Unusual presentation of pulmonary tumor thrombotic microangiopathy with no detectable primary tumorN Seppala1, A Cala2, S Klebe1
1 Department of Anatomical Pathology, Flinders Medical Centre, Bedford Park, SA 5042, Australia
2 Newcastle Forensic Medicine Unit, John Hunter Hospital, Newcastle, NSW, Australia
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.48439
Source of Support: None, Conflict of Interest: None
Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare condition characterized by the presence of diffuse thrombotic microthrombi and fibrocellular intimal proliferation in the pulmonary vasculature. Its development is linked to the presence of pulmonary tumor microemboli (PTM) and should be suspected in patients with unexplained dyspnea, especially in the presence of adenocarcinoma. PTTM presents in a similar fashion to respiratory disease such as pulmonary embolism, pulmonary hypertension or pneumonia and is usually only diagnosed post-mortem. We report a case of PTTM identified ante-mortem by bronchial biopsy in an 82-year-old woman presenting with a clinical picture of atypical pneumonia. Autopsy confirmed PTTM, from an unknown primary neoplasm.
Keywords: Pulmonary embolism, thrombotic syndromes, tumor, unknown primary tumors
Pulmonary tumor thrombotic microangiopathy (PTTM) is an uncommon pathological entity that involves diffuse thrombotic microemboli and fibrocellular intimal proliferation of the pulmonary vasculature. These features result from the spread of tumor microthrombi to the small arteries, arterioles and capillaries of the lung. PTTM has been observed in 3.3% of autopsy cases with malignancy and is most frequently diagnosed post-mortem.  We present a case of a patient who was clinically diagnosed with organizing pneumonia, however, transbronchial biopsy established the presence of pulmonary tumor microemboli (PTM) with a fibrointimal vascular proliferation conforming to PTTM. These findings were confirmed at autopsy, but no primary tumor could be identified despite a full post-mortem examination.
An 82-year-old woman presented with a two-month history of worsening left chest pain and dyspnea on exertion. She also had a dry, non-productive cough. During a previous admission 10 days earlier, she was diagnosed with atypical pneumonia and treated with doxycycline.
Physical examination, revealed an afebrile patient with tachycardia, a respiratory rate of 20 and a blood pressure of 152/80. Jugular vein pressure was elevated 5-6 cm above the sternal angle and bilateral pitting edema of the ankles was present. There was no hepatomegaly and cardiac auscultation was normal. Bilateral basal crepitations in the lungs were heard.
On oxygen, arterial blood gases showed hypoxemia (68 mm Hg) with pCO 2 and pH values of 33 mm Hg and 7.48 respectively. GGT enzyme levels were elevated (261 U/L). The chest radiograph showed an enlarged heart and areas of confluent opacity in both upper lobes and right middle zone. Echocardiography was not performed, but during an admission for dyspnea two months prior, the patient was shown to have pulmonary hypertension (31-36 mm Hg). The pulmonary arterial phase of the contrast enhanced chest computer tomography demonstrated no filling defects in the pulmonary arteries but several areas of bilateral patchy lung infiltrate were evident [Figure 1]. These findings were thought to represent bronchiolitis obliterans organizing pneumonia. Serology and microbiology testing of sputum and aspirated fluid for microorganisms were negative. Bronchoscopy did not reveal any focal lesions but a transbronchial biopsy obtained from the left lingual lobe demonstrated adenocarcinoma in small pulmonary arteries and arterioles. No solid parenchymal tumor was identified or biopsied, and due to the poor condition of the patient a wedge biopsy was deemed unsuitable. Immunohistochemical labeling revealed positive staining for cytokeratin 7 but not for cytokeratin 20. Immunohistochemical studies for thyroid transcription factor (TTF-1, a marker relatively specific for lung adenocarcinoma) and hormone receptors were negative.
The patient's condition deteriorated and she died three weeks after admission. Lung scintigraphy was not performed at any stage. Post-mortem examination demonstrated edematous lungs with focal areas of hemorrhage seen throughout but mainly in the right upper and middle lobes. No solid parenchymal tumor deposits were found, and there was no significant inflammatory response. Thrombo-emboli occupied the lower lung segments, the largest of which were found in vessels 5 mm in diameter. Gross pathological examination revealed a congested liver (1260 g), marked right atrial, and right ventricular dilatation, and a benign uterine fibrolipoma. No other mass lesions were found, and in particular, no primary tumor mass was identified either in the lungs or elsewhere despite a thorough autopsy.
Microscopically, sections of lung showed diffuse groups of tumor cells occluding many small arteries and arterioles. Thrombi were organized around the malignant cells and there was considerable fibrocellular proliferation of the intimal and medial layers of many vessels resulting in near complete occlusion [Figure 2a],[Figure 2b]. Microscopic metastatic deposits and intravascular tumor were identified in the cerebral white matter, cerebellum and pituitary, but again, solid intraparenchymal tumor was not found [Figure 3].
PTTM is an uncommon complication in individuals with metastatic cancer. In a retrospective study conducted on 630 autopsies of patients with metastatic carcinoma, PTTM was present in 21 (3.3%) of the cases.  Gastric adenocarcinoma (19 cases) is the tumor most commonly associated with PTTM.  The designation PTTM was suggested by Von Herbray et al. , in an attempt to label a pathological process that had accumulated several names in the literature.  The incidence of PTTM is likely underestimated because authors often describe additional features of intimal proliferation (a feature of PTTM) when discussing cases of pulmonary tumour microembolism without specifically referring to the condition. , Distinct from tumor embolism, PTTM requires the presence of intimal proliferation.
Generally speaking, tumor cells can affect the pulmonary vasculature in three different ways. Large tumor emboli can directly occlude the main vessels of the pulmonary tree. Secondly, malignant cells can spread via the lymphatic channels in a process termed carcinomatous lymphangitis. Finally, tumor microemboli in the small pulmonary arterioles may activate tissue factor and serotonin, trigger the formation of microthrombi and stimulate the proliferation of myofibroblasts in the intimal layer.  This proliferative reaction characteristic of PTTM is the result of tumor microemboli in the pulmonary vessels.
PTTM should be included in the differential diagnosis of dyspnea of unknown origin, particularly in patients with previously diagnosed mucin-secreting adenocarcinoma. It may mimic pulmonary thromboembolism, and dyspnea, cough, and pleuritic chest pain are all reported symptoms of the condition.  It is important to make the correct diagnosis to spare the patient from unnecessary thrombolysis, because the major component of PTTM is fibrocelluar proliferation rather than thrombus formation. 
A diagnosis of PTTM is generally made by pulmonary wedge biopsy. Very rarely, as in our case, is a diagnosis achieved by bronchial biopsy or cytology. Because the diagnosis is seldom suspected and the clinical symptoms mistaken, these investigations are rarely performed and the disease is rarely diagnosed pre-mortem. Our case is unusual in that the diagnosis was made on a bronchial biopsy, and prior to the patient's death.
Reports in the literature of pulmonary tumor microembolism mimicking infection are rare. , In our case PTTM simulated bronchiolitis obliterans organizing pneumonia clinically. The diagnostic imaging appearance of PTTM is variable, as it may mimic atypical pneumonia, interstitial lung disease, pulmonary arterial hypertension, miliary TB, or even appear normal. ,,
No treatment was administered in this current case, but chemotherapy is believed to reduce the burden of tumor cells, and thereby lessen the stimulus for intimal proliferation.  Serotonin antagonists may also be of benefit by blocking the pathways leading to intimal fibrocellular proliferation. ,
PTTM represents an important differential diagnosis of dyspnea and may mimic pulmonary thromboembolism, acute pulmonary infection, and pulmonary hypertension. Symptomatic therapies are available, but to be of use clinically, the incidence of pre-mortem diagnoses must increase.
We wish to thank Mr Les Scott for expert help in the preparation of the figures.
[Figure 1], [Figure 2a], [Figure 2b], [Figure 3]