellular phase of disease with mega-karyocyte atypia with an increase in numbering and clustering. Cytogenetic analysis for the presence of t(9;22) and molecular analysis for Bcr-Abl1 translocation were negative, ruling out chronic myeloid leukemia. The patient did not receive any treatment.

In April 2004, his liver (+19 cm) and spleen (+27 cm) significantly increased in size. Laboratory results included a hemoglobin (Hb) 88 g/L, MCV 83 fL, WBC 4,7 × 10⁹/L (WBC formula: myeloblasts 12%, myelocytes 8%, metamyelocytes 7%, bands 4%, segmented 44%, eosinophils 1%, basophils 1%, lymphocytes 19%, monocytes 4%), and the platelet count 89 × 10⁹/L. Many dakryocytes were found in the peripheral blood smear. The bone marrow histology showed a pronounced fibrotic, hypocellular phase of PMF. The karyotype was 46,XY, and the analysis for JAK2 mutation was negative. Ultrasound examination revealed splenomegaly (270 × 90 mm). The patient was treated with 1.0 g of hydroxyurea daily and remained asymptomatic until February 2007.

At that time he developed anemia requiring bimonthly transfusions averaging 2 units of packed red blood cells (RBCs). In October 2007 he noticed a firm mass in his left testicle, which was 6 cm in diameter, with a palpable smooth-surfaced 1×1 cm nodule. After 4 months an oval, reddish, painful swelling appeared on the skin of his left upper arm (20 mm) (Image 1) and left wrist. The lesion in left wrist was 6 cm in size, and there was swelling of the index and middle fingers. A radical left orchiectomy was performed. Macroscopic examination of the left testicle showed that it was 35 × 25 × 10 mm in diameter with a smooth surface. Adjacent to the testicle was a grayish round elastic tumor of 25 mm in diameter which stemmed from epidydimis. Pathologic and immunohistochemical examination of the testicular tumor showed that tumor cells were LCA+, CD34+, CD117+, MPO+, CD13+, CD15+, lysozyme+, CD43+, and negative for CD3− (Images 2A, 2B, and 2C). Histological examination was consistent with an extramedullary myeloid cell tumor with monocytic differentiation.

A biopsy of the tumor in his left wrist revealed mononuclear cell infiltrates with vesicular and prominent nuclei and abundant, bright cytoplasm. Immunohistochemistry showed that the cells were EMA−, LCA+, CD34weak+, CD117−, CD68−, HLA-DR−/+, lysozyme +, Tdt−, CD15+, CD79alfa−/+, CD20−, CD10−, CD38−, CD138−, CD3−, CD5−, and CD30−. Proliferative activity measured by Ki-67 was moderate (50% of cells positive). This finding was consistent with MS as an extramedullary manifestation of the blastic transformation of the PMF. Radiography of the left hand showed the presence of osteolytic bone lesions (Image 3). The patient received local radiotherapy to the tumor.

In January 2008 his blood hematology results included: Hb 72 g/L, WBC 4,2, × 10⁹/L (myelocytes 7%, metamyelocytes 5%, bands 5%, segmented 59%, lymphocytes 20%, monocytes 4%), and platelets 79 × 10⁹/L. The serum lactate dehydrogenase (LDH) activity was 2951 U/L. He was transfused with packed RBC units weekly. Splenomegaly (+36 cm) occupying most of his abdomen developed in February 2007, and cytogenetic analysis showed 46,XY,-6,del(20)(q11),+r [13]/ 46XY[2].

In June 2008 a bone marrow trephine biopsy revealed numerous fibrocytes and gross reticular and collagen fiber proliferation (fibrosis gradus IV). The main cellular population in medular spaces was composed of fibroblasts and blast cells of irregular and polymorphic shape, which were MPO+, CD34+/CD117+. The extent of blast cell infiltration was impossible to determine in bone marrow aspirates due to its irregular dispersion, but histologic examination showed blastic transformation against a backdrop of primary fibrotic and sclerotic bone marrow changes. The patient was treated with chemotherapy (daunorubicin i.v. 80 mg, on days 1, 2, and 3, and cytosin-arabinoside iv. in continuous infusion 2 × 180 mg days 1 through 7). Following the first cycle of chemotherapy his spleen reduced in size to +6 cm and the left wrist tumor resolved completely. Soon after chemotherapy, new skin tumors appeared on his left shoulder, right forearm, and in the region of the left ankle joint, which was 4 cm in diameter. Hematologic parameters were: Hb 72 g/L, platelets 105 × 10⁹/L, WBC 4 × 10⁹/L (2% promyelocytes, 4% metamyelocytes, 2% myelocytes, 3% bands, 68% segmented neutrophils, 17% lymphocytes, and 4% monocytes). He received another cycle of the same chemotherapy. The third cycle of chemotherapy was given according to the MiDAC protocol⁶ (mitoxantrone 10 mg/m² i.v. (days 1–5) and citosine-arabinoside 1.0 g/m² i.v. (days 1–3). Tumors reduced in size promptly but transiently. After 4 months, new tumors appeared on both legs and were treated radiatively with brief success. Another course of cytosine-arabonoside 2 × 50 mg i.v. for 5 days and etoposide 100 mg i.v. for 5 days was administered. The patient died in July 2009 of cachexia and cardiorespiratory insufficiency.

Discussion

MS is a localized extramedullary solid tumor composed of immature WBCs that is usually associated with AML.^7,8 MS may develop along the course of AML or at its relapse, or may present as initial manifestation of AML. Less frequently, MS is associated with the myelodysplastic syndrome or myeloproliferative neoplasm.^2,9 MS is rare and its prevalence is about 2.9% among patients with acute and chronic leukemias.⁹ It may develop in any part of the body but the most common sites are the bones, soft tissue, skin, central nervous system, testes, and lymph nodes. In a group of 92 patients with MS studied by Italian authors, 6.5% had localized testicular tumors and 28.5% had skin tumors; MS was observed in only 3 patients with PMF.² On the skin, MS appears as a rapidly growing papulonodular lesion which can be solitary, multiple, or disseminated, and is localized on the scalp, trunk, and face.¹¹ MS appears at multiple anatomical sites in less than 10% of patients.²

MS may be difficult to diagnose based solely on light microscopy. It is frequently misinterpreted as a large B-cell non-Hodgkin lymphoma, or a non-hematological neoplasm.¹¹ Morphologically, MS is characterized by the presence of granulocytes in different stages of maturation ranging from poorly differentiated blasts to neutrophil granulocyte. The WHO classifies MS into 3 types depending upon the degree of maturation: Blastic, with predominance of myeloblasts; immature, composed of myeloblasts and promyelocytes; and differentiated with the preponderance of promyelocytes and more mature myeloid cells.¹²

Immunophenotyping is essential for accurate diagnosis of MS. In our patient, the tumor cells were poorly differentiated and immunohistochemically positive for LCA, CD34, CD117, MPO, and CD43. CD117 and CD34 positivity in bone marrow aspirates suggested proliferation of hematopoietic cells committed to the myeloid lineage. The European Group for the immunological Classification of Leukemias has proposed that AML can be diagnosed if 2 or more myeloid markers are expressed; this was the case in our patient, with additional lysozyme positivity as a marker of monocyte differentation.¹³ The bone marrow in our patient was fibrotic with rare and scattered cells mainly composed of fibroblasts and blasts; the subtype of proliferating blast cells was difficult to determine. Blast cells in the testicular and wrist tumors resembled myeloblasts with signs of monocytic differentation. Most cases of MS of the testis are associated with AML, rarely with myelodysplastic syndrome, and least often with a myeloproliferative neoplasm.^14,15 Testicular involvement is usually associated with extensive involvement of other organs such as skin.¹³

Karyotypic aberrations in patients with MS have been observed in 54% of AML patients. Cytogenetic aberrations may be more frequent in MS based on FISH analysis.³ Del20q was found in 1 case of MS using the FISH technique. Our patient had a complex chromosome aberration 46,XY,-6,del(20)(q11),+r [13]/ 46XY[2] in the bone marrow which has not, to our knowledge, been reported so far in the patients with MS.¹⁶

Treatment options for MS include radiation, chemotherapy, and surgery, depending upon the stage of the disease. For localized MS, radiation therapy is recommended. Surgery is indicated if the tumor compresses neighboring organs. Chemotherapy is indicated in patients with AML and MS to prolong life and prevent relapse of AML. Radiotherapy is considered palliative because it does not prevent relapse and the progression of AML. Patients with myloproliferative neoplasms and MS have a poor prognosis due to leukemic transformation. Early diagnosis of MS is important, particularly in younger patients for whom chemotherapy and allogeneic bone marrow transplantaion may be effective.

Abbreviations

 
• PMF

  primary myelofibrosis;

 
• AML

  acute myeloblastic leukemia;

 
• MS

  myeloid sarcoma;

 
• WBC

  white blood cells;

 
• RBC

  red blood cells;

 
• Hb

  Hemoglobin;

 
• LDH

  lactate dehydrogenase;

 
• CNS

  central nervous system

This study was supported by project No. 41004 from the Ministry of Education and Science Republic of Serbia.

References