As many as one-quarter of human cancers are related to chronic inflammation, chronic infection, or both.¹ Extrinsic inflammation leads to generation of proinflammatory cytokines that in turn recruit other inflammatory cells, which is thought to generate a positive amplification loop.² Intrinsic stimuli from proto-oncogenes and mutations in tumor suppressor genes lead to transformed cancer cells that also secrete proinflammatory cytokines, thus propagating the cycle.

Numerous factors have been observed in association with tumor growth, progression, invasion, and metastasis.³ One factor for the development of squamous cell carcinoma (SCC) may be chronic inflammatory dermatoses. To date, reviews of chronic inflammation–associated malignancy have focused on solid organ cancers. We sought to provide an up-to-date review of SCC arising within chronic dermatoses, with an emphasis on the anatomic location of dermatoses involved in the transformation of cancer cells, the lag time from onset of dermatosis to diagnosis of SCC, and the distinctive mechanisms thought to be involved in the tumorigenesis in particular dermatoses.

Discoid Lupus Erythematosus

Discoid lupus erythematosus (DLE) is a chronic cutaneous lupus erythematosus variant with a female to male predominance of 3:1,⁴ and DLE lesions are prone to malignant transformation. Retrospective cohort studies have attempted to characterize who is at risk for SCC and how SCCs behave depending on their location. Cohorts from China,⁵ India,⁶ and Japan⁷ have noted a higher rate of SCC within DLE lesions in men (female to male ratios of 1:2.2, 1:1.6, and 1:2, respectively) and shorter lag times for SCC onset within DLE lesions of the lips (13, 5, and 10 years, respectively) compared to SCC arising in DLE elsewhere (19.2, 11.2, and 26 years, respectively). Studies have noted that DLE lesions of the lips may be prone to more rapid SCC tumorigenesis compared to DLE on cutaneous sites. One study reported SCC in DLE recurrence, metastasis, and death rates of 29%, 16.1%, and 19.4%, respectively,⁵ which exceeds reported rates in non-DLE SCCs (20%, 0.5% to 6%, and 1%, respectively).^5,8

Because SCC arising within DLE is most common on the lips (Figure 1), it has been hypothesized that the high rate of transformation of DLE lesions on the lips may be due to constant exposure to irritation and tobacco, which may accelerate carcinogenesis.⁵ It also has been hypothesized that atrophic discoid lesions have lost sun protection and are more prone to mutagenic UV radiation,⁹ as SCCs arising in DLE lesions virtually always display prominent solar elastosis⁶; however, SCC has been observed to arise in non–sun-exposed DLE lesions in both White and Black patients.¹⁰

Photograph courtesy of Andrea Murina, MD.

Additionally, use of immunosuppressant medications may accelerate the emergence of malignancy or more aggressive forms of malignancy; however, patients with autoimmune disease have a greater risk for malignancy at baseline,¹¹ thus making it difficult to determine the excess risk from medications. There also may be a role for human papillomavirus (HPV) accelerating SCC development in DLE lesions, as demonstrated in a case of SCC arising in DLE lesions of the ears, with viral staining evident within the tumors.¹² However, testing for HPV is not routinely performed in these cases.

Dermatologists need to be aware of the relatively rapid tumorigenesis and aggressive behavior of transformation and aggression seen with SCC arising within orolabial DLE lesions compared to cutaneous lesions, especially those on the lips.

Lichen Planus

Although patients with typical cutaneous lichen planus lesions do not have an increased risk for SCC,¹³ variants of lichen planus may predispose patients to SCC.

Oral Lichen Planus—Oral lichen planus (OLP) lesions are prone to malignant transformation. A systematic review of 16 studies evaluating the risk for OLP-associated SCC revealed an overall transformation rate of 1.09%, with a mean lag time of 4.3 years,¹⁴ compared to a reference rate of 0.2% for oral SCC.¹⁵ A meta-analysis of 19,676 patients with OLP and other oral lichenoid lesions revealed an oral SCC rate of 1.1%, with higher rates of transformation seen in cigarette smokers, alcoholics, and patients with hepatitis C virus infection.¹⁶ The ulcerative subtype of OLP appears to present a greater risk for malignant transformation.¹⁵ Dermatologists also should be cognizant that treatments for OLP such as topical calcineurin inhibitors may support the development of malignancy within inflammatory lesions.¹⁷

Hypertrophic Lichen Planus—The hypertrophic variant of lichen planus (HLP) also is prone to malignant transformation. A 1991 epidemiologic study from Sweden of malignancy arising in lichen planus revealed a disproportionate number of cases arising in verrucous or hypertrophic lesions, with a mean of 12.2 years from onset of the dermatosis to malignancy diagnosis.¹³ A subsequent 2015 retrospective study of 38 patients revealed that SCC had a propensity for the lower limb, favoring the pretibial region and the calf over the foot and the ankle with a reported lag time of 11 years.¹⁸

Although metastatic SCC arising in HLP is rare, 2 cases have been reported. A 24-year-old woman presented with an HLP plaque on the lower leg that developed during childhood and rapidly enlarged 2 months prior to presentation; she eventually died from metastatic disease.¹⁹ In another case, a 34-year-old man presented with an HLP lesion of approximately 10 years’ duration. A well-differentiated SCC was excised, and he developed lymph node metastases 5 months later.²⁰

It is important to note that HLP on the legs often is misdiagnosed as SCC, as pseudoepitheliomatous hyperplasia and squamous metaplasia can be difficult to differentiate clinically and histologically.^21,22 In the case of multiple eruptive SCCs of the lower leg, clinical correlation is essential to avoid unnecessary and ineffective surgical treatment.

Patients with HLP may exhibit Wickham striae, follicular accentuation, and mucocutaneous lichen planus at other sites, or a correlative initiation of possible culprit medications.²³ Because true SCC arising within HLP is relatively rare, its malignant potential is not as clear as those arising within DLE; however, the lower limb appears to be the most common location for SCC within HLP.Nail Lichen Planus—Squamous cell carcinoma arising in nail lichen planus is rare. A report of 2 patients were diagnosed with lichen planus approximately 15 years prior to diagnosis of ungual SCC.²⁴ Given the rarity of this presentation, it is difficult to ascertain the approximate lag time and other risk factors. Furthermore, the role of HPV in these cases was not ruled out. Oncogenic HPV strains have been reported in patients with periungual SCC.^25,26

Lichen Sclerosus

Lichen sclerosus (LS) is a chronic inflammatory dermatosis that favors the anogenital area in a female to male ratio of 10:1.²⁷ It is considered a premalignant condition for SCC tumorigenesis and may be a strong predictor of vulvar SCC (Figure 2), as 62% of vulvar SCC cases (N=78) may have adjacent LS.²⁸

Photograph courtesy of Laura C. Williams, MD (New Orleans, Louisiana).

In a Dutch cohort of 3038 women with LS, 2.6% of patients developed vulvar SCC at a median of 3.3 years after LS diagnosis.²⁹ Other studies have estimated a lag time of 4 years until SCC presentation.³⁰ An Italian cohort of 976 women similarly observed that 2.7% of patients developed premalignancy or SCC.³¹ It was previously estimated that 3% to 5% of patients with LS developed SCC; however, prior studies may have included cases of vulvar intraepithelial neoplasia with low risk for invasive SCC, which might have overestimated true risk of SCC.³² Another confounding factor for elucidating SCC on a background of LS may be the presence of HPV.³³ Extragenital LS does not appear to have similar potential for malignant transformation.³⁴

In a prospective Australian cohort of 507 women with LS (mean age, 55.4 years), remission was induced with potent topical corticosteroids.³⁵ Patients who were adherent to a topical regimen did not develop SCC during follow-up. Those who were nonadherent or partially adherent had a 4.7% risk for SCC.³⁵ In a similar prospective study of 83 women in France, the SCC rate was 9.6% in lesions that were untreated or irregularly treated.³⁶ These studies provide essential evidence that appropriately treating LS can prevent SCC at a later date, though longer-term data are lacking.

The rate of SCC arising in male genital LS may approach 8.4%,³⁷ with a lag time of 17 years from onset of LS to SCC diagnosis.³⁸ Although circumcision often is considered curative for male genital LS, patients have been observed to develop penile SCC at least 5 years after circumcision.³⁹ Male penile SCC in a background of LS may not necessarily be HPV associated.⁴⁰

Marjolin Ulcer

Chronic ulcers or scars, typically postburn scars, may undergo malignant transformation, with SCC being the most common carcinoma.⁴¹ Squamous cell carcinoma in the context of a chronic ulcer or wound is known as a Marjolin ulcer (MU). Up to 2% of burn scars have been observed to undergo malignant transformation.⁴² Marjolin ulcers tend to behave aggressively once they form, and it has been proposed that removal of scar tissue may be a preventive therapeutic strategy.⁴³ Cohort studies of MU on the lower extremities have observed lag times of 26.4⁴⁴ and 37.9⁴⁵ years, with both studies also noting relatively high rates of local recurrence.

The pathogenesis of MU appears to be multifactorial. Chronic inflammation and scar formation have been implicated. Chronic inflammation and irritation of lesions at natural creases are thought to increase mitotic activity,⁴¹ and local accumulation of toxin may promote mutagenesis.⁴⁶ Scar formation may create a locally immunoprivileged site, allowing for developing tumors to evade the immune system⁴⁷ and become even more aggressive as the tumor accumulates.⁴⁸ Scar formation also may prevent the ability of immune cells to penetrate the tumor microenvironment and access lymphatic channels.⁴⁹

Hidradenitis Suppurativa

As many as 3.2% of patients with chronic hidradenitis suppurativa (HS) experience malignant transformation to SCC.⁵⁰ Early HS displays subclinical lymphedema in affected sites, which can progress to chronic fibrosis, stasis, and accumulation of protein-rich fluid.⁵¹ Stasis changes have been associated with altered local inflammatory proteins, such as toll-like receptors, β-defensins, and interleukins.⁵²

A retrospective cohort study of 12 patients revealed a lag time of 28.5 years from HS diagnosis to the manifestation of malignancy.⁵³ After local excision, 7 patients developed recurrence, with 100% mortality. Squamous cell carcinomas were well differentiated and moderately differentiated.⁵³ A 2017 literature review of 62 case reports calculated a mean lag time of 27 years. Despite 85% of SCCs being well differentiated and moderately differentiated, nearly half of patients died within 2 years.⁵⁴ As seen in other inflammatory conditions, HPV can complicate perineal HS and promote SCC tumorigenesis.⁵⁵

Squamous cell carcinomas arising within HS lesions are more prevalent in males (6.75:1 ratio),^54,56 despite HS being more prevalent in females (2:1 ratio).⁵⁷ Similar to DLE, SCCs arising in HS are aggressive and are seen more in males, despite both conditions being female predominant. Incidence and mortality rates for primary cutaneous SCC are higher for men vs women⁵⁸; however, the discordance in aggressive behavior seen more commonly in SCC arising from HS or DLE in male patients has yet to be explained.

Malignancy arising within necrobiosis lipoidica diabeticorum (NLD) is rare. A review of 14 published cases noted that 13 were SCC and 1 was leiomyosarcoma.⁵⁹ The lag time was 21.5 years; 31% of cases (N=14) presented with regional lymph node metastasis. Although chronic ulceration is a risk factor for SCC and occurs in as many as one-third of NLD cases, its correlation with ulceration and malignant transformation has not been characterized.

Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a noninflammatory inherited blistering disease, and patients have an inherently high risk for aggressive SCC.⁶⁰ Other forms of epidermolysis bullosa can lead to SCC, but the rarer RDEB accounts for 69% of SCC cases, with a median age of 36 years at presentation.⁶¹ Although SCCs tend to be well differentiated in RDEB (73.9%),⁶¹ they also exhibit highly aggressive behavior.⁶² In the most severe variant—RDEB-generalized severe—the cumulative risk for SCC-related death in an Australian population was 84.4% at 34 years of age.⁶³

As RDEB is an inherited disorder with potential for malignancy at a young age, the pathogenesis is plausibly different from the previously discussed inflammatory dermatoses. This disease is characterized by a mutation in the collagen VII gene, leading to loss of anchoring fibrils and a basement membrane zone split.⁶⁴ There also can be inherent fibroblast alterations; RDEB fibroblasts create an environment for tumor growth by supporting malignant-cell adhesion and invasion.⁶⁵ Mutations in p53,⁶⁶ local alterations in transforming growth factor β activity,⁶⁷ and downstream matrix metalloproteinase activity⁶⁸ have been implicated.

Additionally, keratinocytes may retain the N-terminal noncollagenous (NC1) domain of truncated collagen VII while losing the anchoring NC2 domain in mutated collagen VII RDEB, thereby supporting anchorless keratinocyte survival and higher metastatic potential.⁶⁹ Retention of this truncated NC1 domain has shown conversion of RDEB keratinocytes to tumor in a xenotransplant mouse model.⁷⁰ A high level of type VII collagen itself may inherently be protumorigenic for keratinocytes.⁷¹

There does not appear to be evidence for HPV involvement in RDEB-associated SCC.⁷² Squamous cell carcinoma development in RDEB appears to be multifactorial,⁷³ but validated tumor models are lacking. Other than conventional oncologic therapy, future directions in the management of RDEB may include gene-, protein- and cell-targeted therapies.⁷³

Conclusion

Squamous cell carcinomas are known to arise within chronic cutaneous inflammatory dermatoses. Tumorigenesis peaks relatively early in new orolabial DLE, LS, and OLP cases, and can occur over many decades in cutaneous DLE, HLP, HS, NLD, and chronic wounds or scars, summarized in the Table. Frequent SCCs are observed in high-risk subtypes of epidermolysis bullosa. Dermatologists must examine areas affected by these diseases at regular intervals, being mindful of the possibility of SCC development. Furthermore, dermatologists should adopt a lower threshold to biopsy suspicious lesions, especially those that develop within relatively new orolabial DLE, chronic HS, or chronic wound cases, as SCC in these settings is particularly aggressive and displays mortality and metastasis rates that exceed those of common cutaneous SCC.


As many as one-quarter of human cancers are related to chronic inflammation, chronic infection, or both.¹ Extrinsic inflammation leads to generation of proinflammatory cytokines that in turn recruit other inflammatory cells, which is thought to generate a positive amplification loop.² Intrinsic stimuli from proto-oncogenes and mutations in tumor suppressor genes lead to transformed cancer cells that also secrete proinflammatory cytokines, thus propagating the cycle.

Numerous factors have been observed in association with tumor growth, progression, invasion, and metastasis.³ One factor for the development of squamous cell carcinoma (SCC) may be chronic inflammatory dermatoses. To date, reviews of chronic inflammation–associated malignancy have focused on solid organ cancers. We sought to provide an up-to-date review of SCC arising within chronic dermatoses, with an emphasis on the anatomic location of dermatoses involved in the transformation of cancer cells, the lag time from onset of dermatosis to diagnosis of SCC, and the distinctive mechanisms thought to be involved in the tumorigenesis in particular dermatoses.

Discoid Lupus Erythematosus

Discoid lupus erythematosus (DLE) is a chronic cutaneous lupus erythematosus variant with a female to male predominance of 3:1,⁴ and DLE lesions are prone to malignant transformation. Retrospective cohort studies have attempted to characterize who is at risk for SCC and how SCCs behave depending on their location. Cohorts from China,⁵ India,⁶ and Japan⁷ have noted a higher rate of SCC within DLE lesions in men (female to male ratios of 1:2.2, 1:1.6, and 1:2, respectively) and shorter lag times for SCC onset within DLE lesions of the lips (13, 5, and 10 years, respectively) compared to SCC arising in DLE elsewhere (19.2, 11.2, and 26 years, respectively). Studies have noted that DLE lesions of the lips may be prone to more rapid SCC tumorigenesis compared to DLE on cutaneous sites. One study reported SCC in DLE recurrence, metastasis, and death rates of 29%, 16.1%, and 19.4%, respectively,⁵ which exceeds reported rates in non-DLE SCCs (20%, 0.5% to 6%, and 1%, respectively).^5,8

Because SCC arising within DLE is most common on the lips (Figure 1), it has been hypothesized that the high rate of transformation of DLE lesions on the lips may be due to constant exposure to irritation and tobacco, which may accelerate carcinogenesis.⁵ It also has been hypothesized that atrophic discoid lesions have lost sun protection and are more prone to mutagenic UV radiation,⁹ as SCCs arising in DLE lesions virtually always display prominent solar elastosis⁶; however, SCC has been observed to arise in non–sun-exposed DLE lesions in both White and Black patients.¹⁰

Photograph courtesy of Andrea Murina, MD.

Additionally, use of immunosuppressant medications may accelerate the emergence of malignancy or more aggressive forms of malignancy; however, patients with autoimmune disease have a greater risk for malignancy at baseline,¹¹ thus making it difficult to determine the excess risk from medications. There also may be a role for human papillomavirus (HPV) accelerating SCC development in DLE lesions, as demonstrated in a case of SCC arising in DLE lesions of the ears, with viral staining evident within the tumors.¹² However, testing for HPV is not routinely performed in these cases.

Dermatologists need to be aware of the relatively rapid tumorigenesis and aggressive behavior of transformation and aggression seen with SCC arising within orolabial DLE lesions compared to cutaneous lesions, especially those on the lips.

Lichen Planus

Although patients with typical cutaneous lichen planus lesions do not have an increased risk for SCC,¹³ variants of lichen planus may predispose patients to SCC.

Oral Lichen Planus—Oral lichen planus (OLP) lesions are prone to malignant transformation. A systematic review of 16 studies evaluating the risk for OLP-associated SCC revealed an overall transformation rate of 1.09%, with a mean lag time of 4.3 years,¹⁴ compared to a reference rate of 0.2% for oral SCC.¹⁵ A meta-analysis of 19,676 patients with OLP and other oral lichenoid lesions revealed an oral SCC rate of 1.1%, with higher rates of transformation seen in cigarette smokers, alcoholics, and patients with hepatitis C virus infection.¹⁶ The ulcerative subtype of OLP appears to present a greater risk for malignant transformation.¹⁵ Dermatologists also should be cognizant that treatments for OLP such as topical calcineurin inhibitors may support the development of malignancy within inflammatory lesions.¹⁷

Hypertrophic Lichen Planus—The hypertrophic variant of lichen planus (HLP) also is prone to malignant transformation. A 1991 epidemiologic study from Sweden of malignancy arising in lichen planus revealed a disproportionate number of cases arising in verrucous or hypertrophic lesions, with a mean of 12.2 years from onset of the dermatosis to malignancy diagnosis.¹³ A subsequent 2015 retrospective study of 38 patients revealed that SCC had a propensity for the lower limb, favoring the pretibial region and the calf over the foot and the ankle with a reported lag time of 11 years.¹⁸

Although metastatic SCC arising in HLP is rare, 2 cases have been reported. A 24-year-old woman presented with an HLP plaque on the lower leg that developed during childhood and rapidly enlarged 2 months prior to presentation; she eventually died from metastatic disease.¹⁹ In another case, a 34-year-old man presented with an HLP lesion of approximately 10 years’ duration. A well-differentiated SCC was excised, and he developed lymph node metastases 5 months later.²⁰

It is important to note that HLP on the legs often is misdiagnosed as SCC, as pseudoepitheliomatous hyperplasia and squamous metaplasia can be difficult to differentiate clinically and histologically.^21,22 In the case of multiple eruptive SCCs of the lower leg, clinical correlation is essential to avoid unnecessary and ineffective surgical treatment.

Patients with HLP may exhibit Wickham striae, follicular accentuation, and mucocutaneous lichen planus at other sites, or a correlative initiation of possible culprit medications.²³ Because true SCC arising within HLP is relatively rare, its malignant potential is not as clear as those arising within DLE; however, the lower limb appears to be the most common location for SCC within HLP.Nail Lichen Planus—Squamous cell carcinoma arising in nail lichen planus is rare. A report of 2 patients were diagnosed with lichen planus approximately 15 years prior to diagnosis of ungual SCC.²⁴ Given the rarity of this presentation, it is difficult to ascertain the approximate lag time and other risk factors. Furthermore, the role of HPV in these cases was not ruled out. Oncogenic HPV strains have been reported in patients with periungual SCC.^25,26

Lichen Sclerosus

Lichen sclerosus (LS) is a chronic inflammatory dermatosis that favors the anogenital area in a female to male ratio of 10:1.²⁷ It is considered a premalignant condition for SCC tumorigenesis and may be a strong predictor of vulvar SCC (Figure 2), as 62% of vulvar SCC cases (N=78) may have adjacent LS.²⁸

Photograph courtesy of Laura C. Williams, MD (New Orleans, Louisiana).

In a Dutch cohort of 3038 women with LS, 2.6% of patients developed vulvar SCC at a median of 3.3 years after LS diagnosis.²⁹ Other studies have estimated a lag time of 4 years until SCC presentation.³⁰ An Italian cohort of 976 women similarly observed that 2.7% of patients developed premalignancy or SCC.³¹ It was previously estimated that 3% to 5% of patients with LS developed SCC; however, prior studies may have included cases of vulvar intraepithelial neoplasia with low risk for invasive SCC, which might have overestimated true risk of SCC.³² Another confounding factor for elucidating SCC on a background of LS may be the presence of HPV.³³ Extragenital LS does not appear to have similar potential for malignant transformation.³⁴

In a prospective Australian cohort of 507 women with LS (mean age, 55.4 years), remission was induced with potent topical corticosteroids.³⁵ Patients who were adherent to a topical regimen did not develop SCC during follow-up. Those who were nonadherent or partially adherent had a 4.7% risk for SCC.³⁵ In a similar prospective study of 83 women in France, the SCC rate was 9.6% in lesions that were untreated or irregularly treated.³⁶ These studies provide essential evidence that appropriately treating LS can prevent SCC at a later date, though longer-term data are lacking.

The rate of SCC arising in male genital LS may approach 8.4%,³⁷ with a lag time of 17 years from onset of LS to SCC diagnosis.³⁸ Although circumcision often is considered curative for male genital LS, patients have been observed to develop penile SCC at least 5 years after circumcision.³⁹ Male penile SCC in a background of LS may not necessarily be HPV associated.⁴⁰

Marjolin Ulcer

Chronic ulcers or scars, typically postburn scars, may undergo malignant transformation, with SCC being the most common carcinoma.⁴¹ Squamous cell carcinoma in the context of a chronic ulcer or wound is known as a Marjolin ulcer (MU). Up to 2% of burn scars have been observed to undergo malignant transformation.⁴² Marjolin ulcers tend to behave aggressively once they form, and it has been proposed that removal of scar tissue may be a preventive therapeutic strategy.⁴³ Cohort studies of MU on the lower extremities have observed lag times of 26.4⁴⁴ and 37.9⁴⁵ years, with both studies also noting relatively high rates of local recurrence.

The pathogenesis of MU appears to be multifactorial. Chronic inflammation and scar formation have been implicated. Chronic inflammation and irritation of lesions at natural creases are thought to increase mitotic activity,⁴¹ and local accumulation of toxin may promote mutagenesis.⁴⁶ Scar formation may create a locally immunoprivileged site, allowing for developing tumors to evade the immune system⁴⁷ and become even more aggressive as the tumor accumulates.⁴⁸ Scar formation also may prevent the ability of immune cells to penetrate the tumor microenvironment and access lymphatic channels.⁴⁹

Hidradenitis Suppurativa

As many as 3.2% of patients with chronic hidradenitis suppurativa (HS) experience malignant transformation to SCC.⁵⁰ Early HS displays subclinical lymphedema in affected sites, which can progress to chronic fibrosis, stasis, and accumulation of protein-rich fluid.⁵¹ Stasis changes have been associated with altered local inflammatory proteins, such as toll-like receptors, β-defensins, and interleukins.⁵²

A retrospective cohort study of 12 patients revealed a lag time of 28.5 years from HS diagnosis to the manifestation of malignancy.⁵³ After local excision, 7 patients developed recurrence, with 100% mortality. Squamous cell carcinomas were well differentiated and moderately differentiated.⁵³ A 2017 literature review of 62 case reports calculated a mean lag time of 27 years. Despite 85% of SCCs being well differentiated and moderately differentiated, nearly half of patients died within 2 years.⁵⁴ As seen in other inflammatory conditions, HPV can complicate perineal HS and promote SCC tumorigenesis.⁵⁵

Squamous cell carcinomas arising within HS lesions are more prevalent in males (6.75:1 ratio),^54,56 despite HS being more prevalent in females (2:1 ratio).⁵⁷ Similar to DLE, SCCs arising in HS are aggressive and are seen more in males, despite both conditions being female predominant. Incidence and mortality rates for primary cutaneous SCC are higher for men vs women⁵⁸; however, the discordance in aggressive behavior seen more commonly in SCC arising from HS or DLE in male patients has yet to be explained.

Malignancy arising within necrobiosis lipoidica diabeticorum (NLD) is rare. A review of 14 published cases noted that 13 were SCC and 1 was leiomyosarcoma.⁵⁹ The lag time was 21.5 years; 31% of cases (N=14) presented with regional lymph node metastasis. Although chronic ulceration is a risk factor for SCC and occurs in as many as one-third of NLD cases, its correlation with ulceration and malignant transformation has not been characterized.

Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a noninflammatory inherited blistering disease, and patients have an inherently high risk for aggressive SCC.⁶⁰ Other forms of epidermolysis bullosa can lead to SCC, but the rarer RDEB accounts for 69% of SCC cases, with a median age of 36 years at presentation.⁶¹ Although SCCs tend to be well differentiated in RDEB (73.9%),⁶¹ they also exhibit highly aggressive behavior.⁶² In the most severe variant—RDEB-generalized severe—the cumulative risk for SCC-related death in an Australian population was 84.4% at 34 years of age.⁶³

As RDEB is an inherited disorder with potential for malignancy at a young age, the pathogenesis is plausibly different from the previously discussed inflammatory dermatoses. This disease is characterized by a mutation in the collagen VII gene, leading to loss of anchoring fibrils and a basement membrane zone split.⁶⁴ There also can be inherent fibroblast alterations; RDEB fibroblasts create an environment for tumor growth by supporting malignant-cell adhesion and invasion.⁶⁵ Mutations in p53,⁶⁶ local alterations in transforming growth factor β activity,⁶⁷ and downstream matrix metalloproteinase activity⁶⁸ have been implicated.

Additionally, keratinocytes may retain the N-terminal noncollagenous (NC1) domain of truncated collagen VII while losing the anchoring NC2 domain in mutated collagen VII RDEB, thereby supporting anchorless keratinocyte survival and higher metastatic potential.⁶⁹ Retention of this truncated NC1 domain has shown conversion of RDEB keratinocytes to tumor in a xenotransplant mouse model.⁷⁰ A high level of type VII collagen itself may inherently be protumorigenic for keratinocytes.⁷¹

There does not appear to be evidence for HPV involvement in RDEB-associated SCC.⁷² Squamous cell carcinoma development in RDEB appears to be multifactorial,⁷³ but validated tumor models are lacking. Other than conventional oncologic therapy, future directions in the management of RDEB may include gene-, protein- and cell-targeted therapies.⁷³

Conclusion

Squamous cell carcinomas are known to arise within chronic cutaneous inflammatory dermatoses. Tumorigenesis peaks relatively early in new orolabial DLE, LS, and OLP cases, and can occur over many decades in cutaneous DLE, HLP, HS, NLD, and chronic wounds or scars, summarized in the Table. Frequent SCCs are observed in high-risk subtypes of epidermolysis bullosa. Dermatologists must examine areas affected by these diseases at regular intervals, being mindful of the possibility of SCC development. Furthermore, dermatologists should adopt a lower threshold to biopsy suspicious lesions, especially those that develop within relatively new orolabial DLE, chronic HS, or chronic wound cases, as SCC in these settings is particularly aggressive and displays mortality and metastasis rates that exceed those of common cutaneous SCC.


As many as one-quarter of human cancers are related to chronic inflammation, chronic infection, or both.¹ Extrinsic inflammation leads to generation of proinflammatory cytokines that in turn recruit other inflammatory cells, which is thought to generate a positive amplification loop.² Intrinsic stimuli from proto-oncogenes and mutations in tumor suppressor genes lead to transformed cancer cells that also secrete proinflammatory cytokines, thus propagating the cycle.

Numerous factors have been observed in association with tumor growth, progression, invasion, and metastasis.³ One factor for the development of squamous cell carcinoma (SCC) may be chronic inflammatory dermatoses. To date, reviews of chronic inflammation–associated malignancy have focused on solid organ cancers. We sought to provide an up-to-date review of SCC arising within chronic dermatoses, with an emphasis on the anatomic location of dermatoses involved in the transformation of cancer cells, the lag time from onset of dermatosis to diagnosis of SCC, and the distinctive mechanisms thought to be involved in the tumorigenesis in particular dermatoses.

Discoid Lupus Erythematosus

Discoid lupus erythematosus (DLE) is a chronic cutaneous lupus erythematosus variant with a female to male predominance of 3:1,⁴ and DLE lesions are prone to malignant transformation. Retrospective cohort studies have attempted to characterize who is at risk for SCC and how SCCs behave depending on their location. Cohorts from China,⁵ India,⁶ and Japan⁷ have noted a higher rate of SCC within DLE lesions in men (female to male ratios of 1:2.2, 1:1.6, and 1:2, respectively) and shorter lag times for SCC onset within DLE lesions of the lips (13, 5, and 10 years, respectively) compared to SCC arising in DLE elsewhere (19.2, 11.2, and 26 years, respectively). Studies have noted that DLE lesions of the lips may be prone to more rapid SCC tumorigenesis compared to DLE on cutaneous sites. One study reported SCC in DLE recurrence, metastasis, and death rates of 29%, 16.1%, and 19.4%, respectively,⁵ which exceeds reported rates in non-DLE SCCs (20%, 0.5% to 6%, and 1%, respectively).^5,8

Because SCC arising within DLE is most common on the lips (Figure 1), it has been hypothesized that the high rate of transformation of DLE lesions on the lips may be due to constant exposure to irritation and tobacco, which may accelerate carcinogenesis.⁵ It also has been hypothesized that atrophic discoid lesions have lost sun protection and are more prone to mutagenic UV radiation,⁹ as SCCs arising in DLE lesions virtually always display prominent solar elastosis⁶; however, SCC has been observed to arise in non–sun-exposed DLE lesions in both White and Black patients.¹⁰

Photograph courtesy of Andrea Murina, MD.

Additionally, use of immunosuppressant medications may accelerate the emergence of malignancy or more aggressive forms of malignancy; however, patients with autoimmune disease have a greater risk for malignancy at baseline,¹¹ thus making it difficult to determine the excess risk from medications. There also may be a role for human papillomavirus (HPV) accelerating SCC development in DLE lesions, as demonstrated in a case of SCC arising in DLE lesions of the ears, with viral staining evident within the tumors.¹² However, testing for HPV is not routinely performed in these cases.

Dermatologists need to be aware of the relatively rapid tumorigenesis and aggressive behavior of transformation and aggression seen with SCC arising within orolabial DLE lesions compared to cutaneous lesions, especially those on the lips.

Lichen Planus

Although patients with typical cutaneous lichen planus lesions do not have an increased risk for SCC,¹³ variants of lichen planus may predispose patients to SCC.

Oral Lichen Planus—Oral lichen planus (OLP) lesions are prone to malignant transformation. A systematic review of 16 studies evaluating the risk for OLP-associated SCC revealed an overall transformation rate of 1.09%, with a mean lag time of 4.3 years,¹⁴ compared to a reference rate of 0.2% for oral SCC.¹⁵ A meta-analysis of 19,676 patients with OLP and other oral lichenoid lesions revealed an oral SCC rate of 1.1%, with higher rates of transformation seen in cigarette smokers, alcoholics, and patients with hepatitis C virus infection.¹⁶ The ulcerative subtype of OLP appears to present a greater risk for malignant transformation.¹⁵ Dermatologists also should be cognizant that treatments for OLP such as topical calcineurin inhibitors may support the development of malignancy within inflammatory lesions.¹⁷

Hypertrophic Lichen Planus—The hypertrophic variant of lichen planus (HLP) also is prone to malignant transformation. A 1991 epidemiologic study from Sweden of malignancy arising in lichen planus revealed a disproportionate number of cases arising in verrucous or hypertrophic lesions, with a mean of 12.2 years from onset of the dermatosis to malignancy diagnosis.¹³ A subsequent 2015 retrospective study of 38 patients revealed that SCC had a propensity for the lower limb, favoring the pretibial region and the calf over the foot and the ankle with a reported lag time of 11 years.¹⁸

Although metastatic SCC arising in HLP is rare, 2 cases have been reported. A 24-year-old woman presented with an HLP plaque on the lower leg that developed during childhood and rapidly enlarged 2 months prior to presentation; she eventually died from metastatic disease.¹⁹ In another case, a 34-year-old man presented with an HLP lesion of approximately 10 years’ duration. A well-differentiated SCC was excised, and he developed lymph node metastases 5 months later.²⁰

It is important to note that HLP on the legs often is misdiagnosed as SCC, as pseudoepitheliomatous hyperplasia and squamous metaplasia can be difficult to differentiate clinically and histologically.^21,22 In the case of multiple eruptive SCCs of the lower leg, clinical correlation is essential to avoid unnecessary and ineffective surgical treatment.

Patients with HLP may exhibit Wickham striae, follicular accentuation, and mucocutaneous lichen planus at other sites, or a correlative initiation of possible culprit medications.²³ Because true SCC arising within HLP is relatively rare, its malignant potential is not as clear as those arising within DLE; however, the lower limb appears to be the most common location for SCC within HLP.Nail Lichen Planus—Squamous cell carcinoma arising in nail lichen planus is rare. A report of 2 patients were diagnosed with lichen planus approximately 15 years prior to diagnosis of ungual SCC.²⁴ Given the rarity of this presentation, it is difficult to ascertain the approximate lag time and other risk factors. Furthermore, the role of HPV in these cases was not ruled out. Oncogenic HPV strains have been reported in patients with periungual SCC.^25,26

Lichen Sclerosus

Lichen sclerosus (LS) is a chronic inflammatory dermatosis that favors the anogenital area in a female to male ratio of 10:1.²⁷ It is considered a premalignant condition for SCC tumorigenesis and may be a strong predictor of vulvar SCC (Figure 2), as 62% of vulvar SCC cases (N=78) may have adjacent LS.²⁸

Photograph courtesy of Laura C. Williams, MD (New Orleans, Louisiana).

In a Dutch cohort of 3038 women with LS, 2.6% of patients developed vulvar SCC at a median of 3.3 years after LS diagnosis.²⁹ Other studies have estimated a lag time of 4 years until SCC presentation.³⁰ An Italian cohort of 976 women similarly observed that 2.7% of patients developed premalignancy or SCC.³¹ It was previously estimated that 3% to 5% of patients with LS developed SCC; however, prior studies may have included cases of vulvar intraepithelial neoplasia with low risk for invasive SCC, which might have overestimated true risk of SCC.³² Another confounding factor for elucidating SCC on a background of LS may be the presence of HPV.³³ Extragenital LS does not appear to have similar potential for malignant transformation.³⁴

In a prospective Australian cohort of 507 women with LS (mean age, 55.4 years), remission was induced with potent topical corticosteroids.³⁵ Patients who were adherent to a topical regimen did not develop SCC during follow-up. Those who were nonadherent or partially adherent had a 4.7% risk for SCC.³⁵ In a similar prospective study of 83 women in France, the SCC rate was 9.6% in lesions that were untreated or irregularly treated.³⁶ These studies provide essential evidence that appropriately treating LS can prevent SCC at a later date, though longer-term data are lacking.

The rate of SCC arising in male genital LS may approach 8.4%,³⁷ with a lag time of 17 years from onset of LS to SCC diagnosis.³⁸ Although circumcision often is considered curative for male genital LS, patients have been observed to develop penile SCC at least 5 years after circumcision.³⁹ Male penile SCC in a background of LS may not necessarily be HPV associated.⁴⁰

Marjolin Ulcer

Chronic ulcers or scars, typically postburn scars, may undergo malignant transformation, with SCC being the most common carcinoma.⁴¹ Squamous cell carcinoma in the context of a chronic ulcer or wound is known as a Marjolin ulcer (MU). Up to 2% of burn scars have been observed to undergo malignant transformation.⁴² Marjolin ulcers tend to behave aggressively once they form, and it has been proposed that removal of scar tissue may be a preventive therapeutic strategy.⁴³ Cohort studies of MU on the lower extremities have observed lag times of 26.4⁴⁴ and 37.9⁴⁵ years, with both studies also noting relatively high rates of local recurrence.

The pathogenesis of MU appears to be multifactorial. Chronic inflammation and scar formation have been implicated. Chronic inflammation and irritation of lesions at natural creases are thought to increase mitotic activity,⁴¹ and local accumulation of toxin may promote mutagenesis.⁴⁶ Scar formation may create a locally immunoprivileged site, allowing for developing tumors to evade the immune system⁴⁷ and become even more aggressive as the tumor accumulates.⁴⁸ Scar formation also may prevent the ability of immune cells to penetrate the tumor microenvironment and access lymphatic channels.⁴⁹

Hidradenitis Suppurativa

As many as 3.2% of patients with chronic hidradenitis suppurativa (HS) experience malignant transformation to SCC.⁵⁰ Early HS displays subclinical lymphedema in affected sites, which can progress to chronic fibrosis, stasis, and accumulation of protein-rich fluid.⁵¹ Stasis changes have been associated with altered local inflammatory proteins, such as toll-like receptors, β-defensins, and interleukins.⁵²

A retrospective cohort study of 12 patients revealed a lag time of 28.5 years from HS diagnosis to the manifestation of malignancy.⁵³ After local excision, 7 patients developed recurrence, with 100% mortality. Squamous cell carcinomas were well differentiated and moderately differentiated.⁵³ A 2017 literature review of 62 case reports calculated a mean lag time of 27 years. Despite 85% of SCCs being well differentiated and moderately differentiated, nearly half of patients died within 2 years.⁵⁴ As seen in other inflammatory conditions, HPV can complicate perineal HS and promote SCC tumorigenesis.⁵⁵

Squamous cell carcinomas arising within HS lesions are more prevalent in males (6.75:1 ratio),^54,56 despite HS being more prevalent in females (2:1 ratio).⁵⁷ Similar to DLE, SCCs arising in HS are aggressive and are seen more in males, despite both conditions being female predominant. Incidence and mortality rates for primary cutaneous SCC are higher for men vs women⁵⁸; however, the discordance in aggressive behavior seen more commonly in SCC arising from HS or DLE in male patients has yet to be explained.

Malignancy arising within necrobiosis lipoidica diabeticorum (NLD) is rare. A review of 14 published cases noted that 13 were SCC and 1 was leiomyosarcoma.⁵⁹ The lag time was 21.5 years; 31% of cases (N=14) presented with regional lymph node metastasis. Although chronic ulceration is a risk factor for SCC and occurs in as many as one-third of NLD cases, its correlation with ulceration and malignant transformation has not been characterized.

Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a noninflammatory inherited blistering disease, and patients have an inherently high risk for aggressive SCC.⁶⁰ Other forms of epidermolysis bullosa can lead to SCC, but the rarer RDEB accounts for 69% of SCC cases, with a median age of 36 years at presentation.⁶¹ Although SCCs tend to be well differentiated in RDEB (73.9%),⁶¹ they also exhibit highly aggressive behavior.⁶² In the most severe variant—RDEB-generalized severe—the cumulative risk for SCC-related death in an Australian population was 84.4% at 34 years of age.⁶³

As RDEB is an inherited disorder with potential for malignancy at a young age, the pathogenesis is plausibly different from the previously discussed inflammatory dermatoses. This disease is characterized by a mutation in the collagen VII gene, leading to loss of anchoring fibrils and a basement membrane zone split.⁶⁴ There also can be inherent fibroblast alterations; RDEB fibroblasts create an environment for tumor growth by supporting malignant-cell adhesion and invasion.⁶⁵ Mutations in p53,⁶⁶ local alterations in transforming growth factor β activity,⁶⁷ and downstream matrix metalloproteinase activity⁶⁸ have been implicated.

Additionally, keratinocytes may retain the N-terminal noncollagenous (NC1) domain of truncated collagen VII while losing the anchoring NC2 domain in mutated collagen VII RDEB, thereby supporting anchorless keratinocyte survival and higher metastatic potential.⁶⁹ Retention of this truncated NC1 domain has shown conversion of RDEB keratinocytes to tumor in a xenotransplant mouse model.⁷⁰ A high level of type VII collagen itself may inherently be protumorigenic for keratinocytes.⁷¹

There does not appear to be evidence for HPV involvement in RDEB-associated SCC.⁷² Squamous cell carcinoma development in RDEB appears to be multifactorial,⁷³ but validated tumor models are lacking. Other than conventional oncologic therapy, future directions in the management of RDEB may include gene-, protein- and cell-targeted therapies.⁷³

Conclusion

Squamous cell carcinomas are known to arise within chronic cutaneous inflammatory dermatoses. Tumorigenesis peaks relatively early in new orolabial DLE, LS, and OLP cases, and can occur over many decades in cutaneous DLE, HLP, HS, NLD, and chronic wounds or scars, summarized in the Table. Frequent SCCs are observed in high-risk subtypes of epidermolysis bullosa. Dermatologists must examine areas affected by these diseases at regular intervals, being mindful of the possibility of SCC development. Furthermore, dermatologists should adopt a lower threshold to biopsy suspicious lesions, especially those that develop within relatively new orolabial DLE, chronic HS, or chronic wound cases, as SCC in these settings is particularly aggressive and displays mortality and metastasis rates that exceed those of common cutaneous SCC.


America was already facing a critical health care workforce shortage before the COVID-19 pandemic exacerbated the problem. The American Medical Association (AMA) projects that there will be a national shortage of up to 48,000 primary care physicians and 77,100 non-primary care physicians by 2034.

The dearth is particularly striking among physicians who practice in rural areas and those who are Native American. As of 2021, fewer than 3000 physicians—of 841,322—identified as American Indian or Alaska Native, according to the latest statistics from the Physician Specialty Data Report, published by the Association of American Medical Colleges (AAMC).

The lack of Native American physicians is “nothing new, it’s been going on for decades,” says Mary Owen (Tlingit), MD, director of the Center of American Indian and Minority Health and associate dean of Native American Health at the University of Minnesota Medical School, speaking in a Native America Calling podcast in October.

“These numbers are… actually lessening—and we had paltry numbers to begin with,” said Owen. “It doesn’t take a genius to look back and figure out where it’s from. We don’t have enough students coming through the pathways in the first place. For instance, our high school graduation rate in this country is easily 10 points below that of non-Natives. In Duluth, Minnesota, the high school graduation rate is only 43%… We have to recognize that this is an area we have to work on.”

Senators Tim Kaine (D-VA) and Alex Padilla (D-CA) have introduced the Expanding Medical Education Act, legislation to get more students from underrepresented groups into the physician pipeline. The bill would provide grants through the Health Resources and Services Administration (HRSA) for colleges and universities to establish or expand allopathic (MD-granting) or osteopathic (DO-granting) medical schools in underserved areas or at institutions for underrepresented populations, including Historically Black Colleges and Universities (HBCUs).

Addressing Rural Needs

However, projections on the growth of health care professions show that supply will not meet demand over the next 10 years. The shortage is more dire in rural areas. According to the US Department of Health and Human Services (HHS), since 2010, more than 150 rural hospitals have either closed their doors entirely or stopped providing inpatient hospital services. Often, rural communities have fewer local HCPs available.

More than half (54%) of American Indian or Alaska Native people live in rural and small-town areas, and 68% live on or near their tribal homelands, according to the nonprofit First Nations Development Institute. Many live far—even hours—away from the nearest health care facility. But according to Population Health in Rural America in 2020: Proceedings of a Workshop, only 10% of primary care practitioners and < 7% of specialty care practitioners live in rural areas. About 5% of rural counties do not have any family physicians. What’s more, language and culture differ among the nearly 600 tribes across the country. The Indian Health Council, for instance, counts 9 individual reservations and tribes within a 5-mile radius in San Diego County, “all of which have their own unique customs,” which contribute to the “level of care they deem appropriate.”

“If you’re a rural impoverished community, it’s hard to recruit doctors. We’re more likely to return to our communities,” said Donald K. Warne (Oglala Lakota), MD, MPH, Associate Dean for Diversity, Equity, and Inclusion at the University of North Dakota School of Medicine and Health Sciences, during the 2019 American Indian or Alaska Native Physicians Summit, which was cosponsored by the AMA, Association of American Indian Physicians (AAIP), and the AAMC.

“Communities of color and those living in rural and underserved areas have long faced significant barriers to health care, including a lack of providers that look like them or practice close by,” said Senator Kaine in a statement. “Since research shows that physicians are more likely to practice in the areas they’re from, supporting medical schools at minority-serving institutions and HBCUs in underserved areas can help improve care in those communities.”

Where Are the Native Medical Students?

Only 9% of medical schools have more than 4 American Indian or Alaska Native students; 43% have none, says Siobhan M. Wescott, MD, MPH, chair of the AMA Minority Affairs Section (MAS), and an assistant professor at the University of North Dakota. Dr. Wescott, who hosted the AMA co-sponsored summit on behalf of the AMA-MAS, is an Alaska Native and 1 of only 3 physicians from her tribe. The AAMC has also found that less than half of MD-granting medical schools in the US have enrolled more than 5 Native students.

Among other things, the Expanding Medical Education Act would prioritize grants to institutions of higher education that propose to use the funds to establish a medical school or branch campus in an area in which no other such school is based and is a medically underserved community or “health professional shortage” area. Eligible uses for the grants include hiring diverse faculty and other staff, and recruiting students from underrepresented racial and ethnic minorities, students from rural and underserved areas, low-income students, and first-generation college students.

The legislation has been endorsed by the AAMC, American Association of Colleges of Osteopathic Medicine, Association of American Indian Physicians, Association of Clinicians for the Underserved, National Hispanic Medical Association, Society for Advancement of Chicanos/Hispanics and Native Americans in Science, and Ochsner Health.

Funding Is Key

Federal agencies are investing in funding and training. Medicare is allocating 1000 new training slots for medical residents, prioritizing rural and underserved areas. Centers for Medicare and Medicaid Services (CMS) is offering another 200 slots, at least 100 of which are specifically for psychiatry residencies in 2026. HHS awarded more than $11 million through the Rural Residency Planning and Development Program (RRPD) to help establish new rural residency programs. Accredited RRPD-funded programs are already training more than 300 resident physicians in family medicine, internal medicine, psychiatry, and general surgery. HRSA published an opportunity for $5 million in FY 2024 to develop and implement clinical rotations for physician assistant students in rural areas that will integrate behavioral health with primary care services.

The Biden-Harris Administration has already taken several steps to improve access to health care for the more than 60 million people who live in rural areas, including: building on the Affordable Care Act and Inflation Reduction Act to increase access to affordable health coverage and care for those living in rural communities; keeping more rural hospitals open to provide critical services in their communities; and bolstering the rural health workforce, including for primary care and behavioral HCPs.

The administration also has funded small rural hospitals and Medicare-certified Rural Health Clinics. Critical access hospitals and small hospitals in rural areas have a new option: to convert to a Rural Emergency Hospital (REH), a new Medicare provider type. CMS has changed the payment method for Tribal and Indian Health Services–operated REHs, to address certain barriers that may have discouraged Tribal and Indian Health Service (IHS)–operated hospitals from converting to REHs. Beginning in FY 2022, HHS, through HRSA, dedicated $5 million to provide technical assistance to rural hospitals that are considering converting to the REH designation.

HHS also has several grant opportunities to support rural communities, including $28 million to provide direct health services and expand infrastructure and $16 million to provide technical assistance to rural hospitals facing financial distress. This year, 60 rural hospitals will receive technical assistance to maintain financial viability and ensure continued access to care.

The HRSA National Health Service Corps Rural Community Loan Repayment Program has invested $80 million to support substance use disorder treatment, assist in recovery, and prevent overdose deaths. Medicare will also cover opioid use disorder treatment services delivered by mobile units of registered opioid treatment programs, which can now be accessed via telehealth or audio-only communications.

Curricula Also Lack Native Diversity

As of 2017, only 11% of MD-granting schools in the US say they have included Native American health content in their curricula. Dr. Owen notes some of the challenges indigenous students face: They are in a crowd that is primarily non-Native, far from their own family and community; unlike White students, they usually do not have mentors; they may not have the wherewithal to continue school and graduate.

A 2022 study of the association of sociodemographic characteristics with US medical student attrition, published in JAMA Internal Medicine, found that American Indian, Alaska Native, Native Hawaiian, and Pacific Islander students were more than 4 times as likely to drop out compared with White students. More than 10% of Indigenous medical students don’t graduate—the highest of any group the researchers examined.

In 1973 the University of North Dakota, for instance, launched Indians Into Medicine (INMED), a program that has since recruited, supported, and trained 250 American Indian doctors, and, in 2019, the country’s first PhD program in indigenous health. Dr. Warne, the director of INMED, calls it “by far, the most successful indigenous medical training program in the world,” having helped 228 American Indians and Alaska Natives graduate since its inception. A new cohort of 6 students has just enrolled.

Oregon Health & Science University (OHSU) received $800,000 in federal funding for its Future Leaders in Indigenous Health (FLIGHT) project, managed through OHSU’s Northwest Native American Center of Excellence (NNACoE). In 2012, just 8 Native students were enrolled in the OHSU School of Medicine; a decade later, there were 29. In 2022, the newest medical class included 12 American Indian or Alaska Native students. According to the school, it is believed to be the largest group of Natives in any single US medical school MD class in history. The number of Native faculty in the OHSU School of Medicine grew from 7 in 2014 to 13 in 2022.

America was already facing a critical health care workforce shortage before the COVID-19 pandemic exacerbated the problem. The American Medical Association (AMA) projects that there will be a national shortage of up to 48,000 primary care physicians and 77,100 non-primary care physicians by 2034.

The dearth is particularly striking among physicians who practice in rural areas and those who are Native American. As of 2021, fewer than 3000 physicians—of 841,322—identified as American Indian or Alaska Native, according to the latest statistics from the Physician Specialty Data Report, published by the Association of American Medical Colleges (AAMC).

The lack of Native American physicians is “nothing new, it’s been going on for decades,” says Mary Owen (Tlingit), MD, director of the Center of American Indian and Minority Health and associate dean of Native American Health at the University of Minnesota Medical School, speaking in a Native America Calling podcast in October.

“These numbers are… actually lessening—and we had paltry numbers to begin with,” said Owen. “It doesn’t take a genius to look back and figure out where it’s from. We don’t have enough students coming through the pathways in the first place. For instance, our high school graduation rate in this country is easily 10 points below that of non-Natives. In Duluth, Minnesota, the high school graduation rate is only 43%… We have to recognize that this is an area we have to work on.”

Senators Tim Kaine (D-VA) and Alex Padilla (D-CA) have introduced the Expanding Medical Education Act, legislation to get more students from underrepresented groups into the physician pipeline. The bill would provide grants through the Health Resources and Services Administration (HRSA) for colleges and universities to establish or expand allopathic (MD-granting) or osteopathic (DO-granting) medical schools in underserved areas or at institutions for underrepresented populations, including Historically Black Colleges and Universities (HBCUs).

Addressing Rural Needs

However, projections on the growth of health care professions show that supply will not meet demand over the next 10 years. The shortage is more dire in rural areas. According to the US Department of Health and Human Services (HHS), since 2010, more than 150 rural hospitals have either closed their doors entirely or stopped providing inpatient hospital services. Often, rural communities have fewer local HCPs available.

More than half (54%) of American Indian or Alaska Native people live in rural and small-town areas, and 68% live on or near their tribal homelands, according to the nonprofit First Nations Development Institute. Many live far—even hours—away from the nearest health care facility. But according to Population Health in Rural America in 2020: Proceedings of a Workshop, only 10% of primary care practitioners and < 7% of specialty care practitioners live in rural areas. About 5% of rural counties do not have any family physicians. What’s more, language and culture differ among the nearly 600 tribes across the country. The Indian Health Council, for instance, counts 9 individual reservations and tribes within a 5-mile radius in San Diego County, “all of which have their own unique customs,” which contribute to the “level of care they deem appropriate.”

“If you’re a rural impoverished community, it’s hard to recruit doctors. We’re more likely to return to our communities,” said Donald K. Warne (Oglala Lakota), MD, MPH, Associate Dean for Diversity, Equity, and Inclusion at the University of North Dakota School of Medicine and Health Sciences, during the 2019 American Indian or Alaska Native Physicians Summit, which was cosponsored by the AMA, Association of American Indian Physicians (AAIP), and the AAMC.

“Communities of color and those living in rural and underserved areas have long faced significant barriers to health care, including a lack of providers that look like them or practice close by,” said Senator Kaine in a statement. “Since research shows that physicians are more likely to practice in the areas they’re from, supporting medical schools at minority-serving institutions and HBCUs in underserved areas can help improve care in those communities.”

Where Are the Native Medical Students?

Only 9% of medical schools have more than 4 American Indian or Alaska Native students; 43% have none, says Siobhan M. Wescott, MD, MPH, chair of the AMA Minority Affairs Section (MAS), and an assistant professor at the University of North Dakota. Dr. Wescott, who hosted the AMA co-sponsored summit on behalf of the AMA-MAS, is an Alaska Native and 1 of only 3 physicians from her tribe. The AAMC has also found that less than half of MD-granting medical schools in the US have enrolled more than 5 Native students.

Among other things, the Expanding Medical Education Act would prioritize grants to institutions of higher education that propose to use the funds to establish a medical school or branch campus in an area in which no other such school is based and is a medically underserved community or “health professional shortage” area. Eligible uses for the grants include hiring diverse faculty and other staff, and recruiting students from underrepresented racial and ethnic minorities, students from rural and underserved areas, low-income students, and first-generation college students.

The legislation has been endorsed by the AAMC, American Association of Colleges of Osteopathic Medicine, Association of American Indian Physicians, Association of Clinicians for the Underserved, National Hispanic Medical Association, Society for Advancement of Chicanos/Hispanics and Native Americans in Science, and Ochsner Health.

Funding Is Key

Federal agencies are investing in funding and training. Medicare is allocating 1000 new training slots for medical residents, prioritizing rural and underserved areas. Centers for Medicare and Medicaid Services (CMS) is offering another 200 slots, at least 100 of which are specifically for psychiatry residencies in 2026. HHS awarded more than $11 million through the Rural Residency Planning and Development Program (RRPD) to help establish new rural residency programs. Accredited RRPD-funded programs are already training more than 300 resident physicians in family medicine, internal medicine, psychiatry, and general surgery. HRSA published an opportunity for $5 million in FY 2024 to develop and implement clinical rotations for physician assistant students in rural areas that will integrate behavioral health with primary care services.

The Biden-Harris Administration has already taken several steps to improve access to health care for the more than 60 million people who live in rural areas, including: building on the Affordable Care Act and Inflation Reduction Act to increase access to affordable health coverage and care for those living in rural communities; keeping more rural hospitals open to provide critical services in their communities; and bolstering the rural health workforce, including for primary care and behavioral HCPs.

The administration also has funded small rural hospitals and Medicare-certified Rural Health Clinics. Critical access hospitals and small hospitals in rural areas have a new option: to convert to a Rural Emergency Hospital (REH), a new Medicare provider type. CMS has changed the payment method for Tribal and Indian Health Services–operated REHs, to address certain barriers that may have discouraged Tribal and Indian Health Service (IHS)–operated hospitals from converting to REHs. Beginning in FY 2022, HHS, through HRSA, dedicated $5 million to provide technical assistance to rural hospitals that are considering converting to the REH designation.

HHS also has several grant opportunities to support rural communities, including $28 million to provide direct health services and expand infrastructure and $16 million to provide technical assistance to rural hospitals facing financial distress. This year, 60 rural hospitals will receive technical assistance to maintain financial viability and ensure continued access to care.

The HRSA National Health Service Corps Rural Community Loan Repayment Program has invested $80 million to support substance use disorder treatment, assist in recovery, and prevent overdose deaths. Medicare will also cover opioid use disorder treatment services delivered by mobile units of registered opioid treatment programs, which can now be accessed via telehealth or audio-only communications.

Curricula Also Lack Native Diversity

As of 2017, only 11% of MD-granting schools in the US say they have included Native American health content in their curricula. Dr. Owen notes some of the challenges indigenous students face: They are in a crowd that is primarily non-Native, far from their own family and community; unlike White students, they usually do not have mentors; they may not have the wherewithal to continue school and graduate.

A 2022 study of the association of sociodemographic characteristics with US medical student attrition, published in JAMA Internal Medicine, found that American Indian, Alaska Native, Native Hawaiian, and Pacific Islander students were more than 4 times as likely to drop out compared with White students. More than 10% of Indigenous medical students don’t graduate—the highest of any group the researchers examined.

In 1973 the University of North Dakota, for instance, launched Indians Into Medicine (INMED), a program that has since recruited, supported, and trained 250 American Indian doctors, and, in 2019, the country’s first PhD program in indigenous health. Dr. Warne, the director of INMED, calls it “by far, the most successful indigenous medical training program in the world,” having helped 228 American Indians and Alaska Natives graduate since its inception. A new cohort of 6 students has just enrolled.

Oregon Health & Science University (OHSU) received $800,000 in federal funding for its Future Leaders in Indigenous Health (FLIGHT) project, managed through OHSU’s Northwest Native American Center of Excellence (NNACoE). In 2012, just 8 Native students were enrolled in the OHSU School of Medicine; a decade later, there were 29. In 2022, the newest medical class included 12 American Indian or Alaska Native students. According to the school, it is believed to be the largest group of Natives in any single US medical school MD class in history. The number of Native faculty in the OHSU School of Medicine grew from 7 in 2014 to 13 in 2022.

America was already facing a critical health care workforce shortage before the COVID-19 pandemic exacerbated the problem. The American Medical Association (AMA) projects that there will be a national shortage of up to 48,000 primary care physicians and 77,100 non-primary care physicians by 2034.

The dearth is particularly striking among physicians who practice in rural areas and those who are Native American. As of 2021, fewer than 3000 physicians—of 841,322—identified as American Indian or Alaska Native, according to the latest statistics from the Physician Specialty Data Report, published by the Association of American Medical Colleges (AAMC).

The lack of Native American physicians is “nothing new, it’s been going on for decades,” says Mary Owen (Tlingit), MD, director of the Center of American Indian and Minority Health and associate dean of Native American Health at the University of Minnesota Medical School, speaking in a Native America Calling podcast in October.

“These numbers are… actually lessening—and we had paltry numbers to begin with,” said Owen. “It doesn’t take a genius to look back and figure out where it’s from. We don’t have enough students coming through the pathways in the first place. For instance, our high school graduation rate in this country is easily 10 points below that of non-Natives. In Duluth, Minnesota, the high school graduation rate is only 43%… We have to recognize that this is an area we have to work on.”

Senators Tim Kaine (D-VA) and Alex Padilla (D-CA) have introduced the Expanding Medical Education Act, legislation to get more students from underrepresented groups into the physician pipeline. The bill would provide grants through the Health Resources and Services Administration (HRSA) for colleges and universities to establish or expand allopathic (MD-granting) or osteopathic (DO-granting) medical schools in underserved areas or at institutions for underrepresented populations, including Historically Black Colleges and Universities (HBCUs).

Addressing Rural Needs

However, projections on the growth of health care professions show that supply will not meet demand over the next 10 years. The shortage is more dire in rural areas. According to the US Department of Health and Human Services (HHS), since 2010, more than 150 rural hospitals have either closed their doors entirely or stopped providing inpatient hospital services. Often, rural communities have fewer local HCPs available.

More than half (54%) of American Indian or Alaska Native people live in rural and small-town areas, and 68% live on or near their tribal homelands, according to the nonprofit First Nations Development Institute. Many live far—even hours—away from the nearest health care facility. But according to Population Health in Rural America in 2020: Proceedings of a Workshop, only 10% of primary care practitioners and < 7% of specialty care practitioners live in rural areas. About 5% of rural counties do not have any family physicians. What’s more, language and culture differ among the nearly 600 tribes across the country. The Indian Health Council, for instance, counts 9 individual reservations and tribes within a 5-mile radius in San Diego County, “all of which have their own unique customs,” which contribute to the “level of care they deem appropriate.”

“If you’re a rural impoverished community, it’s hard to recruit doctors. We’re more likely to return to our communities,” said Donald K. Warne (Oglala Lakota), MD, MPH, Associate Dean for Diversity, Equity, and Inclusion at the University of North Dakota School of Medicine and Health Sciences, during the 2019 American Indian or Alaska Native Physicians Summit, which was cosponsored by the AMA, Association of American Indian Physicians (AAIP), and the AAMC.

“Communities of color and those living in rural and underserved areas have long faced significant barriers to health care, including a lack of providers that look like them or practice close by,” said Senator Kaine in a statement. “Since research shows that physicians are more likely to practice in the areas they’re from, supporting medical schools at minority-serving institutions and HBCUs in underserved areas can help improve care in those communities.”

Where Are the Native Medical Students?

Only 9% of medical schools have more than 4 American Indian or Alaska Native students; 43% have none, says Siobhan M. Wescott, MD, MPH, chair of the AMA Minority Affairs Section (MAS), and an assistant professor at the University of North Dakota. Dr. Wescott, who hosted the AMA co-sponsored summit on behalf of the AMA-MAS, is an Alaska Native and 1 of only 3 physicians from her tribe. The AAMC has also found that less than half of MD-granting medical schools in the US have enrolled more than 5 Native students.

Among other things, the Expanding Medical Education Act would prioritize grants to institutions of higher education that propose to use the funds to establish a medical school or branch campus in an area in which no other such school is based and is a medically underserved community or “health professional shortage” area. Eligible uses for the grants include hiring diverse faculty and other staff, and recruiting students from underrepresented racial and ethnic minorities, students from rural and underserved areas, low-income students, and first-generation college students.

The legislation has been endorsed by the AAMC, American Association of Colleges of Osteopathic Medicine, Association of American Indian Physicians, Association of Clinicians for the Underserved, National Hispanic Medical Association, Society for Advancement of Chicanos/Hispanics and Native Americans in Science, and Ochsner Health.

Funding Is Key

Federal agencies are investing in funding and training. Medicare is allocating 1000 new training slots for medical residents, prioritizing rural and underserved areas. Centers for Medicare and Medicaid Services (CMS) is offering another 200 slots, at least 100 of which are specifically for psychiatry residencies in 2026. HHS awarded more than $11 million through the Rural Residency Planning and Development Program (RRPD) to help establish new rural residency programs. Accredited RRPD-funded programs are already training more than 300 resident physicians in family medicine, internal medicine, psychiatry, and general surgery. HRSA published an opportunity for $5 million in FY 2024 to develop and implement clinical rotations for physician assistant students in rural areas that will integrate behavioral health with primary care services.

The Biden-Harris Administration has already taken several steps to improve access to health care for the more than 60 million people who live in rural areas, including: building on the Affordable Care Act and Inflation Reduction Act to increase access to affordable health coverage and care for those living in rural communities; keeping more rural hospitals open to provide critical services in their communities; and bolstering the rural health workforce, including for primary care and behavioral HCPs.

The administration also has funded small rural hospitals and Medicare-certified Rural Health Clinics. Critical access hospitals and small hospitals in rural areas have a new option: to convert to a Rural Emergency Hospital (REH), a new Medicare provider type. CMS has changed the payment method for Tribal and Indian Health Services–operated REHs, to address certain barriers that may have discouraged Tribal and Indian Health Service (IHS)–operated hospitals from converting to REHs. Beginning in FY 2022, HHS, through HRSA, dedicated $5 million to provide technical assistance to rural hospitals that are considering converting to the REH designation.

HHS also has several grant opportunities to support rural communities, including $28 million to provide direct health services and expand infrastructure and $16 million to provide technical assistance to rural hospitals facing financial distress. This year, 60 rural hospitals will receive technical assistance to maintain financial viability and ensure continued access to care.

The HRSA National Health Service Corps Rural Community Loan Repayment Program has invested $80 million to support substance use disorder treatment, assist in recovery, and prevent overdose deaths. Medicare will also cover opioid use disorder treatment services delivered by mobile units of registered opioid treatment programs, which can now be accessed via telehealth or audio-only communications.

Curricula Also Lack Native Diversity

As of 2017, only 11% of MD-granting schools in the US say they have included Native American health content in their curricula. Dr. Owen notes some of the challenges indigenous students face: They are in a crowd that is primarily non-Native, far from their own family and community; unlike White students, they usually do not have mentors; they may not have the wherewithal to continue school and graduate.

A 2022 study of the association of sociodemographic characteristics with US medical student attrition, published in JAMA Internal Medicine, found that American Indian, Alaska Native, Native Hawaiian, and Pacific Islander students were more than 4 times as likely to drop out compared with White students. More than 10% of Indigenous medical students don’t graduate—the highest of any group the researchers examined.

In 1973 the University of North Dakota, for instance, launched Indians Into Medicine (INMED), a program that has since recruited, supported, and trained 250 American Indian doctors, and, in 2019, the country’s first PhD program in indigenous health. Dr. Warne, the director of INMED, calls it “by far, the most successful indigenous medical training program in the world,” having helped 228 American Indians and Alaska Natives graduate since its inception. A new cohort of 6 students has just enrolled.

Oregon Health & Science University (OHSU) received $800,000 in federal funding for its Future Leaders in Indigenous Health (FLIGHT) project, managed through OHSU’s Northwest Native American Center of Excellence (NNACoE). In 2012, just 8 Native students were enrolled in the OHSU School of Medicine; a decade later, there were 29. In 2022, the newest medical class included 12 American Indian or Alaska Native students. According to the school, it is believed to be the largest group of Natives in any single US medical school MD class in history. The number of Native faculty in the OHSU School of Medicine grew from 7 in 2014 to 13 in 2022.

SAN DIEGO — Clinicians are encountering unique challenges as the American Society of Hematology (ASH) develops the first-ever clinical practice guidelines for treating acute lymphocytic leukemia (ALL) in adolescents and young adults, a wide-ranging age span that runs from older teenagers to thirtysomethings on the cusp of middle age.

At the crux of the matter is the unusual nature of ALL, said University of Chicago leukemia specialist Wendy Stock, MD, in a presentation at the annual meeting of the American Society of Hematology in December 2023. The disease is both rare and unique since it spans the entire lifetime from infancy to old age, she said.

The guidelines will focus on adolescents and young adults, which the National Cancer Institute defines as those aged 15-39. For these patients, “treatment is administered by the whole gamut of practitioners in the world of hematology, from pediatricians to adult hematologist/oncologists, which provides unique challenges in terms of understanding and access to care,” Dr. Stock said.

As she explained, ALL “is the bread and butter of pediatric oncology, but in the world of adult hematology-oncology, many patients are treated in small-practice settings where there have been very few uniform approaches available to the treating practitioners,” she said. “There’s not going to ever be the ability to get every — or even the majority — of adults into those big academic centers.”

Meanwhile, research from around the world has highlighted major mortality gaps between pediatric and adult care in ALL. “This has been our huge challenge: Is it the treatment approach? Is it the disease biology, the patient biology, the doctors who treat these diseases? Is it the geographic location where they’re treated? Well, we now know that, of course, it’s probably all of the above, and a lot more than that.”

In light of the need for guidance in ALL treatment, it will be crucial to disseminate data and recommendations via the guidelines, she said.

In 2021, ASH members approved the development of new clinical practice guidelines for this population. The process so far has been difficult, said pediatric oncologist Sumit Gupta, MD, PhD, of the Hospital for Sick Children in Toronto, Ontario, at the ASH presentation.

“At one point,” Dr. Gupta recalled, “someone on our methodology team said this was the most challenging systematic review and guideline creation that they’d ever worked on, which is not what you want to hear as a co-chair.”

One major challenge for the guideline drafters is to balance ALL research findings that cover only certain ages, Dr. Gupta said. A study, for example, may only include patients up to age 21 or over age 35, making it difficult to decide how it fits into a larger evidence base for adolescents and young adults.

“We don’t always have perfect evidence. But we’re trying to take all of that and translate it into a formalized systematic review,” he said. “This is tricky for any guideline. But ALL poses a particular challenge because of how the evidence base is spread out.”

Another challenge is figuring out how to review psychosocial interventions in ALL. They are obviously crucial, he said. But should guidelines only take into account strategies that were tested in ALL? Or should they look at a wider perspective and encompass research into non–ALL-specific approaches?

In terms of guidance about frontline treatment, the guideline developers are focusing on several topics, said University of Rochester hematologist/oncologist Kristen O’Dwyer, MD, at the ASH presentation. These include: Should adolescents and young adults receive pediatric or adult regimens? Where do targeted therapy, immunotherapy, steroids, allogeneic stem cell transplants, and central nervous system (CNS) prophylaxis fit in?

“Finally, there are a series of questions that are addressing the toxicity prevention and management that go along with these intensive chemotherapy regimens,” she said.

On one front, there’s a “knowledge gap” about the value of stem cell transplant vs pediatric-inspired chemotherapy as postremission therapies, Dr. O’Dwyer said, because there are no direct comparisons. What to do? “There are retrospective comparisons that are emerging along with population-level analysis, single-arm observational studies that suggest that a pediatric-based chemotherapy approach is superior with similar relapse rates and less treatment-related mortality,” she said.

ASH expects to release a draft of its ALL guidelines for adolescents and young adults later this year and publish final recommendations in late 2024 or early 2025.

Dr. Stock, Dr. Gupta, and Dr. O’Dwyer have no disclosures.

SAN DIEGO — Clinicians are encountering unique challenges as the American Society of Hematology (ASH) develops the first-ever clinical practice guidelines for treating acute lymphocytic leukemia (ALL) in adolescents and young adults, a wide-ranging age span that runs from older teenagers to thirtysomethings on the cusp of middle age.

At the crux of the matter is the unusual nature of ALL, said University of Chicago leukemia specialist Wendy Stock, MD, in a presentation at the annual meeting of the American Society of Hematology in December 2023. The disease is both rare and unique since it spans the entire lifetime from infancy to old age, she said.

The guidelines will focus on adolescents and young adults, which the National Cancer Institute defines as those aged 15-39. For these patients, “treatment is administered by the whole gamut of practitioners in the world of hematology, from pediatricians to adult hematologist/oncologists, which provides unique challenges in terms of understanding and access to care,” Dr. Stock said.

As she explained, ALL “is the bread and butter of pediatric oncology, but in the world of adult hematology-oncology, many patients are treated in small-practice settings where there have been very few uniform approaches available to the treating practitioners,” she said. “There’s not going to ever be the ability to get every — or even the majority — of adults into those big academic centers.”

Meanwhile, research from around the world has highlighted major mortality gaps between pediatric and adult care in ALL. “This has been our huge challenge: Is it the treatment approach? Is it the disease biology, the patient biology, the doctors who treat these diseases? Is it the geographic location where they’re treated? Well, we now know that, of course, it’s probably all of the above, and a lot more than that.”

In light of the need for guidance in ALL treatment, it will be crucial to disseminate data and recommendations via the guidelines, she said.

In 2021, ASH members approved the development of new clinical practice guidelines for this population. The process so far has been difficult, said pediatric oncologist Sumit Gupta, MD, PhD, of the Hospital for Sick Children in Toronto, Ontario, at the ASH presentation.

“At one point,” Dr. Gupta recalled, “someone on our methodology team said this was the most challenging systematic review and guideline creation that they’d ever worked on, which is not what you want to hear as a co-chair.”

One major challenge for the guideline drafters is to balance ALL research findings that cover only certain ages, Dr. Gupta said. A study, for example, may only include patients up to age 21 or over age 35, making it difficult to decide how it fits into a larger evidence base for adolescents and young adults.

“We don’t always have perfect evidence. But we’re trying to take all of that and translate it into a formalized systematic review,” he said. “This is tricky for any guideline. But ALL poses a particular challenge because of how the evidence base is spread out.”

Another challenge is figuring out how to review psychosocial interventions in ALL. They are obviously crucial, he said. But should guidelines only take into account strategies that were tested in ALL? Or should they look at a wider perspective and encompass research into non–ALL-specific approaches?

In terms of guidance about frontline treatment, the guideline developers are focusing on several topics, said University of Rochester hematologist/oncologist Kristen O’Dwyer, MD, at the ASH presentation. These include: Should adolescents and young adults receive pediatric or adult regimens? Where do targeted therapy, immunotherapy, steroids, allogeneic stem cell transplants, and central nervous system (CNS) prophylaxis fit in?

“Finally, there are a series of questions that are addressing the toxicity prevention and management that go along with these intensive chemotherapy regimens,” she said.

On one front, there’s a “knowledge gap” about the value of stem cell transplant vs pediatric-inspired chemotherapy as postremission therapies, Dr. O’Dwyer said, because there are no direct comparisons. What to do? “There are retrospective comparisons that are emerging along with population-level analysis, single-arm observational studies that suggest that a pediatric-based chemotherapy approach is superior with similar relapse rates and less treatment-related mortality,” she said.

ASH expects to release a draft of its ALL guidelines for adolescents and young adults later this year and publish final recommendations in late 2024 or early 2025.

Dr. Stock, Dr. Gupta, and Dr. O’Dwyer have no disclosures.

SAN DIEGO — Clinicians are encountering unique challenges as the American Society of Hematology (ASH) develops the first-ever clinical practice guidelines for treating acute lymphocytic leukemia (ALL) in adolescents and young adults, a wide-ranging age span that runs from older teenagers to thirtysomethings on the cusp of middle age.

At the crux of the matter is the unusual nature of ALL, said University of Chicago leukemia specialist Wendy Stock, MD, in a presentation at the annual meeting of the American Society of Hematology in December 2023. The disease is both rare and unique since it spans the entire lifetime from infancy to old age, she said.

The guidelines will focus on adolescents and young adults, which the National Cancer Institute defines as those aged 15-39. For these patients, “treatment is administered by the whole gamut of practitioners in the world of hematology, from pediatricians to adult hematologist/oncologists, which provides unique challenges in terms of understanding and access to care,” Dr. Stock said.

As she explained, ALL “is the bread and butter of pediatric oncology, but in the world of adult hematology-oncology, many patients are treated in small-practice settings where there have been very few uniform approaches available to the treating practitioners,” she said. “There’s not going to ever be the ability to get every — or even the majority — of adults into those big academic centers.”

Meanwhile, research from around the world has highlighted major mortality gaps between pediatric and adult care in ALL. “This has been our huge challenge: Is it the treatment approach? Is it the disease biology, the patient biology, the doctors who treat these diseases? Is it the geographic location where they’re treated? Well, we now know that, of course, it’s probably all of the above, and a lot more than that.”

In light of the need for guidance in ALL treatment, it will be crucial to disseminate data and recommendations via the guidelines, she said.

In 2021, ASH members approved the development of new clinical practice guidelines for this population. The process so far has been difficult, said pediatric oncologist Sumit Gupta, MD, PhD, of the Hospital for Sick Children in Toronto, Ontario, at the ASH presentation.

“At one point,” Dr. Gupta recalled, “someone on our methodology team said this was the most challenging systematic review and guideline creation that they’d ever worked on, which is not what you want to hear as a co-chair.”

One major challenge for the guideline drafters is to balance ALL research findings that cover only certain ages, Dr. Gupta said. A study, for example, may only include patients up to age 21 or over age 35, making it difficult to decide how it fits into a larger evidence base for adolescents and young adults.

“We don’t always have perfect evidence. But we’re trying to take all of that and translate it into a formalized systematic review,” he said. “This is tricky for any guideline. But ALL poses a particular challenge because of how the evidence base is spread out.”

Another challenge is figuring out how to review psychosocial interventions in ALL. They are obviously crucial, he said. But should guidelines only take into account strategies that were tested in ALL? Or should they look at a wider perspective and encompass research into non–ALL-specific approaches?

In terms of guidance about frontline treatment, the guideline developers are focusing on several topics, said University of Rochester hematologist/oncologist Kristen O’Dwyer, MD, at the ASH presentation. These include: Should adolescents and young adults receive pediatric or adult regimens? Where do targeted therapy, immunotherapy, steroids, allogeneic stem cell transplants, and central nervous system (CNS) prophylaxis fit in?

“Finally, there are a series of questions that are addressing the toxicity prevention and management that go along with these intensive chemotherapy regimens,” she said.

On one front, there’s a “knowledge gap” about the value of stem cell transplant vs pediatric-inspired chemotherapy as postremission therapies, Dr. O’Dwyer said, because there are no direct comparisons. What to do? “There are retrospective comparisons that are emerging along with population-level analysis, single-arm observational studies that suggest that a pediatric-based chemotherapy approach is superior with similar relapse rates and less treatment-related mortality,” she said.

ASH expects to release a draft of its ALL guidelines for adolescents and young adults later this year and publish final recommendations in late 2024 or early 2025.

Dr. Stock, Dr. Gupta, and Dr. O’Dwyer have no disclosures.

TOPLINE:

A new study shows sudden cardiac deaths among collegiate athletes decreased over a recent 20-year period, but risks are still elevated among males, Black players, and basketball players, suggesting more intensive screening among these groups is needed.

METHODOLOGY:

• The study examined incidence and surrounding circumstances of sudden cardiac death (SCD) among student athletes who competed in at least one varsity sport at National Collegiate Athletic Association (NCAA) Division I, II, or III institutions in the 20 years from July 1, 2002, to June 30, 2022.
• Researchers determined causes of death and gathered demographic characteristics using multiple methods, including review of autopsy and other official documents, Internet searches, and contacts to next of kin, coaches, athletic trainers, coroners, medical examiners, scholarship foundations, and physicians involved in the case.
• SCD was defined as sudden unexpected death attributable to a cardiac cause, or a sudden death in a structurally normal heart with no other explanation for death and a history consistent with cardiac-related death that occurred within an hour of symptom onset, or an unwitnessed death occurring within 24 hours of the person being alive.
• Researchers calculated incidence rates over a typical 4-year collegiate career and reported these as athlete-years.

TAKEAWAY:

• The incidence of SCD, which accounted for 13% of the 1102 total deaths during the study period, decreased over time, with a 5-year incidence rate ratio (IRR) of 0.71 (95% CI, 0.61-0.82), while noncardiovascular deaths remained stable.
• IRR for males versus females was 3.79 (95% CI, 2.45-5.88) and for Black versus White athletes was 2.79 (95% CI, 1.98-3.94).
• Basketball and football players were at increased risk of SCD; for example, the incidence rate among Division I Black male basketball athletes was 1:1924 per 4-year athlete-years.
• The most common postmortem finding was autopsy-negative sudden unexplained death, at 19%, followed by idiopathic left ventricular hypertrophy/possible cardiomyopathy (17%) and hypertrophic cardiomyopathy (13%), with no cases of death attributable to COVID-19 myocarditis.

IN PRACTICE:

Although the reason for the decrease in SCD is unknown, “our data suggest that strategies to reduce SCD among competing athletes may be having a positive effect,” wrote the authors. More intensive screening strategies among groups with high SCD incidence may be warranted, they added.

SOURCE:

The study was conducted by Bradley J. Petek, MD, Sports Cardiology Program, Knight Cardiovascular Institute, Oregon Health & Science University, Portland. It was published online November 13 in Circulation and presented at the American Heart Association scientific sessions (abstract 479).

LIMITATIONS:

Some cases of SCD may have been missed as there is no mandatory reporting system in the United States. Approaches to cardiac autopsy and reporting varied significantly. The cause of death was unknown in 16 cases, and postmortem genetic testing was available for only 3% of athletes. As the study didn’t have data on resuscitated sudden cardiac arrest or preparticipation cardiovascular screening practices and findings, definitive conclusions couldn’t be drawn regarding causal factors underlying the decreased incidence of SCD.

DISCLOSURES:

There was no outside funding source. Dr. Petek has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

A version of this article appeared on Medscape.com.

TOPLINE:

A new study shows sudden cardiac deaths among collegiate athletes decreased over a recent 20-year period, but risks are still elevated among males, Black players, and basketball players, suggesting more intensive screening among these groups is needed.

METHODOLOGY:

• The study examined incidence and surrounding circumstances of sudden cardiac death (SCD) among student athletes who competed in at least one varsity sport at National Collegiate Athletic Association (NCAA) Division I, II, or III institutions in the 20 years from July 1, 2002, to June 30, 2022.
• Researchers determined causes of death and gathered demographic characteristics using multiple methods, including review of autopsy and other official documents, Internet searches, and contacts to next of kin, coaches, athletic trainers, coroners, medical examiners, scholarship foundations, and physicians involved in the case.
• SCD was defined as sudden unexpected death attributable to a cardiac cause, or a sudden death in a structurally normal heart with no other explanation for death and a history consistent with cardiac-related death that occurred within an hour of symptom onset, or an unwitnessed death occurring within 24 hours of the person being alive.
• Researchers calculated incidence rates over a typical 4-year collegiate career and reported these as athlete-years.

TAKEAWAY:

• The incidence of SCD, which accounted for 13% of the 1102 total deaths during the study period, decreased over time, with a 5-year incidence rate ratio (IRR) of 0.71 (95% CI, 0.61-0.82), while noncardiovascular deaths remained stable.
• IRR for males versus females was 3.79 (95% CI, 2.45-5.88) and for Black versus White athletes was 2.79 (95% CI, 1.98-3.94).
• Basketball and football players were at increased risk of SCD; for example, the incidence rate among Division I Black male basketball athletes was 1:1924 per 4-year athlete-years.
• The most common postmortem finding was autopsy-negative sudden unexplained death, at 19%, followed by idiopathic left ventricular hypertrophy/possible cardiomyopathy (17%) and hypertrophic cardiomyopathy (13%), with no cases of death attributable to COVID-19 myocarditis.

IN PRACTICE:

Although the reason for the decrease in SCD is unknown, “our data suggest that strategies to reduce SCD among competing athletes may be having a positive effect,” wrote the authors. More intensive screening strategies among groups with high SCD incidence may be warranted, they added.

SOURCE:

The study was conducted by Bradley J. Petek, MD, Sports Cardiology Program, Knight Cardiovascular Institute, Oregon Health & Science University, Portland. It was published online November 13 in Circulation and presented at the American Heart Association scientific sessions (abstract 479).

LIMITATIONS:

Some cases of SCD may have been missed as there is no mandatory reporting system in the United States. Approaches to cardiac autopsy and reporting varied significantly. The cause of death was unknown in 16 cases, and postmortem genetic testing was available for only 3% of athletes. As the study didn’t have data on resuscitated sudden cardiac arrest or preparticipation cardiovascular screening practices and findings, definitive conclusions couldn’t be drawn regarding causal factors underlying the decreased incidence of SCD.

DISCLOSURES:

There was no outside funding source. Dr. Petek has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

A version of this article appeared on Medscape.com.

TOPLINE:

A new study shows sudden cardiac deaths among collegiate athletes decreased over a recent 20-year period, but risks are still elevated among males, Black players, and basketball players, suggesting more intensive screening among these groups is needed.

METHODOLOGY:

• The study examined incidence and surrounding circumstances of sudden cardiac death (SCD) among student athletes who competed in at least one varsity sport at National Collegiate Athletic Association (NCAA) Division I, II, or III institutions in the 20 years from July 1, 2002, to June 30, 2022.
• Researchers determined causes of death and gathered demographic characteristics using multiple methods, including review of autopsy and other official documents, Internet searches, and contacts to next of kin, coaches, athletic trainers, coroners, medical examiners, scholarship foundations, and physicians involved in the case.
• SCD was defined as sudden unexpected death attributable to a cardiac cause, or a sudden death in a structurally normal heart with no other explanation for death and a history consistent with cardiac-related death that occurred within an hour of symptom onset, or an unwitnessed death occurring within 24 hours of the person being alive.
• Researchers calculated incidence rates over a typical 4-year collegiate career and reported these as athlete-years.

TAKEAWAY:

• The incidence of SCD, which accounted for 13% of the 1102 total deaths during the study period, decreased over time, with a 5-year incidence rate ratio (IRR) of 0.71 (95% CI, 0.61-0.82), while noncardiovascular deaths remained stable.
• IRR for males versus females was 3.79 (95% CI, 2.45-5.88) and for Black versus White athletes was 2.79 (95% CI, 1.98-3.94).
• Basketball and football players were at increased risk of SCD; for example, the incidence rate among Division I Black male basketball athletes was 1:1924 per 4-year athlete-years.
• The most common postmortem finding was autopsy-negative sudden unexplained death, at 19%, followed by idiopathic left ventricular hypertrophy/possible cardiomyopathy (17%) and hypertrophic cardiomyopathy (13%), with no cases of death attributable to COVID-19 myocarditis.

IN PRACTICE:

Although the reason for the decrease in SCD is unknown, “our data suggest that strategies to reduce SCD among competing athletes may be having a positive effect,” wrote the authors. More intensive screening strategies among groups with high SCD incidence may be warranted, they added.

SOURCE:

The study was conducted by Bradley J. Petek, MD, Sports Cardiology Program, Knight Cardiovascular Institute, Oregon Health & Science University, Portland. It was published online November 13 in Circulation and presented at the American Heart Association scientific sessions (abstract 479).

LIMITATIONS:

Some cases of SCD may have been missed as there is no mandatory reporting system in the United States. Approaches to cardiac autopsy and reporting varied significantly. The cause of death was unknown in 16 cases, and postmortem genetic testing was available for only 3% of athletes. As the study didn’t have data on resuscitated sudden cardiac arrest or preparticipation cardiovascular screening practices and findings, definitive conclusions couldn’t be drawn regarding causal factors underlying the decreased incidence of SCD.

DISCLOSURES:

There was no outside funding source. Dr. Petek has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

A version of this article appeared on Medscape.com.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

In 2023, CHEST awarded $300,000 in clinical research and community impact grants to 15 individuals. Grant recipients are recognized for their scientifically meritorious achievements, with rigorous metrics to track their project’s progress, and have innovative, novel approaches to addressing their research topic.

CHEST grants have made a difference in patients’ lives by leading to breakthroughs in the treatment and/or management of chest diseases and patient care. This year’s grant-funded projects run the gamut of topics within chest medicine, ranging from lung cancer and COPD to tuberculosis and idiopathic pulmonary fibrosis.

Here’s a glimpse into two of this year’s grant winners and their projects.

For a full list of the 2023 grant winners, visit chestnet.org/grant-recipients.
 

Air pollution in sarcoidosis

This year, the John R. Addrizzo, MD, FCCP Research Grant in Sarcoidosis was awarded to Ali Mustafa, MD, of the Johns Hopkins Hospital in Baltimore, MD, for his project “Air Pollution in Sarcoidosis.”

Courtesy CHEST

The project’s aim is to investigate the feasibility of studying indoor and outdoor air pollution in patients with pulmonary sarcoidosis.

According to Dr. Mustafa’s application, pulmonary sarcoidosis is one of the most common interstitial lung diseases in the United States, and mortality due to sarcoidosis has risen by more than 3% in recent decades.

While the etiology of sarcoidosis remains elusive, evidence points toward a combination of genetic predisposition with external environmental triggers affecting disease onset. One small study of 16 individuals with fibrotic pulmonary sarcoidosis assessed the association between local levels of outdoor air pollutants to clinical outcomes. This study found that increased short-term exposure was associated with increased respiratory symptom severity and worse health-related quality of life.

Additionally, significant health disparities exist in sarcoidosis. Black individuals with sarcoidosis have worse pulmonary function, higher rates of multiorgan disease, and as much as a 12-fold increase in mortality compared with non-Hispanic White individuals with sarcoidosis. Socioeconomic status and Black race have also been associated with increased exposure to air pollution and closer proximity to high toxic emission facilities, suggesting higher exposure to outdoor air pollution.

Racial disparities are present and particularly important in sarcoidosis. Black individuals are more likely to have more advanced disease at diagnosis, have a six-fold increase in hospitalization, and a 12-fold increase in mortality compared with non-Hispanic White individuals with sarcoidosis. Little is known about the drivers of these disparities; however, environmental exposure has been implicated in sarcoidosis pathogenesis and incidence and may be an important contributor.

Dr. Mustafa’s preliminary work suggests disparities in exposure to air pollution among individuals with sarcoidosis may be contributing to inequities in clinical outcomes.
 

Determinants of medication non-adherence among adults with chronic obstructive pulmonary disease

The CHEST/ALA/ATS Respiratory Health Equity Research Award was given to Stephanie LaBedz, MD, of the University of Illinois Chicago. The Respiratory Health Equity Research Award is jointly supported by the American Lung Association, the American Thoracic Society, and CHEST.

Courtesy CHEST

Dr. LaBedz’s project, “Determinants of Medication Non-Adherence Among Adults With Chronic Obstructive Pulmonary Disease,” aims to use behavioral science theory to identify barriers and facilitators to COPD medication adherence.

Studies suggest racial minorities and individuals of low socioeconomic status (SES) are less likely to be adherent to COPD medications compared with White and high SES patients with COPD. Interventions designed to improve COPD medication adherence must address barriers to adherence experienced by these groups to avoid perpetuating disparities in adherence and downstream outcomes disparities.

For her project, Dr. LaBedz will focus on examining barriers and facilitators of COPD medication adherence, including social determinants of health and other structural barriers faced by these vulnerable populations. She will use the information gained from the qualitative study to design interventions that address the barriers to adherence faced by these groups.

Her long-term goal is to improve COPD medication adherence in vulnerable patients with COPD in order to improve the health status and reduce health disparities experienced by racial/ethnic minority and low SES patients with COPD.

In 2023, CHEST awarded $300,000 in clinical research and community impact grants to 15 individuals. Grant recipients are recognized for their scientifically meritorious achievements, with rigorous metrics to track their project’s progress, and have innovative, novel approaches to addressing their research topic.

CHEST grants have made a difference in patients’ lives by leading to breakthroughs in the treatment and/or management of chest diseases and patient care. This year’s grant-funded projects run the gamut of topics within chest medicine, ranging from lung cancer and COPD to tuberculosis and idiopathic pulmonary fibrosis.

Here’s a glimpse into two of this year’s grant winners and their projects.

For a full list of the 2023 grant winners, visit chestnet.org/grant-recipients.
 

Air pollution in sarcoidosis

This year, the John R. Addrizzo, MD, FCCP Research Grant in Sarcoidosis was awarded to Ali Mustafa, MD, of the Johns Hopkins Hospital in Baltimore, MD, for his project “Air Pollution in Sarcoidosis.”

Courtesy CHEST

The project’s aim is to investigate the feasibility of studying indoor and outdoor air pollution in patients with pulmonary sarcoidosis.

According to Dr. Mustafa’s application, pulmonary sarcoidosis is one of the most common interstitial lung diseases in the United States, and mortality due to sarcoidosis has risen by more than 3% in recent decades.

While the etiology of sarcoidosis remains elusive, evidence points toward a combination of genetic predisposition with external environmental triggers affecting disease onset. One small study of 16 individuals with fibrotic pulmonary sarcoidosis assessed the association between local levels of outdoor air pollutants to clinical outcomes. This study found that increased short-term exposure was associated with increased respiratory symptom severity and worse health-related quality of life.

Additionally, significant health disparities exist in sarcoidosis. Black individuals with sarcoidosis have worse pulmonary function, higher rates of multiorgan disease, and as much as a 12-fold increase in mortality compared with non-Hispanic White individuals with sarcoidosis. Socioeconomic status and Black race have also been associated with increased exposure to air pollution and closer proximity to high toxic emission facilities, suggesting higher exposure to outdoor air pollution.

Racial disparities are present and particularly important in sarcoidosis. Black individuals are more likely to have more advanced disease at diagnosis, have a six-fold increase in hospitalization, and a 12-fold increase in mortality compared with non-Hispanic White individuals with sarcoidosis. Little is known about the drivers of these disparities; however, environmental exposure has been implicated in sarcoidosis pathogenesis and incidence and may be an important contributor.

Dr. Mustafa’s preliminary work suggests disparities in exposure to air pollution among individuals with sarcoidosis may be contributing to inequities in clinical outcomes.
 

Determinants of medication non-adherence among adults with chronic obstructive pulmonary disease

The CHEST/ALA/ATS Respiratory Health Equity Research Award was given to Stephanie LaBedz, MD, of the University of Illinois Chicago. The Respiratory Health Equity Research Award is jointly supported by the American Lung Association, the American Thoracic Society, and CHEST.

Courtesy CHEST

Dr. LaBedz’s project, “Determinants of Medication Non-Adherence Among Adults With Chronic Obstructive Pulmonary Disease,” aims to use behavioral science theory to identify barriers and facilitators to COPD medication adherence.

Studies suggest racial minorities and individuals of low socioeconomic status (SES) are less likely to be adherent to COPD medications compared with White and high SES patients with COPD. Interventions designed to improve COPD medication adherence must address barriers to adherence experienced by these groups to avoid perpetuating disparities in adherence and downstream outcomes disparities.

For her project, Dr. LaBedz will focus on examining barriers and facilitators of COPD medication adherence, including social determinants of health and other structural barriers faced by these vulnerable populations. She will use the information gained from the qualitative study to design interventions that address the barriers to adherence faced by these groups.

Her long-term goal is to improve COPD medication adherence in vulnerable patients with COPD in order to improve the health status and reduce health disparities experienced by racial/ethnic minority and low SES patients with COPD.

In 2023, CHEST awarded $300,000 in clinical research and community impact grants to 15 individuals. Grant recipients are recognized for their scientifically meritorious achievements, with rigorous metrics to track their project’s progress, and have innovative, novel approaches to addressing their research topic.

CHEST grants have made a difference in patients’ lives by leading to breakthroughs in the treatment and/or management of chest diseases and patient care. This year’s grant-funded projects run the gamut of topics within chest medicine, ranging from lung cancer and COPD to tuberculosis and idiopathic pulmonary fibrosis.

Here’s a glimpse into two of this year’s grant winners and their projects.

For a full list of the 2023 grant winners, visit chestnet.org/grant-recipients.
 

Air pollution in sarcoidosis

This year, the John R. Addrizzo, MD, FCCP Research Grant in Sarcoidosis was awarded to Ali Mustafa, MD, of the Johns Hopkins Hospital in Baltimore, MD, for his project “Air Pollution in Sarcoidosis.”

Courtesy CHEST

The project’s aim is to investigate the feasibility of studying indoor and outdoor air pollution in patients with pulmonary sarcoidosis.

According to Dr. Mustafa’s application, pulmonary sarcoidosis is one of the most common interstitial lung diseases in the United States, and mortality due to sarcoidosis has risen by more than 3% in recent decades.

While the etiology of sarcoidosis remains elusive, evidence points toward a combination of genetic predisposition with external environmental triggers affecting disease onset. One small study of 16 individuals with fibrotic pulmonary sarcoidosis assessed the association between local levels of outdoor air pollutants to clinical outcomes. This study found that increased short-term exposure was associated with increased respiratory symptom severity and worse health-related quality of life.

Additionally, significant health disparities exist in sarcoidosis. Black individuals with sarcoidosis have worse pulmonary function, higher rates of multiorgan disease, and as much as a 12-fold increase in mortality compared with non-Hispanic White individuals with sarcoidosis. Socioeconomic status and Black race have also been associated with increased exposure to air pollution and closer proximity to high toxic emission facilities, suggesting higher exposure to outdoor air pollution.

Racial disparities are present and particularly important in sarcoidosis. Black individuals are more likely to have more advanced disease at diagnosis, have a six-fold increase in hospitalization, and a 12-fold increase in mortality compared with non-Hispanic White individuals with sarcoidosis. Little is known about the drivers of these disparities; however, environmental exposure has been implicated in sarcoidosis pathogenesis and incidence and may be an important contributor.

Dr. Mustafa’s preliminary work suggests disparities in exposure to air pollution among individuals with sarcoidosis may be contributing to inequities in clinical outcomes.
 

Determinants of medication non-adherence among adults with chronic obstructive pulmonary disease

The CHEST/ALA/ATS Respiratory Health Equity Research Award was given to Stephanie LaBedz, MD, of the University of Illinois Chicago. The Respiratory Health Equity Research Award is jointly supported by the American Lung Association, the American Thoracic Society, and CHEST.

Courtesy CHEST

Dr. LaBedz’s project, “Determinants of Medication Non-Adherence Among Adults With Chronic Obstructive Pulmonary Disease,” aims to use behavioral science theory to identify barriers and facilitators to COPD medication adherence.

Studies suggest racial minorities and individuals of low socioeconomic status (SES) are less likely to be adherent to COPD medications compared with White and high SES patients with COPD. Interventions designed to improve COPD medication adherence must address barriers to adherence experienced by these groups to avoid perpetuating disparities in adherence and downstream outcomes disparities.

For her project, Dr. LaBedz will focus on examining barriers and facilitators of COPD medication adherence, including social determinants of health and other structural barriers faced by these vulnerable populations. She will use the information gained from the qualitative study to design interventions that address the barriers to adherence faced by these groups.

Her long-term goal is to improve COPD medication adherence in vulnerable patients with COPD in order to improve the health status and reduce health disparities experienced by racial/ethnic minority and low SES patients with COPD.

The practice of initiating early and adequate nutrition in critically ill patients is a cornerstone of ICU management. Adequate nutrition combats the dangerous catabolic state that accompanies critical illness. A few of the benefits of this practice are a decrease in disease severity with resultant lessened hospital and ICU lengths of stay, reduced infection rates, and a decrease in hospital mortality. Enteral nutrition (EN) is the route of nutritional support most associated with safe and effective provision of enhanced immunologic function and the ability to preserve the patient’s lean body mass while avoiding metabolic and infectious complications.

The practice of initiating early and adequate nutrition in critically ill patients is a cornerstone of ICU management. Adequate nutrition combats the dangerous catabolic state that accompanies critical illness. A few of the benefits of this practice are a decrease in disease severity with resultant lessened hospital and ICU lengths of stay, reduced infection rates, and a decrease in hospital mortality. Enteral nutrition (EN) is the route of nutritional support most associated with safe and effective provision of enhanced immunologic function and the ability to preserve the patient’s lean body mass while avoiding metabolic and infectious complications.

The practice of initiating early and adequate nutrition in critically ill patients is a cornerstone of ICU management. Adequate nutrition combats the dangerous catabolic state that accompanies critical illness. A few of the benefits of this practice are a decrease in disease severity with resultant lessened hospital and ICU lengths of stay, reduced infection rates, and a decrease in hospital mortality. Enteral nutrition (EN) is the route of nutritional support most associated with safe and effective provision of enhanced immunologic function and the ability to preserve the patient’s lean body mass while avoiding metabolic and infectious complications.

Pulmonary physicians and particularly interventional bronchoscopists have been receiving denials when CPT^® codes 31628 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transbronchial lung biopsy(s), single lobe and 31629 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transbronchial needle aspiration biopsy(s), trachea, main stem and/or lobar bronchus(i) are billed during the same procedure.

While the difference between a transbronchial forceps biopsy and transbronchial needle biopsy are obvious to bronchoscopists, there has been confusion with payers. This could have been partly on the basis of a CPT Assistant article from March 2021 describing the use of both codes that stated, “Note that performing two types of lung biopsy (forceps and needle aspiration) on the same lesion would be considered unusual and documentation of medical necessity should clearly describe why both types of biopsy were clinically necessary.” This may have been interpreted by coders and/or payers to mean that the two codes should be billed together rarely or not at all. It is also possible that computer-based coding programs (eg, Optum/Encoder Pro, etc) are responsible for these inappropriate denials. There are, however, no NCCI edits that disallow this nor was this the intent of the CPT codes when they were developed.

The previous statement from the CPT Assistant article was clarified in the following sentences, “For example, if needle aspiration were performed and immediate screening of the sample were insufficient for diagnosis, a forceps biopsy would be appropriate and reported separately. On the other hand, if a physician performed a needle aspiration out of concern that the lesion was vascular and found that it was not and proceeded with a forceps biopsy, then the needle aspiration would be integral to the forceps biopsy and not separately reported.” Importantly, with the increasing use of navigational bronchoscopy and robotic bronchoscopy, these codes will be used together more frequently, appropriately, and correctly, especially on distal lesions.

Remember, these codes are used for procedures in a single lobe. If multiple lobes are sampled then CPT codes 31632 and 31633 would be added to 31628 and 31629, respectively. If one is receiving denials for these procedures, coders and payers should be notified of these errors, and denials should be appealed.

Q&A

Question: My practice is wondering if we can use the newer codes for online digital E/M services? We know they are time-based, but we are confused about when they cannot be used. Can you please help? For example, I had an established COPD patient send a message through the electronic health record’s patient portal reporting new symptoms of headache, cough, and sputum production. They asked me to review the chest x-ray that was done two days prior when they went to urgent care. The patient is asking for an assessment and management plan. We message back and forth over the next day for a total of 13 minutes. Three days later, the patient developed more symptoms and then scheduled an office visit. How would I bill for this? 99212-99215 (Established Office E/M) or 99422 (Online digital E/M 11-20 minutes?

Answer: Online Digital E/M services (99421, 99422, 99423) are to be used for established patients, only. They are time-based codes and cumulative up to seven days. They are to be reported for asynchronous communication via HIPAA-compliance secure platforms, such as through the electronic health record portal, portal email, etc. They may not be reported if an E/M occurs within seven days before or after, though the time may be incorporated into the subsequent E/M. These codes are not to be used for communication of test results, scheduling of appointments, or other communication that does not include E/M. In your example, you would report the appropriate Office/ Outpatient Established CPT code (99212-99215).


99421 – Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 5-10 minutes

99422 - Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 11-20 minutes

99423 - Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 21 or more minutes


Question: Is Cardiopulmonary Resuscitation in the Intensive Care Unit considered to be part of Critical Care services? (99291- 99292)? There appears to be confusion in our billing department on this issue.

Answer: 92959 Cardiopulmonary resuscitation is not bundled into 99291-99292. Consider it as a procedure. To code for this service in addition to Critical Care, the time for the CPR must be separate from the time for Critical Care (99291-99292). A separate procedure note must also be documented. There is no minimum time for this service, and a 25 modifier must be included, as well. 92950 reimburses at 4.00 wRVUs and may be reported two times per calendar day.

Originally published in the September 2023 issue of the American Thoracic Society’s ATS Coding & Billing Quarterly. Republished with permission from the American Thoracic Society.

Pulmonary physicians and particularly interventional bronchoscopists have been receiving denials when CPT^® codes 31628 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transbronchial lung biopsy(s), single lobe and 31629 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transbronchial needle aspiration biopsy(s), trachea, main stem and/or lobar bronchus(i) are billed during the same procedure.

While the difference between a transbronchial forceps biopsy and transbronchial needle biopsy are obvious to bronchoscopists, there has been confusion with payers. This could have been partly on the basis of a CPT Assistant article from March 2021 describing the use of both codes that stated, “Note that performing two types of lung biopsy (forceps and needle aspiration) on the same lesion would be considered unusual and documentation of medical necessity should clearly describe why both types of biopsy were clinically necessary.” This may have been interpreted by coders and/or payers to mean that the two codes should be billed together rarely or not at all. It is also possible that computer-based coding programs (eg, Optum/Encoder Pro, etc) are responsible for these inappropriate denials. There are, however, no NCCI edits that disallow this nor was this the intent of the CPT codes when they were developed.

The previous statement from the CPT Assistant article was clarified in the following sentences, “For example, if needle aspiration were performed and immediate screening of the sample were insufficient for diagnosis, a forceps biopsy would be appropriate and reported separately. On the other hand, if a physician performed a needle aspiration out of concern that the lesion was vascular and found that it was not and proceeded with a forceps biopsy, then the needle aspiration would be integral to the forceps biopsy and not separately reported.” Importantly, with the increasing use of navigational bronchoscopy and robotic bronchoscopy, these codes will be used together more frequently, appropriately, and correctly, especially on distal lesions.

Remember, these codes are used for procedures in a single lobe. If multiple lobes are sampled then CPT codes 31632 and 31633 would be added to 31628 and 31629, respectively. If one is receiving denials for these procedures, coders and payers should be notified of these errors, and denials should be appealed.

Q&A

Question: My practice is wondering if we can use the newer codes for online digital E/M services? We know they are time-based, but we are confused about when they cannot be used. Can you please help? For example, I had an established COPD patient send a message through the electronic health record’s patient portal reporting new symptoms of headache, cough, and sputum production. They asked me to review the chest x-ray that was done two days prior when they went to urgent care. The patient is asking for an assessment and management plan. We message back and forth over the next day for a total of 13 minutes. Three days later, the patient developed more symptoms and then scheduled an office visit. How would I bill for this? 99212-99215 (Established Office E/M) or 99422 (Online digital E/M 11-20 minutes?

Answer: Online Digital E/M services (99421, 99422, 99423) are to be used for established patients, only. They are time-based codes and cumulative up to seven days. They are to be reported for asynchronous communication via HIPAA-compliance secure platforms, such as through the electronic health record portal, portal email, etc. They may not be reported if an E/M occurs within seven days before or after, though the time may be incorporated into the subsequent E/M. These codes are not to be used for communication of test results, scheduling of appointments, or other communication that does not include E/M. In your example, you would report the appropriate Office/ Outpatient Established CPT code (99212-99215).


99421 – Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 5-10 minutes

99422 - Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 11-20 minutes

99423 - Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 21 or more minutes


Question: Is Cardiopulmonary Resuscitation in the Intensive Care Unit considered to be part of Critical Care services? (99291- 99292)? There appears to be confusion in our billing department on this issue.

Answer: 92959 Cardiopulmonary resuscitation is not bundled into 99291-99292. Consider it as a procedure. To code for this service in addition to Critical Care, the time for the CPR must be separate from the time for Critical Care (99291-99292). A separate procedure note must also be documented. There is no minimum time for this service, and a 25 modifier must be included, as well. 92950 reimburses at 4.00 wRVUs and may be reported two times per calendar day.

Originally published in the September 2023 issue of the American Thoracic Society’s ATS Coding & Billing Quarterly. Republished with permission from the American Thoracic Society.

Pulmonary physicians and particularly interventional bronchoscopists have been receiving denials when CPT^® codes 31628 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transbronchial lung biopsy(s), single lobe and 31629 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transbronchial needle aspiration biopsy(s), trachea, main stem and/or lobar bronchus(i) are billed during the same procedure.

While the difference between a transbronchial forceps biopsy and transbronchial needle biopsy are obvious to bronchoscopists, there has been confusion with payers. This could have been partly on the basis of a CPT Assistant article from March 2021 describing the use of both codes that stated, “Note that performing two types of lung biopsy (forceps and needle aspiration) on the same lesion would be considered unusual and documentation of medical necessity should clearly describe why both types of biopsy were clinically necessary.” This may have been interpreted by coders and/or payers to mean that the two codes should be billed together rarely or not at all. It is also possible that computer-based coding programs (eg, Optum/Encoder Pro, etc) are responsible for these inappropriate denials. There are, however, no NCCI edits that disallow this nor was this the intent of the CPT codes when they were developed.

The previous statement from the CPT Assistant article was clarified in the following sentences, “For example, if needle aspiration were performed and immediate screening of the sample were insufficient for diagnosis, a forceps biopsy would be appropriate and reported separately. On the other hand, if a physician performed a needle aspiration out of concern that the lesion was vascular and found that it was not and proceeded with a forceps biopsy, then the needle aspiration would be integral to the forceps biopsy and not separately reported.” Importantly, with the increasing use of navigational bronchoscopy and robotic bronchoscopy, these codes will be used together more frequently, appropriately, and correctly, especially on distal lesions.

Remember, these codes are used for procedures in a single lobe. If multiple lobes are sampled then CPT codes 31632 and 31633 would be added to 31628 and 31629, respectively. If one is receiving denials for these procedures, coders and payers should be notified of these errors, and denials should be appealed.

Q&A

Question: My practice is wondering if we can use the newer codes for online digital E/M services? We know they are time-based, but we are confused about when they cannot be used. Can you please help? For example, I had an established COPD patient send a message through the electronic health record’s patient portal reporting new symptoms of headache, cough, and sputum production. They asked me to review the chest x-ray that was done two days prior when they went to urgent care. The patient is asking for an assessment and management plan. We message back and forth over the next day for a total of 13 minutes. Three days later, the patient developed more symptoms and then scheduled an office visit. How would I bill for this? 99212-99215 (Established Office E/M) or 99422 (Online digital E/M 11-20 minutes?

Answer: Online Digital E/M services (99421, 99422, 99423) are to be used for established patients, only. They are time-based codes and cumulative up to seven days. They are to be reported for asynchronous communication via HIPAA-compliance secure platforms, such as through the electronic health record portal, portal email, etc. They may not be reported if an E/M occurs within seven days before or after, though the time may be incorporated into the subsequent E/M. These codes are not to be used for communication of test results, scheduling of appointments, or other communication that does not include E/M. In your example, you would report the appropriate Office/ Outpatient Established CPT code (99212-99215).


99421 – Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 5-10 minutes

99422 - Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 11-20 minutes

99423 - Online digital evaluation and management service, for an established patient, for up to 7 days, cumulative time during the 7 days; 21 or more minutes


Question: Is Cardiopulmonary Resuscitation in the Intensive Care Unit considered to be part of Critical Care services? (99291- 99292)? There appears to be confusion in our billing department on this issue.

Answer: 92959 Cardiopulmonary resuscitation is not bundled into 99291-99292. Consider it as a procedure. To code for this service in addition to Critical Care, the time for the CPR must be separate from the time for Critical Care (99291-99292). A separate procedure note must also be documented. There is no minimum time for this service, and a 25 modifier must be included, as well. 92950 reimburses at 4.00 wRVUs and may be reported two times per calendar day.

Originally published in the September 2023 issue of the American Thoracic Society’s ATS Coding & Billing Quarterly. Republished with permission from the American Thoracic Society.

Looking ahead to 2024, one notable accomplishment of the past 12 months that will guide our organization for years to come was to establish CHEST organizational values. The result of a collaborative process that was led by the Value-Setting Work Group and informed by CHEST leaders, members, and staff, the CHEST values are Community, Inclusivity, Innovation, Advocacy, and Integrity.

The process to arrive at these values was intentionally designed to ensure input from all corners of the organization. Over the course of 5 months, CHEST members had the opportunity to participate in focus groups or submit written feedback about the proposed values. The feedback shaped subsequent iterations of the values that the work group produced, finally arriving at these five.

“These values are meant to be reflective of the CHEST organization and all of its leaders, members, and staff,” said Co-Chair of the Value-Setting Work Group and CHEST Board of Regents Member Nneka Sederstrom, PhD, FCCP. “As a society, we’ve come to a point where we can’t pretend that real life issues don’t matter to our patients and to our members. It’s become a pivotal point in our world for our systems to be clear on who they are. All too often, the question of, ‘Is this our lane?’ comes up. These values are a succinct way to show not only what falls into our ‘lane,’ but that we celebrate where we stand. It was a big undertaking, but seeing the collaboration and passion was exceptional.”

The work group was co-chaired by Dr. Sederstrom and Elizabeth Stigler, PhD, and was supported by David Zielinski, MD, FCCP; Bravein Amalakuhan, MD; Alisha Young, MD; Steven Simpson, MD, FCCP; Nehan Sher, MD; and CHEST staff members, Teresa Rodriguez, Manager, CHEST Annual Meeting; Terri Horton-O’Connell, MSW, Director, Grant and Proposal Development; and Vanessa Rancine, Recruiting Specialist.

Beyond solidifying the five succinct values, the work group strategically defined each value to clarify its intent.
 

• Community: We invest in the support, growth, and development of everyone involved with CHEST, both individually and collectively, and are tireless champions for one another.
• Inclusivity: We cherish the diverse perspectives and experiences of our community members and amplify their unique voices.
• Innovation: We strive for excellence in all that we do with an adaptable and ever-evolving perspective. We pursue bold, future-oriented possibilities for constant improvement and continual growth.
• Advocacy: We courageously and intentionally create and foster positive changes for our patients and their families, our members and staff, and the next generation of CHEST clinicians.
• Integrity: We take pride in acting responsibly with respect, honesty, and accountability that engenders trust.

“With the new values in place, hopefully, our members will feel a shift in how we, as an organization, show up when anything occurs,” Dr. Sederstrom said. “The values will be reflected through community engagement and support and will be deeply integrated into the CHEST Annual Meeting. When someone asks CHEST, ‘Who are you?’ -we can now answer it with certitude.”

Looking ahead to 2024, one notable accomplishment of the past 12 months that will guide our organization for years to come was to establish CHEST organizational values. The result of a collaborative process that was led by the Value-Setting Work Group and informed by CHEST leaders, members, and staff, the CHEST values are Community, Inclusivity, Innovation, Advocacy, and Integrity.

The process to arrive at these values was intentionally designed to ensure input from all corners of the organization. Over the course of 5 months, CHEST members had the opportunity to participate in focus groups or submit written feedback about the proposed values. The feedback shaped subsequent iterations of the values that the work group produced, finally arriving at these five.

“These values are meant to be reflective of the CHEST organization and all of its leaders, members, and staff,” said Co-Chair of the Value-Setting Work Group and CHEST Board of Regents Member Nneka Sederstrom, PhD, FCCP. “As a society, we’ve come to a point where we can’t pretend that real life issues don’t matter to our patients and to our members. It’s become a pivotal point in our world for our systems to be clear on who they are. All too often, the question of, ‘Is this our lane?’ comes up. These values are a succinct way to show not only what falls into our ‘lane,’ but that we celebrate where we stand. It was a big undertaking, but seeing the collaboration and passion was exceptional.”

The work group was co-chaired by Dr. Sederstrom and Elizabeth Stigler, PhD, and was supported by David Zielinski, MD, FCCP; Bravein Amalakuhan, MD; Alisha Young, MD; Steven Simpson, MD, FCCP; Nehan Sher, MD; and CHEST staff members, Teresa Rodriguez, Manager, CHEST Annual Meeting; Terri Horton-O’Connell, MSW, Director, Grant and Proposal Development; and Vanessa Rancine, Recruiting Specialist.

Beyond solidifying the five succinct values, the work group strategically defined each value to clarify its intent.
 

• Community: We invest in the support, growth, and development of everyone involved with CHEST, both individually and collectively, and are tireless champions for one another.
• Inclusivity: We cherish the diverse perspectives and experiences of our community members and amplify their unique voices.
• Innovation: We strive for excellence in all that we do with an adaptable and ever-evolving perspective. We pursue bold, future-oriented possibilities for constant improvement and continual growth.
• Advocacy: We courageously and intentionally create and foster positive changes for our patients and their families, our members and staff, and the next generation of CHEST clinicians.
• Integrity: We take pride in acting responsibly with respect, honesty, and accountability that engenders trust.

“With the new values in place, hopefully, our members will feel a shift in how we, as an organization, show up when anything occurs,” Dr. Sederstrom said. “The values will be reflected through community engagement and support and will be deeply integrated into the CHEST Annual Meeting. When someone asks CHEST, ‘Who are you?’ -we can now answer it with certitude.”

Looking ahead to 2024, one notable accomplishment of the past 12 months that will guide our organization for years to come was to establish CHEST organizational values. The result of a collaborative process that was led by the Value-Setting Work Group and informed by CHEST leaders, members, and staff, the CHEST values are Community, Inclusivity, Innovation, Advocacy, and Integrity.

The process to arrive at these values was intentionally designed to ensure input from all corners of the organization. Over the course of 5 months, CHEST members had the opportunity to participate in focus groups or submit written feedback about the proposed values. The feedback shaped subsequent iterations of the values that the work group produced, finally arriving at these five.

“These values are meant to be reflective of the CHEST organization and all of its leaders, members, and staff,” said Co-Chair of the Value-Setting Work Group and CHEST Board of Regents Member Nneka Sederstrom, PhD, FCCP. “As a society, we’ve come to a point where we can’t pretend that real life issues don’t matter to our patients and to our members. It’s become a pivotal point in our world for our systems to be clear on who they are. All too often, the question of, ‘Is this our lane?’ comes up. These values are a succinct way to show not only what falls into our ‘lane,’ but that we celebrate where we stand. It was a big undertaking, but seeing the collaboration and passion was exceptional.”

The work group was co-chaired by Dr. Sederstrom and Elizabeth Stigler, PhD, and was supported by David Zielinski, MD, FCCP; Bravein Amalakuhan, MD; Alisha Young, MD; Steven Simpson, MD, FCCP; Nehan Sher, MD; and CHEST staff members, Teresa Rodriguez, Manager, CHEST Annual Meeting; Terri Horton-O’Connell, MSW, Director, Grant and Proposal Development; and Vanessa Rancine, Recruiting Specialist.

Beyond solidifying the five succinct values, the work group strategically defined each value to clarify its intent.
 

• Community: We invest in the support, growth, and development of everyone involved with CHEST, both individually and collectively, and are tireless champions for one another.
• Inclusivity: We cherish the diverse perspectives and experiences of our community members and amplify their unique voices.
• Innovation: We strive for excellence in all that we do with an adaptable and ever-evolving perspective. We pursue bold, future-oriented possibilities for constant improvement and continual growth.
• Advocacy: We courageously and intentionally create and foster positive changes for our patients and their families, our members and staff, and the next generation of CHEST clinicians.
• Integrity: We take pride in acting responsibly with respect, honesty, and accountability that engenders trust.

“With the new values in place, hopefully, our members will feel a shift in how we, as an organization, show up when anything occurs,” Dr. Sederstrom said. “The values will be reflected through community engagement and support and will be deeply integrated into the CHEST Annual Meeting. When someone asks CHEST, ‘Who are you?’ -we can now answer it with certitude.”

TOPLINE:

Paramagnetic seeds work just as well as standard guidewires for breast tumor localization and are easier for surgeons, radiologists, and operating room planners to use.

METHODOLOGY:

• Paramagnetic seeds have shown promise over standard guidewire localization, but the two methods of tagging breast lesions for surgical removal have never been compared head-to-head in a randomized trial.
• Paramagnetic seeds are magnetic markers smaller than a grain of rice that are injected into the lesion under ultrasound or x-ray guidance. While traditional guidewires are placed on the day of surgery, seeds can be placed up to 4 weeks ahead of time.
• In the current study, investigators at three hospitals in Sweden randomized 426 women undergoing breast-conserving surgery for early breast cancer to either paramagnetic seed (Magseed, Endomag, Cambridge, UK) or guidewire localization.
• Sentinel lymph nodes were also marked magnetically for removal by superparamagnetic iron oxide (Magtrace, Endomag, Cambridge, UK ) injected into the breast before surgery. This approach — an alternative to traditional radioisotopes and blue dye — can be done days before surgery.

TAKEAWAY:

• The investigators found no significant difference in re-excision rates (2.84% vs 2.87%), sentinel lymph node detection (98.1% vs 99.0%), or resection ratios — a metric of surgical precision — between the guidewire and seed approaches.
• The rate of failed localizations was significantly higher in the guidewire group (10.1% vs 1.9%; P < .001).
• Median operative time was significantly shorter in the seed localization group (69 min vs 75.5 min; P = .03).
• Surgery coordinators reported greater ease of planning with the seeds, radiologists reported easier preoperative localization, and surgeons reported easier detection of marked tumors during surgery.

IN PRACTICE:

Overall, the randomized trial found that “a paramagnetic marker was equivalent to the guidewire in re-excisions and excised specimen volumes, with advantages of shorter operative time, safer localization, and preferable logistics,” the authors concluded.

Another advantage of paramagnetic seeds: Surgical staff and patients were not confined to the same-day “restrictions posed by guidewire localization or radioisotope-based methods, making it an attractive alternative for numerous and diverse clinical settings,” the authors added.

SOURCE:

The work, led by Eirini Pantiora, MD, of Uppsala University, Sweden, was published in JAMA Surgery .

LIMITATIONS:

The investigators don’t yet know whether the benefits of implementing seed localization outweigh the costs.

DISCLOSURES:

The work was funded by Uppsala University, the Swedish Breast Cancer Association, and others. The senior investigator reported receiving grants from Endomag, the maker of the technology tested in the trial.

A version of this article appeared on Medscape.com.

TOPLINE:

Paramagnetic seeds work just as well as standard guidewires for breast tumor localization and are easier for surgeons, radiologists, and operating room planners to use.

METHODOLOGY:

• Paramagnetic seeds have shown promise over standard guidewire localization, but the two methods of tagging breast lesions for surgical removal have never been compared head-to-head in a randomized trial.
• Paramagnetic seeds are magnetic markers smaller than a grain of rice that are injected into the lesion under ultrasound or x-ray guidance. While traditional guidewires are placed on the day of surgery, seeds can be placed up to 4 weeks ahead of time.
• In the current study, investigators at three hospitals in Sweden randomized 426 women undergoing breast-conserving surgery for early breast cancer to either paramagnetic seed (Magseed, Endomag, Cambridge, UK) or guidewire localization.
• Sentinel lymph nodes were also marked magnetically for removal by superparamagnetic iron oxide (Magtrace, Endomag, Cambridge, UK ) injected into the breast before surgery. This approach — an alternative to traditional radioisotopes and blue dye — can be done days before surgery.

TAKEAWAY:

• The investigators found no significant difference in re-excision rates (2.84% vs 2.87%), sentinel lymph node detection (98.1% vs 99.0%), or resection ratios — a metric of surgical precision — between the guidewire and seed approaches.
• The rate of failed localizations was significantly higher in the guidewire group (10.1% vs 1.9%; P < .001).
• Median operative time was significantly shorter in the seed localization group (69 min vs 75.5 min; P = .03).
• Surgery coordinators reported greater ease of planning with the seeds, radiologists reported easier preoperative localization, and surgeons reported easier detection of marked tumors during surgery.

IN PRACTICE:

Overall, the randomized trial found that “a paramagnetic marker was equivalent to the guidewire in re-excisions and excised specimen volumes, with advantages of shorter operative time, safer localization, and preferable logistics,” the authors concluded.

Another advantage of paramagnetic seeds: Surgical staff and patients were not confined to the same-day “restrictions posed by guidewire localization or radioisotope-based methods, making it an attractive alternative for numerous and diverse clinical settings,” the authors added.

SOURCE:

The work, led by Eirini Pantiora, MD, of Uppsala University, Sweden, was published in JAMA Surgery .

LIMITATIONS:

The investigators don’t yet know whether the benefits of implementing seed localization outweigh the costs.

DISCLOSURES:

The work was funded by Uppsala University, the Swedish Breast Cancer Association, and others. The senior investigator reported receiving grants from Endomag, the maker of the technology tested in the trial.

A version of this article appeared on Medscape.com.

TOPLINE:

Paramagnetic seeds work just as well as standard guidewires for breast tumor localization and are easier for surgeons, radiologists, and operating room planners to use.

METHODOLOGY:

• Paramagnetic seeds have shown promise over standard guidewire localization, but the two methods of tagging breast lesions for surgical removal have never been compared head-to-head in a randomized trial.
• Paramagnetic seeds are magnetic markers smaller than a grain of rice that are injected into the lesion under ultrasound or x-ray guidance. While traditional guidewires are placed on the day of surgery, seeds can be placed up to 4 weeks ahead of time.
• In the current study, investigators at three hospitals in Sweden randomized 426 women undergoing breast-conserving surgery for early breast cancer to either paramagnetic seed (Magseed, Endomag, Cambridge, UK) or guidewire localization.
• Sentinel lymph nodes were also marked magnetically for removal by superparamagnetic iron oxide (Magtrace, Endomag, Cambridge, UK ) injected into the breast before surgery. This approach — an alternative to traditional radioisotopes and blue dye — can be done days before surgery.

TAKEAWAY:

• The investigators found no significant difference in re-excision rates (2.84% vs 2.87%), sentinel lymph node detection (98.1% vs 99.0%), or resection ratios — a metric of surgical precision — between the guidewire and seed approaches.
• The rate of failed localizations was significantly higher in the guidewire group (10.1% vs 1.9%; P < .001).
• Median operative time was significantly shorter in the seed localization group (69 min vs 75.5 min; P = .03).
• Surgery coordinators reported greater ease of planning with the seeds, radiologists reported easier preoperative localization, and surgeons reported easier detection of marked tumors during surgery.

IN PRACTICE:

Overall, the randomized trial found that “a paramagnetic marker was equivalent to the guidewire in re-excisions and excised specimen volumes, with advantages of shorter operative time, safer localization, and preferable logistics,” the authors concluded.

Another advantage of paramagnetic seeds: Surgical staff and patients were not confined to the same-day “restrictions posed by guidewire localization or radioisotope-based methods, making it an attractive alternative for numerous and diverse clinical settings,” the authors added.

SOURCE:

The work, led by Eirini Pantiora, MD, of Uppsala University, Sweden, was published in JAMA Surgery .

LIMITATIONS:

The investigators don’t yet know whether the benefits of implementing seed localization outweigh the costs.

DISCLOSURES:

The work was funded by Uppsala University, the Swedish Breast Cancer Association, and others. The senior investigator reported receiving grants from Endomag, the maker of the technology tested in the trial.

A version of this article appeared on Medscape.com.