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Occult Gastric Cancer Presenting as Hypoxia from Pulmonary Tumor Thrombotic Microangiopathy

Pulmonary tumor thrombotic microangiopathy (PTTM) causing fatal pulmonary hypertension is a rare presentation of malignancy. In general, patients with PTTM rapidly succumb to death due to severe hypoxia. To date, very few cases of PTTM have been reported in the literature; and most of these cases were from gastric cancer and were diagnosed on post mortem autopsy, as it is extremely challenging to make an ante mortem diagnosis. We here report on a case of undiagnosed diffuse gastric cancer, presenting as worsening hypoxia. The clinical, radiographic, and echocardiographic features, and laboratory and pathological results were consistent with PTTM from gastric cancer. The patient was started on anticoagulation therapy, corticosteroids, and high-flow oxygen. However, her hypoxia worsened to the extent that she required ventilator support, and she died soon after intubation due to cardiac arrest. Since diffuse gastric cancer is associated with hereditary diffuse gastric cancer syndrome, cadherin 1 gene mutation analysis was performed to estimate the risk to her daughters. The test came back negative.


Introduction
Pulmonary tumor thrombotic microangiopathy (PTTM), first defined by von Herbay et al. 1 in 1990, is a rare and fatal pulmonary complication associated with various malignancies. Based on limited retrospective case series and reports, it has been shown to be most frequently associated with gastric cancer. 1

Case Report
A 41-year-old previously healthy woman presented to the hospital with dyspnea on exertion and dry cough for 1 week. A computed tomography (CT) scan of the chest revealed small medi-astinal lymph nodes. The patient was discharged on a tapering dose of oral steroids and albuterol inhalation with a follow-up outpatient appointment with a pulmonologist. An endobronchial ultrasoundguided biopsy of the mediastinal lymph nodes was performed 1 week later. The patient had worsening dyspnea and was again admitted to the hospital. She denied any orthopnea or paroxysmal nocturnal dyspnea. On admission, the physical examination, including chest auscultation, was unremarkable. Initial basic blood work, including complete cell count and metabolic profile, revealed no abnormalities. Her serum cardiac brain natriuretic peptide level was elevated at 1,500 U/L, along with mild elevation of cardiac troponin. The chest radiograph was unremarkable. A CT scan of the chest revealed new small nodular opacities with a tree in bud appearance in the peripheral centrilobular area (Fig. 1). Subsequent transthoracic echocardiogram revealed extremely elevated right ventricular systolic pressures with flattening of the interventricular septum and severely high pulmonary artery pressures, suggestive of acute cor pulmonale from severe pulmonary hypertension. Within a day of admission, the patient's dyspnea worsened and she required high-flow oxygen. Meanwhile, mediastinal lymph node biopsy revealed signet ring cell poorly differentiated adenocarcinoma (Fig. 2), and mucicarmine staining confirmed mucin secreting signet ring cells (Fig. 3). A CT scan of the abdomen was performed to look for the primary tumor, and revealed a diffusely thickened stomach wall with enhancement consistent with diffuse gastric cancer ( Fig.   4), in accordance with the signet ring adenocarcinomatous cells observed in the lymph node biopsy. At that time, the patient's plasma    prothrombin time was elevated at 80 seconds, and further testing showed a plasma D-dimer level of more than 5,000 μg/L with a low fibrinogen level of 100 mg/dl, suggestive of disseminated intravascular coagulation (DIC). The CT scan appearance of the chest, acute severe right-sided heart failure from severe pulmonary hypertension, and DIC were characteristic of PTTM. Accordingly, the patient was started on empiric anticoagulation with heparin and intravenous corticosteroids for PTTM based on anecdotal case reports. The patient was scheduled to receive chemotherapy for the gastric adenocarcinoma; however, the hypoxia worsened and the patient required ventilator support. Unfortunately, she rapidly progressed to death within an hour due to extreme hypoxia and cardiac arrest. The patient's family declined autopsy.
Since diffuse gastric cancer is associated with hereditary diffuse gastric cancer (HDGC), it was important to know if the patient's three daughters were at risk. The updated guidelines recommend testing for cadherin 1 (CDH1) gene mutation in a patient's blood when the diagnosis of diffuse gastric cancer occurs at the age of 40 years or less. Thus, we decided to test for the CDH1 genetic mutation in the patient's stored blood. Fortunately, the test came back negative, ruling out HDGC in principle.

Discussion
Gastric cancer remains the second most common cause of cancer-related deaths worldwide. [3][4][5] Gastric carcinoma cells have a high tendency to metastasize to the lymph nodes and distant organs, 6 which is likely strongly associated with its poor prognosis. 7 In particular, carcinoma cells in the pulmonary artery significantly influence the risks of tumor recurrence and death after resection. 8 Moreover, these cells may also cause remodeling, especially asymmetric thickening of the intima of the pulmonary artery, which in turn may induce an increase in the pressure of the right ventricle.
One condition of remodeling is PTTM. PTTM, first described by von Herbay et al. 1 in 1990, is a rare but fatal pulmonary complication in patients with cancer, and is associated with a high risk of severe pulmonary hypertension. It has been found to be more with previous studies, the authors found that the most frequent primary cancer complicated by PTTM was gastric cancer (58 cases).
The details of the pathophysiology of this condition are sparse, but a proposed mechanism of PTTM is that tumor cells might not only occlude the small arteries and arterioles, but also activate the coagulation system and release inflammatory mediators and growth factors, including VEGF, thereby resulting in thrombosis, fibrocellular intimal proliferation, and luminal stenosis. 10,11 The reason for the higher incidence of PTTM in gastric cancer is unknown, and previously published reports have not been focused on explaining this high association. However, we hypothesize that it may be related to the high VEGF expression in gastric cancer 12  Diffuse gastric cancer, also known as signet ring carcinoma, is a poorly differentiated adenocarcinoma that infiltrates into the stomach wall, causing thickening of the wall (linitis plastica) without forming a distinct mass. HDGC is a subgroup of diffuse gastric cancer. 22 The average age of onset of HDGC is 38 years, and the CDH1 gene mutation is the only genetic mutation described so far that has been associated with the occurrence of HDGC (25%~50% of cases). 23 The recent consensus guidelines in 2010 have broadened the criteria of testing for the CDH1 gene mutation as follows: 23 1. Histological confirmation of diffuse gastric cancer is only required for one family member 2. Inclusion of individuals with diffuse gastric cancer before the age of 40 years without a family history 3. Inclusion of individuals and families with diagnoses of both diffuse gastric cancer (including one before the age of 50 years) and lobular breast cancer If positive, their offspring should subsequently be tested for the mutation as it has a high penetrance rate of 70% to 80%. In mutation-positive individuals, prophylactic total gastrectomy at a center of excellence should be strongly considered, as a systematic histological study of prophylactic gastrectomies almost universally showed pre-invasive lesions, including in situ signet ring carcinoma. 23 Our patient almost met the second criteria and since she had three children, we pursued genetic testing of the patient's serum.
Fortunately, the test was negative. Thus, it is important to consider the possibility of HDGC in similar patients.
In conclusion, PTTM is a lethal condition that tends to be frequently associated with gastric cancer especially poorly differentiated diffuse gastric cancer. It is important to increase the awareness of this condition and have high a clinical suspicion of this entity in appropriate setting as early diagnosis may improve the mortality from this fatal condition.