Article

Moral injury was identified by health care professionals (HCPs) as a driver of occupational distress prior to the COVID-19 pandemic, but the crisis expanded the appeal and investigation of the term.¹ HCPs now consider moral injury an essential component of the framework to describe their distress, because using the term burnout alone fails to capture their full experience and has proven resistant to interventions.² Moral injury goes beyond the transdiagnostic symptoms of exhaustion and cynicism and beyond operational, demand-resource mismatches that characterize burnout. It describes the frustration, anger, and helplessness associated with relational ruptures and the existential threats to a clinician’s professional identity as business interests erode their ability to put their patients’ needs ahead of corporate and health care system obligations.³

Proper characterization of moral injury in health care—separate from the military environments where it originated—is stymied by an ill-defined relationship between 2 definitions of the term and by an unclear relationship between moral injury and the long-standing body of scholarship in burnout. To clarify the concept, inform research agendas, and open avenues for more effective solutions to the crisis of HCP distress, we propose a unified conceptualization of moral injury and its association with burnout in health care.

CONTEXTUAL DISTINCTIONS

It is important to properly distinguish between the original use of moral injury in the military and its expanded use in civilian circumstances. Health care and the military are both professions whereupon donning the “uniform” of a physician—or soldier, sailor, airman, or marine—members must comport with strict expectations of behavior, including the refusal to engage in illegal actions or those contrary to professional ethics. Individuals in both professions acquire a highly specialized body of knowledge and enter an implied contract to provide critical services to society, specifically healing and protection, respectively. Members of both professions are trained to make complex judgments with integrity under conditions of technical and ethical uncertainty, upon which they take highly skilled action. Medical and military professionals must be free to act on their ethical principles, without confounding demands.⁴ However, the context of each profession’s commitment to society carries different moral implications.

The risk of moral injury is inherent in military service. The military promises protection with an implicit acknowledgment of the need to use lethal force to uphold the agreement. In contrast, HCPs promise healing and care. The military promises to protect our society, with an implicit acknowledgment of the need to use lethal force to uphold the agreement. Some military actions may inflict harm without the hope of benefitting an individual, and are therefore potentially morally injurious. The health care contract with society, promising healing and care, is devoid of inherent moral injury due to harm without potential individual benefit. Therefore, the presence of moral injury in health care settings are warning signs of a dysfunctional environment.

One complex example of the dysfunctional environments is illustrative. The military and health care are among the few industries where supply creates demand. For example, the more bad state actors there are, the more demand for the military. As we have seen since the 1950s, the more technology and therapeutics we create in health care, coupled with a larger share paid for by third parties, the greater the demand for and use of them.⁵ In a fee for service environment, corporate greed feeds on this reality. In most other environments, more technological and therapeutic options inevitably pit clinicians against multiple other factions: payers, who do not want to underwrite them; patients, who sometimes demand them without justification or later rail against spiraling health care costs; and administrators, especially in capitated systems, who watch their bottom lines erode. The moral injury risk in this instance demands a collective conversation among stakeholders regarding the structural determinants of health—how we choose to distribute limited resources. The intermediary of moral injury is a useful measure of the harm that results from ignoring or avoiding such challenges.

Moral injury is inherently nuanced. The 2 dominant definitions arise from work with combat veterans and create additional and perhaps unnecessary complexity. Unifying these 2 definitions eliminates inadvertent confusion, preventing the risk of unbridled interdisciplinary investigation which leads to a lack of precision in the meaning of moral injury and other related concepts, such as burnout.⁶

The first definition was developed by Jonathan Shay in 1994 and outlines 3 necessarycomponents, viewing the violator as a powerholder: (1) betrayal of what is right, (2) by someone who holds legitimate authority, (3) in a high stakes situation.⁷ Litz and colleagues describe moral injury another way: “Perpetrating, failing to prevent, bearing witness to, or learning about acts that transgress deeply held moral beliefs and expectations.”⁸ The violator is posited to be either the self or others.

Rather than representing “self” or “other” imposed moral injury, we propose the 2 definitions are related as exposure (ie, the perceived betrayal) and response (ie, the resulting transgression). An individual who experiences a betrayal by a legitimate authority has an opportunity to choose their response. They may acquiesce and transgress their moral beliefs (eg, their oath to provide ethical health care), or they could refuse, by speaking out, or in some way resisting the authority’s betrayal. The case of Ray Brovont is a useful illustration of reconciling the definitions (Box).⁹

Myriad factors—known as potentially morally injurious events—drive moral injury, such as resource-constrained decision making, witnessing the behaviors of colleagues that violate deeply held moral beliefs, questionable billing practices, and more. Each begins with a betrayal. Spotlighting the betrayal, refusing to perpetuate it, or taking actions toward change, may reduce the risk of experiencing moral injury.⁹ Conversely, acquiescing and transgressing one’s oath, the profession’s covenant with society, increases the risk of experiencing moral injury.⁸

Many HCPs believe they are not always free to resist betrayal, fearing retaliation, job loss, blacklisting, or worse. They feel constrained by debt accrued while receiving their education, being their household’s primary earner, community ties, practicing a niche specialty that requires working for a tertiary referral center, or perhaps believing the situation will be the same elsewhere. To not stand up or speak out is to choose complicity with corporate greed that uses HCPs to undermine their professional duties, which significantly increases the risk of experiencing moral injury.

MORAL INJURY AND BURNOUT

In addition to reconciling the definitions of moral injury, the relationship between moral injury and burnout are still being elucidated. We suggest that moral injury and burnout represent independent and potentially interrelated pathways to distress (Figure). Exposure to chronic, inconsonant, and transactional demands, which things like shorter work hours, better self-care, or improved health system operations might mitigate, manifests as burnout. In contrast, moral injury arises when a superior’s actions or a system’s policies and practices—such as justifiable but unnecessary testing, or referral restrictions to prevent revenue leakage—undermine one’s professional obligations to prioritize the patient’s best interest.

If concerns from HCPs about transactional demands are persistently dismissed, such inaction may be perceived as a betrayal, raising the risk of moral injury. Additionally, the resignation or helplessness of moral injury perceived as inescapable may present with emotional exhaustion, ineffectiveness, and depersonalization, all hallmarks of burnout. Both conditions can mediate and moderate the relationship between triggers for workplace distress and resulting psychological, physical, and existential harm.

CONCLUSIONS

Moral injury is increasingly recognized as a source of distress among HCPs, resulting from structural constraints on their ability to deliver optimal care and their own unwillingness to stand up for their patients, their oaths, and their professions.¹ Unlike the military, where moral injury is inherent in the contract with society, moral injury in health care (and the relational rupture it connotes) is a signal of systemic dysfunction, fractured trust, and the need for relational repair.

Health care is at a crossroads, experiencing a workforce retention crisis while simultaneously predicting a significant increase in care needs by Baby Boomers over the next 3 decades. The pandemic served as a stress test for our health care system and most institutions failed. Instead, the system was held together by staff, which is not a plan for sustained organizational resilience.

Health care does not have the luxury of experimenting another 30 years with interventions that have limited impact. We must design a new generation of approaches, shaped by lessons learned from the pandemic while acknowledging that prepandemic standards were already failing the workforce. A unified definition of moral injury must be integrated to frame clinician distress alongside burnout, recentering ethical decision making, rather than profit, at the heart of health care. Harmonizing the definitions of moral injury and clarifying the relationship of moral injury with burnout reduces the need for further reinterpretations, allowing for more robust, easily comparable studies focused on identifying risk factors, as well as rapidly implementing effective mitigation strategies.

Moral injury was identified by health care professionals (HCPs) as a driver of occupational distress prior to the COVID-19 pandemic, but the crisis expanded the appeal and investigation of the term.¹ HCPs now consider moral injury an essential component of the framework to describe their distress, because using the term burnout alone fails to capture their full experience and has proven resistant to interventions.² Moral injury goes beyond the transdiagnostic symptoms of exhaustion and cynicism and beyond operational, demand-resource mismatches that characterize burnout. It describes the frustration, anger, and helplessness associated with relational ruptures and the existential threats to a clinician’s professional identity as business interests erode their ability to put their patients’ needs ahead of corporate and health care system obligations.³

Proper characterization of moral injury in health care—separate from the military environments where it originated—is stymied by an ill-defined relationship between 2 definitions of the term and by an unclear relationship between moral injury and the long-standing body of scholarship in burnout. To clarify the concept, inform research agendas, and open avenues for more effective solutions to the crisis of HCP distress, we propose a unified conceptualization of moral injury and its association with burnout in health care.

CONTEXTUAL DISTINCTIONS

It is important to properly distinguish between the original use of moral injury in the military and its expanded use in civilian circumstances. Health care and the military are both professions whereupon donning the “uniform” of a physician—or soldier, sailor, airman, or marine—members must comport with strict expectations of behavior, including the refusal to engage in illegal actions or those contrary to professional ethics. Individuals in both professions acquire a highly specialized body of knowledge and enter an implied contract to provide critical services to society, specifically healing and protection, respectively. Members of both professions are trained to make complex judgments with integrity under conditions of technical and ethical uncertainty, upon which they take highly skilled action. Medical and military professionals must be free to act on their ethical principles, without confounding demands.⁴ However, the context of each profession’s commitment to society carries different moral implications.

The risk of moral injury is inherent in military service. The military promises protection with an implicit acknowledgment of the need to use lethal force to uphold the agreement. In contrast, HCPs promise healing and care. The military promises to protect our society, with an implicit acknowledgment of the need to use lethal force to uphold the agreement. Some military actions may inflict harm without the hope of benefitting an individual, and are therefore potentially morally injurious. The health care contract with society, promising healing and care, is devoid of inherent moral injury due to harm without potential individual benefit. Therefore, the presence of moral injury in health care settings are warning signs of a dysfunctional environment.

One complex example of the dysfunctional environments is illustrative. The military and health care are among the few industries where supply creates demand. For example, the more bad state actors there are, the more demand for the military. As we have seen since the 1950s, the more technology and therapeutics we create in health care, coupled with a larger share paid for by third parties, the greater the demand for and use of them.⁵ In a fee for service environment, corporate greed feeds on this reality. In most other environments, more technological and therapeutic options inevitably pit clinicians against multiple other factions: payers, who do not want to underwrite them; patients, who sometimes demand them without justification or later rail against spiraling health care costs; and administrators, especially in capitated systems, who watch their bottom lines erode. The moral injury risk in this instance demands a collective conversation among stakeholders regarding the structural determinants of health—how we choose to distribute limited resources. The intermediary of moral injury is a useful measure of the harm that results from ignoring or avoiding such challenges.

Moral injury is inherently nuanced. The 2 dominant definitions arise from work with combat veterans and create additional and perhaps unnecessary complexity. Unifying these 2 definitions eliminates inadvertent confusion, preventing the risk of unbridled interdisciplinary investigation which leads to a lack of precision in the meaning of moral injury and other related concepts, such as burnout.⁶

The first definition was developed by Jonathan Shay in 1994 and outlines 3 necessarycomponents, viewing the violator as a powerholder: (1) betrayal of what is right, (2) by someone who holds legitimate authority, (3) in a high stakes situation.⁷ Litz and colleagues describe moral injury another way: “Perpetrating, failing to prevent, bearing witness to, or learning about acts that transgress deeply held moral beliefs and expectations.”⁸ The violator is posited to be either the self or others.

Rather than representing “self” or “other” imposed moral injury, we propose the 2 definitions are related as exposure (ie, the perceived betrayal) and response (ie, the resulting transgression). An individual who experiences a betrayal by a legitimate authority has an opportunity to choose their response. They may acquiesce and transgress their moral beliefs (eg, their oath to provide ethical health care), or they could refuse, by speaking out, or in some way resisting the authority’s betrayal. The case of Ray Brovont is a useful illustration of reconciling the definitions (Box).⁹

Myriad factors—known as potentially morally injurious events—drive moral injury, such as resource-constrained decision making, witnessing the behaviors of colleagues that violate deeply held moral beliefs, questionable billing practices, and more. Each begins with a betrayal. Spotlighting the betrayal, refusing to perpetuate it, or taking actions toward change, may reduce the risk of experiencing moral injury.⁹ Conversely, acquiescing and transgressing one’s oath, the profession’s covenant with society, increases the risk of experiencing moral injury.⁸

Many HCPs believe they are not always free to resist betrayal, fearing retaliation, job loss, blacklisting, or worse. They feel constrained by debt accrued while receiving their education, being their household’s primary earner, community ties, practicing a niche specialty that requires working for a tertiary referral center, or perhaps believing the situation will be the same elsewhere. To not stand up or speak out is to choose complicity with corporate greed that uses HCPs to undermine their professional duties, which significantly increases the risk of experiencing moral injury.

MORAL INJURY AND BURNOUT

In addition to reconciling the definitions of moral injury, the relationship between moral injury and burnout are still being elucidated. We suggest that moral injury and burnout represent independent and potentially interrelated pathways to distress (Figure). Exposure to chronic, inconsonant, and transactional demands, which things like shorter work hours, better self-care, or improved health system operations might mitigate, manifests as burnout. In contrast, moral injury arises when a superior’s actions or a system’s policies and practices—such as justifiable but unnecessary testing, or referral restrictions to prevent revenue leakage—undermine one’s professional obligations to prioritize the patient’s best interest.

If concerns from HCPs about transactional demands are persistently dismissed, such inaction may be perceived as a betrayal, raising the risk of moral injury. Additionally, the resignation or helplessness of moral injury perceived as inescapable may present with emotional exhaustion, ineffectiveness, and depersonalization, all hallmarks of burnout. Both conditions can mediate and moderate the relationship between triggers for workplace distress and resulting psychological, physical, and existential harm.

CONCLUSIONS

Moral injury is increasingly recognized as a source of distress among HCPs, resulting from structural constraints on their ability to deliver optimal care and their own unwillingness to stand up for their patients, their oaths, and their professions.¹ Unlike the military, where moral injury is inherent in the contract with society, moral injury in health care (and the relational rupture it connotes) is a signal of systemic dysfunction, fractured trust, and the need for relational repair.

Health care is at a crossroads, experiencing a workforce retention crisis while simultaneously predicting a significant increase in care needs by Baby Boomers over the next 3 decades. The pandemic served as a stress test for our health care system and most institutions failed. Instead, the system was held together by staff, which is not a plan for sustained organizational resilience.

Health care does not have the luxury of experimenting another 30 years with interventions that have limited impact. We must design a new generation of approaches, shaped by lessons learned from the pandemic while acknowledging that prepandemic standards were already failing the workforce. A unified definition of moral injury must be integrated to frame clinician distress alongside burnout, recentering ethical decision making, rather than profit, at the heart of health care. Harmonizing the definitions of moral injury and clarifying the relationship of moral injury with burnout reduces the need for further reinterpretations, allowing for more robust, easily comparable studies focused on identifying risk factors, as well as rapidly implementing effective mitigation strategies.

Moral injury was identified by health care professionals (HCPs) as a driver of occupational distress prior to the COVID-19 pandemic, but the crisis expanded the appeal and investigation of the term.¹ HCPs now consider moral injury an essential component of the framework to describe their distress, because using the term burnout alone fails to capture their full experience and has proven resistant to interventions.² Moral injury goes beyond the transdiagnostic symptoms of exhaustion and cynicism and beyond operational, demand-resource mismatches that characterize burnout. It describes the frustration, anger, and helplessness associated with relational ruptures and the existential threats to a clinician’s professional identity as business interests erode their ability to put their patients’ needs ahead of corporate and health care system obligations.³

Proper characterization of moral injury in health care—separate from the military environments where it originated—is stymied by an ill-defined relationship between 2 definitions of the term and by an unclear relationship between moral injury and the long-standing body of scholarship in burnout. To clarify the concept, inform research agendas, and open avenues for more effective solutions to the crisis of HCP distress, we propose a unified conceptualization of moral injury and its association with burnout in health care.

CONTEXTUAL DISTINCTIONS

It is important to properly distinguish between the original use of moral injury in the military and its expanded use in civilian circumstances. Health care and the military are both professions whereupon donning the “uniform” of a physician—or soldier, sailor, airman, or marine—members must comport with strict expectations of behavior, including the refusal to engage in illegal actions or those contrary to professional ethics. Individuals in both professions acquire a highly specialized body of knowledge and enter an implied contract to provide critical services to society, specifically healing and protection, respectively. Members of both professions are trained to make complex judgments with integrity under conditions of technical and ethical uncertainty, upon which they take highly skilled action. Medical and military professionals must be free to act on their ethical principles, without confounding demands.⁴ However, the context of each profession’s commitment to society carries different moral implications.

The risk of moral injury is inherent in military service. The military promises protection with an implicit acknowledgment of the need to use lethal force to uphold the agreement. In contrast, HCPs promise healing and care. The military promises to protect our society, with an implicit acknowledgment of the need to use lethal force to uphold the agreement. Some military actions may inflict harm without the hope of benefitting an individual, and are therefore potentially morally injurious. The health care contract with society, promising healing and care, is devoid of inherent moral injury due to harm without potential individual benefit. Therefore, the presence of moral injury in health care settings are warning signs of a dysfunctional environment.

One complex example of the dysfunctional environments is illustrative. The military and health care are among the few industries where supply creates demand. For example, the more bad state actors there are, the more demand for the military. As we have seen since the 1950s, the more technology and therapeutics we create in health care, coupled with a larger share paid for by third parties, the greater the demand for and use of them.⁵ In a fee for service environment, corporate greed feeds on this reality. In most other environments, more technological and therapeutic options inevitably pit clinicians against multiple other factions: payers, who do not want to underwrite them; patients, who sometimes demand them without justification or later rail against spiraling health care costs; and administrators, especially in capitated systems, who watch their bottom lines erode. The moral injury risk in this instance demands a collective conversation among stakeholders regarding the structural determinants of health—how we choose to distribute limited resources. The intermediary of moral injury is a useful measure of the harm that results from ignoring or avoiding such challenges.

Moral injury is inherently nuanced. The 2 dominant definitions arise from work with combat veterans and create additional and perhaps unnecessary complexity. Unifying these 2 definitions eliminates inadvertent confusion, preventing the risk of unbridled interdisciplinary investigation which leads to a lack of precision in the meaning of moral injury and other related concepts, such as burnout.⁶

The first definition was developed by Jonathan Shay in 1994 and outlines 3 necessarycomponents, viewing the violator as a powerholder: (1) betrayal of what is right, (2) by someone who holds legitimate authority, (3) in a high stakes situation.⁷ Litz and colleagues describe moral injury another way: “Perpetrating, failing to prevent, bearing witness to, or learning about acts that transgress deeply held moral beliefs and expectations.”⁸ The violator is posited to be either the self or others.

Rather than representing “self” or “other” imposed moral injury, we propose the 2 definitions are related as exposure (ie, the perceived betrayal) and response (ie, the resulting transgression). An individual who experiences a betrayal by a legitimate authority has an opportunity to choose their response. They may acquiesce and transgress their moral beliefs (eg, their oath to provide ethical health care), or they could refuse, by speaking out, or in some way resisting the authority’s betrayal. The case of Ray Brovont is a useful illustration of reconciling the definitions (Box).⁹

Myriad factors—known as potentially morally injurious events—drive moral injury, such as resource-constrained decision making, witnessing the behaviors of colleagues that violate deeply held moral beliefs, questionable billing practices, and more. Each begins with a betrayal. Spotlighting the betrayal, refusing to perpetuate it, or taking actions toward change, may reduce the risk of experiencing moral injury.⁹ Conversely, acquiescing and transgressing one’s oath, the profession’s covenant with society, increases the risk of experiencing moral injury.⁸

Many HCPs believe they are not always free to resist betrayal, fearing retaliation, job loss, blacklisting, or worse. They feel constrained by debt accrued while receiving their education, being their household’s primary earner, community ties, practicing a niche specialty that requires working for a tertiary referral center, or perhaps believing the situation will be the same elsewhere. To not stand up or speak out is to choose complicity with corporate greed that uses HCPs to undermine their professional duties, which significantly increases the risk of experiencing moral injury.

MORAL INJURY AND BURNOUT

In addition to reconciling the definitions of moral injury, the relationship between moral injury and burnout are still being elucidated. We suggest that moral injury and burnout represent independent and potentially interrelated pathways to distress (Figure). Exposure to chronic, inconsonant, and transactional demands, which things like shorter work hours, better self-care, or improved health system operations might mitigate, manifests as burnout. In contrast, moral injury arises when a superior’s actions or a system’s policies and practices—such as justifiable but unnecessary testing, or referral restrictions to prevent revenue leakage—undermine one’s professional obligations to prioritize the patient’s best interest.

If concerns from HCPs about transactional demands are persistently dismissed, such inaction may be perceived as a betrayal, raising the risk of moral injury. Additionally, the resignation or helplessness of moral injury perceived as inescapable may present with emotional exhaustion, ineffectiveness, and depersonalization, all hallmarks of burnout. Both conditions can mediate and moderate the relationship between triggers for workplace distress and resulting psychological, physical, and existential harm.

CONCLUSIONS

Moral injury is increasingly recognized as a source of distress among HCPs, resulting from structural constraints on their ability to deliver optimal care and their own unwillingness to stand up for their patients, their oaths, and their professions.¹ Unlike the military, where moral injury is inherent in the contract with society, moral injury in health care (and the relational rupture it connotes) is a signal of systemic dysfunction, fractured trust, and the need for relational repair.

Health care is at a crossroads, experiencing a workforce retention crisis while simultaneously predicting a significant increase in care needs by Baby Boomers over the next 3 decades. The pandemic served as a stress test for our health care system and most institutions failed. Instead, the system was held together by staff, which is not a plan for sustained organizational resilience.

Health care does not have the luxury of experimenting another 30 years with interventions that have limited impact. We must design a new generation of approaches, shaped by lessons learned from the pandemic while acknowledging that prepandemic standards were already failing the workforce. A unified definition of moral injury must be integrated to frame clinician distress alongside burnout, recentering ethical decision making, rather than profit, at the heart of health care. Harmonizing the definitions of moral injury and clarifying the relationship of moral injury with burnout reduces the need for further reinterpretations, allowing for more robust, easily comparable studies focused on identifying risk factors, as well as rapidly implementing effective mitigation strategies.

High-grade B-cell lymphomas (HGBCLs) are aggressive lymphoproliferative disorders (LPDs) that require fluorescence in-situ hybridization to identify gene rearrangements within MYC and BCL2 and/or BCL6 oncogenes. Traditionally referred to as double-hit or triple-hit lymphomas, HGBCL is a newer entity in the 2016 updated World Health Organization classification of lymphoid neoplasms.¹ More than 90% of patients with HGBCL present with advanced clinical features, such as central nervous system involvement, leukocytosis, or lactose dehydrogenase (LDH) greater than 3 times the upper limit of normal. Treatment outcomes with aggressive multiagent chemotherapy combined with anti-CD20–targeted therapy are generally worse for patients with double-hit disease, especially among frail patients with advanced age. Patients with underlying autoimmune and rheumatologic conditions, such as rheumatoid arthritis (RA), are at higher risk for developing LPDs. These include highly aggressive subtypes of non-Hodgkin lymphoma, such as HGBCL, likely due to cascading events secondary to chronic inflammation and/or immunosuppressive medications. These immunodeficiency-associated LPDs often express positivity for Epstein-Barr virus-encoded small RNA (EBER).

We present a case of double-hit HGBCL that was EBER negative with MYC and BCL6 rearrangements in an older veteran with RA managed with methotrexate. An excellent sustained response was observed for the patient’s stage IV double-hit HGBCL disease within 4 weeks of methotrexate discontinuation. To our knowledge, this is the first reported response to methotrexate discontinuation for a patient with HGBCL.

CASE PRESENTATION

A male veteran aged 81 years presented to the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, with an unintentional 25-pound weight loss over 18 months. Pertinent history included RA managed with methotrexate 15 mg weekly for 6 years and a previous remote seizure. The patients prior prostate cancer was treated with radiation at the time of diagnosis and ongoing androgen deprivation therapy. Initial workup with chest X-ray and chest computed tomography (CT) indicated loculated left pleural fluid collection with a suspected splenic tumor.

A positron-emission tomography (PET)/CT was ordered given his history of prostate cancer, which showed potential splenic and sternal metastases with corresponding fludeoxyglucose F18 uptake (Figure 1A). Biopsy was not pursued due to the potential for splenic hemorrhage. Based on the patient’s RA and methotrexate use, the collection of findings was initially thought to represent a non-Hodgkin lymphoma, with knowledge that metastatic prostate cancer refractory to androgen deprivation therapy was possible. Because he was unable to undergo a splenic biopsy, an observation strategy involving repeat PET/CT every 6 months was started.

The surveillance PET/CT 6 months later conveyed worsened disease burden with increased avidity in the manubrium (Figure 1B). The patient’s case was discussed at the RGMVAMC tumor board, and the recommendation was to continue with surveillance follow-up imaging because image-guided biopsy might not definitively yield a diagnosis. Repeat PET/CT3 months later indicated continued worsening of disease (Figure 1C) with a rapidly enlarging hypermetabolic mass in the manubrium that extended anteriorly into the subcutaneous tissues and encased the bilateral anterior jugular veins. On physical examination, this sternal mass had become painful and was clearly evident. Additionally, increased avidity in multiple upper abdominal and retroperitoneal lymph nodes was observed.

Interventional radiology was consulted to assist with a percutaneous fine-needle aspiration of the manubrial mass, which revealed a dense aggregate of large, atypical lymphocytes confirmed to be of B-cell origin (CD20 and PAX5 positive) (Figure 2). The atypical B cells demonstrated co-expression of BCL6, BCL2, MUM1, and MYC but were negative for CD30 and EBER by in situ hybridization. The overall morphologic and immunophenotypic findings were consistent with a large B-cell lymphoma. Fluorescent in-situ hybridization identified the presence of MYC and BCL6 gene rearrangements, and the mass was consequently best classified as a double-hit HGBCL.

Given the patient’s history of long-term methotrexate use, we thought the HGBCL may have reflected an immunodeficiency-associated LPD, although the immunophenotype was not classic because of the CD30 and EBER negativity. With the known toxicity and poor treatment outcomes of aggressive multiagent chemotherapy for patients with double-hit HGBCL—particularly in the older adult population—methotrexate was discontinued on a trial basis.

A PET/CT was completed 4 weeks after methotrexate was discontinued due to concerns about managing an HGBCL without chemotherapy or anti-CD20–directed therapy. The updated PET/CT showed significant improvement with marked reduction in avidity of his manubrial lesion (Figure 1D). Three months after methotrexate discontinuation, the patient remained in partial remission for his double-hit HGBCL, as evidenced by no findings of sternal mass on repeat examinations with continued decrease in hypermetabolic findings on PET/CT. The patient's RA symptoms rebounded, and rheumatology colleagues prescribed sulfasalazine and periodic steroid tapers to help control his inflammatory arthritis. Fourteen months after discontinuation of methotrexate, the patient died after developing pneumonia, which led to multisystemic organ failure.

DISCUSSION

HGBCL with MYC and BCL2 and/or BCL6 rearrangements is an aggressive LPD.¹ A definitive diagnosis requires collection of morphologic and immunophenotypic evaluations of suspicious tissue. Approximately 60% of patients with HGBCL have translocations in MYC and BCL2, 20% have MYC and BCL6 translocations, and the remaining 20% have MYC, BCL2 and BCL6 translocations (triple-hit disease).¹

The MYC and BCL gene rearrangements are thought to synergistically drive tumorigenesis, leading to accelerated lymphoma progression and a lesser response to standard multiagent chemotherapy than seen in diffuse large B-cell lymphoma.^1-3 Consequently, there have been several attempts to increase treatment efficacy with intense chemotherapy regimens, namely DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), or by adding targeted agents, such as ibrutinib and venetoclax to a standard R-CHOP (rituximab with reduced cyclophosphamide, doxorubicin, vincristine, and prednisone) backbone.^4-7 Though the standard choice of therapy for fit patients harboring HGBCL remains controversial, these aggressive regimens at standard doses are typically difficult to tolerate for patients aged > 80 years.

Patients with immunosuppression are at higher risk for developing LPDs, including aggressive B-cell non-Hodgkin lymphomas such as diffuse large B-cell lymphoma. These patients are frequently classified into 2 groups: those with underlying autoimmune conditions (RA-associated LPDs), or those who have undergone solid-organ or allogeneic hematopoietic stem-cell transplants, which drives the development of posttransplant LPDs (Table).^8-11 Both types of LPDs are often EBER positive, indicating some association with Epstein-Barr virus infection driven by ongoing immunosuppression, with knowledge that this finding is not absolute and is less frequent among patients with autoimmune conditions than those with posttransplant LPD.^8,12

For indolent and early-stage aggressive LPDs, reduction of immunosuppression is a reasonable frontline treatment. In fact, Tokuyama and colleagues reported a previous case in which an methotrexate-associated EBER-positive early-stage diffuse large B-cell lymphoma responded well to methotrexate withdrawal.¹³ For advanced, aggressive LPDs associated with immunosuppression, a combination strategy of reducing immunosuppression and initiating a standard multiagent systemic therapy such as with R-CHOP is more common. Reducing immunosuppression without adding systemic anticancer therapy can certainly be considered in patients with EBER-negative LPDs; however, there is less evidence supporting this approach in the literature.

A case series of patients with EBER-positive double-hit HGBCL has been described previously, and response rates were low despite aggressive treatment.¹⁴ The current case differs from that case series in 2 ways. First, our patient did not have EBER-positive disease despite having an HGBCL associated with RA and methotrexate use. Second, our patient had a very rapid and excellent partial response simply with methotrexate discontinuation. Aggressive treatment was considered initially; however, given the patient’s age and performance status, reduction of immunosuppression alone was considered the frontline approach.

This case indicates that methotrexate withdrawal may lead to remission in patients with double-hit lymphoma, even without clear signs of Epstein-Barr virus infection being present. We are not sure why our patient with EBER-negative HGBCL responded differently to methotrexate withdrawal than the patients in the aforementioned case series with EBER-positive disease; nevertheless, a short trial of methotrexate withdrawal with repeat imaging 4 to 8 weeks after discontinuation seems reasonable for patients who are older, frail, and seemingly not fit for more aggressive treatment.

CONCLUSIONS

For our older patient with RA and biopsy-proven, stage IV EBER-negative HGBCL bearing MYC and BCL6 rearrangements (double hit), discontinuation of methotrexate led to a rapid and sustained marked response. Reducing immunosuppression should be considered for patients with LPDs associated with autoimmune conditions or immunosuppressive medications, regardless of additional multiagent systemic therapy administration. In older patients who are frail with aggressive B-cell lymphomas, a short trial of methotrexate withdrawal with quick interval imaging is a reasonable frontline option, regardless of EBER status.

High-grade B-cell lymphomas (HGBCLs) are aggressive lymphoproliferative disorders (LPDs) that require fluorescence in-situ hybridization to identify gene rearrangements within MYC and BCL2 and/or BCL6 oncogenes. Traditionally referred to as double-hit or triple-hit lymphomas, HGBCL is a newer entity in the 2016 updated World Health Organization classification of lymphoid neoplasms.¹ More than 90% of patients with HGBCL present with advanced clinical features, such as central nervous system involvement, leukocytosis, or lactose dehydrogenase (LDH) greater than 3 times the upper limit of normal. Treatment outcomes with aggressive multiagent chemotherapy combined with anti-CD20–targeted therapy are generally worse for patients with double-hit disease, especially among frail patients with advanced age. Patients with underlying autoimmune and rheumatologic conditions, such as rheumatoid arthritis (RA), are at higher risk for developing LPDs. These include highly aggressive subtypes of non-Hodgkin lymphoma, such as HGBCL, likely due to cascading events secondary to chronic inflammation and/or immunosuppressive medications. These immunodeficiency-associated LPDs often express positivity for Epstein-Barr virus-encoded small RNA (EBER).

We present a case of double-hit HGBCL that was EBER negative with MYC and BCL6 rearrangements in an older veteran with RA managed with methotrexate. An excellent sustained response was observed for the patient’s stage IV double-hit HGBCL disease within 4 weeks of methotrexate discontinuation. To our knowledge, this is the first reported response to methotrexate discontinuation for a patient with HGBCL.

CASE PRESENTATION

A male veteran aged 81 years presented to the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, with an unintentional 25-pound weight loss over 18 months. Pertinent history included RA managed with methotrexate 15 mg weekly for 6 years and a previous remote seizure. The patients prior prostate cancer was treated with radiation at the time of diagnosis and ongoing androgen deprivation therapy. Initial workup with chest X-ray and chest computed tomography (CT) indicated loculated left pleural fluid collection with a suspected splenic tumor.

A positron-emission tomography (PET)/CT was ordered given his history of prostate cancer, which showed potential splenic and sternal metastases with corresponding fludeoxyglucose F18 uptake (Figure 1A). Biopsy was not pursued due to the potential for splenic hemorrhage. Based on the patient’s RA and methotrexate use, the collection of findings was initially thought to represent a non-Hodgkin lymphoma, with knowledge that metastatic prostate cancer refractory to androgen deprivation therapy was possible. Because he was unable to undergo a splenic biopsy, an observation strategy involving repeat PET/CT every 6 months was started.

The surveillance PET/CT 6 months later conveyed worsened disease burden with increased avidity in the manubrium (Figure 1B). The patient’s case was discussed at the RGMVAMC tumor board, and the recommendation was to continue with surveillance follow-up imaging because image-guided biopsy might not definitively yield a diagnosis. Repeat PET/CT3 months later indicated continued worsening of disease (Figure 1C) with a rapidly enlarging hypermetabolic mass in the manubrium that extended anteriorly into the subcutaneous tissues and encased the bilateral anterior jugular veins. On physical examination, this sternal mass had become painful and was clearly evident. Additionally, increased avidity in multiple upper abdominal and retroperitoneal lymph nodes was observed.

Interventional radiology was consulted to assist with a percutaneous fine-needle aspiration of the manubrial mass, which revealed a dense aggregate of large, atypical lymphocytes confirmed to be of B-cell origin (CD20 and PAX5 positive) (Figure 2). The atypical B cells demonstrated co-expression of BCL6, BCL2, MUM1, and MYC but were negative for CD30 and EBER by in situ hybridization. The overall morphologic and immunophenotypic findings were consistent with a large B-cell lymphoma. Fluorescent in-situ hybridization identified the presence of MYC and BCL6 gene rearrangements, and the mass was consequently best classified as a double-hit HGBCL.

Given the patient’s history of long-term methotrexate use, we thought the HGBCL may have reflected an immunodeficiency-associated LPD, although the immunophenotype was not classic because of the CD30 and EBER negativity. With the known toxicity and poor treatment outcomes of aggressive multiagent chemotherapy for patients with double-hit HGBCL—particularly in the older adult population—methotrexate was discontinued on a trial basis.

A PET/CT was completed 4 weeks after methotrexate was discontinued due to concerns about managing an HGBCL without chemotherapy or anti-CD20–directed therapy. The updated PET/CT showed significant improvement with marked reduction in avidity of his manubrial lesion (Figure 1D). Three months after methotrexate discontinuation, the patient remained in partial remission for his double-hit HGBCL, as evidenced by no findings of sternal mass on repeat examinations with continued decrease in hypermetabolic findings on PET/CT. The patient's RA symptoms rebounded, and rheumatology colleagues prescribed sulfasalazine and periodic steroid tapers to help control his inflammatory arthritis. Fourteen months after discontinuation of methotrexate, the patient died after developing pneumonia, which led to multisystemic organ failure.

DISCUSSION

HGBCL with MYC and BCL2 and/or BCL6 rearrangements is an aggressive LPD.¹ A definitive diagnosis requires collection of morphologic and immunophenotypic evaluations of suspicious tissue. Approximately 60% of patients with HGBCL have translocations in MYC and BCL2, 20% have MYC and BCL6 translocations, and the remaining 20% have MYC, BCL2 and BCL6 translocations (triple-hit disease).¹

The MYC and BCL gene rearrangements are thought to synergistically drive tumorigenesis, leading to accelerated lymphoma progression and a lesser response to standard multiagent chemotherapy than seen in diffuse large B-cell lymphoma.^1-3 Consequently, there have been several attempts to increase treatment efficacy with intense chemotherapy regimens, namely DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), or by adding targeted agents, such as ibrutinib and venetoclax to a standard R-CHOP (rituximab with reduced cyclophosphamide, doxorubicin, vincristine, and prednisone) backbone.^4-7 Though the standard choice of therapy for fit patients harboring HGBCL remains controversial, these aggressive regimens at standard doses are typically difficult to tolerate for patients aged > 80 years.

Patients with immunosuppression are at higher risk for developing LPDs, including aggressive B-cell non-Hodgkin lymphomas such as diffuse large B-cell lymphoma. These patients are frequently classified into 2 groups: those with underlying autoimmune conditions (RA-associated LPDs), or those who have undergone solid-organ or allogeneic hematopoietic stem-cell transplants, which drives the development of posttransplant LPDs (Table).^8-11 Both types of LPDs are often EBER positive, indicating some association with Epstein-Barr virus infection driven by ongoing immunosuppression, with knowledge that this finding is not absolute and is less frequent among patients with autoimmune conditions than those with posttransplant LPD.^8,12

For indolent and early-stage aggressive LPDs, reduction of immunosuppression is a reasonable frontline treatment. In fact, Tokuyama and colleagues reported a previous case in which an methotrexate-associated EBER-positive early-stage diffuse large B-cell lymphoma responded well to methotrexate withdrawal.¹³ For advanced, aggressive LPDs associated with immunosuppression, a combination strategy of reducing immunosuppression and initiating a standard multiagent systemic therapy such as with R-CHOP is more common. Reducing immunosuppression without adding systemic anticancer therapy can certainly be considered in patients with EBER-negative LPDs; however, there is less evidence supporting this approach in the literature.

A case series of patients with EBER-positive double-hit HGBCL has been described previously, and response rates were low despite aggressive treatment.¹⁴ The current case differs from that case series in 2 ways. First, our patient did not have EBER-positive disease despite having an HGBCL associated with RA and methotrexate use. Second, our patient had a very rapid and excellent partial response simply with methotrexate discontinuation. Aggressive treatment was considered initially; however, given the patient’s age and performance status, reduction of immunosuppression alone was considered the frontline approach.

This case indicates that methotrexate withdrawal may lead to remission in patients with double-hit lymphoma, even without clear signs of Epstein-Barr virus infection being present. We are not sure why our patient with EBER-negative HGBCL responded differently to methotrexate withdrawal than the patients in the aforementioned case series with EBER-positive disease; nevertheless, a short trial of methotrexate withdrawal with repeat imaging 4 to 8 weeks after discontinuation seems reasonable for patients who are older, frail, and seemingly not fit for more aggressive treatment.

CONCLUSIONS

For our older patient with RA and biopsy-proven, stage IV EBER-negative HGBCL bearing MYC and BCL6 rearrangements (double hit), discontinuation of methotrexate led to a rapid and sustained marked response. Reducing immunosuppression should be considered for patients with LPDs associated with autoimmune conditions or immunosuppressive medications, regardless of additional multiagent systemic therapy administration. In older patients who are frail with aggressive B-cell lymphomas, a short trial of methotrexate withdrawal with quick interval imaging is a reasonable frontline option, regardless of EBER status.

High-grade B-cell lymphomas (HGBCLs) are aggressive lymphoproliferative disorders (LPDs) that require fluorescence in-situ hybridization to identify gene rearrangements within MYC and BCL2 and/or BCL6 oncogenes. Traditionally referred to as double-hit or triple-hit lymphomas, HGBCL is a newer entity in the 2016 updated World Health Organization classification of lymphoid neoplasms.¹ More than 90% of patients with HGBCL present with advanced clinical features, such as central nervous system involvement, leukocytosis, or lactose dehydrogenase (LDH) greater than 3 times the upper limit of normal. Treatment outcomes with aggressive multiagent chemotherapy combined with anti-CD20–targeted therapy are generally worse for patients with double-hit disease, especially among frail patients with advanced age. Patients with underlying autoimmune and rheumatologic conditions, such as rheumatoid arthritis (RA), are at higher risk for developing LPDs. These include highly aggressive subtypes of non-Hodgkin lymphoma, such as HGBCL, likely due to cascading events secondary to chronic inflammation and/or immunosuppressive medications. These immunodeficiency-associated LPDs often express positivity for Epstein-Barr virus-encoded small RNA (EBER).

We present a case of double-hit HGBCL that was EBER negative with MYC and BCL6 rearrangements in an older veteran with RA managed with methotrexate. An excellent sustained response was observed for the patient’s stage IV double-hit HGBCL disease within 4 weeks of methotrexate discontinuation. To our knowledge, this is the first reported response to methotrexate discontinuation for a patient with HGBCL.

CASE PRESENTATION

A male veteran aged 81 years presented to the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, with an unintentional 25-pound weight loss over 18 months. Pertinent history included RA managed with methotrexate 15 mg weekly for 6 years and a previous remote seizure. The patients prior prostate cancer was treated with radiation at the time of diagnosis and ongoing androgen deprivation therapy. Initial workup with chest X-ray and chest computed tomography (CT) indicated loculated left pleural fluid collection with a suspected splenic tumor.

A positron-emission tomography (PET)/CT was ordered given his history of prostate cancer, which showed potential splenic and sternal metastases with corresponding fludeoxyglucose F18 uptake (Figure 1A). Biopsy was not pursued due to the potential for splenic hemorrhage. Based on the patient’s RA and methotrexate use, the collection of findings was initially thought to represent a non-Hodgkin lymphoma, with knowledge that metastatic prostate cancer refractory to androgen deprivation therapy was possible. Because he was unable to undergo a splenic biopsy, an observation strategy involving repeat PET/CT every 6 months was started.

The surveillance PET/CT 6 months later conveyed worsened disease burden with increased avidity in the manubrium (Figure 1B). The patient’s case was discussed at the RGMVAMC tumor board, and the recommendation was to continue with surveillance follow-up imaging because image-guided biopsy might not definitively yield a diagnosis. Repeat PET/CT3 months later indicated continued worsening of disease (Figure 1C) with a rapidly enlarging hypermetabolic mass in the manubrium that extended anteriorly into the subcutaneous tissues and encased the bilateral anterior jugular veins. On physical examination, this sternal mass had become painful and was clearly evident. Additionally, increased avidity in multiple upper abdominal and retroperitoneal lymph nodes was observed.

Interventional radiology was consulted to assist with a percutaneous fine-needle aspiration of the manubrial mass, which revealed a dense aggregate of large, atypical lymphocytes confirmed to be of B-cell origin (CD20 and PAX5 positive) (Figure 2). The atypical B cells demonstrated co-expression of BCL6, BCL2, MUM1, and MYC but were negative for CD30 and EBER by in situ hybridization. The overall morphologic and immunophenotypic findings were consistent with a large B-cell lymphoma. Fluorescent in-situ hybridization identified the presence of MYC and BCL6 gene rearrangements, and the mass was consequently best classified as a double-hit HGBCL.

Given the patient’s history of long-term methotrexate use, we thought the HGBCL may have reflected an immunodeficiency-associated LPD, although the immunophenotype was not classic because of the CD30 and EBER negativity. With the known toxicity and poor treatment outcomes of aggressive multiagent chemotherapy for patients with double-hit HGBCL—particularly in the older adult population—methotrexate was discontinued on a trial basis.

A PET/CT was completed 4 weeks after methotrexate was discontinued due to concerns about managing an HGBCL without chemotherapy or anti-CD20–directed therapy. The updated PET/CT showed significant improvement with marked reduction in avidity of his manubrial lesion (Figure 1D). Three months after methotrexate discontinuation, the patient remained in partial remission for his double-hit HGBCL, as evidenced by no findings of sternal mass on repeat examinations with continued decrease in hypermetabolic findings on PET/CT. The patient's RA symptoms rebounded, and rheumatology colleagues prescribed sulfasalazine and periodic steroid tapers to help control his inflammatory arthritis. Fourteen months after discontinuation of methotrexate, the patient died after developing pneumonia, which led to multisystemic organ failure.

DISCUSSION

HGBCL with MYC and BCL2 and/or BCL6 rearrangements is an aggressive LPD.¹ A definitive diagnosis requires collection of morphologic and immunophenotypic evaluations of suspicious tissue. Approximately 60% of patients with HGBCL have translocations in MYC and BCL2, 20% have MYC and BCL6 translocations, and the remaining 20% have MYC, BCL2 and BCL6 translocations (triple-hit disease).¹

The MYC and BCL gene rearrangements are thought to synergistically drive tumorigenesis, leading to accelerated lymphoma progression and a lesser response to standard multiagent chemotherapy than seen in diffuse large B-cell lymphoma.^1-3 Consequently, there have been several attempts to increase treatment efficacy with intense chemotherapy regimens, namely DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), or by adding targeted agents, such as ibrutinib and venetoclax to a standard R-CHOP (rituximab with reduced cyclophosphamide, doxorubicin, vincristine, and prednisone) backbone.^4-7 Though the standard choice of therapy for fit patients harboring HGBCL remains controversial, these aggressive regimens at standard doses are typically difficult to tolerate for patients aged > 80 years.

Patients with immunosuppression are at higher risk for developing LPDs, including aggressive B-cell non-Hodgkin lymphomas such as diffuse large B-cell lymphoma. These patients are frequently classified into 2 groups: those with underlying autoimmune conditions (RA-associated LPDs), or those who have undergone solid-organ or allogeneic hematopoietic stem-cell transplants, which drives the development of posttransplant LPDs (Table).^8-11 Both types of LPDs are often EBER positive, indicating some association with Epstein-Barr virus infection driven by ongoing immunosuppression, with knowledge that this finding is not absolute and is less frequent among patients with autoimmune conditions than those with posttransplant LPD.^8,12

For indolent and early-stage aggressive LPDs, reduction of immunosuppression is a reasonable frontline treatment. In fact, Tokuyama and colleagues reported a previous case in which an methotrexate-associated EBER-positive early-stage diffuse large B-cell lymphoma responded well to methotrexate withdrawal.¹³ For advanced, aggressive LPDs associated with immunosuppression, a combination strategy of reducing immunosuppression and initiating a standard multiagent systemic therapy such as with R-CHOP is more common. Reducing immunosuppression without adding systemic anticancer therapy can certainly be considered in patients with EBER-negative LPDs; however, there is less evidence supporting this approach in the literature.

A case series of patients with EBER-positive double-hit HGBCL has been described previously, and response rates were low despite aggressive treatment.¹⁴ The current case differs from that case series in 2 ways. First, our patient did not have EBER-positive disease despite having an HGBCL associated with RA and methotrexate use. Second, our patient had a very rapid and excellent partial response simply with methotrexate discontinuation. Aggressive treatment was considered initially; however, given the patient’s age and performance status, reduction of immunosuppression alone was considered the frontline approach.

This case indicates that methotrexate withdrawal may lead to remission in patients with double-hit lymphoma, even without clear signs of Epstein-Barr virus infection being present. We are not sure why our patient with EBER-negative HGBCL responded differently to methotrexate withdrawal than the patients in the aforementioned case series with EBER-positive disease; nevertheless, a short trial of methotrexate withdrawal with repeat imaging 4 to 8 weeks after discontinuation seems reasonable for patients who are older, frail, and seemingly not fit for more aggressive treatment.

CONCLUSIONS

For our older patient with RA and biopsy-proven, stage IV EBER-negative HGBCL bearing MYC and BCL6 rearrangements (double hit), discontinuation of methotrexate led to a rapid and sustained marked response. Reducing immunosuppression should be considered for patients with LPDs associated with autoimmune conditions or immunosuppressive medications, regardless of additional multiagent systemic therapy administration. In older patients who are frail with aggressive B-cell lymphomas, a short trial of methotrexate withdrawal with quick interval imaging is a reasonable frontline option, regardless of EBER status.