Case Reports

Epistaxis is a relatively common event that is estimated to occur at least once in 60% of the U.S. population. Epistaxis is also reported to cause 1.7 emergency department (ED) visits per 1,000 population annually.¹ Although epistaxis can occur at any age, it typically occurs with a bimodal age distribution and most commonly affects individuals aged < 18 years and adults aged > 50 years.² The episodes of epistaxis involving the younger age group are more often minor and self-limited. Most bleeds occur along the anterior nasal septum from Kiesselbach’s plexus.

Posterior bleeds occur more often in older patients.² In addition, epistaxis in the older population tends to be more severe.³ Medical intervention is required in 6% of those experiencing epistaxis. Because the median age for male veterans was 64 years in 2011 compared with a median age of 37.² years for the average U.S. population in 2010, veterans are among those at greatest risk to develop epistaxis that requires intervention.^4,5

Most episodes of epistaxis are not life-threatening, particularly when modern methods of diagnosis and treatment are used. Nevertheless, comorbid diseases, complications of treatment, and normal physiologic responses can sometimes combine to create an adverse outcome.⁶ This report reviews the case of a veteran patient who experienced a fatal cardiopulmonary arrest after therapeutic interventions for epistaxis. It is believed that his death was due to the well-described but little known trigeminocardiac reflex (TCR).

Case Report

A 65-year-old man visited the ED and reported that his nose had been bleeding intermittently for 1 day. He estimated that he had lost 1 cup of blood over a 24-hour period. He reported no rhinosinusitis, nasal congestion, or recent allergy or upper respiratory infections. He also reported no nasal trauma. In the ED, blood was oozing from his right nares and into his throat, causing him to cough. External compression failed to control the oozing. Topical vasoconstrictors were not applied.

His past medical history included a pulmonary embolism, well-controlled chronic obstructive pulmonary disease (COPD), and sleep apnea. The thrombotic site of origin for his pulmonary embolism had not been identified, despite a thorough examination. He had been on warfarin therapy for 3 months, and his international normalized ratio (INR) had been monitored in an anticoagulation clinic and was well regulated. He was also on inhaled medications for COPD (formoterol and budesonide as a combination preparation twice daily and albuterol every 6 hours as needed as a rescue medication). He adhered to his noninvasive positive airway pressure (PAP) device treatment for sleep apnea. He did not take aspirin or other antiplatelet medications. He reported no use of topical nasal preparations. He also reported no use of illicit drugs or over-the-counter medications, including nonsteroidal anti-inflammatory medications and herbal remedies. He reported no bleeding from other sites or easy bruising.

The patient was alert, oriented, and in no distress. His vital signs were normal. Examination of his nasal passages failed to identify an active site of bleeding. Fresh blood was present in the right nasal passage and the posterior pharynx. Examination of his chest was normal. His hemoglobin was 13.1 g/dL (13.6-17.3 g/dL) with 216 x 103/μL platelets (166-383 x 103/μL). His INR was therapeutic at 2.38. Laboratory assessments of his electrolytes, liver function, and renal function were normal. A chest radiograph demonstrated no acute process. A computed tomography failed to demonstrate sinusitis or an anatomical abnormality that could account for his epistaxis.

Due to the amount of blood loss by epistaxis complicated by anticoagulation for his recent pulmonary embolism, the patient was admitted to the hospital for observation. Reversal of the anticoagulation was considered by the admitting service, but because the patient was only oozing blood, this intervention was not undertaken. Instead, he was continued on warfarin, was treated with an oral antibiotic, and was continued on his inhaled medications for his COPD. He also used his noninvasive PAP device to sleep.

The next day, the patient began to bleed freely from his right nares. The bleeding was initially controlled with compression and positioning and resolved without additional intervention. An otolaryngologist performed silver nitrate cauterization of Kiesselbach’s plexus. The patient experienced no further bleeding, and his hemoglobin remained stable.

The next day, his nose began to bleed briskly. He passed large clots from his nose and mouth. The patient was alert and oriented. He remained hemodynamically stable. His INR was 2.1. Nasal packing was proposed, and the procedure, including the risks and benefits, were explained to the patient.

After obtaining consent from thepatient, the nasal mucosa was prepared with topical 2% lidocaine and 1% phenylephrine. Anterior and posterior nasal packing was successfully achieved with paraffin gauze. This procedure was completed in a monitored environment by an experienced otolaryngologist. However, the patient became agitated 15 to 20 minutes after the nasal packing had been accomplished. He rapidly became apneic, bradycardic, and hypotensive. His oxygen saturation on room air as measured by pulse oximetry decreased precipitously to 50%. These developments were quickly followed by asystole.

Advanced cardiac life support measures were initiated. His airway was secured by oral endotracheal intubation, and oxygen was delivered at 100% fraction of inspired oxygen by bag ventilation. At intubation, only a few small clots were present in the posterior pharynx. No blood was suctioned from the endotracheal tube; therefore, active bleeding was not suspected. The nasal packing remained in place and was not removed. The patient failed to regain spontaneous circulation and died. An arterial blood gas analysis obtained during cardiopulmonary resuscitation demonstrated no methemoglobin on co-oximetry.

Discussion

Because of the high prevalence of epistaxis in the general population, many health care providers (HCPs) are confronted with this problem. Epistaxis in most patients remits without consequence. However, HCPs may be required to intervene. Treatment modalities include simple compression and positioning maneuvers, the application of topical medications, anterior and posterior nasal packing, chemical cauterization, endoscopic electric cauterization, embolization therapy, and surgical arterial ligation.⁷ The choice of therapy depends on several factors, including the site of the bleeding, the severity of the bleeding, the availability of resources, and the expertise of the HCP. A localized cause of epistaxis is discovered in only 15% of patients, making a conservative therapeutic approach an attractive initial intervention.⁸

Nasal packing is a successful intervention in 70% of patients with posterior epistaxis. In addition, nasal packing is the preferred method for hemostasis in anterior epistaxis when cauterization fails.^3,9 This patient failed simple compression and positioning maneuvers as well as chemical cauterization. For this reason, nasal packing was proposed as a therapeutic intervention. He was hemodynamically stable when the nasal packing procedure was initiated.

Although epistaxis may often have the appearance of significant blood loss and can be frightening for both the patient and HCP, most episodes are not life threatening. Death, when it occurs in association with epistaxis, is very rarely due to exsanguination.3 More commonly, death from epistaxis is related to complications of the treatment intervention or to an exacerbation of an underlying comorbid disease.10 The external overt blood loss in this patient was not significant enough to explain his cardiopulmonary collapse. Although he had experienced a recent pulmonary embolism, he had been on continuous anticoagulation for 3 months and remained adequately anticoagulated during his hospitalization. It therefore seems unlikely that he had experienced a recurrent pulmonary
embolism.

Complications

The treatment of epistaxis can be associated with serious infectious complications, including toxic shock syndrome due to nasal packing and infective endocarditis.^11,12 Because patients with malignancies, autoimmune disorders, or organ failure may have epistaxis from decreased platelet production or increased platelet destruction, an infection can be devastating. Many HCPs anticipate this occurrence and provide the patient with epistaxis prophylactic antibiotics.¹³ Life-threatening infectious complications are usually delayed events and are generally easily recognized. An infectious process was not suspected in this patient. Nevertheless, he was treated with an oral antibiotic.

Dislodgement of the nasal packing with resultant aspiration and asphyxiation has been described as a fatal complication associated with the treatment of epistaxis.¹⁴ This complication was not observed in this patient. The otolaryngologist responsible for the placement of the nasal packing was in attendance during the cardiopulmonary resuscitation and insured oral pharyngeal airway patency. Moreover, endotracheal intubation also failed to identify an upper airway obstruction. Aspiration of the packing material was not the cause of this patient’s hemodynamic collapse.

Epidemiology

Florian Kratschmer (1843-1922) was the first researcher to provide a comprehensive analysis of changes in breathing, blood pressure, and heart rate that can occur when mucosa of the nasal airways are stimulated mechanically or chemically.¹⁵ His report is considered the first description of trigeminal-mediated bradycardia and asystole, a phenomenon that is sometimes referred to as Kratschmer’s reflex. In current terminology, it is referred to as the nasopulmonary reflex or TCR.

The trigeminal nerve is the largest of the cranial nerves. It provides sensory innervation to the face, scalp, and mucosa of the nose and mouth. The TCR may occur with manipulation of the branches of the trigeminal nerve anywhere along its intracranial or extracranial course. The TCR is described as a sudden onset of parasympathetic arrhythmia, sympathetic hypotension, or apnea elicited by central or peripheral stimulation of any of the sensory branches of the trigeminal nerve.¹⁶ The TCR may result in an immediate decrease of the mean arterial blood pressure and heart rate of > 20% when compared with the baseline levels with surgical, mechanical, electrical, or chemical stimulation of the central part of the sensory branches of the trigeminal nerve.¹⁷ The TCR represents one of the most powerful autonomous reflexes.^18,19

Stimulation of trigeminal receptors that innervate the nose and nasal passage in animals can be an important stimulus for respiratory dysfunction and cardiac arrhythmias.^15,16 However, the inability to accurately document the neuroanatomy of this reflex coupled with its variable and rare expression in humans has hindered the appreciation of the importance of the TCR. These observations have led some researchers to dismiss the reflex as inconsequential in humans. However, other physicians, particularly surgeons who manipulate craniofacial structures, have witnessed the effects of the TCR firsthand.^20-25

In studies of neurosurgical procedures utilizing the nasal passages and transsphenoid approaches, the TCR has occurred in 10% to 18% of patients.^16,24 The TCR has been consistently, although infrequently, noted by otolaryngologists in the management of epistaxis.^10,26 Even when performed properly, posterior nasal packing has been reported to cause apnea, hypoxemia, and dysrhythmia.¹⁰ Although there has been debate about the importance of the TCR in humans, this response explains the sequence of events in and the death of this patient.²⁷

The mechanism of the TCR is not well understood. The available data suggest that the response of the TCR when triggered by peripheral stimulation is different from the response when the TCR is triggered by central stimulation.¹⁸ There is additional anatomic evidence that different areas can be distinguished within the nasal mucosa with regard to stimulation site and stimulus properties.²⁵ Specifically, it has been demonstrated in animals that mechanoreceptors are not equally sensitive throughout the nasal mucosa. The most sensitive areas for mechanical stimuli are located in the posterior parts of the nasal passages. In many animals, including humans, pronounced respiratory and cardiovascular responses can be elicited by appropriate stimulation of the nasal mucosa. These responses have been studied by many researchers in various animals and may be evoked by mechanical, electrical, and chemical stimuli.^18,25

Risk Factors

Several risk factors for heightening the TCR have been described.²⁵ Risk factors known to enhance the expression of TCR include hypercapnia, hypoxemia, light general anesthesia, the nature of provoking stimulus, the strength and duration of the stimulus, and medications. The specific pharmaceutical agents known to increase the manifestation of the TCR are narcotics, such as sufentanil and alfentanil, beta blockers, and calcium channel blockers.^16,24 This patient was not on any of these medications. In addition, he had not been hypoxemic. He had no known risk for elevation of the TCR.

Evidence suggests that the intensity of the TCR corresponds with the intensity of the mechanical stimulation of the trigeminal pathway.²⁴ Abrupt and sustained traction is more likely to evoke the TCR than is smooth and gentle manipulation. Immediate cessation of the stimulus, such as removal of the nasal packing, may be helpful in the prevention of fatal complications.¹⁶ Unfortunately, this was not accomplished in this patient. Other interventions, including the administration of atropine, local anesthetic infiltrations, or blockage of the nerve, may be helpful in preventing fatal complications.

The TCR may be elicited without prior hemodynamic changes. Nevertheless, it is important to anticipate hypoxemia and bradycardia as the first indication of a cardiopulmonary response.²⁶ Administration of the anticholinergic atropine may be required in some cases where bradycardia is severe or persists despite cessation of the stimulus.

However, premedication with intramuscular administration of an anticholinergic medication has not been effective in preventing this reflex. Moreover, the TCR may at times be refractory to the conventional methods of treatment, and use of vasopressors and immediate cardiac life support may be required. Thus, if mechanical stimulation to the trigeminal nerve is anticipated, continuous monitoring of hemodynamic parameters may allow the clinician to more readily identify the TCR and immediately interrupt the inciting stimulus.²⁴

This patient was being monitored, but his cardiopulmonary collapse occurred suddenly and rapidly. He received immediate resuscitation following advanced cardiac life support protocols. Unfortunately, there was no attempt to remove the material that had been employed as packing to control his epistaxis. It remains conjecture whether removal of this material could have altered his outcome. However, the gauze probably should have been removed to maximize his chance of survival.

Conclusion

This case demonstrates the clinical importance of the TCR to providers in the VA health care system, particularly to those who treat epistaxis. Because they are typically older, veterans are a high-risk group. Age is important due to the higher incidence of epistaxis in the older populace, and interventions are more often necessary in older patients with epistaxis. In addition, posterior bleeds occur more frequently in older patients. The resulting stimulation of the trigeminal nerve from interventions to control a posterior bleed may be a more potent provocation for the TCR. Finally, older patients often have comorbid illnesses requiring medications that may augment the TCR. Therefore, the veteran’s age and comorbid illnesses and medications may lead to greater susceptibility of a poor outcome, should the TCR occur as a result of interventions undertaken to control epistaxis.

VA practitioners should, therefore, be aware of the possible occurrence of the TCR in all patients with epistaxis, particularly when invasive manipulations of areas innervated by the trigeminal nerve are required. Evidence suggests that complications of the TCR range from mild bradycardia that responds to simple maneuvers to severe bradycardia and asystole requiring intervention with vagolytics. In rare cases, cardiac dysfunction may lead to death if the TCR is not suspected and early appropriate measures, such as removal of packing materials, are not undertaken.

Although the estimated complication rate of epistaxis and its treatment remains low (about 3%), the authors hope that this report will alert HCPs and that they will remain aware of the TCR as a potentially serious occurrence, even with mild to moderate manipulation of areas innervated by the trigeminal nerve.⁶

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Epistaxis is a relatively common event that is estimated to occur at least once in 60% of the U.S. population. Epistaxis is also reported to cause 1.7 emergency department (ED) visits per 1,000 population annually.¹ Although epistaxis can occur at any age, it typically occurs with a bimodal age distribution and most commonly affects individuals aged < 18 years and adults aged > 50 years.² The episodes of epistaxis involving the younger age group are more often minor and self-limited. Most bleeds occur along the anterior nasal septum from Kiesselbach’s plexus.

Posterior bleeds occur more often in older patients.² In addition, epistaxis in the older population tends to be more severe.³ Medical intervention is required in 6% of those experiencing epistaxis. Because the median age for male veterans was 64 years in 2011 compared with a median age of 37.² years for the average U.S. population in 2010, veterans are among those at greatest risk to develop epistaxis that requires intervention.^4,5

Most episodes of epistaxis are not life-threatening, particularly when modern methods of diagnosis and treatment are used. Nevertheless, comorbid diseases, complications of treatment, and normal physiologic responses can sometimes combine to create an adverse outcome.⁶ This report reviews the case of a veteran patient who experienced a fatal cardiopulmonary arrest after therapeutic interventions for epistaxis. It is believed that his death was due to the well-described but little known trigeminocardiac reflex (TCR).

Case Report

A 65-year-old man visited the ED and reported that his nose had been bleeding intermittently for 1 day. He estimated that he had lost 1 cup of blood over a 24-hour period. He reported no rhinosinusitis, nasal congestion, or recent allergy or upper respiratory infections. He also reported no nasal trauma. In the ED, blood was oozing from his right nares and into his throat, causing him to cough. External compression failed to control the oozing. Topical vasoconstrictors were not applied.

His past medical history included a pulmonary embolism, well-controlled chronic obstructive pulmonary disease (COPD), and sleep apnea. The thrombotic site of origin for his pulmonary embolism had not been identified, despite a thorough examination. He had been on warfarin therapy for 3 months, and his international normalized ratio (INR) had been monitored in an anticoagulation clinic and was well regulated. He was also on inhaled medications for COPD (formoterol and budesonide as a combination preparation twice daily and albuterol every 6 hours as needed as a rescue medication). He adhered to his noninvasive positive airway pressure (PAP) device treatment for sleep apnea. He did not take aspirin or other antiplatelet medications. He reported no use of topical nasal preparations. He also reported no use of illicit drugs or over-the-counter medications, including nonsteroidal anti-inflammatory medications and herbal remedies. He reported no bleeding from other sites or easy bruising.

The patient was alert, oriented, and in no distress. His vital signs were normal. Examination of his nasal passages failed to identify an active site of bleeding. Fresh blood was present in the right nasal passage and the posterior pharynx. Examination of his chest was normal. His hemoglobin was 13.1 g/dL (13.6-17.3 g/dL) with 216 x 103/μL platelets (166-383 x 103/μL). His INR was therapeutic at 2.38. Laboratory assessments of his electrolytes, liver function, and renal function were normal. A chest radiograph demonstrated no acute process. A computed tomography failed to demonstrate sinusitis or an anatomical abnormality that could account for his epistaxis.

Due to the amount of blood loss by epistaxis complicated by anticoagulation for his recent pulmonary embolism, the patient was admitted to the hospital for observation. Reversal of the anticoagulation was considered by the admitting service, but because the patient was only oozing blood, this intervention was not undertaken. Instead, he was continued on warfarin, was treated with an oral antibiotic, and was continued on his inhaled medications for his COPD. He also used his noninvasive PAP device to sleep.

The next day, the patient began to bleed freely from his right nares. The bleeding was initially controlled with compression and positioning and resolved without additional intervention. An otolaryngologist performed silver nitrate cauterization of Kiesselbach’s plexus. The patient experienced no further bleeding, and his hemoglobin remained stable.

The next day, his nose began to bleed briskly. He passed large clots from his nose and mouth. The patient was alert and oriented. He remained hemodynamically stable. His INR was 2.1. Nasal packing was proposed, and the procedure, including the risks and benefits, were explained to the patient.

After obtaining consent from thepatient, the nasal mucosa was prepared with topical 2% lidocaine and 1% phenylephrine. Anterior and posterior nasal packing was successfully achieved with paraffin gauze. This procedure was completed in a monitored environment by an experienced otolaryngologist. However, the patient became agitated 15 to 20 minutes after the nasal packing had been accomplished. He rapidly became apneic, bradycardic, and hypotensive. His oxygen saturation on room air as measured by pulse oximetry decreased precipitously to 50%. These developments were quickly followed by asystole.

Advanced cardiac life support measures were initiated. His airway was secured by oral endotracheal intubation, and oxygen was delivered at 100% fraction of inspired oxygen by bag ventilation. At intubation, only a few small clots were present in the posterior pharynx. No blood was suctioned from the endotracheal tube; therefore, active bleeding was not suspected. The nasal packing remained in place and was not removed. The patient failed to regain spontaneous circulation and died. An arterial blood gas analysis obtained during cardiopulmonary resuscitation demonstrated no methemoglobin on co-oximetry.

Discussion

Because of the high prevalence of epistaxis in the general population, many health care providers (HCPs) are confronted with this problem. Epistaxis in most patients remits without consequence. However, HCPs may be required to intervene. Treatment modalities include simple compression and positioning maneuvers, the application of topical medications, anterior and posterior nasal packing, chemical cauterization, endoscopic electric cauterization, embolization therapy, and surgical arterial ligation.⁷ The choice of therapy depends on several factors, including the site of the bleeding, the severity of the bleeding, the availability of resources, and the expertise of the HCP. A localized cause of epistaxis is discovered in only 15% of patients, making a conservative therapeutic approach an attractive initial intervention.⁸

Nasal packing is a successful intervention in 70% of patients with posterior epistaxis. In addition, nasal packing is the preferred method for hemostasis in anterior epistaxis when cauterization fails.^3,9 This patient failed simple compression and positioning maneuvers as well as chemical cauterization. For this reason, nasal packing was proposed as a therapeutic intervention. He was hemodynamically stable when the nasal packing procedure was initiated.

Although epistaxis may often have the appearance of significant blood loss and can be frightening for both the patient and HCP, most episodes are not life threatening. Death, when it occurs in association with epistaxis, is very rarely due to exsanguination.3 More commonly, death from epistaxis is related to complications of the treatment intervention or to an exacerbation of an underlying comorbid disease.10 The external overt blood loss in this patient was not significant enough to explain his cardiopulmonary collapse. Although he had experienced a recent pulmonary embolism, he had been on continuous anticoagulation for 3 months and remained adequately anticoagulated during his hospitalization. It therefore seems unlikely that he had experienced a recurrent pulmonary
embolism.

Complications

The treatment of epistaxis can be associated with serious infectious complications, including toxic shock syndrome due to nasal packing and infective endocarditis.^11,12 Because patients with malignancies, autoimmune disorders, or organ failure may have epistaxis from decreased platelet production or increased platelet destruction, an infection can be devastating. Many HCPs anticipate this occurrence and provide the patient with epistaxis prophylactic antibiotics.¹³ Life-threatening infectious complications are usually delayed events and are generally easily recognized. An infectious process was not suspected in this patient. Nevertheless, he was treated with an oral antibiotic.

Dislodgement of the nasal packing with resultant aspiration and asphyxiation has been described as a fatal complication associated with the treatment of epistaxis.¹⁴ This complication was not observed in this patient. The otolaryngologist responsible for the placement of the nasal packing was in attendance during the cardiopulmonary resuscitation and insured oral pharyngeal airway patency. Moreover, endotracheal intubation also failed to identify an upper airway obstruction. Aspiration of the packing material was not the cause of this patient’s hemodynamic collapse.

Epidemiology

Florian Kratschmer (1843-1922) was the first researcher to provide a comprehensive analysis of changes in breathing, blood pressure, and heart rate that can occur when mucosa of the nasal airways are stimulated mechanically or chemically.¹⁵ His report is considered the first description of trigeminal-mediated bradycardia and asystole, a phenomenon that is sometimes referred to as Kratschmer’s reflex. In current terminology, it is referred to as the nasopulmonary reflex or TCR.

The trigeminal nerve is the largest of the cranial nerves. It provides sensory innervation to the face, scalp, and mucosa of the nose and mouth. The TCR may occur with manipulation of the branches of the trigeminal nerve anywhere along its intracranial or extracranial course. The TCR is described as a sudden onset of parasympathetic arrhythmia, sympathetic hypotension, or apnea elicited by central or peripheral stimulation of any of the sensory branches of the trigeminal nerve.¹⁶ The TCR may result in an immediate decrease of the mean arterial blood pressure and heart rate of > 20% when compared with the baseline levels with surgical, mechanical, electrical, or chemical stimulation of the central part of the sensory branches of the trigeminal nerve.¹⁷ The TCR represents one of the most powerful autonomous reflexes.^18,19

Stimulation of trigeminal receptors that innervate the nose and nasal passage in animals can be an important stimulus for respiratory dysfunction and cardiac arrhythmias.^15,16 However, the inability to accurately document the neuroanatomy of this reflex coupled with its variable and rare expression in humans has hindered the appreciation of the importance of the TCR. These observations have led some researchers to dismiss the reflex as inconsequential in humans. However, other physicians, particularly surgeons who manipulate craniofacial structures, have witnessed the effects of the TCR firsthand.^20-25

In studies of neurosurgical procedures utilizing the nasal passages and transsphenoid approaches, the TCR has occurred in 10% to 18% of patients.^16,24 The TCR has been consistently, although infrequently, noted by otolaryngologists in the management of epistaxis.^10,26 Even when performed properly, posterior nasal packing has been reported to cause apnea, hypoxemia, and dysrhythmia.¹⁰ Although there has been debate about the importance of the TCR in humans, this response explains the sequence of events in and the death of this patient.²⁷

The mechanism of the TCR is not well understood. The available data suggest that the response of the TCR when triggered by peripheral stimulation is different from the response when the TCR is triggered by central stimulation.¹⁸ There is additional anatomic evidence that different areas can be distinguished within the nasal mucosa with regard to stimulation site and stimulus properties.²⁵ Specifically, it has been demonstrated in animals that mechanoreceptors are not equally sensitive throughout the nasal mucosa. The most sensitive areas for mechanical stimuli are located in the posterior parts of the nasal passages. In many animals, including humans, pronounced respiratory and cardiovascular responses can be elicited by appropriate stimulation of the nasal mucosa. These responses have been studied by many researchers in various animals and may be evoked by mechanical, electrical, and chemical stimuli.^18,25

Risk Factors

Several risk factors for heightening the TCR have been described.²⁵ Risk factors known to enhance the expression of TCR include hypercapnia, hypoxemia, light general anesthesia, the nature of provoking stimulus, the strength and duration of the stimulus, and medications. The specific pharmaceutical agents known to increase the manifestation of the TCR are narcotics, such as sufentanil and alfentanil, beta blockers, and calcium channel blockers.^16,24 This patient was not on any of these medications. In addition, he had not been hypoxemic. He had no known risk for elevation of the TCR.

Evidence suggests that the intensity of the TCR corresponds with the intensity of the mechanical stimulation of the trigeminal pathway.²⁴ Abrupt and sustained traction is more likely to evoke the TCR than is smooth and gentle manipulation. Immediate cessation of the stimulus, such as removal of the nasal packing, may be helpful in the prevention of fatal complications.¹⁶ Unfortunately, this was not accomplished in this patient. Other interventions, including the administration of atropine, local anesthetic infiltrations, or blockage of the nerve, may be helpful in preventing fatal complications.

The TCR may be elicited without prior hemodynamic changes. Nevertheless, it is important to anticipate hypoxemia and bradycardia as the first indication of a cardiopulmonary response.²⁶ Administration of the anticholinergic atropine may be required in some cases where bradycardia is severe or persists despite cessation of the stimulus.

However, premedication with intramuscular administration of an anticholinergic medication has not been effective in preventing this reflex. Moreover, the TCR may at times be refractory to the conventional methods of treatment, and use of vasopressors and immediate cardiac life support may be required. Thus, if mechanical stimulation to the trigeminal nerve is anticipated, continuous monitoring of hemodynamic parameters may allow the clinician to more readily identify the TCR and immediately interrupt the inciting stimulus.²⁴

This patient was being monitored, but his cardiopulmonary collapse occurred suddenly and rapidly. He received immediate resuscitation following advanced cardiac life support protocols. Unfortunately, there was no attempt to remove the material that had been employed as packing to control his epistaxis. It remains conjecture whether removal of this material could have altered his outcome. However, the gauze probably should have been removed to maximize his chance of survival.

Conclusion

This case demonstrates the clinical importance of the TCR to providers in the VA health care system, particularly to those who treat epistaxis. Because they are typically older, veterans are a high-risk group. Age is important due to the higher incidence of epistaxis in the older populace, and interventions are more often necessary in older patients with epistaxis. In addition, posterior bleeds occur more frequently in older patients. The resulting stimulation of the trigeminal nerve from interventions to control a posterior bleed may be a more potent provocation for the TCR. Finally, older patients often have comorbid illnesses requiring medications that may augment the TCR. Therefore, the veteran’s age and comorbid illnesses and medications may lead to greater susceptibility of a poor outcome, should the TCR occur as a result of interventions undertaken to control epistaxis.

VA practitioners should, therefore, be aware of the possible occurrence of the TCR in all patients with epistaxis, particularly when invasive manipulations of areas innervated by the trigeminal nerve are required. Evidence suggests that complications of the TCR range from mild bradycardia that responds to simple maneuvers to severe bradycardia and asystole requiring intervention with vagolytics. In rare cases, cardiac dysfunction may lead to death if the TCR is not suspected and early appropriate measures, such as removal of packing materials, are not undertaken.

Although the estimated complication rate of epistaxis and its treatment remains low (about 3%), the authors hope that this report will alert HCPs and that they will remain aware of the TCR as a potentially serious occurrence, even with mild to moderate manipulation of areas innervated by the trigeminal nerve.⁶

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Epistaxis is a relatively common event that is estimated to occur at least once in 60% of the U.S. population. Epistaxis is also reported to cause 1.7 emergency department (ED) visits per 1,000 population annually.¹ Although epistaxis can occur at any age, it typically occurs with a bimodal age distribution and most commonly affects individuals aged < 18 years and adults aged > 50 years.² The episodes of epistaxis involving the younger age group are more often minor and self-limited. Most bleeds occur along the anterior nasal septum from Kiesselbach’s plexus.

Posterior bleeds occur more often in older patients.² In addition, epistaxis in the older population tends to be more severe.³ Medical intervention is required in 6% of those experiencing epistaxis. Because the median age for male veterans was 64 years in 2011 compared with a median age of 37.² years for the average U.S. population in 2010, veterans are among those at greatest risk to develop epistaxis that requires intervention.^4,5

Most episodes of epistaxis are not life-threatening, particularly when modern methods of diagnosis and treatment are used. Nevertheless, comorbid diseases, complications of treatment, and normal physiologic responses can sometimes combine to create an adverse outcome.⁶ This report reviews the case of a veteran patient who experienced a fatal cardiopulmonary arrest after therapeutic interventions for epistaxis. It is believed that his death was due to the well-described but little known trigeminocardiac reflex (TCR).

Case Report

A 65-year-old man visited the ED and reported that his nose had been bleeding intermittently for 1 day. He estimated that he had lost 1 cup of blood over a 24-hour period. He reported no rhinosinusitis, nasal congestion, or recent allergy or upper respiratory infections. He also reported no nasal trauma. In the ED, blood was oozing from his right nares and into his throat, causing him to cough. External compression failed to control the oozing. Topical vasoconstrictors were not applied.

His past medical history included a pulmonary embolism, well-controlled chronic obstructive pulmonary disease (COPD), and sleep apnea. The thrombotic site of origin for his pulmonary embolism had not been identified, despite a thorough examination. He had been on warfarin therapy for 3 months, and his international normalized ratio (INR) had been monitored in an anticoagulation clinic and was well regulated. He was also on inhaled medications for COPD (formoterol and budesonide as a combination preparation twice daily and albuterol every 6 hours as needed as a rescue medication). He adhered to his noninvasive positive airway pressure (PAP) device treatment for sleep apnea. He did not take aspirin or other antiplatelet medications. He reported no use of topical nasal preparations. He also reported no use of illicit drugs or over-the-counter medications, including nonsteroidal anti-inflammatory medications and herbal remedies. He reported no bleeding from other sites or easy bruising.

The patient was alert, oriented, and in no distress. His vital signs were normal. Examination of his nasal passages failed to identify an active site of bleeding. Fresh blood was present in the right nasal passage and the posterior pharynx. Examination of his chest was normal. His hemoglobin was 13.1 g/dL (13.6-17.3 g/dL) with 216 x 103/μL platelets (166-383 x 103/μL). His INR was therapeutic at 2.38. Laboratory assessments of his electrolytes, liver function, and renal function were normal. A chest radiograph demonstrated no acute process. A computed tomography failed to demonstrate sinusitis or an anatomical abnormality that could account for his epistaxis.

Due to the amount of blood loss by epistaxis complicated by anticoagulation for his recent pulmonary embolism, the patient was admitted to the hospital for observation. Reversal of the anticoagulation was considered by the admitting service, but because the patient was only oozing blood, this intervention was not undertaken. Instead, he was continued on warfarin, was treated with an oral antibiotic, and was continued on his inhaled medications for his COPD. He also used his noninvasive PAP device to sleep.

The next day, the patient began to bleed freely from his right nares. The bleeding was initially controlled with compression and positioning and resolved without additional intervention. An otolaryngologist performed silver nitrate cauterization of Kiesselbach’s plexus. The patient experienced no further bleeding, and his hemoglobin remained stable.

The next day, his nose began to bleed briskly. He passed large clots from his nose and mouth. The patient was alert and oriented. He remained hemodynamically stable. His INR was 2.1. Nasal packing was proposed, and the procedure, including the risks and benefits, were explained to the patient.

After obtaining consent from thepatient, the nasal mucosa was prepared with topical 2% lidocaine and 1% phenylephrine. Anterior and posterior nasal packing was successfully achieved with paraffin gauze. This procedure was completed in a monitored environment by an experienced otolaryngologist. However, the patient became agitated 15 to 20 minutes after the nasal packing had been accomplished. He rapidly became apneic, bradycardic, and hypotensive. His oxygen saturation on room air as measured by pulse oximetry decreased precipitously to 50%. These developments were quickly followed by asystole.

Advanced cardiac life support measures were initiated. His airway was secured by oral endotracheal intubation, and oxygen was delivered at 100% fraction of inspired oxygen by bag ventilation. At intubation, only a few small clots were present in the posterior pharynx. No blood was suctioned from the endotracheal tube; therefore, active bleeding was not suspected. The nasal packing remained in place and was not removed. The patient failed to regain spontaneous circulation and died. An arterial blood gas analysis obtained during cardiopulmonary resuscitation demonstrated no methemoglobin on co-oximetry.

Discussion

Because of the high prevalence of epistaxis in the general population, many health care providers (HCPs) are confronted with this problem. Epistaxis in most patients remits without consequence. However, HCPs may be required to intervene. Treatment modalities include simple compression and positioning maneuvers, the application of topical medications, anterior and posterior nasal packing, chemical cauterization, endoscopic electric cauterization, embolization therapy, and surgical arterial ligation.⁷ The choice of therapy depends on several factors, including the site of the bleeding, the severity of the bleeding, the availability of resources, and the expertise of the HCP. A localized cause of epistaxis is discovered in only 15% of patients, making a conservative therapeutic approach an attractive initial intervention.⁸

Nasal packing is a successful intervention in 70% of patients with posterior epistaxis. In addition, nasal packing is the preferred method for hemostasis in anterior epistaxis when cauterization fails.^3,9 This patient failed simple compression and positioning maneuvers as well as chemical cauterization. For this reason, nasal packing was proposed as a therapeutic intervention. He was hemodynamically stable when the nasal packing procedure was initiated.

Although epistaxis may often have the appearance of significant blood loss and can be frightening for both the patient and HCP, most episodes are not life threatening. Death, when it occurs in association with epistaxis, is very rarely due to exsanguination.3 More commonly, death from epistaxis is related to complications of the treatment intervention or to an exacerbation of an underlying comorbid disease.10 The external overt blood loss in this patient was not significant enough to explain his cardiopulmonary collapse. Although he had experienced a recent pulmonary embolism, he had been on continuous anticoagulation for 3 months and remained adequately anticoagulated during his hospitalization. It therefore seems unlikely that he had experienced a recurrent pulmonary
embolism.

Complications

The treatment of epistaxis can be associated with serious infectious complications, including toxic shock syndrome due to nasal packing and infective endocarditis.^11,12 Because patients with malignancies, autoimmune disorders, or organ failure may have epistaxis from decreased platelet production or increased platelet destruction, an infection can be devastating. Many HCPs anticipate this occurrence and provide the patient with epistaxis prophylactic antibiotics.¹³ Life-threatening infectious complications are usually delayed events and are generally easily recognized. An infectious process was not suspected in this patient. Nevertheless, he was treated with an oral antibiotic.

Dislodgement of the nasal packing with resultant aspiration and asphyxiation has been described as a fatal complication associated with the treatment of epistaxis.¹⁴ This complication was not observed in this patient. The otolaryngologist responsible for the placement of the nasal packing was in attendance during the cardiopulmonary resuscitation and insured oral pharyngeal airway patency. Moreover, endotracheal intubation also failed to identify an upper airway obstruction. Aspiration of the packing material was not the cause of this patient’s hemodynamic collapse.

Epidemiology

Florian Kratschmer (1843-1922) was the first researcher to provide a comprehensive analysis of changes in breathing, blood pressure, and heart rate that can occur when mucosa of the nasal airways are stimulated mechanically or chemically.¹⁵ His report is considered the first description of trigeminal-mediated bradycardia and asystole, a phenomenon that is sometimes referred to as Kratschmer’s reflex. In current terminology, it is referred to as the nasopulmonary reflex or TCR.

The trigeminal nerve is the largest of the cranial nerves. It provides sensory innervation to the face, scalp, and mucosa of the nose and mouth. The TCR may occur with manipulation of the branches of the trigeminal nerve anywhere along its intracranial or extracranial course. The TCR is described as a sudden onset of parasympathetic arrhythmia, sympathetic hypotension, or apnea elicited by central or peripheral stimulation of any of the sensory branches of the trigeminal nerve.¹⁶ The TCR may result in an immediate decrease of the mean arterial blood pressure and heart rate of > 20% when compared with the baseline levels with surgical, mechanical, electrical, or chemical stimulation of the central part of the sensory branches of the trigeminal nerve.¹⁷ The TCR represents one of the most powerful autonomous reflexes.^18,19

Stimulation of trigeminal receptors that innervate the nose and nasal passage in animals can be an important stimulus for respiratory dysfunction and cardiac arrhythmias.^15,16 However, the inability to accurately document the neuroanatomy of this reflex coupled with its variable and rare expression in humans has hindered the appreciation of the importance of the TCR. These observations have led some researchers to dismiss the reflex as inconsequential in humans. However, other physicians, particularly surgeons who manipulate craniofacial structures, have witnessed the effects of the TCR firsthand.^20-25

In studies of neurosurgical procedures utilizing the nasal passages and transsphenoid approaches, the TCR has occurred in 10% to 18% of patients.^16,24 The TCR has been consistently, although infrequently, noted by otolaryngologists in the management of epistaxis.^10,26 Even when performed properly, posterior nasal packing has been reported to cause apnea, hypoxemia, and dysrhythmia.¹⁰ Although there has been debate about the importance of the TCR in humans, this response explains the sequence of events in and the death of this patient.²⁷

The mechanism of the TCR is not well understood. The available data suggest that the response of the TCR when triggered by peripheral stimulation is different from the response when the TCR is triggered by central stimulation.¹⁸ There is additional anatomic evidence that different areas can be distinguished within the nasal mucosa with regard to stimulation site and stimulus properties.²⁵ Specifically, it has been demonstrated in animals that mechanoreceptors are not equally sensitive throughout the nasal mucosa. The most sensitive areas for mechanical stimuli are located in the posterior parts of the nasal passages. In many animals, including humans, pronounced respiratory and cardiovascular responses can be elicited by appropriate stimulation of the nasal mucosa. These responses have been studied by many researchers in various animals and may be evoked by mechanical, electrical, and chemical stimuli.^18,25

Risk Factors

Several risk factors for heightening the TCR have been described.²⁵ Risk factors known to enhance the expression of TCR include hypercapnia, hypoxemia, light general anesthesia, the nature of provoking stimulus, the strength and duration of the stimulus, and medications. The specific pharmaceutical agents known to increase the manifestation of the TCR are narcotics, such as sufentanil and alfentanil, beta blockers, and calcium channel blockers.^16,24 This patient was not on any of these medications. In addition, he had not been hypoxemic. He had no known risk for elevation of the TCR.

Evidence suggests that the intensity of the TCR corresponds with the intensity of the mechanical stimulation of the trigeminal pathway.²⁴ Abrupt and sustained traction is more likely to evoke the TCR than is smooth and gentle manipulation. Immediate cessation of the stimulus, such as removal of the nasal packing, may be helpful in the prevention of fatal complications.¹⁶ Unfortunately, this was not accomplished in this patient. Other interventions, including the administration of atropine, local anesthetic infiltrations, or blockage of the nerve, may be helpful in preventing fatal complications.

The TCR may be elicited without prior hemodynamic changes. Nevertheless, it is important to anticipate hypoxemia and bradycardia as the first indication of a cardiopulmonary response.²⁶ Administration of the anticholinergic atropine may be required in some cases where bradycardia is severe or persists despite cessation of the stimulus.

However, premedication with intramuscular administration of an anticholinergic medication has not been effective in preventing this reflex. Moreover, the TCR may at times be refractory to the conventional methods of treatment, and use of vasopressors and immediate cardiac life support may be required. Thus, if mechanical stimulation to the trigeminal nerve is anticipated, continuous monitoring of hemodynamic parameters may allow the clinician to more readily identify the TCR and immediately interrupt the inciting stimulus.²⁴

This patient was being monitored, but his cardiopulmonary collapse occurred suddenly and rapidly. He received immediate resuscitation following advanced cardiac life support protocols. Unfortunately, there was no attempt to remove the material that had been employed as packing to control his epistaxis. It remains conjecture whether removal of this material could have altered his outcome. However, the gauze probably should have been removed to maximize his chance of survival.

Conclusion

This case demonstrates the clinical importance of the TCR to providers in the VA health care system, particularly to those who treat epistaxis. Because they are typically older, veterans are a high-risk group. Age is important due to the higher incidence of epistaxis in the older populace, and interventions are more often necessary in older patients with epistaxis. In addition, posterior bleeds occur more frequently in older patients. The resulting stimulation of the trigeminal nerve from interventions to control a posterior bleed may be a more potent provocation for the TCR. Finally, older patients often have comorbid illnesses requiring medications that may augment the TCR. Therefore, the veteran’s age and comorbid illnesses and medications may lead to greater susceptibility of a poor outcome, should the TCR occur as a result of interventions undertaken to control epistaxis.

VA practitioners should, therefore, be aware of the possible occurrence of the TCR in all patients with epistaxis, particularly when invasive manipulations of areas innervated by the trigeminal nerve are required. Evidence suggests that complications of the TCR range from mild bradycardia that responds to simple maneuvers to severe bradycardia and asystole requiring intervention with vagolytics. In rare cases, cardiac dysfunction may lead to death if the TCR is not suspected and early appropriate measures, such as removal of packing materials, are not undertaken.

Although the estimated complication rate of epistaxis and its treatment remains low (about 3%), the authors hope that this report will alert HCPs and that they will remain aware of the TCR as a potentially serious occurrence, even with mild to moderate manipulation of areas innervated by the trigeminal nerve.⁶

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Mr. F. is a 67-year-old man with a medical history significant for hypertension, hyperlipidemia, gastroesophageal reflux disease, abdominal aortic aneurysm repair, and lung nodules (8-mm nodules in his right lower lobe and left upper lobe) since 2009 for which he had been followed in the pulmonary clinic. His last radiologic imaging had been performed in November 2010. The patient had failed to show for a serial scan and follow-up pulmonary appointments. He had seen his primary care practitioner annually. He reporteded a 60 pack-year smoking history and drank up to 10 to 15 beers a day, 3 days a week. He also reported exposure to asbestos while in the U.S. Navy as well as having worked in a sheet metal yard. He reported no family history of lung cancer.

In January 2014, Mr. F. presented to his primary care doctor with a nonpainful neck lump noted by the patient for a few months. On physical examination, the patient appeared healthy and without change in weight, loss of appetite, dysphagia, hemoptysis, or any other remarkable symptoms except for the pain in the left-sided neck mass. On oral examination, the patient did not have any oral lesions but was noted to have poor dentition. He had decreased breath sounds on the right side but no adventitious breath sounds. His cardiac status was within normal limits with a regular heart rate, warm skin, and well-perfused extremities. His abdomen was soft and nontender with good bowel sounds.

A neck computed tomography (CT) done on January 17, 2014, showed 2 left neck masses in the tail of the parotid gland or in level 2 adjacent to the parotid gland. The ear, nose, and throat (ENT) clinic noted that he had a 3-cm level 2 mass, which was mobile and nontender. A fine needle aspiration biopsy showed poorly differentiated rare malignant cells, but the small size of the biopsy precluded identification of the cells. For that reason, the patient was scheduled for an operative laryngoscopy.

A combined positron emission tomography and CT (PET/CT) scan on February 5, 2014, showed multiple areas of hypermetabolic activity. A highly metabolic 2.6 x 1.9-cm mass was noted in the left neck inseparable from the inferior border of the left parotid gland; whether this represented a parotid neoplasm or neoplastic lymph node could not be determined. Positive level 5 neck lymph nodes were suggestive of metastatic disease. There were also 2 foci of mild nonspecific metabolic activity in the right parotid gland. A spiculated mass in the right lower lung, measuring 2.3 x 3.5 cm, demonstrated intense fludeoxyglucose F 18 (FDG) uptake with maximum standardized uptake value (SUV) of 12.7, which was consistent with neoplasm. Thickening of the middistal esophageal wall with intense FDG uptake (SUV of 7.9) was suggestive of esophageal carcinoma.

The patient underwent an endoscopic ultrasound (EUS) esophageal biopsy, which demonstrated poorly differentiated adenocarcinoma (Figure 1). The tumor seemed to have originated at this site, as the biopsy fragments also contained foci of Barrett’s metaplasia and in situ carcinoma. He was presented in the hospital tumor board about whether he should undergo a high-risk lung biopsy due to the location of the mass or have his left neck mass rebiopsied, assuming that he had metastatic esophageal cancer in both the lung and neck. The safer procedure of redoing the neck biopsy in the Ear, Nose, and Throat clinic was pursued, and the patient underwent a biopsy and surgical excision of his left neck mass with positive pathology of highgrade sarcoma (Figure 2).

The tumor consisted of spindle and epithelioid cell proliferation within a lymph node. The neoplastic cells exhibited prominent nuclear atypia, multinucleation, frequent mitoses, and focal necrosis. By immunohistochemistry, the tumor cells were diffusely positive for vimentin, CD68, and CD34 and were negative for pankeratin, CK7, CAM 5.2, CD30, CD15, tyrosine, melan-a, HMB-45, epithelial membrane antigen, keratin 903, desmin protein, CD56, CD99, actin protein, and CD1a. A differential diagnosis included malignant fibrous histiocytoma and histiocytic sarcoma.

Knowing the patient had 2 tumors, a percutaneous lung biopsy was scheduled. It was assumed that the lung mass would be metastatic from esophagus vs sarcoma, but the biopsy showed small cell cancer (Figure 3). The tumor was composed of small cells with finely granular chromatin and a sparse amount of cytoplasm. By immunohistochemistry, the tumor cells were positive for TTF-1, CK7, CAM 5.2, CD56, and synaptophysin and were negative for CK5, CK6, and p63. The patient was represented at the tumor board with diagnostic recommendations to undergo a magnetic resonance imaging of the brain (negative for metastasis) and a PET/CT scan (stable disease).

A lengthy discussion ensued regarding treatment for the 3 cancers. The AJCC Cancer Staging Manual, 7th edition, was used as the framework for all staging.¹ The patient had a stage IIA (T1bN0MX), grade 3 sarcoma, which could be removed by neck dissection. He had a stage IIIB esophageal carcinoma (T3N2MX), which would require concurrent chemoradiation. His limited stage small cell lung cancer might have been amenable to a lobectomy if a mediastinoscopy was negative. The standard of care for limited stage small cell lung cancer is that if the cancer is precisely staged and the patient is a good surgical candidate, then surgery can be considered. The rationale for considering resection in this case was that if his other cancers could be cured, then surgery would be an excellent option.² These options were presented to the patient, who opted for chemotherapy. The oncologist treating the patient elected to target the small cell cancer initially, because it was likely the fastest growing cancer. The patient started treatment with etoposide/carboplatin shortly thereafter. Mr. F. was also referred to palliative care.

Discussion

When a patient presents with several tumor masses detected either clinically or radiologically, it is reasonable to assume, at least initially, that all the lesions can be attributed to the same disease (ie, a primary neoplasm and distant metastases). Based on this assumption, it is rational to establish a tissue diagnosis by sampling the most accessible lesion. In the correct clinical context, this may be sufficient to initiate an appropriate therapy. However, health care providers should be aware that unrelated neoplasms can develop simultaneously, and about 8% of patients have > 1 malignancy at presentation.³

This patient presented with 3 different malignant neoplasms: esophageal adenocarcinoma, pulmonary small-cell carcinoma, and high-grade sarcoma. These types of tumors have completely different histogenesis. Esophageal adenocarcinoma develops from glandular cells of Barrett’s esophagus, small-cell carcinoma develops from neuroendocrine Kulchitsky cells, and sarcoma arises from mesenchymal cells. This constellation of neoplasms does not represent any known multicancer syndrome, such as Li-Fraumeni syndrome or Lynch syndrome. Whether these concomitant tumors represent coincidental neoplasms or have common underlying molecular alterations remains unknown.

The treatment for each of this patient’s cancers was very different and required a multidisciplinary, staged approach for management. This could have been arranged for him had he wanted to pursue multiple resections of the neck and lung plus have chemotherapy and radiation for the esophageal cancer. The patient opted for chemotherapy for the most aggressive cancer, but other options would have been possible had he wanted to pursue them.

Conclusion

This complex case demonstrates the role for careful review of all data and the importance of not making assumptions when analyzing images and history despite all the procedures and time to diagnosis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Mr. F. is a 67-year-old man with a medical history significant for hypertension, hyperlipidemia, gastroesophageal reflux disease, abdominal aortic aneurysm repair, and lung nodules (8-mm nodules in his right lower lobe and left upper lobe) since 2009 for which he had been followed in the pulmonary clinic. His last radiologic imaging had been performed in November 2010. The patient had failed to show for a serial scan and follow-up pulmonary appointments. He had seen his primary care practitioner annually. He reporteded a 60 pack-year smoking history and drank up to 10 to 15 beers a day, 3 days a week. He also reported exposure to asbestos while in the U.S. Navy as well as having worked in a sheet metal yard. He reported no family history of lung cancer.

In January 2014, Mr. F. presented to his primary care doctor with a nonpainful neck lump noted by the patient for a few months. On physical examination, the patient appeared healthy and without change in weight, loss of appetite, dysphagia, hemoptysis, or any other remarkable symptoms except for the pain in the left-sided neck mass. On oral examination, the patient did not have any oral lesions but was noted to have poor dentition. He had decreased breath sounds on the right side but no adventitious breath sounds. His cardiac status was within normal limits with a regular heart rate, warm skin, and well-perfused extremities. His abdomen was soft and nontender with good bowel sounds.

A neck computed tomography (CT) done on January 17, 2014, showed 2 left neck masses in the tail of the parotid gland or in level 2 adjacent to the parotid gland. The ear, nose, and throat (ENT) clinic noted that he had a 3-cm level 2 mass, which was mobile and nontender. A fine needle aspiration biopsy showed poorly differentiated rare malignant cells, but the small size of the biopsy precluded identification of the cells. For that reason, the patient was scheduled for an operative laryngoscopy.

A combined positron emission tomography and CT (PET/CT) scan on February 5, 2014, showed multiple areas of hypermetabolic activity. A highly metabolic 2.6 x 1.9-cm mass was noted in the left neck inseparable from the inferior border of the left parotid gland; whether this represented a parotid neoplasm or neoplastic lymph node could not be determined. Positive level 5 neck lymph nodes were suggestive of metastatic disease. There were also 2 foci of mild nonspecific metabolic activity in the right parotid gland. A spiculated mass in the right lower lung, measuring 2.3 x 3.5 cm, demonstrated intense fludeoxyglucose F 18 (FDG) uptake with maximum standardized uptake value (SUV) of 12.7, which was consistent with neoplasm. Thickening of the middistal esophageal wall with intense FDG uptake (SUV of 7.9) was suggestive of esophageal carcinoma.

The patient underwent an endoscopic ultrasound (EUS) esophageal biopsy, which demonstrated poorly differentiated adenocarcinoma (Figure 1). The tumor seemed to have originated at this site, as the biopsy fragments also contained foci of Barrett’s metaplasia and in situ carcinoma. He was presented in the hospital tumor board about whether he should undergo a high-risk lung biopsy due to the location of the mass or have his left neck mass rebiopsied, assuming that he had metastatic esophageal cancer in both the lung and neck. The safer procedure of redoing the neck biopsy in the Ear, Nose, and Throat clinic was pursued, and the patient underwent a biopsy and surgical excision of his left neck mass with positive pathology of highgrade sarcoma (Figure 2).

The tumor consisted of spindle and epithelioid cell proliferation within a lymph node. The neoplastic cells exhibited prominent nuclear atypia, multinucleation, frequent mitoses, and focal necrosis. By immunohistochemistry, the tumor cells were diffusely positive for vimentin, CD68, and CD34 and were negative for pankeratin, CK7, CAM 5.2, CD30, CD15, tyrosine, melan-a, HMB-45, epithelial membrane antigen, keratin 903, desmin protein, CD56, CD99, actin protein, and CD1a. A differential diagnosis included malignant fibrous histiocytoma and histiocytic sarcoma.

Knowing the patient had 2 tumors, a percutaneous lung biopsy was scheduled. It was assumed that the lung mass would be metastatic from esophagus vs sarcoma, but the biopsy showed small cell cancer (Figure 3). The tumor was composed of small cells with finely granular chromatin and a sparse amount of cytoplasm. By immunohistochemistry, the tumor cells were positive for TTF-1, CK7, CAM 5.2, CD56, and synaptophysin and were negative for CK5, CK6, and p63. The patient was represented at the tumor board with diagnostic recommendations to undergo a magnetic resonance imaging of the brain (negative for metastasis) and a PET/CT scan (stable disease).

A lengthy discussion ensued regarding treatment for the 3 cancers. The AJCC Cancer Staging Manual, 7th edition, was used as the framework for all staging.¹ The patient had a stage IIA (T1bN0MX), grade 3 sarcoma, which could be removed by neck dissection. He had a stage IIIB esophageal carcinoma (T3N2MX), which would require concurrent chemoradiation. His limited stage small cell lung cancer might have been amenable to a lobectomy if a mediastinoscopy was negative. The standard of care for limited stage small cell lung cancer is that if the cancer is precisely staged and the patient is a good surgical candidate, then surgery can be considered. The rationale for considering resection in this case was that if his other cancers could be cured, then surgery would be an excellent option.² These options were presented to the patient, who opted for chemotherapy. The oncologist treating the patient elected to target the small cell cancer initially, because it was likely the fastest growing cancer. The patient started treatment with etoposide/carboplatin shortly thereafter. Mr. F. was also referred to palliative care.

Discussion

When a patient presents with several tumor masses detected either clinically or radiologically, it is reasonable to assume, at least initially, that all the lesions can be attributed to the same disease (ie, a primary neoplasm and distant metastases). Based on this assumption, it is rational to establish a tissue diagnosis by sampling the most accessible lesion. In the correct clinical context, this may be sufficient to initiate an appropriate therapy. However, health care providers should be aware that unrelated neoplasms can develop simultaneously, and about 8% of patients have > 1 malignancy at presentation.³

This patient presented with 3 different malignant neoplasms: esophageal adenocarcinoma, pulmonary small-cell carcinoma, and high-grade sarcoma. These types of tumors have completely different histogenesis. Esophageal adenocarcinoma develops from glandular cells of Barrett’s esophagus, small-cell carcinoma develops from neuroendocrine Kulchitsky cells, and sarcoma arises from mesenchymal cells. This constellation of neoplasms does not represent any known multicancer syndrome, such as Li-Fraumeni syndrome or Lynch syndrome. Whether these concomitant tumors represent coincidental neoplasms or have common underlying molecular alterations remains unknown.

The treatment for each of this patient’s cancers was very different and required a multidisciplinary, staged approach for management. This could have been arranged for him had he wanted to pursue multiple resections of the neck and lung plus have chemotherapy and radiation for the esophageal cancer. The patient opted for chemotherapy for the most aggressive cancer, but other options would have been possible had he wanted to pursue them.

Conclusion

This complex case demonstrates the role for careful review of all data and the importance of not making assumptions when analyzing images and history despite all the procedures and time to diagnosis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Mr. F. is a 67-year-old man with a medical history significant for hypertension, hyperlipidemia, gastroesophageal reflux disease, abdominal aortic aneurysm repair, and lung nodules (8-mm nodules in his right lower lobe and left upper lobe) since 2009 for which he had been followed in the pulmonary clinic. His last radiologic imaging had been performed in November 2010. The patient had failed to show for a serial scan and follow-up pulmonary appointments. He had seen his primary care practitioner annually. He reporteded a 60 pack-year smoking history and drank up to 10 to 15 beers a day, 3 days a week. He also reported exposure to asbestos while in the U.S. Navy as well as having worked in a sheet metal yard. He reported no family history of lung cancer.

In January 2014, Mr. F. presented to his primary care doctor with a nonpainful neck lump noted by the patient for a few months. On physical examination, the patient appeared healthy and without change in weight, loss of appetite, dysphagia, hemoptysis, or any other remarkable symptoms except for the pain in the left-sided neck mass. On oral examination, the patient did not have any oral lesions but was noted to have poor dentition. He had decreased breath sounds on the right side but no adventitious breath sounds. His cardiac status was within normal limits with a regular heart rate, warm skin, and well-perfused extremities. His abdomen was soft and nontender with good bowel sounds.

A neck computed tomography (CT) done on January 17, 2014, showed 2 left neck masses in the tail of the parotid gland or in level 2 adjacent to the parotid gland. The ear, nose, and throat (ENT) clinic noted that he had a 3-cm level 2 mass, which was mobile and nontender. A fine needle aspiration biopsy showed poorly differentiated rare malignant cells, but the small size of the biopsy precluded identification of the cells. For that reason, the patient was scheduled for an operative laryngoscopy.

A combined positron emission tomography and CT (PET/CT) scan on February 5, 2014, showed multiple areas of hypermetabolic activity. A highly metabolic 2.6 x 1.9-cm mass was noted in the left neck inseparable from the inferior border of the left parotid gland; whether this represented a parotid neoplasm or neoplastic lymph node could not be determined. Positive level 5 neck lymph nodes were suggestive of metastatic disease. There were also 2 foci of mild nonspecific metabolic activity in the right parotid gland. A spiculated mass in the right lower lung, measuring 2.3 x 3.5 cm, demonstrated intense fludeoxyglucose F 18 (FDG) uptake with maximum standardized uptake value (SUV) of 12.7, which was consistent with neoplasm. Thickening of the middistal esophageal wall with intense FDG uptake (SUV of 7.9) was suggestive of esophageal carcinoma.

The patient underwent an endoscopic ultrasound (EUS) esophageal biopsy, which demonstrated poorly differentiated adenocarcinoma (Figure 1). The tumor seemed to have originated at this site, as the biopsy fragments also contained foci of Barrett’s metaplasia and in situ carcinoma. He was presented in the hospital tumor board about whether he should undergo a high-risk lung biopsy due to the location of the mass or have his left neck mass rebiopsied, assuming that he had metastatic esophageal cancer in both the lung and neck. The safer procedure of redoing the neck biopsy in the Ear, Nose, and Throat clinic was pursued, and the patient underwent a biopsy and surgical excision of his left neck mass with positive pathology of highgrade sarcoma (Figure 2).

The tumor consisted of spindle and epithelioid cell proliferation within a lymph node. The neoplastic cells exhibited prominent nuclear atypia, multinucleation, frequent mitoses, and focal necrosis. By immunohistochemistry, the tumor cells were diffusely positive for vimentin, CD68, and CD34 and were negative for pankeratin, CK7, CAM 5.2, CD30, CD15, tyrosine, melan-a, HMB-45, epithelial membrane antigen, keratin 903, desmin protein, CD56, CD99, actin protein, and CD1a. A differential diagnosis included malignant fibrous histiocytoma and histiocytic sarcoma.

Knowing the patient had 2 tumors, a percutaneous lung biopsy was scheduled. It was assumed that the lung mass would be metastatic from esophagus vs sarcoma, but the biopsy showed small cell cancer (Figure 3). The tumor was composed of small cells with finely granular chromatin and a sparse amount of cytoplasm. By immunohistochemistry, the tumor cells were positive for TTF-1, CK7, CAM 5.2, CD56, and synaptophysin and were negative for CK5, CK6, and p63. The patient was represented at the tumor board with diagnostic recommendations to undergo a magnetic resonance imaging of the brain (negative for metastasis) and a PET/CT scan (stable disease).

A lengthy discussion ensued regarding treatment for the 3 cancers. The AJCC Cancer Staging Manual, 7th edition, was used as the framework for all staging.¹ The patient had a stage IIA (T1bN0MX), grade 3 sarcoma, which could be removed by neck dissection. He had a stage IIIB esophageal carcinoma (T3N2MX), which would require concurrent chemoradiation. His limited stage small cell lung cancer might have been amenable to a lobectomy if a mediastinoscopy was negative. The standard of care for limited stage small cell lung cancer is that if the cancer is precisely staged and the patient is a good surgical candidate, then surgery can be considered. The rationale for considering resection in this case was that if his other cancers could be cured, then surgery would be an excellent option.² These options were presented to the patient, who opted for chemotherapy. The oncologist treating the patient elected to target the small cell cancer initially, because it was likely the fastest growing cancer. The patient started treatment with etoposide/carboplatin shortly thereafter. Mr. F. was also referred to palliative care.

Discussion

When a patient presents with several tumor masses detected either clinically or radiologically, it is reasonable to assume, at least initially, that all the lesions can be attributed to the same disease (ie, a primary neoplasm and distant metastases). Based on this assumption, it is rational to establish a tissue diagnosis by sampling the most accessible lesion. In the correct clinical context, this may be sufficient to initiate an appropriate therapy. However, health care providers should be aware that unrelated neoplasms can develop simultaneously, and about 8% of patients have > 1 malignancy at presentation.³

This patient presented with 3 different malignant neoplasms: esophageal adenocarcinoma, pulmonary small-cell carcinoma, and high-grade sarcoma. These types of tumors have completely different histogenesis. Esophageal adenocarcinoma develops from glandular cells of Barrett’s esophagus, small-cell carcinoma develops from neuroendocrine Kulchitsky cells, and sarcoma arises from mesenchymal cells. This constellation of neoplasms does not represent any known multicancer syndrome, such as Li-Fraumeni syndrome or Lynch syndrome. Whether these concomitant tumors represent coincidental neoplasms or have common underlying molecular alterations remains unknown.

The treatment for each of this patient’s cancers was very different and required a multidisciplinary, staged approach for management. This could have been arranged for him had he wanted to pursue multiple resections of the neck and lung plus have chemotherapy and radiation for the esophageal cancer. The patient opted for chemotherapy for the most aggressive cancer, but other options would have been possible had he wanted to pursue them.

Conclusion

This complex case demonstrates the role for careful review of all data and the importance of not making assumptions when analyzing images and history despite all the procedures and time to diagnosis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Cyclophosphamide, an agent used to treat various malignant and autoimmune disorders, can cause severe hyponatremia with seizures in rare cases. The exact mechanism of cyclophosphamide-induced hyponatremia is poorly understood, but is thought to occur from a drug- associated antidiuretic hormone (ADH) release leading to free water retention.¹ This unusual phenomenon of cyclophosphamide-associated syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been described only in case reports, most of which reported the development of severe hyponatremia within a week after administration of cyclophosphamide.^2-5 We report a unique case of a patient who developed severe, symptomatic hyponatremia with seizures, with her serum sodium decreasing from 137 mEq to 112 mEq within 30 hours after her first dose of low-dose cyclophosphamide (600 mg/m²).

Case presentation and summary

A 68-year-old white woman with a history of bilateral invasive ductal carcinoma of the breast (status-post bilateral mastectomy) presented to the emergency department (ED) at our facility with new onset seizure. The patient had been diagnosed 8 months earlier with stage I (T1c, N0, M0) poorly differentiated infiltrating ductal carcinoma (triple negative) of the left breast for which she underwent left segmental mastectomy about 1 month after diagnosis. She was subsequently found to have progressive disease with stage IIIC (T2, N3, and M0) infiltrating ductal carcinoma with lobular features (ER/PR+, Her2) of the right breast. She underwent a right modified radical mastectomy 5 months after her stage IIIC breast cancer diagnosis. She received her first cycle of adjuvant chemotherapy with intravenous doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²), which included pre-hydration, a day before presenting to our facility.

According to the patient’s family who provided the initial history, the patient reported tightness in her left arm while sitting at the dinner table. She was confused and subsequently had jerking movement of her right upper extremity with left facial twitching which lasted about 40 seconds. There was no loss of consciousness, or bowel or bladder control. She became unresponsive after the episode. Review of systems was negative except for a report of nausea a few hours before the onset of seizures, which resolved with ondansetron. Her past medical history was significant for breast cancer as already mentioned, seasonal allergic rhinitis, and hypertension. Home medications included hydrochlorothiazide 12.5 mg oral daily, aspirin 81 mg oral daily, and fexofenadine and loratadine oral daily as needed for allergies. There were no other significant surgical history other than already stated. The patient lived at home with her family and was independent with her instrumental activities of daily living. She is a former smoker of tobacco and quit smoking 30 years ago.

On arrival at our facility, the patient had normal vital signs. Significant findings on physical examination were an elderly female who seemed somnolent; not able to follow commands with a documented Glasgow Coma Scale of 10 with eyes opening spontaneously, incomprehensible sounds, and flexion withdrawal from pain as her best responses. She had an increased tone in her left upper extremity and had a brisk, deep tendon reflexes without clonus or 3+ (range, 0-5+, with 2+ being normal). The remainder of her physical exam was unremarkable. Laboratory testing revealed a glucose level of 120 mg/dL (normal, 65-110 mg/dL), sodium of 112 mEq/L (normal, 135-145 mmol/L), and chloride of 78 mEq/L (normal, 95-105 mmol/L). Serum osmolality and urine osmolality were 242 mOsm/kg (normal, 282-295 mOsm/kg) and 449 mOsm/kg (normal, 500-800 mOsm/kg) respectively, indicative of suboptimally dilute urine despite relatively low serum osmolality or SIADH. Urine electrolytes were not obtained.

Imaging studies including computed-tomography scans of the head and chest x-ray performed in the ED were unremarkable. After a phenytoin load, an electroencephalogram was obtained which showed diffuse encephalopathy without active seizure foci. A non-contrast magnetic-resonance imaging (MRI) of the brain was performed but it failed to show acute infarct, mass, mass effect, or brain herniation. There was nonspecific white matter abnormality with compromise of the bilateral cerebral hemispheres, calloseptal junction, left posterior pillar, and bilateral anterior pillars of the fornix, possibly representative of chronic white matter microvascular ischemic changes or less likely vasculitis or demyelination. Correction of her hyponatremia with normal saline was started in the ED with a change in serum sodium from 112 mEq/L to 115 mEq/L within 2 hours. She was admitted to the intensive care unit (ICU) where her sodium correction with normal saline and free water restriction was continued with a goal correction rate of 8-12 mEq/L in 24 hours. The patient’s serum sodium as well as level of consciousness improved gradually over the course of her ICU stay. After 64 hours in the hospital, her sodium had corrected to 137 mEq/L (normal, 135-145 mmol/L; Figure). She was then alert and oriented to person, place, and time. All motor findings noted on presentation had resolved. Her saline infusion was discontinued and serum sodium remained within normal range. She was discharged to a rehabilitation facility. Her hydrochlorothiazide was also discontinued.

Discussion

Hyponatremia is a common finding in cancer patients caused usually by paraneoplastic syndrome, chemotherapy, immunotherapy, or other associated treatment.⁶ SIADH is a frequent cause of hyponatremia in cancer patients and should be suspected in patients with hyponatremia, hypo-osmolality, and a urine osmolality above 100 mOsmol/kg.⁷

Our patient’s presentation and laboratory findings suggested SIADH as the likely cause of hyponatremia with a low sodium, a serum osmolality 242 mOsm/kg and urine osmolality of 449 mOsm/kg.^8-10 She had no known underlying contributory comorbid condition relating to her serum lipids, thyroid, adrenal, kidney, or heart to date. Her use of a thiazide diuretic was the only confounding factor. The most plausible cause of hyponatremia/SIADH in our patient was likely cyclophosphamide based on her history, timeline of symptoms, and the absence of other possible causes. Though the mechanism for many of the previously mentioned etiologies are known, the mechanism of cyclophosphamide-induced SIADH is difficult to elucidate since the imminent complication of hemorrhagic cystitis means patients receiving this drug are often aggressively hydrated to prevent this complication.^11,12 The result is that there is marked retention of water leading to potentially fatal hyponatremia in selected cases.¹¹ This phenomenon has been fairly well described in patients receiving doses of 6 g/m² as given in the STAMP protocol for stem cell mobilization or at doses of 30-50 mg/kg used to treat malignancy.¹² Our patient clearly falls in this category given that she received a dose of 600 mg/m². We found no evidence in her history to suggest post-operative, genetic or other cause for her hyponatremia. Our case mirrors a report by Koo and colleagues who described severe hyponatremia occurring within 24 hours following a single dose of intravenous cyclophosphamide 700 mg followed by saline infusion.¹³ In the case reported by Jayachandra and colleagues in which suspected cyclophosphamide-induced hyponatremia led to seizures, the patient received 500 mg IV of cyclophosphamide and had serum sodium as low as 106 mEq/L within a 24-hour period,² similar to our patient.

There is a paucity of data on cyclophosphamide-induced SIADH. The mechanism by which cyclophosphamide causes SIADH is currently unknown. In addition, there are currently no set criteria that help identify at-risk patients who may develop such an event, including the dosage of cyclophosphamide that may trigger the SIADH, because lower doses of the drug have been associated with this complication.¹⁴

In a retrospective analysis by Lee and colleagues, cyclophosphamide-induced hyponatremia was found to be associated with male sex on a univariate analysis, but no risk factors were found in a multivariate analysis.¹⁵ It is likely that the concomitant use of diuretics, hydration, and high-dose cyclophosphamide contributed to hyponatremia/SIADH in our patient, though it is not clear through what mechanism. Harlow and colleagues proposed a mechanism for this phenomenon in 1979 based on the autopsy of a patient who had received high-dose cyclophosphamide involving degranulation of hypothalamic neurosecretory organelles and loss of Herring’s bodies. They inferred that metabolites of cyclophosphamide indirectly triggered inappropriate secretion of antidiuretic hormone as seen with a use of the structurally related analogue ifosfamide,¹⁶ but to our knowledge, this has yet to be replicated. Cyclophosphamide metabolite may have a direct tubular effect on the collecting duct epithelium leading to water retention¹⁵ as established by Campbell and colleagues. In one case, an established diabetes insipidus patient developed cyclophosphamide-induced antidiuresis without vasopressin secretion.¹⁷ It is imperative that the scientific community conduct research into the risk factors, underlying mechanisms, and methods of prevention to reduce and/or eliminate SIADH associated with use of cyclophosphamide.

Cyclophosphamide, an agent used to treat various malignant and autoimmune disorders, can cause severe hyponatremia with seizures in rare cases. The exact mechanism of cyclophosphamide-induced hyponatremia is poorly understood, but is thought to occur from a drug- associated antidiuretic hormone (ADH) release leading to free water retention.¹ This unusual phenomenon of cyclophosphamide-associated syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been described only in case reports, most of which reported the development of severe hyponatremia within a week after administration of cyclophosphamide.^2-5 We report a unique case of a patient who developed severe, symptomatic hyponatremia with seizures, with her serum sodium decreasing from 137 mEq to 112 mEq within 30 hours after her first dose of low-dose cyclophosphamide (600 mg/m²).

Case presentation and summary

A 68-year-old white woman with a history of bilateral invasive ductal carcinoma of the breast (status-post bilateral mastectomy) presented to the emergency department (ED) at our facility with new onset seizure. The patient had been diagnosed 8 months earlier with stage I (T1c, N0, M0) poorly differentiated infiltrating ductal carcinoma (triple negative) of the left breast for which she underwent left segmental mastectomy about 1 month after diagnosis. She was subsequently found to have progressive disease with stage IIIC (T2, N3, and M0) infiltrating ductal carcinoma with lobular features (ER/PR+, Her2) of the right breast. She underwent a right modified radical mastectomy 5 months after her stage IIIC breast cancer diagnosis. She received her first cycle of adjuvant chemotherapy with intravenous doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²), which included pre-hydration, a day before presenting to our facility.

According to the patient’s family who provided the initial history, the patient reported tightness in her left arm while sitting at the dinner table. She was confused and subsequently had jerking movement of her right upper extremity with left facial twitching which lasted about 40 seconds. There was no loss of consciousness, or bowel or bladder control. She became unresponsive after the episode. Review of systems was negative except for a report of nausea a few hours before the onset of seizures, which resolved with ondansetron. Her past medical history was significant for breast cancer as already mentioned, seasonal allergic rhinitis, and hypertension. Home medications included hydrochlorothiazide 12.5 mg oral daily, aspirin 81 mg oral daily, and fexofenadine and loratadine oral daily as needed for allergies. There were no other significant surgical history other than already stated. The patient lived at home with her family and was independent with her instrumental activities of daily living. She is a former smoker of tobacco and quit smoking 30 years ago.

On arrival at our facility, the patient had normal vital signs. Significant findings on physical examination were an elderly female who seemed somnolent; not able to follow commands with a documented Glasgow Coma Scale of 10 with eyes opening spontaneously, incomprehensible sounds, and flexion withdrawal from pain as her best responses. She had an increased tone in her left upper extremity and had a brisk, deep tendon reflexes without clonus or 3+ (range, 0-5+, with 2+ being normal). The remainder of her physical exam was unremarkable. Laboratory testing revealed a glucose level of 120 mg/dL (normal, 65-110 mg/dL), sodium of 112 mEq/L (normal, 135-145 mmol/L), and chloride of 78 mEq/L (normal, 95-105 mmol/L). Serum osmolality and urine osmolality were 242 mOsm/kg (normal, 282-295 mOsm/kg) and 449 mOsm/kg (normal, 500-800 mOsm/kg) respectively, indicative of suboptimally dilute urine despite relatively low serum osmolality or SIADH. Urine electrolytes were not obtained.

Imaging studies including computed-tomography scans of the head and chest x-ray performed in the ED were unremarkable. After a phenytoin load, an electroencephalogram was obtained which showed diffuse encephalopathy without active seizure foci. A non-contrast magnetic-resonance imaging (MRI) of the brain was performed but it failed to show acute infarct, mass, mass effect, or brain herniation. There was nonspecific white matter abnormality with compromise of the bilateral cerebral hemispheres, calloseptal junction, left posterior pillar, and bilateral anterior pillars of the fornix, possibly representative of chronic white matter microvascular ischemic changes or less likely vasculitis or demyelination. Correction of her hyponatremia with normal saline was started in the ED with a change in serum sodium from 112 mEq/L to 115 mEq/L within 2 hours. She was admitted to the intensive care unit (ICU) where her sodium correction with normal saline and free water restriction was continued with a goal correction rate of 8-12 mEq/L in 24 hours. The patient’s serum sodium as well as level of consciousness improved gradually over the course of her ICU stay. After 64 hours in the hospital, her sodium had corrected to 137 mEq/L (normal, 135-145 mmol/L; Figure). She was then alert and oriented to person, place, and time. All motor findings noted on presentation had resolved. Her saline infusion was discontinued and serum sodium remained within normal range. She was discharged to a rehabilitation facility. Her hydrochlorothiazide was also discontinued.

Discussion

Hyponatremia is a common finding in cancer patients caused usually by paraneoplastic syndrome, chemotherapy, immunotherapy, or other associated treatment.⁶ SIADH is a frequent cause of hyponatremia in cancer patients and should be suspected in patients with hyponatremia, hypo-osmolality, and a urine osmolality above 100 mOsmol/kg.⁷

Our patient’s presentation and laboratory findings suggested SIADH as the likely cause of hyponatremia with a low sodium, a serum osmolality 242 mOsm/kg and urine osmolality of 449 mOsm/kg.^8-10 She had no known underlying contributory comorbid condition relating to her serum lipids, thyroid, adrenal, kidney, or heart to date. Her use of a thiazide diuretic was the only confounding factor. The most plausible cause of hyponatremia/SIADH in our patient was likely cyclophosphamide based on her history, timeline of symptoms, and the absence of other possible causes. Though the mechanism for many of the previously mentioned etiologies are known, the mechanism of cyclophosphamide-induced SIADH is difficult to elucidate since the imminent complication of hemorrhagic cystitis means patients receiving this drug are often aggressively hydrated to prevent this complication.^11,12 The result is that there is marked retention of water leading to potentially fatal hyponatremia in selected cases.¹¹ This phenomenon has been fairly well described in patients receiving doses of 6 g/m² as given in the STAMP protocol for stem cell mobilization or at doses of 30-50 mg/kg used to treat malignancy.¹² Our patient clearly falls in this category given that she received a dose of 600 mg/m². We found no evidence in her history to suggest post-operative, genetic or other cause for her hyponatremia. Our case mirrors a report by Koo and colleagues who described severe hyponatremia occurring within 24 hours following a single dose of intravenous cyclophosphamide 700 mg followed by saline infusion.¹³ In the case reported by Jayachandra and colleagues in which suspected cyclophosphamide-induced hyponatremia led to seizures, the patient received 500 mg IV of cyclophosphamide and had serum sodium as low as 106 mEq/L within a 24-hour period,² similar to our patient.

There is a paucity of data on cyclophosphamide-induced SIADH. The mechanism by which cyclophosphamide causes SIADH is currently unknown. In addition, there are currently no set criteria that help identify at-risk patients who may develop such an event, including the dosage of cyclophosphamide that may trigger the SIADH, because lower doses of the drug have been associated with this complication.¹⁴

In a retrospective analysis by Lee and colleagues, cyclophosphamide-induced hyponatremia was found to be associated with male sex on a univariate analysis, but no risk factors were found in a multivariate analysis.¹⁵ It is likely that the concomitant use of diuretics, hydration, and high-dose cyclophosphamide contributed to hyponatremia/SIADH in our patient, though it is not clear through what mechanism. Harlow and colleagues proposed a mechanism for this phenomenon in 1979 based on the autopsy of a patient who had received high-dose cyclophosphamide involving degranulation of hypothalamic neurosecretory organelles and loss of Herring’s bodies. They inferred that metabolites of cyclophosphamide indirectly triggered inappropriate secretion of antidiuretic hormone as seen with a use of the structurally related analogue ifosfamide,¹⁶ but to our knowledge, this has yet to be replicated. Cyclophosphamide metabolite may have a direct tubular effect on the collecting duct epithelium leading to water retention¹⁵ as established by Campbell and colleagues. In one case, an established diabetes insipidus patient developed cyclophosphamide-induced antidiuresis without vasopressin secretion.¹⁷ It is imperative that the scientific community conduct research into the risk factors, underlying mechanisms, and methods of prevention to reduce and/or eliminate SIADH associated with use of cyclophosphamide.

Cyclophosphamide, an agent used to treat various malignant and autoimmune disorders, can cause severe hyponatremia with seizures in rare cases. The exact mechanism of cyclophosphamide-induced hyponatremia is poorly understood, but is thought to occur from a drug- associated antidiuretic hormone (ADH) release leading to free water retention.¹ This unusual phenomenon of cyclophosphamide-associated syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been described only in case reports, most of which reported the development of severe hyponatremia within a week after administration of cyclophosphamide.^2-5 We report a unique case of a patient who developed severe, symptomatic hyponatremia with seizures, with her serum sodium decreasing from 137 mEq to 112 mEq within 30 hours after her first dose of low-dose cyclophosphamide (600 mg/m²).

Case presentation and summary

A 68-year-old white woman with a history of bilateral invasive ductal carcinoma of the breast (status-post bilateral mastectomy) presented to the emergency department (ED) at our facility with new onset seizure. The patient had been diagnosed 8 months earlier with stage I (T1c, N0, M0) poorly differentiated infiltrating ductal carcinoma (triple negative) of the left breast for which she underwent left segmental mastectomy about 1 month after diagnosis. She was subsequently found to have progressive disease with stage IIIC (T2, N3, and M0) infiltrating ductal carcinoma with lobular features (ER/PR+, Her2) of the right breast. She underwent a right modified radical mastectomy 5 months after her stage IIIC breast cancer diagnosis. She received her first cycle of adjuvant chemotherapy with intravenous doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²), which included pre-hydration, a day before presenting to our facility.

According to the patient’s family who provided the initial history, the patient reported tightness in her left arm while sitting at the dinner table. She was confused and subsequently had jerking movement of her right upper extremity with left facial twitching which lasted about 40 seconds. There was no loss of consciousness, or bowel or bladder control. She became unresponsive after the episode. Review of systems was negative except for a report of nausea a few hours before the onset of seizures, which resolved with ondansetron. Her past medical history was significant for breast cancer as already mentioned, seasonal allergic rhinitis, and hypertension. Home medications included hydrochlorothiazide 12.5 mg oral daily, aspirin 81 mg oral daily, and fexofenadine and loratadine oral daily as needed for allergies. There were no other significant surgical history other than already stated. The patient lived at home with her family and was independent with her instrumental activities of daily living. She is a former smoker of tobacco and quit smoking 30 years ago.

On arrival at our facility, the patient had normal vital signs. Significant findings on physical examination were an elderly female who seemed somnolent; not able to follow commands with a documented Glasgow Coma Scale of 10 with eyes opening spontaneously, incomprehensible sounds, and flexion withdrawal from pain as her best responses. She had an increased tone in her left upper extremity and had a brisk, deep tendon reflexes without clonus or 3+ (range, 0-5+, with 2+ being normal). The remainder of her physical exam was unremarkable. Laboratory testing revealed a glucose level of 120 mg/dL (normal, 65-110 mg/dL), sodium of 112 mEq/L (normal, 135-145 mmol/L), and chloride of 78 mEq/L (normal, 95-105 mmol/L). Serum osmolality and urine osmolality were 242 mOsm/kg (normal, 282-295 mOsm/kg) and 449 mOsm/kg (normal, 500-800 mOsm/kg) respectively, indicative of suboptimally dilute urine despite relatively low serum osmolality or SIADH. Urine electrolytes were not obtained.

Imaging studies including computed-tomography scans of the head and chest x-ray performed in the ED were unremarkable. After a phenytoin load, an electroencephalogram was obtained which showed diffuse encephalopathy without active seizure foci. A non-contrast magnetic-resonance imaging (MRI) of the brain was performed but it failed to show acute infarct, mass, mass effect, or brain herniation. There was nonspecific white matter abnormality with compromise of the bilateral cerebral hemispheres, calloseptal junction, left posterior pillar, and bilateral anterior pillars of the fornix, possibly representative of chronic white matter microvascular ischemic changes or less likely vasculitis or demyelination. Correction of her hyponatremia with normal saline was started in the ED with a change in serum sodium from 112 mEq/L to 115 mEq/L within 2 hours. She was admitted to the intensive care unit (ICU) where her sodium correction with normal saline and free water restriction was continued with a goal correction rate of 8-12 mEq/L in 24 hours. The patient’s serum sodium as well as level of consciousness improved gradually over the course of her ICU stay. After 64 hours in the hospital, her sodium had corrected to 137 mEq/L (normal, 135-145 mmol/L; Figure). She was then alert and oriented to person, place, and time. All motor findings noted on presentation had resolved. Her saline infusion was discontinued and serum sodium remained within normal range. She was discharged to a rehabilitation facility. Her hydrochlorothiazide was also discontinued.

Discussion

Hyponatremia is a common finding in cancer patients caused usually by paraneoplastic syndrome, chemotherapy, immunotherapy, or other associated treatment.⁶ SIADH is a frequent cause of hyponatremia in cancer patients and should be suspected in patients with hyponatremia, hypo-osmolality, and a urine osmolality above 100 mOsmol/kg.⁷

Our patient’s presentation and laboratory findings suggested SIADH as the likely cause of hyponatremia with a low sodium, a serum osmolality 242 mOsm/kg and urine osmolality of 449 mOsm/kg.^8-10 She had no known underlying contributory comorbid condition relating to her serum lipids, thyroid, adrenal, kidney, or heart to date. Her use of a thiazide diuretic was the only confounding factor. The most plausible cause of hyponatremia/SIADH in our patient was likely cyclophosphamide based on her history, timeline of symptoms, and the absence of other possible causes. Though the mechanism for many of the previously mentioned etiologies are known, the mechanism of cyclophosphamide-induced SIADH is difficult to elucidate since the imminent complication of hemorrhagic cystitis means patients receiving this drug are often aggressively hydrated to prevent this complication.^11,12 The result is that there is marked retention of water leading to potentially fatal hyponatremia in selected cases.¹¹ This phenomenon has been fairly well described in patients receiving doses of 6 g/m² as given in the STAMP protocol for stem cell mobilization or at doses of 30-50 mg/kg used to treat malignancy.¹² Our patient clearly falls in this category given that she received a dose of 600 mg/m². We found no evidence in her history to suggest post-operative, genetic or other cause for her hyponatremia. Our case mirrors a report by Koo and colleagues who described severe hyponatremia occurring within 24 hours following a single dose of intravenous cyclophosphamide 700 mg followed by saline infusion.¹³ In the case reported by Jayachandra and colleagues in which suspected cyclophosphamide-induced hyponatremia led to seizures, the patient received 500 mg IV of cyclophosphamide and had serum sodium as low as 106 mEq/L within a 24-hour period,² similar to our patient.

There is a paucity of data on cyclophosphamide-induced SIADH. The mechanism by which cyclophosphamide causes SIADH is currently unknown. In addition, there are currently no set criteria that help identify at-risk patients who may develop such an event, including the dosage of cyclophosphamide that may trigger the SIADH, because lower doses of the drug have been associated with this complication.¹⁴

In a retrospective analysis by Lee and colleagues, cyclophosphamide-induced hyponatremia was found to be associated with male sex on a univariate analysis, but no risk factors were found in a multivariate analysis.¹⁵ It is likely that the concomitant use of diuretics, hydration, and high-dose cyclophosphamide contributed to hyponatremia/SIADH in our patient, though it is not clear through what mechanism. Harlow and colleagues proposed a mechanism for this phenomenon in 1979 based on the autopsy of a patient who had received high-dose cyclophosphamide involving degranulation of hypothalamic neurosecretory organelles and loss of Herring’s bodies. They inferred that metabolites of cyclophosphamide indirectly triggered inappropriate secretion of antidiuretic hormone as seen with a use of the structurally related analogue ifosfamide,¹⁶ but to our knowledge, this has yet to be replicated. Cyclophosphamide metabolite may have a direct tubular effect on the collecting duct epithelium leading to water retention¹⁵ as established by Campbell and colleagues. In one case, an established diabetes insipidus patient developed cyclophosphamide-induced antidiuresis without vasopressin secretion.¹⁷ It is imperative that the scientific community conduct research into the risk factors, underlying mechanisms, and methods of prevention to reduce and/or eliminate SIADH associated with use of cyclophosphamide.

Certain cancers have been observed to cause symptoms called paraneoplastic syndromes that are not directly attributed to tumor invasion or compression. This phenomenon is believed to be secondary to a tumor’s secretion of functional hormones, peptides, cytokines, or its immune cross-reactivity. One such variant is a paraneoplastic leukemoid reaction (PLR), defined as a leukocytosis level of >50 x 10³ cells/mm³, where the white blood cell (WBC) count differential exhibits a neutrophilia or left-shift, in which a predominance of early neutrophil precursors is observed. A PLR is believed to be incited by the tumor cell’s production of its own growth factors such as granulocyte-colony stimulating factor (G-CSF) and a number of different cytokines. These reactions may at first be mistaken for infectious processes, and it is only after an infection has been ruled out or when a leukocytosis is disproportionately high in the setting of a treated infection, that a paraneoplastic leukemoid reaction (PLR) is considered and an oncologic work-up pursued.

PLR has been previously described in a variety of malignancies including lung, esophageal, nasopharyngeal and laryngeal, gastric, cholangiocarcinoma, melanoma, multiple myeloma, renal, prostate, and hepatocellular carcinoma, but has rarely been described in urothelial carcinoma.¹ Leukemoid reactions and autocrine growth induced by paraneoplastic production of G-CSF have rarely been associated with urothelial carcinoma of the bladder,² as in the case we present here of a 67-year-old white man with invasive high-grade urothelial carcinoma of the bladder. The case highlights PLR as a negative prognostic marker, secondary to urothelial bladder cancer cells’ presumed production of G-CSF, rarely reported as in the literature previously.

Case presentation and summary

A 67-year-old white man was diagnosed with clinical stage III (T3N0M0), invasive high-grade urothelial carcinoma of the bladder (Figure 1). He received neoadjuvant chemotherapy with the standard gemcitabine-cisplatin combination (1,000 mg/m² of gemcitabine on days 1, 8, and 15 with 70 mg/m² of cisplatin on day 1 of a 28-day cycle for 3 cycles), and had less than partial response at the end of a 3-month course. A computed tomography scan of his pelvis obtained at treatment completion revealed persistent disease with noted enhancement of the right distal ureter and a right posterior bladder mass at the ureterovesical junction measuring 1.7 x 2.6 x 2.6 cm (0.6 x 1 x 1 in), for which, a cystoprostatectomy was recommended to remove remaining disease. The patient was seen in routine follow-up 3 weeks after his last chemotherapy treatment, when his WBC count was noted to be within normal limits at a value of 8.4 x 10³ cells/mm³ (normal range, 4.5-11 x 10³ cells/mm³).

One week later (a month after treatment completion), the patient presented to the emergency department with complaints of dysuria, urinary frequency, and suprapubic pain. He was found to have leukocytosis, with a WBC count of 47 x 10³ cells/mm³, (normal range, 4.5-11 x 10³ cells/mm³), with an elevated neutrophil count of 82.7% (normal range 40%-60%), without clinical signs of systemic infection (fevers, chills, or rigors). A urinalysis revealed pyuria with 25-50 WBC/high power field, negative nitrite, positive leukocyte esterase, and moderate bacteria, consistent with what was presumed to be a urinary tract infection. The patient was discharged home with a 1-week course of the antibiotic levofloxacin and the alpha-blocker tamsulosin to make urination easier. Of note, the final results of the urine culture, which returned 48 hours after discharge, showed no growth.

One week prior to surgery, the patient underwent a cystoscopy for ureteral stent exchange, which revealed a necrotic tumor at the right bladder base surrounding the ureteral orifice and stent. Renal pelvis urine, sampled during stent exchange, revealed >100,000 CFU/ml (colony forming units; normal value, <10³) Candida albicans, for which the patient was started on intravenous fluconazole for fungal infection. We consulted with our colleagues in the infectious disease department and continued to follow the patient throughout his hospital course, which included several antibiotic regimens, a comprehensive hematological work-up and eventual urologic surgery. Work-ups for myeloproliferative disorders, leukemia, JAK-2, and BCR-ABL were all negative. A peripheral blood smear analysis showed mostly neutrophils, no immature cells, and occasional hypersegmented neutrophils, but was overall inconsistent with myeloproliferative disease. Despite the patient’s persistent leukocytosis, he remained completely asymptomatic and his neutrophilia was attributed to his malignancy.

The patient subsequently underwent a cystoprostatectomy with ileal conduit. The surgical pathologic analysis showed a high-grade, invasive urothelial (transitional cell) carcinoma measuring 5.2 x 5.0 x 4.5 cm (2 x 1.9 x 1.8 in) with squamous differentiation, extensive tumor necrosis, lymphovascular invasion, invasion into the adjacent seminal vesicle and prostatic stroma, and negative margins (pT4a pN0 pMX; Figure 2). On the day of surgical resection, the patient’s leukocytosis was 70 x 10³ cells/mm³.

Despite a transient improvement in his leukocytosis to 37.7 x 10³ cells/mm³ on postoperative day 1, the patient remained in the medical intensive care unit for uncontrolled pain and management of his leukocytosis. It is worth noting that the patient remained afebrile throughout his entire 45-day hospitalization, with negative culture data, and despite receiving an extensive broad spectrum antibiotic regimen (levofloxacin, piperacillin-tazobactam, cefazolin, metronidazole, ceftriaxone and fluconazole), his leukocytosis continued to progress, peaking at 161.5 x 10³ cells/mm³ less than a month after his surgery (Figure 3).

Discussion

We report here on the rare occurrence of PLR in a urothelial bladder cancer. Several mechanisms have been proposed to explain the pathophysiology of PLR. The levels of IL-1[alpha and beta], IL-3, G-CSF, GM-CSF, IL-6, and TNF-[alpha] have all been reported to be elevated in various solid tumors and suggested to contribute to an elevated leukocyte count.³ With previous reports that receptors for G-CSF have been found on cell surfaces of several nonhematopoietic cell types, Tachibana and Murai have proposed the mechanism of a cancer cell’s simultaneous acquisition of the ligand promotion and its receptor expression conferring an autocrine growth advantage.⁴ They have also reported on the capability of bladder cancer cells to induce a leukemoid reaction in their host through the stimulation of leukocyte production, which has been associated with aggressive tumor cell growth and a poor clinical outcome. In addition, He and colleagues have also described the correlation between PLR and high degree of malignancy, high probability of metastasis, recurrence, and poor prognosis.⁵

We observed the leukocytosis of 70 x 10³ cells/mm³ on the day of resection with a slight drop postoperatively, peaking at 161.5 x 10³ cells/mm³ less than a month after resection of the tumor. There is no clear understanding of the cause of the persistent and rapid progression of leukocytosis seen in this patient postoperatively. There is also a dearth of literature describing similar occurrences, with even fewer attempting to explain the pathophysiology of this occurrence.

When faced with similar occurrences in patients, clinicians usually treat for occult infection. Once infections and myeloproliferative diseases have been ruled out, clinicians may consider obtaining a patient’s serum G-CSF level or performing an immunohistochemistry analysis of urothelial cells for overexpression of G-CSF, when available.⁵ However, despite any efforts to diagnose earlier, there is little clinicians currently have to offer these patients as treatment.

As presented in this report, PLR portends a worse prognosis for patients because of its ability to not only masquerade as an infection leading to a delay in the proper treatment, but also because of its association with a more aggressive tumor cell behavior and growth, making it critically important for clinicians to be able to identify these patients early on. With further investigation into immune regulation and G-CSF receptor signaling, there may be future discoveries of novel methods to diagnose this condition and also advancements in the treatment options made available to these patients.

Certain cancers have been observed to cause symptoms called paraneoplastic syndromes that are not directly attributed to tumor invasion or compression. This phenomenon is believed to be secondary to a tumor’s secretion of functional hormones, peptides, cytokines, or its immune cross-reactivity. One such variant is a paraneoplastic leukemoid reaction (PLR), defined as a leukocytosis level of >50 x 10³ cells/mm³, where the white blood cell (WBC) count differential exhibits a neutrophilia or left-shift, in which a predominance of early neutrophil precursors is observed. A PLR is believed to be incited by the tumor cell’s production of its own growth factors such as granulocyte-colony stimulating factor (G-CSF) and a number of different cytokines. These reactions may at first be mistaken for infectious processes, and it is only after an infection has been ruled out or when a leukocytosis is disproportionately high in the setting of a treated infection, that a paraneoplastic leukemoid reaction (PLR) is considered and an oncologic work-up pursued.

PLR has been previously described in a variety of malignancies including lung, esophageal, nasopharyngeal and laryngeal, gastric, cholangiocarcinoma, melanoma, multiple myeloma, renal, prostate, and hepatocellular carcinoma, but has rarely been described in urothelial carcinoma.¹ Leukemoid reactions and autocrine growth induced by paraneoplastic production of G-CSF have rarely been associated with urothelial carcinoma of the bladder,² as in the case we present here of a 67-year-old white man with invasive high-grade urothelial carcinoma of the bladder. The case highlights PLR as a negative prognostic marker, secondary to urothelial bladder cancer cells’ presumed production of G-CSF, rarely reported as in the literature previously.

Case presentation and summary

A 67-year-old white man was diagnosed with clinical stage III (T3N0M0), invasive high-grade urothelial carcinoma of the bladder (Figure 1). He received neoadjuvant chemotherapy with the standard gemcitabine-cisplatin combination (1,000 mg/m² of gemcitabine on days 1, 8, and 15 with 70 mg/m² of cisplatin on day 1 of a 28-day cycle for 3 cycles), and had less than partial response at the end of a 3-month course. A computed tomography scan of his pelvis obtained at treatment completion revealed persistent disease with noted enhancement of the right distal ureter and a right posterior bladder mass at the ureterovesical junction measuring 1.7 x 2.6 x 2.6 cm (0.6 x 1 x 1 in), for which, a cystoprostatectomy was recommended to remove remaining disease. The patient was seen in routine follow-up 3 weeks after his last chemotherapy treatment, when his WBC count was noted to be within normal limits at a value of 8.4 x 10³ cells/mm³ (normal range, 4.5-11 x 10³ cells/mm³).

One week later (a month after treatment completion), the patient presented to the emergency department with complaints of dysuria, urinary frequency, and suprapubic pain. He was found to have leukocytosis, with a WBC count of 47 x 10³ cells/mm³, (normal range, 4.5-11 x 10³ cells/mm³), with an elevated neutrophil count of 82.7% (normal range 40%-60%), without clinical signs of systemic infection (fevers, chills, or rigors). A urinalysis revealed pyuria with 25-50 WBC/high power field, negative nitrite, positive leukocyte esterase, and moderate bacteria, consistent with what was presumed to be a urinary tract infection. The patient was discharged home with a 1-week course of the antibiotic levofloxacin and the alpha-blocker tamsulosin to make urination easier. Of note, the final results of the urine culture, which returned 48 hours after discharge, showed no growth.

One week prior to surgery, the patient underwent a cystoscopy for ureteral stent exchange, which revealed a necrotic tumor at the right bladder base surrounding the ureteral orifice and stent. Renal pelvis urine, sampled during stent exchange, revealed >100,000 CFU/ml (colony forming units; normal value, <10³) Candida albicans, for which the patient was started on intravenous fluconazole for fungal infection. We consulted with our colleagues in the infectious disease department and continued to follow the patient throughout his hospital course, which included several antibiotic regimens, a comprehensive hematological work-up and eventual urologic surgery. Work-ups for myeloproliferative disorders, leukemia, JAK-2, and BCR-ABL were all negative. A peripheral blood smear analysis showed mostly neutrophils, no immature cells, and occasional hypersegmented neutrophils, but was overall inconsistent with myeloproliferative disease. Despite the patient’s persistent leukocytosis, he remained completely asymptomatic and his neutrophilia was attributed to his malignancy.

The patient subsequently underwent a cystoprostatectomy with ileal conduit. The surgical pathologic analysis showed a high-grade, invasive urothelial (transitional cell) carcinoma measuring 5.2 x 5.0 x 4.5 cm (2 x 1.9 x 1.8 in) with squamous differentiation, extensive tumor necrosis, lymphovascular invasion, invasion into the adjacent seminal vesicle and prostatic stroma, and negative margins (pT4a pN0 pMX; Figure 2). On the day of surgical resection, the patient’s leukocytosis was 70 x 10³ cells/mm³.

Despite a transient improvement in his leukocytosis to 37.7 x 10³ cells/mm³ on postoperative day 1, the patient remained in the medical intensive care unit for uncontrolled pain and management of his leukocytosis. It is worth noting that the patient remained afebrile throughout his entire 45-day hospitalization, with negative culture data, and despite receiving an extensive broad spectrum antibiotic regimen (levofloxacin, piperacillin-tazobactam, cefazolin, metronidazole, ceftriaxone and fluconazole), his leukocytosis continued to progress, peaking at 161.5 x 10³ cells/mm³ less than a month after his surgery (Figure 3).

Discussion

We report here on the rare occurrence of PLR in a urothelial bladder cancer. Several mechanisms have been proposed to explain the pathophysiology of PLR. The levels of IL-1[alpha and beta], IL-3, G-CSF, GM-CSF, IL-6, and TNF-[alpha] have all been reported to be elevated in various solid tumors and suggested to contribute to an elevated leukocyte count.³ With previous reports that receptors for G-CSF have been found on cell surfaces of several nonhematopoietic cell types, Tachibana and Murai have proposed the mechanism of a cancer cell’s simultaneous acquisition of the ligand promotion and its receptor expression conferring an autocrine growth advantage.⁴ They have also reported on the capability of bladder cancer cells to induce a leukemoid reaction in their host through the stimulation of leukocyte production, which has been associated with aggressive tumor cell growth and a poor clinical outcome. In addition, He and colleagues have also described the correlation between PLR and high degree of malignancy, high probability of metastasis, recurrence, and poor prognosis.⁵

We observed the leukocytosis of 70 x 10³ cells/mm³ on the day of resection with a slight drop postoperatively, peaking at 161.5 x 10³ cells/mm³ less than a month after resection of the tumor. There is no clear understanding of the cause of the persistent and rapid progression of leukocytosis seen in this patient postoperatively. There is also a dearth of literature describing similar occurrences, with even fewer attempting to explain the pathophysiology of this occurrence.

When faced with similar occurrences in patients, clinicians usually treat for occult infection. Once infections and myeloproliferative diseases have been ruled out, clinicians may consider obtaining a patient’s serum G-CSF level or performing an immunohistochemistry analysis of urothelial cells for overexpression of G-CSF, when available.⁵ However, despite any efforts to diagnose earlier, there is little clinicians currently have to offer these patients as treatment.

As presented in this report, PLR portends a worse prognosis for patients because of its ability to not only masquerade as an infection leading to a delay in the proper treatment, but also because of its association with a more aggressive tumor cell behavior and growth, making it critically important for clinicians to be able to identify these patients early on. With further investigation into immune regulation and G-CSF receptor signaling, there may be future discoveries of novel methods to diagnose this condition and also advancements in the treatment options made available to these patients.

Certain cancers have been observed to cause symptoms called paraneoplastic syndromes that are not directly attributed to tumor invasion or compression. This phenomenon is believed to be secondary to a tumor’s secretion of functional hormones, peptides, cytokines, or its immune cross-reactivity. One such variant is a paraneoplastic leukemoid reaction (PLR), defined as a leukocytosis level of >50 x 10³ cells/mm³, where the white blood cell (WBC) count differential exhibits a neutrophilia or left-shift, in which a predominance of early neutrophil precursors is observed. A PLR is believed to be incited by the tumor cell’s production of its own growth factors such as granulocyte-colony stimulating factor (G-CSF) and a number of different cytokines. These reactions may at first be mistaken for infectious processes, and it is only after an infection has been ruled out or when a leukocytosis is disproportionately high in the setting of a treated infection, that a paraneoplastic leukemoid reaction (PLR) is considered and an oncologic work-up pursued.

PLR has been previously described in a variety of malignancies including lung, esophageal, nasopharyngeal and laryngeal, gastric, cholangiocarcinoma, melanoma, multiple myeloma, renal, prostate, and hepatocellular carcinoma, but has rarely been described in urothelial carcinoma.¹ Leukemoid reactions and autocrine growth induced by paraneoplastic production of G-CSF have rarely been associated with urothelial carcinoma of the bladder,² as in the case we present here of a 67-year-old white man with invasive high-grade urothelial carcinoma of the bladder. The case highlights PLR as a negative prognostic marker, secondary to urothelial bladder cancer cells’ presumed production of G-CSF, rarely reported as in the literature previously.

Case presentation and summary

A 67-year-old white man was diagnosed with clinical stage III (T3N0M0), invasive high-grade urothelial carcinoma of the bladder (Figure 1). He received neoadjuvant chemotherapy with the standard gemcitabine-cisplatin combination (1,000 mg/m² of gemcitabine on days 1, 8, and 15 with 70 mg/m² of cisplatin on day 1 of a 28-day cycle for 3 cycles), and had less than partial response at the end of a 3-month course. A computed tomography scan of his pelvis obtained at treatment completion revealed persistent disease with noted enhancement of the right distal ureter and a right posterior bladder mass at the ureterovesical junction measuring 1.7 x 2.6 x 2.6 cm (0.6 x 1 x 1 in), for which, a cystoprostatectomy was recommended to remove remaining disease. The patient was seen in routine follow-up 3 weeks after his last chemotherapy treatment, when his WBC count was noted to be within normal limits at a value of 8.4 x 10³ cells/mm³ (normal range, 4.5-11 x 10³ cells/mm³).

One week later (a month after treatment completion), the patient presented to the emergency department with complaints of dysuria, urinary frequency, and suprapubic pain. He was found to have leukocytosis, with a WBC count of 47 x 10³ cells/mm³, (normal range, 4.5-11 x 10³ cells/mm³), with an elevated neutrophil count of 82.7% (normal range 40%-60%), without clinical signs of systemic infection (fevers, chills, or rigors). A urinalysis revealed pyuria with 25-50 WBC/high power field, negative nitrite, positive leukocyte esterase, and moderate bacteria, consistent with what was presumed to be a urinary tract infection. The patient was discharged home with a 1-week course of the antibiotic levofloxacin and the alpha-blocker tamsulosin to make urination easier. Of note, the final results of the urine culture, which returned 48 hours after discharge, showed no growth.

One week prior to surgery, the patient underwent a cystoscopy for ureteral stent exchange, which revealed a necrotic tumor at the right bladder base surrounding the ureteral orifice and stent. Renal pelvis urine, sampled during stent exchange, revealed >100,000 CFU/ml (colony forming units; normal value, <10³) Candida albicans, for which the patient was started on intravenous fluconazole for fungal infection. We consulted with our colleagues in the infectious disease department and continued to follow the patient throughout his hospital course, which included several antibiotic regimens, a comprehensive hematological work-up and eventual urologic surgery. Work-ups for myeloproliferative disorders, leukemia, JAK-2, and BCR-ABL were all negative. A peripheral blood smear analysis showed mostly neutrophils, no immature cells, and occasional hypersegmented neutrophils, but was overall inconsistent with myeloproliferative disease. Despite the patient’s persistent leukocytosis, he remained completely asymptomatic and his neutrophilia was attributed to his malignancy.

The patient subsequently underwent a cystoprostatectomy with ileal conduit. The surgical pathologic analysis showed a high-grade, invasive urothelial (transitional cell) carcinoma measuring 5.2 x 5.0 x 4.5 cm (2 x 1.9 x 1.8 in) with squamous differentiation, extensive tumor necrosis, lymphovascular invasion, invasion into the adjacent seminal vesicle and prostatic stroma, and negative margins (pT4a pN0 pMX; Figure 2). On the day of surgical resection, the patient’s leukocytosis was 70 x 10³ cells/mm³.

Despite a transient improvement in his leukocytosis to 37.7 x 10³ cells/mm³ on postoperative day 1, the patient remained in the medical intensive care unit for uncontrolled pain and management of his leukocytosis. It is worth noting that the patient remained afebrile throughout his entire 45-day hospitalization, with negative culture data, and despite receiving an extensive broad spectrum antibiotic regimen (levofloxacin, piperacillin-tazobactam, cefazolin, metronidazole, ceftriaxone and fluconazole), his leukocytosis continued to progress, peaking at 161.5 x 10³ cells/mm³ less than a month after his surgery (Figure 3).

Discussion

We report here on the rare occurrence of PLR in a urothelial bladder cancer. Several mechanisms have been proposed to explain the pathophysiology of PLR. The levels of IL-1[alpha and beta], IL-3, G-CSF, GM-CSF, IL-6, and TNF-[alpha] have all been reported to be elevated in various solid tumors and suggested to contribute to an elevated leukocyte count.³ With previous reports that receptors for G-CSF have been found on cell surfaces of several nonhematopoietic cell types, Tachibana and Murai have proposed the mechanism of a cancer cell’s simultaneous acquisition of the ligand promotion and its receptor expression conferring an autocrine growth advantage.⁴ They have also reported on the capability of bladder cancer cells to induce a leukemoid reaction in their host through the stimulation of leukocyte production, which has been associated with aggressive tumor cell growth and a poor clinical outcome. In addition, He and colleagues have also described the correlation between PLR and high degree of malignancy, high probability of metastasis, recurrence, and poor prognosis.⁵

We observed the leukocytosis of 70 x 10³ cells/mm³ on the day of resection with a slight drop postoperatively, peaking at 161.5 x 10³ cells/mm³ less than a month after resection of the tumor. There is no clear understanding of the cause of the persistent and rapid progression of leukocytosis seen in this patient postoperatively. There is also a dearth of literature describing similar occurrences, with even fewer attempting to explain the pathophysiology of this occurrence.

When faced with similar occurrences in patients, clinicians usually treat for occult infection. Once infections and myeloproliferative diseases have been ruled out, clinicians may consider obtaining a patient’s serum G-CSF level or performing an immunohistochemistry analysis of urothelial cells for overexpression of G-CSF, when available.⁵ However, despite any efforts to diagnose earlier, there is little clinicians currently have to offer these patients as treatment.

As presented in this report, PLR portends a worse prognosis for patients because of its ability to not only masquerade as an infection leading to a delay in the proper treatment, but also because of its association with a more aggressive tumor cell behavior and growth, making it critically important for clinicians to be able to identify these patients early on. With further investigation into immune regulation and G-CSF receptor signaling, there may be future discoveries of novel methods to diagnose this condition and also advancements in the treatment options made available to these patients.