Cooccurrence of myelodysplastic neoplasm and myeloid sarcoma with background mediastinal germ cell tumor: an autopsy case

Abstract

Hematological malignancy (HM) is developed in 2–6% patients with primary mediastinal germ cell tumor (MGCT). Symptoms of HM associated with MGCT usually appear after diagnosis of MGCT. Patients with MGCT underlying HM have poor prognosis. We report an extremely rare autopsy case of simultaneous presentation of MGCT, myelodysplastic neoplasm (MDS) with low blasts, and myeloid sarcoma (MS). A 27-year-old man presented with intermittent fever, general fatigue, and cough. Computed tomography revealed 11 cm mass in anterior mediastinum, hepatosplenomegaly, and gastric, pericholedochal, and mesenteric lymphadenopathies. The mass compressed the left pulmonary artery. Laboratory examination revealed thrombocytopenia (59,000 /mm³). Serological tests revealed elevated alpha-fetoprotein 7,219 ng/mL and human chorionic gonadotropin 899 IU/L. Bone marrow aspiration smear showed presence of micromegakaryocytes and blast count of 1.2%. G-banding detected monosomy 13 and complex karyotype. The autopsy revealed that MGCT was mainly composed of teratoma and also included yolk sac tumor, seminoma, and choriocarcinoma components. Transformation to acute myeloid leukemia was not observed in the bone marrow but CD33 and MPO-positive immature myeloid blasts proliferated in the lymph nodes, liver, spleen, and small intestine. Loss of p53 expression was observed in bone marrow and extramedullary immature myeloid blasts. Next gene sequencing detected TP53 c.919+3del splice site variant and KRAS N116H. It is important to consider HMs when extramediastinal lesions or thrombocytopenia appear in patients with MGCT.

INTRODUCTION

Primary mediastinal germ cell tumor (MGCT) accounts for 4% of adult mediastinal tumor.¹ Hematological malignancy (HM) develops in 2–6% of patients with non-seminomatous MGCT,² and is most often accompanied by MGCT with yolk sac tumor (YST) component.^3,4 Acute megakaryoblastic leukemia and acute myeloid leukemia (AML) with monocytic differentiation are most common in HMs associated with MGCT. HMs commonly become apparent within the first year after diagnosis of MGCT.^4–6 Patients with MGCT underlying HM have miserable clinical outcomes: median overall survival of five months.⁵

Myeloid sarcoma (MS) associated with MGCT has been reported in only six cases.^3,7–9 In general, MS is developed mainly in patients with AML and is rare in MDS.¹⁰ There have been no reported cases of MGCT patients developing both MDS and MS. Here, we report an autopsy case of simultaneous presentations of MGCT, MDS, and MS.

CASE REPORT

A 27-year-old Japanese man presenting with intermittent fever, general fatigue, and cough was admitted to a local hospital. Computed tomography revealed 11 cm mass in anterior mediastinum, hepatosplenomegaly, and gastric, pericholedochal, and mesenteric lymphadenopathies (Figure 1). The mediastinal mass compressed the left pulmonary artery and left lung. Radiological diagnosis was suggestive of hepatosplenomegaly due to congestion by pulmonary artery compression from a mediastinal tumor. The patient was referred to our hospital. Laboratory tests revealed white blood cell count of 17,800 /mm³ and platelet count of 59,000 /mm³. Serological testing showed elevated C-reactive protein 5.20 mg/dL, alpha-fetoprotein 7,219 ng/mL, and human chorionic gonadotropin 899 IU/L. Biopsy specimen was obtained from the mediastinal mass and was diagnosed as mixed germ cell tumor, composed of teratoma and YST. Bone marrow aspiration was also obtained in order to investigate the cause of thrombocytopenia. Aspiration smear showed small megakaryocytes and micromegakaryocytes, indicating megakaryocytic dysplasia. Blast count was 1.2%. G-banding showed the -13, i(13)(q10), +mar1, +mar2 abnormality in 20 of the 20 analyzed cells. The patient was diagnosed with MDS with low blasts. He received bleomycin + etoposide + cisplatin regimen chemotherapy for GCT. However, the mediastinal tumor regrew, and he died.

Fig. 1.

Computed tomography findings. 11cm mass was located in the anterior mediastinum and the mass compressed left pulmonary artery (A). Hepatosplenomegaly (B) and mesenteric lymphadenopathies (C) were also observed (arrows).

Autopsy showed that MGCT was mainly composed of teratoma, forming squamous epitheliums, glands, cartilages, and smooth muscles. Immature mesenchymal cells were also observed. YST, seminoma, and choriocarcinoma components were also included. Bone marrow was hypercellular and myelocytes and monocytes increased (Figure 2A). Erythroid islands were inconspicuous, and erythroblasts were distributed in surrounding bone trabeculae (Figure 2B). CD41-positive small megakaryocytes and micromegakaryocytes were scattered (Figure 2A inset). CD34-positive blasts were <1%; the transformation to AML was not observed. p53 expression was lost in bone marrow (Figure 2C). In liver and spleen, not only congestion but also proliferation of CD33 and MPO-positive immature myeloid blasts were observed (Figure 2D). CD117 was weakly expressed in the myeloid blasts but p53 was completely negative. The immature myeloid cells also proliferated in the lymph nodes (Figure 2E) and small intestine. Intravascular aggregates of CD33 and MPO-positive myeloid blasts were observed in MGCT (Figure 2F). Next generation sequencing of small intestine tumor, using Archer VariantPlex Solid Tumor Focus v2 (20 genes) detected TP53 c.919+3del splice site variant and KRAS N116H.

Fig. 2.

Autopsy findings of myelodysplastic neoplasm and myeloid sarcoma. Bone marrow showed hypercellularity and proliferating myelocytes and monocytes (A, HE, ×200). CD41-positive micro-megakaryocytes were observed (A inset, CD41, ×400). CD34-positive blasts were <1% (not shown). Erythroblasts distributed surrounding bone trabecula (B, glycophorin C, ×400). P53 was completely negative in bone marrow (C, p53, ×40). In spleen, congestion and proliferation of immature myeloid blasts were observed (D, HE, ×400, D inset, CD33, ×400). The myeloid blasts also proliferated in lymph nodes (E, HE, ×400, E inset, CD33, ×400). The myeloid blasts were weakly positive for CD117 but completely negative for p53 (not shown). Intravascular aggregates of myeloid blasts were observed in mediastinal germ cell tumor (F, HE, ×200, F inset, CD33, ×400).

DISCUSSION

Patients with MGCT can complicate HM. HM associated with MGCT mainly presents as AML and the symptoms of HM often emerge after diagnosis of MGCT. The present patient had comorbidity, including MGCT, MDS with low blast, and MS. MGCT contained YST component. MDS harbored complex karyotype and showed loss of immunohistochemical p53 expression. The autopsy detected hepatosplenomegaly was caused not only by congestion but also by the invasion of MS.

TP53 is one of tumor suppressor gene and TP53 mutations lead to tumorigenesis. TP53 is usually inactivated when biallelic abnormality occurs, but TP53 haploinsufficiency can also lead to loss of function.¹¹ Taylor et al.⁴ reported that TP53 mutation was observed in 91% of HM associated with MGCT, but only in 9% of de novo AML. In MDS, TP53 mutation is poor prognostic factor, and biallelic TP53 inactivation brings even worse prognosis than monoallelic inactivation.¹² Moreover, MDS with complex karyotype also has poor prognosis and is associated with biallelic TP53 inactivation.¹³ In the present case, MDS showed loss of p53 expression and complex karyotype. P53 immunohistochemistry is a surrogate marker for TP53 inactivation. TP53 mutations cause p53 protein to accumulate or truncate in the nuclei, resulting in diffuse expression or loss of expression. TP53 mutations might be associated with an unfavorable prognosis of MGCT underlying HM.

The presence of isochromosome 12p [i(12p)] in hematologic malignancies arising in patients with MGCT generally suggests a clonal relationship between the two tumors.² However, Taylor et al.⁵ reported that i(12p) was detected in only 45% of MGCT-associated hematologic malignancies. In addition to i(12p), TP53 mutations and RAS/MAPK pathway mutations can be shared between the two.⁵ In our case, it is possible that the HM originated from an atypical MGCT lacking i(12p), and TP53 and KRAS mutations potentially contribute to tumorigenesis.

MS, also known as chloroma, granulocytic sarcoma, monocytic sarcoma, and extramedullary myeloid tumor, occurs mainly in patients with AML. Pileri et al.¹⁰ demonstrated that MDS was observed in 5% of patients with MS. MS can also develop in patients without hematopoietic tumor in bone marrow. However, it is difficult to clinically suspect that a patient has developed MS because MGCT underlying MS is extremely rare.^7–9 In our case, radiologically, hepatosplenomegaly was suspected to be due to congestion, but autopsy detected overlapping MS in liver and spleen. The fact that MGCT can metastasize to extrathoracic sites, including lymph nodes, also makes it difficult to differentiate MS. Thrombocytopenia in MGCT patients might be speculated for co-occurrence of HM.

The majority of HM associated with MGCT was reported in patients with MGCT with YST component. Embryologically, hematopoiesis is initiated in the yolk sac and hematopoietic stem cells migrate to the bone marrow. Extramedullary hematopoiesis is rarely observed in YST.^3,14,15 It hypothesizes that HM developed from YST elements in the MGCT. In our case, MGCT contained YST component and intravascular aggregates of myeloid blasts. Some patients with MGCT can have simultaneous presentation of HM, but it often occurs after diagnosis of MGCT.⁶ The possibility for underlying HM should be carefully examined if YST components are contained in the MGCT.

In conclusion, we reported an extremely rare autopsy case of simultaneous presentation of MGCT, MDS, and MS. MGCT contained YST component. MDS harbored complex karyotype and loss of p53 expression, indicating unfavorable prognosis. It is important to raise awareness of MS associated with MGCT because hepatosplenomegaly in MGCT patients can makes it difficult to diagnosis. Thrombocytopenia with MGCT might be key to suggesting HM. Cooccurrence of HM should be considered when MGCT contains YST components.

AUTHOR CONTRIBUTIONS

YK and TH: writing original draft preparation and diagnosis. KY and YY: Formal analysis. YY and KS: Patient management. All the authors approved the final version of this manuscript.

FUNDING

No funding was received for this study.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

ETHICS APPROVAL STATEMENT

The study was approved by the institutional review board of the National cancer Center (2023-433) and was conducted following the Declaration of Helsinki.

PATIENT CONSENT STATEMENT

Informed consent was obtained from the patient for publication.