Introduction

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare form of pulmonary arterial embolism caused by tumor cells. In PTTM cases, the endothelial attachments of multiple microscopic tumor cell emboli induce fibrocellular intimal proliferation of small pulmonary arteries and arterioles combined with secondary thrombosis, resulting in pulmonary arteriole stenosis or obstruction, which causes pulmonary hypertension (PH), leading to acute or subacute cor pulmonale and respiratory failure [1].

An antemortem PTTM diagnosis is difficult because the chest computed tomography (CT) findings are often trivial or non-specific, and the disease rapidly progresses to death. In a previous study, 7 of 103 patients were pathologically diagnosed with PTTM while still alive [2], and their prognosis was unclear; however, few patients had a survived for several months. We report the case of a patient with PTTM associated with gastric cancer who was diagnosed antemortem and responded to immediate chemotherapy. Written informed consent was obtained from the patient for publishing this case report and any accompanying images.

Case report

A 43-year-old woman presented to a different hospital 1 month prior with complaints of productive cough lasting for 2 months and dyspnea interfering with her daily life (Hugh–Jones IV) that progressed rapidly 1 week before admission to our hospital. Contrast-enhanced CT and upper gastrointestinal endoscopy were performed. She was diagnosed with gastric cancer and referred to our hospital for advanced respiratory failure. Upon clinical examination, her temperature, heart rate, blood pressure, and oxygen saturation were 36.7 °C, 109 beats/min, 100/66 mmHg, and 90%, respectively. Blood tests indicated that inflammatory markers were slightly elevated—white blood cell count (7690/mm3), neutrophil count (78%), C-reactive protein levels (0.61 mg/L), and procalcitonin levels (0.02 ng/mL). She demonstrated slight abnormalities in the coagulation and fibrinolytic systems with D-dimer levels at 3.8 µg/mL (normal: < 1 µg/mL). N-terminal pro-brain natriuretic peptide (NT-proBNP; 316 pg/mL), carcinoembryonic antigen (2.6 ng/mL), cytokeratin 19 fragment (137 ng/mL) were elevated. Chest radiography revealed multiple bilateral granular shadows (Fig. 1). Contrast-enhanced CT demonstrated multiple areas of interlobular septal thickening and ground-glass opacities in both lungs, which were not observed 3 weeks prior, and intra-abdominal lymphadenopathy (Fig. 2). No visible pulmonary embolisms were observed. Upper gastrointestinal endoscopy revealed a 5 cm sized 0–IIc depressed-type lesion on the posterior wall of the lower body of the stomach (Fig. 3a). The pathological diagnosis was signet-ring cell carcinoma (Fig. 3b). Hypoxemia worsened rapidly after admission (SpO2: 88% with a nasal cannula delivering 2 L/min), and PTTM associated with gastric cancer was suspected based on the imaging findings, demonstrating shadows of the rapidly developing bilateral lung fields. Pulmonary blood flow scintigraphy revealed multiple wedge-shaped or small peripheral patchy areas with reduced blood flow (Fig. 4a). Transthoracic echocardiography revealed normal left ventricular systolic function with an ejection fraction of 64%; however, significant enlargement of the right ventricle and atrium, compressed D-shaped left ventricle (Fig. 4b), and elevated tricuspid regurgitation pressure gradient (TRPG; 43 mmHg) were observed. Right heart catheterization was performed and confirmed significant PH (mean pulmonary arterial pressure, 44 mmHg; cardiac index, 2.1 L/min/m2). Cytological examination using the Papanicolaou and Giemsa staining revealed that blood from the right heart catheter did not contain malignant cells. She was unable to tolerate bronchoscopy or lung biopsy because of dyspnea. Without a pathological diagnosis, we diagnosed PTTM based on the following clinical findings: (1) confirmation of gastric cancer, (2) acute progression of respiratory failure with severe PH, (3) no specific CT findings of pulmonary embolism or chronic thromboembolic PH, and (4) multiple subsegmental peripheral perfusion defects.

Fig. 1
figure 1

Chest radiographic findings showing multiple bilateral granular shadows

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Fig. 2
figure 2

Chest computed tomography image showing progressive multiple lung shadows. a At 3 weeks before admission. b On admission day; arrows show interlobular septal thickening and ground-glass opacities. c Swelling of the lymph nodes on the lesser curvature side of the stomach; arrows present intra-abdominal lymphadenopathy. d At 1 month after discharge, chest computed tomography findings showed improvement in the bilateral lung field shadows

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Fig. 3
figure 3

a Upper gastrointestinal endoscopy image showing a 5 cm sized 0–IIc depressed-type lesion on the posterior wall of the lower body of the stomach. b The section of the lesion that was stained with hematoxylin and eosin staining showing poorly differentiated adenocarcinoma involving signet-ring cells (yellow arrows)

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Fig. 4
figure 4

Different imaging techniques used for diagnosing pulmonary tumor thrombotic microangiopathy. a Pulmonary blood flow scintigraphy image showing multiple wedge-shaped or small peripheral patchy areas of reduced blood flow. Red indicates high blood flow and blue indicates low blood flow. b Transthoracic echocardiogram showing a D-shaped left ventricle suggesting right heart overload

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We determined that immediate treatment was required. On the 3rd day after admission, chemotherapy was initiated with S-1 (tegafur/gimeracil/oteracil potassium, 120 mg/m2; days 1–21) and oxaliplatin (130 mg/m2; day 1). Anticoagulation therapy with continuous infusion of heparin (10,000–15,000 U/day) and morphine hydrochloride (20 mg/day) were administered for symptomatic relief. Three days after chemotherapy initiation, cough and hypoxemia rapidly decreased. NT-proBNP and TRPG levels decreased from day 5, and the second course of chemotherapy was maintained and administered 24 days after admission. On day 28, her respiratory distress symptoms improved (Hugh–Jones II), and she could continue her daily activities; she was discharged without supplemental oxygen. At discharge, NT-proBNP levels had improved from 316 to 58 pg/mL, and TRPG had improved from 43 to 22 mmHg. Additionally, imaging findings were improved after discharge (Fig. 2d). Five courses of S-1/ oxaliplatin were maintained, and direct oral anticoagulant (Rivaroxaban) was administered in the outpatient department; however, 3 months after discharge, the patient was readmitted due to respiratory distress. Chest radiographic and CT examinations revealed multiple bilateral granular shadows similar to the previous findings. The NT-proBNP and TRPG levels had increased to 11,571 pg/mL and 52 mmHg, respectively. She was diagnosed with relapsed PTTM. The gastric cancer guidelines in Japan recommend a combination of paclitaxel and ramucirumab as a second-line treatment [3]. However, because of her poor general health condition, it was difficult to administer antitumor drugs. Therefore, ramucirumab (8 mg/kg) only was administered 3 days after re-admission. However, no improvement was observed, and the patient died 3 days after ramucirumab initiation.

Discussion

PTTM is a rare and fatal complication of cancer featuring widespread tumor cell emboli in the small arteries and arterioles of the lung, resulting in thrombus formation. PTTM differs from conventional tumor embolisms by the presence of fibrocellular intimal proliferation [1]. It was first described in 1990 and detected in 3.3% of cancer cases in a retrospective study that examined 630 consecutive metastatic carcinoma cases [1]. Fujishiro et al. [2] reported 103 cases of PPTM; among which, gastric cancer was the most frequent (58 cases), followed by lung (10), breast (seven), unknown primary origin (five), ovaries (five), and bladder (four) cancer. The mean duration from PTTM onset to hospital admission was approximately 1 month, and the median survival after admission was only 5 days [2]. Recently, it has been reported that a prognosis of several months can be obtained by making an antemortem diagnosis and starting chemotherapy [4,5,6,7,8]. The time from PTTM onset to death is limited; hence, although it is clinically challenging, early diagnosis is essential for survival.

Several patients with PTTM have been diagnosed antemortem previously and undergone chemotherapy (Table 1) [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. The median survival time was 90 days for patients who started treatment. Furthermore, all patients with satisfactory outcomes started treatment within 10 days after admission [5, 7, 13, 14, 18, 20]. Early treatment with imatinib was reported to be particularly effective [4, 5, 13, 20]. In our case, satisfactory results were obtained after chemotherapy for primary cancer 3 days after admission with 4 months of survival after treatment initiation. Furthermore, improved respiratory symptoms and general condition were observed.

Table 1 Previously reported antemortem diagnoses of pulmonary tumor thrombotic microangiopathy and treatment details
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Early PTTM diagnosis is critical. Chest CT may help demonstrate ground-glass opacification, septal thickening, nodules, and mediastinal/hilar lymphadenopathy; however, in our case, CT had a low specificity for diagnosing PTTM due to gastric cancer [21]. Although some specific imaging findings exist, it is vital to suspect PTTM based on various characteristics. PH is an important clinical sign of PTTM, strongly contributing to a poor prognosis. The progression rapidity is likely related to the right ventricle’s ability to compensate for the pressure and/or volume overload, and right heart catheterization is important for diagnosis and severity assessment [21]. Furthermore, wedged pulmonary arterial blood cell sampling has high sensitivity and specificity in diagnosing PTTM without a biopsy [22, 23]. In our case, the cytopathology results were negative in blood samples from the right heart catheter; however, right heart overload was diagnosed. Although a pathological diagnosis was not possible, we clinically diagnosed PTTM based on the CT findings, gastric cancer presence, decreased pulmonary blood flow, and right heart load results. The clinical antemortem diagnosis of PTTM was followed by immediate treatment, which made 4-month survival possible.

Several treatments have been attempted for patients diagnosed with or suspected PTTM (i.e., advanced PH therapy and administration of anti-neoplastic agents, anticoagulants, diuretics, and corticosteroids); to the best of our knowledge, a definitive treatment has not been established. Recently, imatinib, an inhibitor of platelet-derived growth factor receptor, which may have a role in reducing the vascular remodeling that promulgates PH, was reported as a therapeutic strategy for PTTM cases and should be studied extensively [5, 7, 13, 14, 20]. In our case, PTTM was improved after using anticoagulants and anticancer drugs other than imatinib. Moreover, vascular endothelial growth factor (VEGF) is suspected to be involved in PTTM and PH, and the VEGF inhibitors, bevacizumab and ramucirumab, are reported to improve PH [4, 8]. However, ramucirumab, a VEGF inhibitor, did not improve the patient outcome after relapse. Chemotherapy removes malignant cells from the pulmonary circulation and may reduce fibrointimal proliferation in PTTM. Here, S-1 and oxaliplatin therapies for treating gastric cancer were effective [3]. Although the chemotherapy regimen remains controversial, PTTM should be diagnosed as early as possible for treatment initiation.

In conclusion, we clinically diagnosed and treated PTTM in this patient. Immediate chemotherapy initiation was initially successful, suggesting that such treatment may extend the survival of patients with cancer and PTTM.