Sudden Development of Fatal Pulmonary due to Suspected Pulmonary Tumoral Thrombotic Microangiopathy among Patients with Cancer: Case Series of Clinical and CT Features in 10 Patients

Abstract

Pulmonary tumoral thrombotic microangiopathy (PTTM) is a rare but fatal complication in patients with cancer that causes death due to sudden respiratory distress, pulmonary hypertension, and right ventricular dysfunction. Early diagnosis and intensive treatment are important for improving patient prognosis. Herein, we describe the clinical and CT findings of 10 patients who were clinically diagnosed with PTTM at our hospital over the past 18 years. In patients with cancer complaining of dyspnea and hypoxia, CT findings such as right ventricular and pulmonary artery dilatation, perivascular or subpleural ground-glass opacity or consolidation, micronodules with a ground-glass halo, peripheral pulmonary vessel dilatation, and interlobular septal thickening may suggest PTTM.

INTRODUCTION

Pulmonary tumoral thrombotic microangiopathy (PTTM) can be fatal with a rapid disease course and poor prognosis in patients with cancer. It is a disease process in which non-occlusive microscopic tumor emboli in pulmonary vasculature activate coagulation cascade with fibrin clot formation and stimulates fibrocellular proliferation of the intimal layer at the blood vessel walls (1). This results in pulmonary artery hypertension, causing right-sided heart failure and even death.

However, recent treatment regimens have shown improved outcomes in terms of treatment response and survival rates (1,2,3,4,5,6,7). Therefore, although the pathological diagnosis of PTTM is mostly confirmed by autopsy, early presumptive diagnosis based on CT and clinical findings is important to enable clinicians to initiate aggressive combination therapy with anticoagulants, corticosteroids, and chemotherapy, which may lead to favorable outcomes or prolong patient survival.

The purpose of this study was to review the chest CT findings of patients with suspected PTTM with an overview of their clinical features and disease course.

DESCRIPTION OF CASES

METERIALS AND METHODS

Ten patients diagnosed with suspected PTTM based on clinical features and imaging findings from October 2005 to November 2022 were enrolled. Patients who met the following criteria were enrolled in this study: 1) known underlying malignancy, 2) chest CT performed due to recently developed dyspnea, 3) pulmonary hypertension on echocardiography diagnosed near the time of CT, and 4) absence of visible pulmonary artery thromboembolism or pulmonary disease, such as pulmonary emphysema or fibrosis, which may cause cor pulmonale.

All clinical information, including patient demographics, signs, and symptoms, laboratory results, including mean PaO₂ (mmHg) and D-dimer (mg/L), and echocardiographic findings, were obtained from electronic medical records. Chest CT was performed using a 16- or 64-channel multi-detector row CT scanner, with or without contrast enhancement. Two radiologists retrospectively reviewed CT images. They measured the diameters of the right and left ventricles (RV/LV), pulmonary trunk, and ascending thoracic aorta and recorded abnormal findings in the lung and the presence of mediastinal or hilar lymphadenopathy and pleural effusion.

The present study was approved by the Institutional Review Board of our hospital, and the requirement for informed consent was waived because of the retrospective nature of this study (IRB No. EUMC 2024-01-011).

RESULTS

DEMOGRAPHICS AND CLINICAL FEATURES

Demographic and clinical features of all patients are summarized in Tables 1 and 2, respectively. Breast cancer was the most common primary malignancy (n = 6).

Table 1. Demographic and Clinical Features of 10 Patients with Suspected Pulmonary Tumoral Thrombotic Microangiopathy.

Age, yrs		54.7 ± 15.7 (26–82)
Sex
	Male	1
	Female	9
Symptoms
	Dyspnea	10
	Cough	3
	Hemoptysis	1
Hypoxemia, mean PaO2, mmHg		1060.6 ± 7.7 (54–79)
D-dimer elevation, mg/L		1016.7 ± 13.9 (0.95–35.2)
Elevated RVSP on echocardiography		10
Primary malignancy
	Breast	6
	Lung	1
	Pancreas	1
	Bladder	1
	Papillary carcinoma of unknown origin*	1
Disease status
	Remission	1
	Metastasis	9
	Interval between onset of symptom and death, days†	49 ± 79.0 (4–240)

Data are presented as numbers or means ± standard deviation (range).

^*Confirmed by supraclavicular lymph node biopsy.

^†Two patients were transferred to other hospitals.

RVSP = right ventricular systolic pressure

Table 2. Summary of Clinical Features in 10 Patients with Suspected Pulmonary Tumoral Thrombotic Microangiopathy.

Case No.	Age	Sex	Symptom	PaO2, mmHg	D-dimer*, mg/L	RVSP†, mmHg	Malignancy	Duration‡, days
1	55	F	Dyspnea	52	35.2	51	Unknown§	18
2	59	F	Dyspnea, cough	63	8.17	74	Breast	14
3	66	F	Dyspnea	79	2.35	69	Bladder	14
4	71	F	Dyspnea, cough	63	22.12	43	Breast	4
5	45	F	Dyspnea	57	9.96	60	Breast	60
6	50	F	Dyspnea, cough	63	35.2	57	Breast	30
7	26	F	Dyspnea	63	35.2	78	Lung	∥
8	45	F	Dyspnea	56	9.96	54	Breast	12
9	82	M	Dyspnea	54	7.76	48	Pancreas	∥
10	48	F	Dyspnea, hemoptysis	56	0.95	88	Breast	240

^*Normal range of D-dimer: -0.59 mg/L.

^†RVSP measured by echocardiography.

^‡Interval duration between onset of symptom and death.

^§Papillary carcinoma of unknown origin confirmed by supraclavicular lymph node biopsy.

^∥Transferred to another hospital and lost to follow-up.

RVSP = right ventricular systolic pressure

The most common symptom was dyspnea, followed by cough and hemoptysis. All the patients had hypoxemia, elevated D-dimer levels, and elevated right ventricular systolic pressure (RVSP). The mean interval between onset of symptom and death was 49.7 (standard deviation, ±79.0; range, 4–240) days in eight patients. Two patients were transferred to another hospital and were lost to follow-up.

CT FINDINGS

CT findings are summarized in Tables 3 and 4. Severe RV dilatation was noted in all 10 patients, with an RV/LV ratio >1. Pulmonary trunk dilatation was observed in eight patients (Figs. 1, 2). In one patient who underwent non-contrast-enhanced chest CT, right ventricular dilatation was recognized by observing the deviation of the anterior interventricular groove to the left (Case 3, Fig. 3A), although ventricular diameters could not be measured. Lung abnormalities included interlobular septal thickening (90%), ground-glass opacity (GGO) (70%), nodules (70%), peripheral pulmonary vessel dilatation (60%), and consolidation (40%) (Figs. 2, 3, 4, 5). GGO and consolidation showed a perivascular, subpleural, or random distribution. Most nodules and dilated peripheral vessels were associated with GGO halos. Pleural effusion (50%) and mediastinal or hilar lymphadenopathy (60%) were also observed.

Table 3. CT Features of 10 Patients with Suspected Pulmonary Tumoral Thrombotic Microangiopathy.

CT Features			No. of Patients (Total = 10)
Heart and pulmonary trunk
	RV/LV ratio (mid ventricular level) >1 (Range; Mean; SD = 1.44 – 2.93; 2.08; 0.55)		10 (100)
	Pulmonary trunk/ASC. aorta ratio >1 (Range; Mean; SD = 1.00 – 1.48; 1.08; 0.17)		8 (80)
Lung
	Interlobular septal thickening		9 (90)
	GGO		7 (70)
		Perivascular	7 (70)
		Subpleural	7 (70)
		Random	2 (20)
Nodules			7 (70)
	≤1 cm		7 (70)
	>1 cm		1 (10)
	Surrounding GGO halo		6 (60)
Peripheral pulmonary vessel dilatation			6 (60)
	Subpleural		6 (60)
	Non-subpleural		3 (30)
	Surrounding GGO		5 (50)
Consolidation			4 (40)
	Subpleural		4 (40)
	Perivascular		3 (40)
Others
	Lymphadenopathy		6 (60)
	Pleural effusion		5 (50)

Data are presented as numbers (%).

ASC. = ascending, GGO = ground-glass opacity, LV = left ventricle, RV = right ventricle, SD = standard deviation

Table 4. Summary of CT Features in 10 Patients with Suspected Pulmonary Tumoral Thrombotic Microangiopathy.

Case No.	Heart and Pulmonary Trunk		Lung									Lymphadenopathy	Pleural Effusion
	RV/LV ratio >1 (ratio)	PT/AA ratio >1 (ratio)	IST	GGO			Nodules		Consolidation		PPVD
				Perivascular	Subpleural	Random	<1 cm	>1 cm	Subpleural	Perivascular
1	+(2.87)	+(1.31)	+									+	+
2	+(1.6)	+(1.13)	+	+	+		+		+		+
3	+		+	+	+		+			+	+	+	+
4	+(2.73)		+	+	+
5	+(2.25)	+(1.06)	+		+						+	+	+
6	+(2.93)	+(1.03)		+			+	+				+
7	+(2.56)	+(1.43)	+	+	+	+	+		+	+	+	+	+
8	+(2.04)	+(1.17)	+	+	+		+		+		+	+
9	+(1.4))	+(1.15)	+				+						+
10	+(1.87)	+(1.48)	+	+	+	+	+		+	+	+

AA = ascending aorta, GGO = ground-glass opacity, IST = interlobular septal thickening, LV = left ventricle, PPVD = peripheral pulmonary vessel dilatation, PT = pulmonary trunk, RV = right ventricle

Fig. 1. A 55-year-old female presented with neck mass and biopsy from supraclavicular lymphadenopathy confirmed papillary carcinoma of unknown origin.

A, B. Initial CT scan shows metastatic mediastinal lymphadenopathy and right pleural effusion.

C, D. Five days later, the patient complained of sudden aggravation of dyspnea with hypoxemia (PaO₂ = 52 mmHg) and markedly elevated D-dimer levels. CT reveals severe enlargement of the right atrium and ventricle with pulmonary trunk dilatation. The patient died on following day.

Fig. 2. A 59-year-old female who visited ER due to dyspnea and was then diagnosed with breast cancer.

A, B. Contrast-enhanced CT scans obtained in the ER show marked dilatation of the right ventricle, suggestive of severe pulmonary hypertension. The pulmonary trunk is also slightly enlarged compared with the ascending aorta.

C-F. CT images of the lung window setting demonstrate a small nodule with a surrounding GGO halo (white arrows in C and E), focal dilatation of subpleural or peripheral pulmonary vessels with perivascular GGO (circles in D and F), focal subpleural consolidations or GGO (black arrows in E and F), and minimal interlobular septal thickening (arrowhead in F). The patient died 1 week after the CT was performed.

ER = emergency room, GGO = ground-glass opacity

Fig. 3. A 66-year-old female with bladder cancer and axillary lymph node and bone metastasis had sudden onset of dyspnea and showed hypoxemia (PaO₂ 79 mmHg).

A. Non-contrast-enhanced CT demonstrates deviation of the anterior interventricular groove to the left (arrow), suggestive of right ventricular dilatation.

B. Axial lung window image shows ill-defined perivascular and subpleural GGO in the right lung (black arrows), a small nodule with surrounding GGO halo in the left upper lobe (white arrow), and interlobular septal thickening in both lungs (arrowheads).

C, D. Coronal images demonstrate focal dilatation of the peripheral pulmonary vessels surrounded by GGO in both upper lobes (circles), diffuse perivascular GGO, and consolidation in the right lung (arrows). With the aggravation of dyspnea, the patient died the following day.

GGO = ground-glass opacity

Fig. 4. A 71- year-old female, who had left mastectomy due to breast cancer 3 months ago with no known metastasis, visited ER due to intermittent cough and sudden aggravation of dyspnea. The patient showed elevation of D-dimer and hypoxemia (PaO₂ 63 mmHg).

A, B. Contrast-enhanced CT shows severe right atrial and ventricular dilatation without significant enlargement of the pulmonary trunk, suggestive of severe acute pulmonary hypertension.

C, D. Lung window images demonstrate focal subpleural (arrows) and extensive perivascular (arrowheads, D) GGO in both lower lobes. A pulmonary vessel connected to the subpleural focal GGO was noted in the right lower lobe (arrowhead, C). The patient died the following day.

GGO = ground-glass opacity

Fig. 5. A 45-year-old female, who had undergone left mastectomy due to breast cancer and was on palliative chemotherapy due to chest wall and skin metastasis.

A. Contrast-enhanced CT scan obtained 8 days prior in an outpatient care center shows diffuse chest wall metastasis at the left mastectomy site.

B. CT performed at the ER reveals newly developed severe right ventricular dilatation.

C, D. Coronal lung window images show dilatation of small peripheral vessels with perivascular ground-glass opacities in subpleural lung of the left upper lobe (circles). The patient showed rapid improvement in dyspnea and right ventricular dilatation after extensive treatment with chemotherapy combined with corticosteroids and diuretics and was discharged. However, she revisited ER because of severe dyspnea and died 75 days after the initial ER visit.

ER = emergency room

CASE SERIES

Case 1

A 55-year-old female visited our hospital with a neck mass and papillary carcinoma of unknown origin was diagnosed by supraclavicular lymph node biopsy. Initial CT showed metastatic mediastinal lymphadenopathy and right pleural effusion (Fig. 1A, B). Five days later, she complained of sudden aggravation of dyspnea with hypoxemia (PaO₂ = 52 mmHg) and a markedly elevated D-dimer level (1861 mg/L). A follow-up CT scan revealed newly developed severe enlargement of the right atrium and ventricle with pulmonary trunk dilatation (Fig. 1C, D). The patient died the following day.

Case 2

A 59-year-old female visited the emergency room (ER) because of dyspnea and was diagnosed with breast cancer during admission. She had hypoxemia (PaO₂ = 63 mmHg) and elevated D-dimer (8.17 mg/L), and echocardiography demonstrated severe pulmonary hypertension (RVSP = 74 mmHg). A contrast-enhanced chest CT scan performed in the ER revealed marked dilatation of the RV, suggestive of severe pulmonary hypertension (Fig. 2A, B). The pulmonary trunk was also slightly enlarged compared with the ascending aorta. CT images of the lung window setting revealed a small nodule with a surrounding GGO halo, focal dilatation of the subpleural or peripheral pulmonary vessels with perivascular GGO, focal subpleural consolidations or GGO, and minimal interlobular septal thickening (Fig. 2C-F). The patient died 1 week after the CT was performed.

Case 3

A 66-year-old female with bladder cancer and axillary lymph node and bone metastases was admitted to our hospital with sudden dyspnea. She had hypoxemia (PaO₂ =79 mmHg) with mild elevation of the D-dimer (2.35 mg/L), and echocardiography demonstrated moderate-to-severe pulmonary hypertension (RVSP = 69 mmHg). A non-enhanced chest CT scan demonstrated deviation of the anterior interventricular groove to the left, suggestive of right ventricular dilatation (Fig. 3A), ill-defined perivascular and subpleural GGO, a small nodule with a surrounding GGO halo, and interlobular septal thickening in both lungs (Fig. 3B). Coronal images showed focal dilatations of the peripheral pulmonary vessels with surrounding GGO in both upper lobes, diffuse perivascular GGO, and consolidation in the right lung (Fig. 3C, D). With the aggravation of dyspnea, the patient died the following day.

Case 4

A 71- year-old female, who had undergone left mastectomy for breast cancer 3 months prior to presentation visited the ER because of intermittent cough and sudden aggravation of dyspnea. The patient had elevated D-dimer (22.12 mg/L) and hypoxemia (PaO₂ = 63 mmHg). Echocardiography revealed mild pulmonary hypertension (RVSP, 43 mmHg). Contrast-enhanced CT showed severe right atrial and ventricular dilatation without significant enlargement of the pulmonary trunk, suggesting severe acute pulmonary hypertension (Fig. 4A, B). Lung window images revealed focal subpleural and extensive perivascular GGO in both lower lobes (Fig. 4C, D). A pulmonary vessel connected to the subpleural focal GGO was observed in the right lower lobe (arrowhead in Fig. 4C). The patient died the following day.

Case 5

A 45-year-old female visited the ER with sudden onset of dyspnea. She had undergone left mastectomy for breast cancer and was receiving palliative chemotherapy for chest wall and skin metastases. In the ER, laboratory findings showed severe hypoxemia (PaO₂ = 52 mmHg) and elevated D-dimer (9.96 mg/L). Echocardiography revealed moderate pulmonary hypertension (RVSP, 60 mmHg). A contrast-enhanced CT scan obtained 8 days prior at the outpatient care center showed diffuse chest wall metastasis at the left mastectomy site (Fig. 5A). However, a CT scan performed in the ER revealed a newly developed severe right ventricular dilatation (Fig. 5B). Coronal lung window images showed dilatation of the small peripheral vessels with perivascular ground-glass opacities in subpleural lung of the left upper lobe (Fig. 5C, D). After extensive treatment with chemotherapy combined with corticosteroids and diuretics, the patient showed rapid improvement in dyspnea and right ventricular dilatation and was discharged. However, a few days later, she revisited ER because of severe dyspnea and died 75 days after the initial ER visit despite aggressive treatment.

DISCUSSION

PTTM, defined by von Herbay et al. (8) in 1990, is characterized by diffuse intimal myofibroblast proliferation in the pulmonary blood vessels of patients with an underlying malignancy. The pathological morphology of PTTM differs from that of pulmonary tumor embolism. Vascular obstruction by tumor emboli is emphasized in tumor embolisms. However, in PTTM, there is marked activation of the coagulation system with intimal proliferation in the small pulmonary arteries, increasing resistance (8). This may lead to pulmonary hypertension and acute right-sided heart failure.

In previous studies, the most frequent tumor associated with PTTM was stomach cancer, and >90% of the cases were adenocarcinomas (8,9). In our study, the primary cancer was breast cancer in most patients, followed by lung, pancreatic, and bladder cancers in one patient each. This is probably due to the increase in early detection of stomach cancer using endoscopy, the increased cure rate due to advanced treatment techniques, and the fact that our institute has a breast cancer center.

The most common symptom of PTTM is subacute or rapidly progressive dyspnea. The pathophysiology of dyspnea may be due to pulmonary hypertension, which results in increased RV afterload, reduced RV cardiac output, and hypoxemia (9). Common abnormalities in laboratory analyses include hypoxemia, elevated D-dimer levels, anemia, thrombocytopenia, and elevated lactate dehydrogenase (9). The elevated D-dimer level observed in all patients in our study was most likely due to the activation of the coagulation cascade, aggregation of platelets, and subsequent breakdown of fibrinogen into fibrin degradation products (10), which is the key pathophysiology of PTTM.

Pulmonary hypertension due to PTTM most likely occurs because of luminal occlusion by tumor cells, fibrin deposition, and fibrocellular intimal hyperplasia. The degree of pulmonary hypertension depends on the degree of stenosis of the pulmonary vessels and the extent of blood vessel involvement. Therefore, patients with PTTM may not show pulmonary hypertension in its early stages. In a study by Herbay et al. (8), in which 21 of 630 consecutive autopsy cases of carcinoma were diagnosed with PTTM, features of increased pulmonary vascular resistance were present in ten of 21 patients. In a systematic review of 160 cases of PTTM, pulmonary hypertension on echocardiography was noted in 89% of patients.

In our study, almost all patients with PTTM underwent CT scans in the ER, and the most notable finding was dilatation of the RV and pulmonary trunk. In patients previously diagnosed with cancer, the finding of RV dilatation on CT was the greatest clue to suspect PTTM when other causes of pulmonary hypertension could be ruled out. However, RV dilatation may not be an evident on CT even in the presence of pulmonary hypertension. In our study, one case did not show RV dilatation on the initial CT at the time the patient was diagnosed with pulmonary hypertension on echocardiography, and RV dilatation developed on follow-up CT with worsening symptoms.

In a systematic review of 160 published cases of PTTM by Godbole et al. (9), the most common CT findings in 94 patients with gastric cancer were lymphadenopathy (84%), followed by septal thickening (71%), nodules (58%), tree-in-bud (55%), and GGO (36%), whereas in patients without gastric cancer, GGO (64%) was the most common, followed by pleural effusion (62%), consolidation (53%), tree-in-bud (45%), nodule (42%), then septal thickening (29%). GGO may reflect tumor infiltration of the alveolar septae (11), interstitial and air space edema, or interstitial inflammation (12,13). Nodules generally seen in a centrilobular distribution are most likely to result from the hematogenous spread of malignancy through the pulmonary arterioles (14). The histological correlation of septal thickening is thought to be engorgement of lymphatic channels (14).

In our study, the most common CT finding was septal thickening, but the unique CT findings were GGO showing perivascular distribution (70%), subpleural wedge-shaped areas of GGO or consolidation (70%), and micronodules (70%) or peripheral linear or branching structures (60%) surrounded by GGO, presumed to be dilated small pulmonary arteries. Peripheral branching structures were more clearly identified as dilated small pulmonary arteries on coronal images than on axial images. In a case report of breast cancer with PTTM, Febres-Aldana et al. (15) described these characteristic CT findings by correlating them with histopathological findings at autopsy. Centrilobular nodules with peripheral GGO opacities corresponded to obliteration of a small-to medium-sized artery by tumor emboli with intimal proliferation, lymphangitic carcinomatosis, and cellular interstitial fibrosis, while peripheral wedge-shaped areas of GGO or consolidation were caused by evolving pulmonary infarction and proximal tumor embolus within a medium-sized pulmonary artery. These characteristic CT findings are useful for differentiating PTTM from other causes of hypoxemia or pulmonary hypertension in patients with cancer.

PTTM is a fatal condition with a rapid disease course and poor prognosis in patients with malignancy. The diagnosis of PTTM is difficult before pathological confirmation through autopsy, whereas the general condition of patients suspected of having PTTM does not allow any invasive procedure for tissue confirmation. Although PTTM shows a rapid clinical course and poor prognosis, several treatments, including advanced pulmonary hypertension therapy, anti-neoplastic agents, anticoagulants, diuretics, and corticosteroids, have been attempted, and there are several case reports in which outcomes were improved by early aggressive treatments (1,2,3,4,5,6,7,16). In our study, the average interval between symptom onset and death was 49 days, and most patients died just a few weeks after the onset of symptoms, except for one who received early aggressive treatment and survived for 240 days after the initial onset of symptoms. Therefore, it is important for clinicians to suspect PTTM early and initiate aggressive treatment to prolong patient survival. Characteristic CT findings of PTTM may lead radiologists to suggest PTTM to clinicians.

Our study has few limitations. First, all the patients were not pathologically confirmed to have PTTM. They were diagnosed with PTTM based on clinical and imaging features because their overall condition did not allow for any invasive procedure for tissue confirmation, and none of them underwent a post-mortem autopsy. However, there are several case reports in which PTTM was clinically diagnosed without lung biopsy, in seven cases (9). Second, the number of cases was small, and more than half of the underlying cancers were breast cancer. Therefore, the results of this study may not represent the survival time after symptom onset or the characteristic CT findings in all patients with PTTM.

In conclusion, PTTM must be considered early in the differential diagnosis of patients with cancer who have unexplained hypoxemia and pulmonary hypertension. CT findings of severe or rapidly progressing RV dilatation and pulmonary abnormalities including perivascular or subpleural wedge-shaped GGO or consolidation, micronodules with GGO halo, peripheral pulmonary vessel dilatation surrounded by GGO, and septal thickening, may be helpful for differential diagnosis.