This case report describes a patient with carcinoma of unknown primary site who died because of rapidly progressive dyspnea and hypoxemia and was ultimately diagnosed with PTTM after her death. Therefore, emergency physicians should consider the possibility of PTTM, which represents an oncologic emergency, in patients who present with carcinoma of unknown primary site and pulmonary hypertension and for whom pulmonary embolism has been ruled out.
PTTM was first described in 1990 by Von Herbay et al. (1) as a life-threatening disease associated with severe respiratory failure with rapidly progressive pulmonary hypertension. Unlike pulmonary tumor embolism, PTTM is characterized by fibrous intimal thickening of the peripheral pulmonary arteries, particularly the small arteries. Clinically, PTTM is difficult to differentiate from pulmonary embolism. PTTM is often identified through pathological autopsies and is most commonly associated with gastric carcinoma (2). 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 (3). Godbole et al. (3) analyzed 160 unique cases and reported the following prevalence rates for predominant PTTM symptoms: hypoxemia, 95%; dyspnea, 94 %; abdominal pain, 86%; cough, 85%; and general pain, 73%. In most reported cases of PTTM, elevated D-dimer levels are noted, which makes it even more difficult to distinguish PTTM from pulmonary embolism (4). Moreover, radiological (chest CT) findings for cases of PTTM are nonspecific and include the presence of centrilobular nodules, ground-glass opacities, linear branching opacities, and interlobular septal thickening (5–8).
Upon admission to the hospital, the patient had a mildly elevated D-dimer blood level. 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 of both lungs, we observed the presence of arterial occlusions due to 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, and this finding is typically associated with PTTM rather than pulmonary embolism.
Although the pathogenesis of PTTM remains unclear, it is considered that an activation of the coagulation system and the release of inflammatory mediators lead to the formation of microthrombi and fibrous intimal thickening of small arteries, which in turn results in the progression of pulmonary hypertension. Furthermore, the congregation of macrophages around blood vessels and cell-to-cell signaling via osteopontin and CD44 is speculated to contribute significantly to the pathogenesis of PTTM (2). As mentioned previously, PTTM progresses rapidly. The average duration from onset to hospital admission for PTTM cases is approximately 1 month. In fatal cases, the median survival time is only 5 days (9). Therefore, PTTM is often diagnosed after the patient’s death, and there are only a few reported cases of PTTM that were diagnosed and treated while the patients were still alive. Pulmonary microvascular cytologic evaluation of samples drawn through a wedged pulmonary artery catheter is the most reasonable diagnostic method when the patient is still alive. The sensitivity and specificity of this technique range from 80–88% and 82–94%, respectively (10, 11).
A unique case of PTTM involved a patient who survived for 7 months after receiving imatinib, in addition to chemotherapy for signet-ring cell carcinoma (12). 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 PTTM-associated pulmonary hypertension have been reported, suggesting that imatinib is effective for the treatment of not only the primary tumor, but also pulmonary hypertension (13–15). According to the comprehensive clinical classification system for pulmonary hypertension of the European Society of Cardiology and the European Respiratory Society, pulmonary arterial hypertension is in the group 1 (16). Upfront combination therapy, including treatment with diuretics, prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors, is recommended for patients with class IV pulmonary hypertension (according to the World Health Organization’s functional classification system for 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 comprehensive clinical classification system. To the best of our knowledge, no randomized controlled trials evaluating the efficacy of drugs for the treatment of pulmonary hypertension associated with tumor embolism have been performed thus far (16). Other drugs such as corticosteroids and anticoagulants are easier to introduce and have been used in many cases; however, clear effects have not been observed (11, 17, 18).