Pediatric and Developmental Pathology 17, 44–49, 2014 DOI: 10.2350/13-05-1339-CR.1 ª 2014 Society for Pediatric Pathology
CASE REPORTS
Myelodysplastic Syndrome with Pulmonary Tumor Thrombotic Microangiopathy in an 11-Year-Old Male Patient CARMEN M. PERRINO,1 LOUIS P. DEHNER,1 MARY E. HARTMAN,2
AND
ASHIMA AGARWAL1*
1 Department of Pathology and Immunology, Washington University, Campus Box 8118, 660 South Euclid Ave., St. Louis, MO 63110, USA 2 Department of Pediatrics, Washington University, Campus Box 8116, 660 S. Euclid Ave., St. Louis, MO 63110, USA
Received May 16, 2013; accepted October 6, 2013; published online October 7, 2013.
ABSTRACT Myelodysplastic syndrome (MDS) and pulmonary tumor thrombotic microangiopathy (PTTM) are independently rare in the pediatric population. This report describes an 11-year-old male patient who initially presented with respiratory distress and cardiovascular collapse. A large left main pulmonary artery embolus and multiple, smaller pulmonary thromboemboli were widely dispersed throughout both lungs. Despite aggressive supportive care, he died within seven hours of admission. A complete postmortem examination was performed, leading to the diagnoses of primary MDS and microthrombi in the lungs, including the characteristic fibroproliferative lesions seen in PTTM. Individually, both conditions are extremely uncommon, and therefore the coincidence of these 2 conditions in a child is singularly unique. Key words: cor pulmonale, myelodysplastic syndrome, pulmonary hypertension, pulmonary tumor thrombotic microangiopathy, right heart failure
INTRODUCTION Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare pathologic phenomenon whose diagnosis is recognized by the presence of small vessel emboli and a fibrocellular intimal proliferation with the presence of neoplastic cells [1]. Fewer than 80 cases have been reported in the literature, with only 3 in the pediatric age group [2–5]. Carcinoma of the stomach is the most common malignancy in adults with PTTM [4]. The initial clinical manifestations are often vague and include respiratory distress with or without acute right-sided heart failure followed by death in a high proportion of *Corresponding author, e-mail:
[email protected]
cases [1–6]. The ultimate diagnosis is more often than not established at autopsy. We describe the clinical presentation and pathologic findings at autopsy in a previously healthy 11-year-old male with primary myelodysplastic syndrome (MDS) and PTTM whose diagnoses were established after death.
CASE REPORT A previously healthy 11-year-old boy initially presented to his primary care physician with complaints of respiratory symptoms for 1 week that had progressed to chest heaviness, tightness, and pain with dyspnea on exertion. A chest radiograph revealed a right middle lobe infiltrate that was interpreted as pneumonia, for which he received antibiotics for 5 days. He continued to complain of persistent symptoms during the interval, culminating in an episode of severe air hunger. He was in respiratory arrest and cardiovascular collapse when he was brought to an outside hospital, presumably due to sepsis. He was emergently intubated, followed by aggressive fluid resuscitation and the administration of broad-spectrum antibiotics. Laboratory studies revealed mixed respiratory and metabolic acidosis and leukocytosis (white blood cells 16 000 K/cumm, normal range 4 500–13 500 K/ cumm) with 11% circulating blasts. He was transferred to our institution, where it was noted that he had poor peripheral perfusion, and resuscitative efforts were continued. A right upper lobe infiltrate was present on chest radiograph. An elevated prothrombin time (21.8 seconds, normal range 12– 16.1 seconds), anemia (hemoglobin 6.9 g/dL, normal range 11.5–15.5 g/dL), thrombocytosis (platelets 547 K/ cumm, normal range 140 000–440 000 K/cumm), a peripheral blood smear with 11% blasts, and a markedly elevated D-dimer (4,429 ng/mL, normal range 110– 230 ng/mL) were the most significant laboratory
Figure 1. A. Postmortem bone marrow core biopsy showing multilineage dysplasia and blasts (3400). B. A CD34 immunostain highlights blasts within the postmortem bone marrow core biopsy (3400). C. Vertebral bone marrow showing 70% cellularity, dysplastic megakaryocytes, and blasts (3400). D. A CD34 immunostain highlights blasts comprising 15% of the nucleated cell population within the vertebral bone marrow (3400). E. A lymph node with prominent erythrophagocytosis (arrows) characterized by numerous macrophages distended with red blood cells (3400). F. Fluorescent in situ hybridization revealed monosomy 7.
abnormalities. The international normalized ratio (1.92, normal range 2–3 with anticoagulation therapy), partial thromboplastin time (36.9 seconds, normal range 23– 40.6 seconds), and fibrinogen (196 mg/dL, normal range 177–401 mg/dL) levels were within normal limits. Urine and serum toxicology screens and blood and urine cultures were negative. An electrocardiogram was consistent with pulmonary embolus, and an echocardiogram revealed right
heart and inferior vena cava dilatation. A computed tomographic scan of the chest disclosed a saddle embolus of the left main pulmonary artery and additional emboli in the right middle and right lower lobe pulmonary arteries. A computed tomographic scan of the brain showed no acute intracranial process. Tissue plasminogen activator therapy was initiated. There was continued cardiopulmonary instability to the point of asystolic cardiac arrest from
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Figure 2. A. Posterior aspect of thoracic organ block with noticeable distension of left main pulmonary artery due to the presence of a large saddle embolus. B. Close-up view of left main pulmonary artery distended due to a large saddle embolus. C. Cut section of the left lung showing large left main pulmonary artery embolus (circle), as well as multiple, smaller thromboemboli dispersed throughout all lobes. D. Thromboembolus in a pulmonary arteriole of the right lower lobe with eccentric, fibrocellular intimal proliferation (3400). E. Nonocclusive and occlusive thromboemboli in pulmonary arterioles of the left upper lobe with similar fibrocellular intimal thickening (3200). F. Occlusive thromboembolus in a pulmonary arteriole of the left upper lobe with fibrocellular intimal thickening (3400).
which the patient could not be successfully resuscitated. The duration of the clinical course from initial admission to death was approximately 7 hours.
POSTMORTEM FINDINGS A complete postmortem examination with a postmortem bone marrow biopsy was performed. The bone marrow aspirate and core biopsy revealed hypocellular bone marrow
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(20%–30% cellularity) with multilineage dysplasia and 15% blasts; these findings were consistent with refractory anemia with excess blasts-2 (Fig. 1A). A CD34 immunostain confirmed the presence of blasts (Fig. 1B). A section of the vertebral bone marrow showed similar findings (Fig. 1C,D). Monosomy 7 was detected in the bone marrow aspirate by fluorescent in situ hybridization (Fig. 1F). The spleen and lymph nodes were grossly unremarkable.
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Chest pain, respiratory distress, fever, emesis
Cough, fever
CXR: Interstitial Pneumoniae infiltrate CT: Mediastinal and abdominal LN CXR: RML Pneumoniae infiltrate CT: Saddle embolus L main pulmonary artery
NR
R heart and IVC dilatation at autopsy/echo
Died ,7 hours after admission d/t cardiac arrest
Antibiotics, intubation, and mechanical ventilation, fluids/pressors, TPA
MDS/RAEB-2 NA (postmortem Dx)
Adenocarcinoma, Stomach (small signet ring type focus, 0.4 3 (postmortem Dx) 0.4 cm) (mets to cervical, hilar, peritoneal lymph nodes) Adenocarcinoma, Stomach (mets signet ring type to lung and (premortem Dx) bone marrow)
DSRCT Small bowel (postmortem Dx) serosa (mets to omentum, liver, pancreas, pleura, lymph nodes)
Increased pulmonary pressure on echo, dilated RA and RV at autopsy/ echo Severe pulmonary HTN on echo, dilated RA and RV at autopsy/ echo
Site of malignancy
Primary malignancy
Cardiac findings
Died 5 months after diagnosis of malignancy
Coughing 3 months prior; died 19 days after admission d/t cardiac and respiratory insufficiency
Pallor 1 week prior; died 19 hours after admission d/t cardiac arrest
Time course
Antibiotics, palliative chemotherapy
Intubation and mechanical ventilation, pressors
Cardiomyopathy, Antibiotics, heart failure, diuretics fluid overload
Cough, dyspnea, CXR: Bilateral Lymphoma pulmonary HTN hilar LN CT: LN suspicious for lymphoma
Pallor, syncope, NR perioral cyanosis
Treatment
CT indicates chest computed tomographic scan; CXR, chest radiograph; d/t, due to; DSRCT, desmoplastic small round cell tumor; Dx, diagnosis; echo, echocardiogram; HTN, hypertension; IVC, inferior vena cava; L, left; LN, lymphadenopathy; M, male; MDS, myelodysplastic syndrome; NA, not applicable; NR, not reported; R, right; RA, right atrium; RAEB-2, refractory anemia with excess blasts-2; RML, right middle lobe of lung; RV, right ventricle; mets, metastases; S/S, signs/symptoms; TPA, tissue plasminogen activator therapy.
Current case 11/M
11/M
17/M
Hara [3]
Bla¨ker [1]
12/M
Sadimin [5]
Initial diagnosis
Age Clinical (years)/sex S/S
Case
Imaging
Characteristics of pulmonary tumor thrombotic microangiopathy in children
Table 1.
However, erythrophagocytosis was evident in both organs upon microscopic examination (Fig. 1E). Epstein–Barr virus in situ hybridization was performed on sections of the lymph nodes and bone marrow and was negative. A large recent thromboembolus was present in the left main pulmonary artery (Fig. 2A,B). The lungs contained multiple, smaller thromboemboli present throughout all lobes (Fig. 2C). Diffuse, occlusive, and nonocclusive thromboemboli and fibrocellular intimal proliferation of arterioles were noted, and the vessels contained CD34-positive cells (Fig. 2D,F). Dysplastic myeloid cells and blasts were also present in the interstitium of the lungs. A dilated right atrium, right ventricle, and inferior vena cava were additionally noted.
DISCUSSION Over the attenuated clinical course, this 11-year-old boy was desperately ill with acute respiratory failure initially thought to be due to acute pneumonia, but it later became apparent that he was also in acute right heart failure. Soon thereafter, a thromboembolus was discovered in the left pulmonary artery. It was also known that he had profound anemia and 11% blasts in the peripheral blood. The totality of the pathology only became evident at autopsy. This child had primary MDS, pulmonary thromboemboli, and PTTM. What remains unanswered is whether an inherited thrombophilia also existed in this child, for which there is no data. Myelodysplastic syndromes are classified among the chronic myeloid malignancies that occur overwhelmingly in adults in the 7th decade and beyond [7]. There are such sufficient differences between adult and pediatric MDS that the latter is actually a subtype of MDS referred to as ‘‘childhood myelodysplastic syndrome’’ in the World Health Organization classification [8]. Less than 10% of all hematologic malignancies in children 15 years old or younger are examples of MDS [9]. Some of the difficulties associated with the diagnosis of MDS in children are discussed by Hasle and associates [10]. Childhood MDS can be divided into primary or secondary MDS. Secondary MDS includes disease-attributed acquired conditions, such as chemotherapy/radiation and aplastic anemia, and constitutional conditions, including bone marrow failure (e.g., Shwachman-Diamond syndrome, Fanconi anemia), trisomy 8 mosaicism, and familial MDS. Primary MDS includes all remaining cases [11–13]. A somatic monosomy 7 was detected in the bone marrow sample in our case, an abnormality that is present in approximately 30% of primary MDS cases in children [11]. There are 2 hematologic categories of MDS in children: (1) refractory cytopenia with less than 2% blasts in the peripheral blood (PB) and less than 5% blasts in the bone marrow (BM) (most common pattern) and (2) refractory anemia with excess blasts with 2%–19% blasts in PB and 5%–19% blasts in BM. Of note, refractory anemia with excess blasts in transformation with 20%– 29% blasts in PB and BM was considered a 3rd category in the past; however, according to the current World
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Health Organization Classification, these cases now fall under the category of acute myeloid leukemia with MDS-related changes [10,11,13]. Our patient was an example of the 2nd category, refractory anemia with excess blasts. Approximately 60% of children with refractory anemia with 20% or greater blasts in the BM or PB undergo leukemic transformation within 2.1 years after initial diagnosis [14]. Patients with monosomy 7 in the same series did not survive their illness [14]. The immediate cause of death in our patient was the presence of a macroscopic pulmonary thromboembolus, microthromboemboli, and microscopic vascular changes characteristic of PTTM. Pulmonary tumor thrombotic microangiopathy occurs mostly in adults, with carcinoma of the stomach being the most common associated malignancy in 60%–70% cases, followed by the pancreas [15–17]. Only 3 cases of PTTM are known to date in children, 2 of which occurred in children with gastric carcinomas (Table 1) [2,3,5]. It is well documented that children with a malignancy have a substantially increased risk for thromboembolic complications [18]. It is no surprise that acute lymphoblastic leukemia is the most common childhood malignancy with symptomatic thromboemboli with an incidence varying from 1% to 15%. A central venous line is one risk factor, but not the only one. It has been estimated that 10%–15% of children with acute myeloid leukemia in MDS are at risk for thromboemboli [19]. Of note, macrophage activation syndrome can contribute to hypercoagulopathy. In our case, there were no antecedent events or interventions to explain the macro- or microscopic thrombotic events. Pulmonary tumor thrombotic microangiopathy is characterized by a fibrointimal proliferation in the microarterioles, a process thought to be initiated by malignant cells [15,19]. It is thought that neoplastic cells adhere to the endothelium, causing activation of the coagulation cascade and the release of inflammatory mediators, and that the vascular endothelial growth factor pathway is responsible in part for the subintimal proliferation of myofibroblast-like cells in the small pulmonary arterioles [15,16]. In addition, platelet-derived growth factor, tissue factor, osteopontin, and type 2A serotonin receptor have also been implicated in the development of PTTM, although their exact molecular mechanisms remain undetermined [20]. The anticipation of PTTM as a cause or co-cause of acute respiratory failure is virtually impossible in a patient who has no history of a previously diagnosed malignancy. Unfortunately, none of the pediatric-aged patients with PTTM, including our patient, had a known diagnosis of a primary malignancy prior to clinical presentation. This case illustrates the point that autopsy is still relevant to the practice of medicine, because not all questions are answered before death. REFERENCES 1. von Herbay A, Illes A, Waldherr R, Otto HF. Pulmonary tumor thrombotic microangiopathy with pulmonary hypertension. Cancer 1990;66:587–592.
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