The findings in a case involving a patient with carcinoma of unknown primary site, who died due to rapidly progressive dyspnea and hypoxemia and was diagnosed after her death as having PTTM, have been highlighted in this report. With respect to cases involving patients with carcinoma of unknown primary site who have pulmonary hypertension, but in whom the presence of pulmonary embolism can be ruled, emergency physicians should remember and consider the possibility of the patients having PTTM, which represents an oncologic emergency.
PTTM is a condition that was first described by Von Herbay et al. in 1990 ; it is a life-threatening disease because it is associated with the occurrence of severe respiratory failure with rapidly progressive pulmonary hypertension. Unlike pulmonary tumor embolism, PTTM is characterized by fibrous intimal thickening of peripheral pulmonary arteries, especially the small arteries. Clinically, it is difficult to differentiate between PTTM and pulmonary embolism; PTTM is often identified through pathological autopsies, and it is most commonly associated with gastric carcinoma . Furthermore, other types of primary cancer that have been reported to be complicated by PTTM include breast cancer, tongue cancer, hepatocellular carcinoma, colorectal cancer, and prostate cancer . RH Godbole et al. found that with respect to the main symptoms reported in 160 unique cases of PTTM, hypoxemia, dyspnea, abdominal pain, cough, and general pain were reported in 95%, 94 %, 86%, 85%, and 73% of the cases, respectively . It has also been reported that in most cases of PTTM, there is an elevation in D-dimer levels, which makes it even more difficult to differentiate PTTM from pulmonary embolism . Moreover, in cases of PTTM, the radiological findings obtained through chest CT, such as the presence of centrilobular nodules, ground-glass opacities, linear branching opacities, and interlobular septal thickening, are nonspecific [5–8].
In the present case, when the patient was admitted to the hospital, there was a mild elevation in the level of D-dimer in the patient’s blood; however, chest CT did not reveal any significant findings, and we could not make a definitive diagnosis before the patient’s death. Through the pathological autopsy performed in this case, over a wide area in both lungs, we observed the presence of arterial occlusions caused by microthrombi and tumor emboli that were present in pulmonary arterioles, accompanied by congestion and hemorrhage. Fibrous intimal thickening of the pulmonary arteries was also noticeable; this finding is typically associated with PTTM rather than pulmonary embolism. Although the pathogenesis of PTTM is still unclear, it is thought that an activation of the coagulation system and release of inflammatory mediators leads to the formation of microthrombi and fibrous intimal thickening of small arteries, which in turn lead to the progression of pulmonary hypertension. It has also been reported that in cases of PTTM, there is a congregation of macrophages around blood vessels, and cell-to-cell signaling via osteopontin and CD44 is thought to contribute significantly to the pathogenesis of PTTM . As mentioned previously, PTTM progresses rapidly, and reports indicate that in cases of PTTM, the average duration from the onset of PTTM in a patient to the patient’s admission to a hospital is about 1 month, and in fatal cases, the median survival time is only 5 days . Therefore, in many cases of PTTM, PTTM is diagnosed after the patients have already died; so far, in only a few reported cases of PTTM, patients were diagnosed and treated while they were still alive. Pulmonary microvascular cytology with the study of samples drawn through a wedged pulmonary artery catheter is the most reasonable method for making a diagnosis when a patient is still alive, it has been reported that the sensitivity and specificity of this technique range from 80–88% and 82–94%, respectively [10, 11].
A unique case regarding a patient with PTTM has been reported previously; in this case, the patient survived for 7 months after receiving imatinib in addition to chemotherapy for signet-ring cell carcinoma . Imatinib is a platelet-derived growth factor receptor-tyrosine kinase inhibitor that has the potential to cause reverse remodeling due to its proliferation-inhibitory, apoptosis-inducing, and vasoconstrictive effects. Several other cases involving the use of imatinib for the treatment of pulmonary hypertension caused by PTTM have been reported, suggesting that imatinib is effective not only for the treatment of the primary tumor but also for the treatment of pulmonary hypertension [13–15]. According to the guidelines of the European Society of Cardiology and the European Respiratory Society for the diagnosis and treatment of pulmonary hypertension, pulmonary arterial hypertension is included in group 1 of the Nice classification of pulmonary hypertension, and upfront combination therapy, such as treatment with diuretics, prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors, is recommended for patients who, according to the World Health Organization’s functional classification of pulmonary hypertension, have class Ⅳ pulmonary hypertension, which is often observed in intensive care units (this therapy should be considered for patients with class Ⅱa disease and may be considered for patients with class IIb disease). However, pulmonary hypertension related to tumor embolism is included in group 5 of the Nice classification. To the best of our knowledge, no randomized controlled trials depicting the efficacy of drugs for the treatment of pulmonary hypertension associated with tumor embolism have been performed so far . Other drugs such as corticosteroids and anticoagulants are easier to introduce and have been used in many cases; however, no clear effects have been observed [11, 17, 18].
Because there is no standard diagnostic approach for PTTM, if there is a sudden worsening of the respiratory status of a patient who has carcinoma of unknown primary site and pulmonary hypertension, emergency physicians and intensivists should remember and consider that in addition to the possibility of the patient having pulmonary embolism, the patient may have PTTM, which is an oncologic emergency. Furthermore, if a patient is suspected of having PTTM, we believe it is necessary to begin the administration of chemotherapy as soon as it is possible to do so according to the etiology of PTTM; additionally, it is important to continue to search for the primary cancer site in the patient.