when you hear hoofbeats , think of horses not zebras , the art of medicine is based on soundness : the higher the pretest probability , the sounder the diagnosis .
the problem with this medical aphorism is that it actively encourages the clinician to turn a deaf ear ( and a blind eye ) to the possibility of lesser known and , therefore , more easily overlooked disease states that mimic or 
this report presents a case in point : a 47-year - old woman with triple - negative breast cancer on a clinical trial called primetime ( nct02518958 ) who received the anti - pd-1 inhibitor nivolumab and the experimental anticancer agent rrx-001 for 18 weeks ; initially treated for pneumonitis , an 
expected autoimmune complication of nivolumab , based on the development of dyspnea and ct abnormalities . the overall clinical picture , nevertheless , was atypical , which prompted the investigating team to aggressively pursue alternate possibilities , ultimately leading to the correct diagnosis : pulmonary tumor thrombotic microangiopathy or pttm .
this example highlights the importance of exercising due diligence and not automatically jumping to conclusions with regard to the diagnosis of immune - related adverse events ( iraes ) such as pneumonitis during treatment with pd-1 or ctla-4 inhibitors .
analogous to another pulmonary medical aphorism ,  all that wheezes is not asthma , the differential diagnosis for breathlessness in the context of immune checkpoint inhibition is broader than only pneumonitis and should involve a systematic investigation for other etiologies , including the rare and rapidly progressive disorder pttm . a case history and review of the literature
are presented for pttm , which we propose to define as a paraneoplastic syndrome ( pns ) . in addition , a potential treatment option based on its pathophysiology is discussed .
the goal of cytotoxic t - lymphocyte antigen-4 ( ctla-4 ) and programmed death-1 ( pd-1 ) pathway blockade , including nivolumab approved for the treatment of melanoma , squamous - cell lung cancer   and renal cell carcinoma , is to overcome the t - cell suppression mediated by these inhibitory receptors ( fig .
1 ) ; a potential side effect of revving up the immune system to attack malignant tumors is the breaking of self - tolerance and the induction of iraes , which include rash , colitis , hepatotoxicities , endocrinopathies , and interstitial pneumonitis . as the most serious irae ,
reportedly responsible for 5 total fatalities across the spectrum of nivolumab - treated patients , the incidence of pneumonitis increased from 3.4% on a melanoma trial to 6% on a nsclc clinical trial , according to a recent bristol myers squibb press release ; this increase in incidence should raise the suspicion that increased awareness of and , consequently , narrowed focus on pneumonitis by oncologists has resulted in erroneous overdiagnosis .
the clinical manifestations of pneumonitis are protean and include fever , chills , malaise , cough , chest tightness , hypoxia , and dyspnea , while the nonspecific radiological characteristics   of ground glass opacities ( i.e. , lung opacities that do not obscure the associated vessels ) , consolidations ( i.e. , lung opacities that do obscure the associated vessels ) , and effusions also overlap with multiple other disease entities including acute respiratory distress syndrome , pneumonia , pulmonary embolism ( pe ) , congestive heart failure , and the subject of this case report , pttm .
pttm is a rare and possibly underdiagnosed   extrapulmonary sequella of metastatic cancer , specifically adenocarcinomas , formally described in 1990 by von herbay et al .  
that presents as acute cor pulmonale , a maladaptive response to pulmonary hypertension , resulting in dyspnea and hypoxemia as well as ground - glass opacity ( or diffuse consolidation ) and pulmonary edema on ct [ 12 , 13 ] .
the available literature on pttm is sparse , existing mostly as case reports or small case series from japan , with a lack of higher - order treatment studies .
adenocarcinomas , and gastric cancer in particular , have been linked with pttm in these japanese case reports , which is not surprising , given the high incidence rate of gastric cancer in japan .
the etiologic mechanism of pttm is related to the intravasation of circulating tumor cells in the pulmonary vasculature ; these circulating tumor cells release a plethora of vascular remodeling factors   including vascular endothelial growth factor ( vegf ) , fibroblast growth factor , osteopontin , and platelet derived growth factor ( pdgf ) associated with abnormal endothelial proliferation , the local activation of the coagulation cascade , and the development of pulmonary hypertension from resultant stenosis of the pulmonary capillaries and arterioles ( fig .
which is only rarely diagnosed antemortem , due to a nearly uniform fatality rate , ( almost all reported patients have died within 2 weeks of dyspnea onset ) , may be suspected in cancer patients ruled out for pe who develop acute or subacute right - sided heart failure , pulmonary hypertension , and abnormal coagulation parameters .
our nivolumab - treated patient with metastatic triple - negative breast cancer who is the subject of this case report recapitulated these clinical and laboratory abnormalities almost  to a t , including , unfortunately , the time interval between onset of first symptoms and death .
while the term  textbook example is not applicable in the context of pttm , since no textbooks on it have been written ( only case reports ) , this patient 's clinical course and trajectory were indeed 
textbook for pttm , even though a default diagnosis of nivolumab - induced pneumonitis was initially made .
however , in light of the atypical presentation , discussed below , and findings that did not quite 
add up , the team , suspecting that pneumonitis was a red herring , decided to trust their intuition , and pursued a further work - up , which ultimately led to the diagnosis of pttm .
a 47-year - old female with rapidly progressive refractory triple - negative metastatic breast cancer , metastatic to the lungs , was treated at walter reed on a clinical trial called primetime ( nct02518958 ) where she received the anti - pd-1 inhibitor nivolumab , 3 mg / kg , every other week in combination with weekly rrx-001 , an experimental epi - immunologic agent . during her week 18 infusion on december 3 , 2015 ,
she developed fever ( 101f , 38.3c ) , headache , palpitations , and diaphoresis ; the presence of fever prompted a sepsis work - up consisting of complete blood count , routine blood culture , urinalysis , and chest x - ray in the hospital to determine the source of the fever and rule out an infection .
her labs were otherwise significant only for anemia ( hemoglobin 9.4 g / dl and hematocrit 30.6% ) and a normal leukocyte count ( 5.8  10/l ) with a high percentage of segmented neutrophils on the differential ( normal 4373% ) and no bandemia . as part of the work - up for sinus tachycardia ,
thyroid function tests were performed but thyroid - stimulating hormone ( tsh ) and free t4 were within normal limits .
her symptoms progressed to dyspnea and hypoxia the next day ( on december 4 , 2015 ) after administration of isotonic normal saline to restore volume .
chest ct , which had been clear on admission , revealed interlobular septal thickening , diffuse ground - glass attenuation , and bilateral effusions ( fig .
3 ) . a shortened list of differential diagnoses included atypical viral or bacterial pneumonia , cardiogenic pulmonary edema ( since the patient had received doxorubicin in the past ) , and treatment - induced pneumonitis . on that basis ,
fluids were withheld , the patient was discontinued from the trial and combination treatment with broad - spectrum empiric antibiotics ( vancomycin , zosyn and levaquin ) and 1 mg / kg prednisone was started .
however , the antibiotics and corticosteroids were withdrawn a week later due to worsening dyspnea and hypoxia .
a ventilation - perfusion scan was performed on december 14 , 2015 and read as low probability for pe ( no perfusion defects ) . to identify the cause of the edema ,
a transthoracic echocardiography was ordered , which revealed a normal left ventricular ejection fraction with right ventricular dilatation and severely reduced right ventricular function secondary to pulmonary hypertension ( a pressure > 50 mm hg is generally accepted as severe   and her estimated right ventricular systolic pressure exceeded 65 mm hg ) .
probnp was also drawn ; it was elevated at 3,226.0 pg / ml , indicative of heart failure ( 5125 nl range ) .
the presence of acute cor pulmonale pointed away from pneumonitis and strongly suggested three rare possibilities : ( 1 ) occlusion of the pulmonary vessels from microscopic tumor emboli ( also known as pulmonary tumor embolism ) , leading to pulmonary arterial hypertension ( pah ) ; ( 2 ) pttm , a related but even rarer pulmonary vasculopathy , associated with adenocarcinomas of the stomach , pancreas , breast , lung , and liver , in which minute tumor emboli in the peripheral pulmonary arteries damage the vascular endothelium , leading to accelerated coagulation   and pah , and ( 3 ) pulmonary venous occlusive disease , the venous form of pah [ 19 , 20 ] , due to fibrous occlusion of the post - capillary vessels , which may or may not be associated with an autoimmune process   ( the association is only anecdotal ) . the pulmonary hypertension was managed with diuretics ( furosemide 40 mg i.v . ) , bosentan 62.5 mg , and oxygen ( 2 liters by nasal cannula ) as well as intravenous epoprostenol , norepinephrine , and dobutamine ; however , no improvement was observed .
since a lung biopsy carried too much risk , the patient was catheterized ; pulmonary artery catheter - derived blood samples were negative for the presence of tumor emboli .
blood was also drawn for the measurement of coagulation parameters , since pttm is associated with coagulopathy .
the results were as follows : elevated d - dimer ( or serum fibrin degradation products ) of 1.04 g / ml ( normal < 0.5 g / ml ) and a prolonged prothrombin time of 16.5 s ( normal 1114 s ) .
platelets were never outside of the normal range . the partial thromboplastin time and thrombin time
were both prolonged at 67.2 s ( normal 2535 s ) and 48 s ( normal 1420 s ) , respectively , due to treatment with a heparin gtt for potential venous clots . in the setting of adenocarcinoma , pulmonary hypertension , and a negative ct and ventilation - perfusion scan for pe ,
pttm is distinct from simple embolic obstruction because it is characterized by ( 1 ) the systemic activation of coagulation with the generation of intravascular fibrin and the consumption of procoagulants , leading to a disseminated intravascular coagulation - like picture , present in this case and ( 2 ) remodeling of the pulmonary vasculature   due to expression of vegf and pdgf from embolic tumor cells ( see fig .
2 ) . based on the proposed involvement of vegf and pdgf in the pathogenesis of pttm , the primary investigator planned to treat the patient with sunitinib , which dually inhibits vegf and pdgf pathways
the observations in this case study strongly suggest that pd-1-induced pneumonitis should be a diagnosis of exclusion rather than a diagnosis by default , requiring a thorough work - up to rule out conditions that may mimic it , including pe , atypical pneumonia , pulmonary venous occlusive disease , congestive heart failure , and pttm . in the case of this acutely dyspneic patient , who initially received a
 pneumonitis by default diagnosis , pttm was only identified when her shortness of breath deteriorated despite treatment with high dose steroids , alerting the principal investigator to the possibility of heart failure , which led to further investigation .
the treating oncologist must be alert to the development or presence of pns , defined as a  pathology caused by tumor cells , which systematically produce a large amount of hormones , growth factors , cytokines and a variety of specific symptoms .
these include : cushing syndrome , carcinoid syndrome , dermatomyositis - polymyositis , myasthenia gravis and syndrome of inappropriate antidiuretic hormone . to this list
, we would add pttm , since its pathogenesis is related to the local release of mitogenic factors associated with vascular remodeling and coagulopathy . as a heretofore unrecognized pns
, pttm requires background knowledge and a high index of clinical suspicion . in the absence of a biopsy ,
even though the case under discussion was refractory to standard therapies and the patient died before sunitinib , the multitargeted tyrosine kinase selective for vegf and pdgf receptors , could be started , it is reasonable to assume that early diagnosis and treatment would have resulted in a better outcome .
the patient described in this case report has given his informed consent as part of the primetime clinical study ( nct02518958 ) .
this study protocol has been approved by the walter reed national military medical center institutional review board .
 a case report of a 47-year - old woman with triple - negative breast cancer on a clinical trial called primetime ( nct02518958 ) who received the anti - pd-1 inhibitor nivolumab and the experimental anticancer agent rrx-001 is presented . although initially diagnosed and treated for anti - pd-1-induced pneumonitis , clinical and radiological abnormalities triggered further investigation , leading to the diagnosis of pulmonary tumor thrombotic microangiopathy ( pttm ) . 
 this example highlights the importance of exercising due diligence in determining immune - related adverse events and suggests that pd-1-induced pneumonitis should be a diagnosis of exclusion rather than a diagnosis by default . 
 a case history and review of the literature are presented for pttm , which we propose to define as a paraneoplastic syndrome . 