Article

Notable advances in breast cancer, presented at the American Association for Cancer Research Annual Meeting 2023, are discussed by Dr Kathy Miller, Ballvé Lantero Professor of Oncology at Indiana University Health, Indianapolis. 

She begins with two studies looking at PARP inhibitors in combination with immune checkpoint inhibitors. 

The TALAVE study suggested that talazoparib induction followed by talazoparib plus avelumab could enhance the benefits of PARP inhibition. In contrast, a study of olaparib vs olaparib plus atezolizumab suggested that the combination offered few clinical improvements at the cost of additional toxicities. 

Dr Miller next discusses the combination of olaparib and the novel agent sapacitabine in BRCA-mutated breast cancer. Although hematologic toxicities were an issue in this small trial, some patients experienced prolonged benefits. 

Finally, she presents early results with a whole tumor cell therapeutic vaccine, before examining some of the future challenges around antibody-drug conjugates. 

--

Ballvé Lantero Professor of Oncology, Indiana University Health, Indianapolis, Indiana 

Kathy D. Miller, MD, has disclosed the following relevant financial relationships: 

Serves on independent Data Monitoring Committees for ongoing trials for: Merck; Genentech/Roche; AstraZeneca; Celcuity 

Notable advances in breast cancer, presented at the American Association for Cancer Research Annual Meeting 2023, are discussed by Dr Kathy Miller, Ballvé Lantero Professor of Oncology at Indiana University Health, Indianapolis. 

She begins with two studies looking at PARP inhibitors in combination with immune checkpoint inhibitors. 

The TALAVE study suggested that talazoparib induction followed by talazoparib plus avelumab could enhance the benefits of PARP inhibition. In contrast, a study of olaparib vs olaparib plus atezolizumab suggested that the combination offered few clinical improvements at the cost of additional toxicities. 

Dr Miller next discusses the combination of olaparib and the novel agent sapacitabine in BRCA-mutated breast cancer. Although hematologic toxicities were an issue in this small trial, some patients experienced prolonged benefits. 

Finally, she presents early results with a whole tumor cell therapeutic vaccine, before examining some of the future challenges around antibody-drug conjugates. 

--

Ballvé Lantero Professor of Oncology, Indiana University Health, Indianapolis, Indiana 

Kathy D. Miller, MD, has disclosed the following relevant financial relationships: 

Serves on independent Data Monitoring Committees for ongoing trials for: Merck; Genentech/Roche; AstraZeneca; Celcuity 

Notable advances in breast cancer, presented at the American Association for Cancer Research Annual Meeting 2023, are discussed by Dr Kathy Miller, Ballvé Lantero Professor of Oncology at Indiana University Health, Indianapolis. 

She begins with two studies looking at PARP inhibitors in combination with immune checkpoint inhibitors. 

The TALAVE study suggested that talazoparib induction followed by talazoparib plus avelumab could enhance the benefits of PARP inhibition. In contrast, a study of olaparib vs olaparib plus atezolizumab suggested that the combination offered few clinical improvements at the cost of additional toxicities. 

Dr Miller next discusses the combination of olaparib and the novel agent sapacitabine in BRCA-mutated breast cancer. Although hematologic toxicities were an issue in this small trial, some patients experienced prolonged benefits. 

Finally, she presents early results with a whole tumor cell therapeutic vaccine, before examining some of the future challenges around antibody-drug conjugates. 

--

Ballvé Lantero Professor of Oncology, Indiana University Health, Indianapolis, Indiana 

Kathy D. Miller, MD, has disclosed the following relevant financial relationships: 

Serves on independent Data Monitoring Committees for ongoing trials for: Merck; Genentech/Roche; AstraZeneca; Celcuity 

Dr Kathy Miller of Indiana University Health in Indianapolis discusses key takeaways in early breast cancer from the American Association for Cancer Research (AACR) Annual Meeting 2023. 

She begins with a novel imaging agent that allows surgeons to visualize residual disease during lumpectomy and reduce the risk for positive margins. It is now being investigated in patients who undergo neoadjuvant therapy. 

Next, Dr Miller focuses on a study of skin toxicity in patients undergoing fractionated radiotherapy, which found that rates varied widely by race/ethnicity. 

She also examines the implications of these findings and other research presented at AACR addressing the effect of genetic ancestry on the biology of breast cancers. 

Finally, Dr Miller looks at a study of disease progression in ductal carcinoma in situ (DCIS), which found that 80% of cases were the result of clonal recurrences of residual cells left behind at the time of treatment. 

--

Kathy D. Miller, MD, Ballvé Lantero Professor of Oncology, Indiana University Health, Indianapolis, Indiana 

Kathy D. Miller, MD, has disclosed the following relevant financial relationships: 

Serve on independent Data Monitoring Committees for ongoing trials for: Merck; Genentech/Roche; AstraZeneca; Celcuity 

Dr Kathy Miller of Indiana University Health in Indianapolis discusses key takeaways in early breast cancer from the American Association for Cancer Research (AACR) Annual Meeting 2023. 

She begins with a novel imaging agent that allows surgeons to visualize residual disease during lumpectomy and reduce the risk for positive margins. It is now being investigated in patients who undergo neoadjuvant therapy. 

Next, Dr Miller focuses on a study of skin toxicity in patients undergoing fractionated radiotherapy, which found that rates varied widely by race/ethnicity. 

She also examines the implications of these findings and other research presented at AACR addressing the effect of genetic ancestry on the biology of breast cancers. 

Finally, Dr Miller looks at a study of disease progression in ductal carcinoma in situ (DCIS), which found that 80% of cases were the result of clonal recurrences of residual cells left behind at the time of treatment. 

--

Kathy D. Miller, MD, Ballvé Lantero Professor of Oncology, Indiana University Health, Indianapolis, Indiana 

Kathy D. Miller, MD, has disclosed the following relevant financial relationships: 

Serve on independent Data Monitoring Committees for ongoing trials for: Merck; Genentech/Roche; AstraZeneca; Celcuity 

Dr Kathy Miller of Indiana University Health in Indianapolis discusses key takeaways in early breast cancer from the American Association for Cancer Research (AACR) Annual Meeting 2023. 

She begins with a novel imaging agent that allows surgeons to visualize residual disease during lumpectomy and reduce the risk for positive margins. It is now being investigated in patients who undergo neoadjuvant therapy. 

Next, Dr Miller focuses on a study of skin toxicity in patients undergoing fractionated radiotherapy, which found that rates varied widely by race/ethnicity. 

She also examines the implications of these findings and other research presented at AACR addressing the effect of genetic ancestry on the biology of breast cancers. 

Finally, Dr Miller looks at a study of disease progression in ductal carcinoma in situ (DCIS), which found that 80% of cases were the result of clonal recurrences of residual cells left behind at the time of treatment. 

--

Kathy D. Miller, MD, Ballvé Lantero Professor of Oncology, Indiana University Health, Indianapolis, Indiana 

Kathy D. Miller, MD, has disclosed the following relevant financial relationships: 

Serve on independent Data Monitoring Committees for ongoing trials for: Merck; Genentech/Roche; AstraZeneca; Celcuity 

The theme of this month's round-up is women's health, specifically as it relates to migraine. Three recent studies have highlighted the connection between estrogen and migraine, in terms of the potential increase in risk for certain conditions, such as gestational hypertension and endometriosis, and the use of potential therapies, such as calcitonin gene-related peptide (CGRP) antagonist medications to treat menstrual migraine.

Although most practitioners know that there is a deep connection between vascular risk and migraine, most are unfamiliar with the specific interplay between these two conditions. Antihypertensive medications are common preventive treatments for migraine, and migraine itself has been associated with an increased risk for specific vascular issues in pregnancy, most notably venous sinus thrombosis. Crowe and colleagues specifically looked at whether women with migraine experience a higher risk for hypertensive disorders of pregnancy.

This was a UK-based prospective cohort study using a large longitudinal database called the Clinical Practice Research Datalink. Over 1 million live-born or stillborn deliveries were analyzed from 1993 through 2020. The data were linked to diagnosis and prescription codes for migraine that were filled or documented before 20 weeks of gestation and compared with diagnosis codes for hypertensive disorders that occurred from week 20 through the pregnancy and delivery. Regression models were then used to estimate risk ratios and CI. Only single pregnancies were counted because multiple pregnancies already are associated with a higher risk for most other vascular conditions.

Any history of migraine prior to pregnancy was associated with an increased risk for gestational hypertension, eclampsia, and preeclampsia (relative risk 1.17). The greatest risk was higher frequency. Migraine that persisted into the first trimester led to a relative risk of 1.84. The use of migraine medications, especially vasoconstrictive-type medications, was also associated with a higher risk compared with women without migraine.

Women with migraine frequently present before family planning to discuss the potential risks and options of migraine treatment during pregnancy. In addition to discussing the most appropriate preventive and acute medications, it would be appropriate also to discuss any potential red flag symptoms that may occur during pregnancy. This discussion should include hypertensive disorders of pregnancy as per this study.

Since the advent of CGRP antagonist treatments for migraine, many practitioners and patients have been curious to know whether specific features of migraine are better treated with this class of medication. There are now both acute and preventive CGRP antagonists, both as small molecule agents and monoclonal antibodies (mAb). Menstrual migraines specifically can be a more difficult-to-treat subtype, and often when other triggers are negated, hormonal fluctuation can still be a significant problem for many patients. Verhagen and colleagues set out to determine whether CGRP mAb are more or less effective for menstrually associated migraine.

This analysis was post hoc, using data from a single-arm study investigating the efficacy of two of the CGRP mAb medications: erenumab and fremanezumab. Patients were included if they had a history of migraine with > 8 monthly migraine days and at least one antihypertensive or antiepileptic preventive treatment for migraine had previously failed. Any other prophylactic medications were tapered before starting this trial; patients were given a validated electronic diary, and adherence to this diary had to be > 80%. Women were also excluded if they did not have regular menses (for instance, if they were on continuous hormonal contraception) or they were postmenopausal. Logistic regression was used to compare the preventive effect of these medications on perimenstrual and non-perimenstrual migraine attacks.

A total of 45 women were included in this observation. The relative reduction in total monthly migraine days was 31.4%; 28% were noted during and around menses, 32% were during other times of the menstrual cycle. Sensitivity analysis showed no significant difference between these two periods of time, and the ratio remained statistically similar as well.

It appears that the relative reduction in monthly migraine days did not fluctuate when the patient was treated with a CGRP antagonist mAb. Although other classes of preventive medication, specifically onabotulinumtoxinA (Botox), may affect menstrually associated migraine less potently, it appears that the CGRP antagonist class may be just as effective regardless of the underlying migraine trigger. It would definitely be worth considering a CGRP antagonist trial, or the addition of a CGRP mAb, if menstrual migraine remains significant despite otherwise effective preventive treatment.

Migraine is strongly affected by fluctuations in estrogen, and women with endometriosis often experience headaches associated with their severe attacks. Pasquini and colleagues specifically looked to see if the headache associated with endometriosis could be better diagnosed. Specifically, were these women experiencing migraine or another headache disorder?

This was a consecutive case-control series of 131 women admitted to a specialty endometriosis clinic. They were given a validated headache questionnaire that was reviewed by a neurologist to determine a diagnosis of migraine vs a diagnosis of another headache disorder. The case group included women with a history of endometriosis who were previously diagnosed with migraine, while the control group consisted of women with endometriosis only who did not have a history of headache.

Diagnosis of migraine was made in 53.4% of all patients: 18.6% of those experienced pure menstrual migraine (defined as migraine only occurring perimenstrually), 46% had some menstrually associated migraine symptoms, and 36% had purely non-menstrual migraine. Painful periods and dysuria were more frequent in patients with endometriosis and migraine compared with those without migraine. Other menstrually related conditions, including the duration of endometriosis, the phenotype of endometriosis, the presence of other systemic comorbidities, or heavy menstrual bleeding did not seem to differ significantly between the migraine and non-migraine groups.

Women of reproductive age consistently are seen most often for migraine and other headache conditions. Much of this is related to menstrual migraine and the effect that hormonal fluctuation has on migraine frequency and severity. Most practitioners work closely with their patient's gynecologist to determine which hormonal treatments and migraine treatments are most appropriate and safe for each individual situation. This study in particular sheds light on the particular phenotypes of headache pain and the specific headache diagnosis that most women with endometriosis experience.

The theme of this month's round-up is women's health, specifically as it relates to migraine. Three recent studies have highlighted the connection between estrogen and migraine, in terms of the potential increase in risk for certain conditions, such as gestational hypertension and endometriosis, and the use of potential therapies, such as calcitonin gene-related peptide (CGRP) antagonist medications to treat menstrual migraine.

Although most practitioners know that there is a deep connection between vascular risk and migraine, most are unfamiliar with the specific interplay between these two conditions. Antihypertensive medications are common preventive treatments for migraine, and migraine itself has been associated with an increased risk for specific vascular issues in pregnancy, most notably venous sinus thrombosis. Crowe and colleagues specifically looked at whether women with migraine experience a higher risk for hypertensive disorders of pregnancy.

This was a UK-based prospective cohort study using a large longitudinal database called the Clinical Practice Research Datalink. Over 1 million live-born or stillborn deliveries were analyzed from 1993 through 2020. The data were linked to diagnosis and prescription codes for migraine that were filled or documented before 20 weeks of gestation and compared with diagnosis codes for hypertensive disorders that occurred from week 20 through the pregnancy and delivery. Regression models were then used to estimate risk ratios and CI. Only single pregnancies were counted because multiple pregnancies already are associated with a higher risk for most other vascular conditions.

Any history of migraine prior to pregnancy was associated with an increased risk for gestational hypertension, eclampsia, and preeclampsia (relative risk 1.17). The greatest risk was higher frequency. Migraine that persisted into the first trimester led to a relative risk of 1.84. The use of migraine medications, especially vasoconstrictive-type medications, was also associated with a higher risk compared with women without migraine.

Women with migraine frequently present before family planning to discuss the potential risks and options of migraine treatment during pregnancy. In addition to discussing the most appropriate preventive and acute medications, it would be appropriate also to discuss any potential red flag symptoms that may occur during pregnancy. This discussion should include hypertensive disorders of pregnancy as per this study.

Since the advent of CGRP antagonist treatments for migraine, many practitioners and patients have been curious to know whether specific features of migraine are better treated with this class of medication. There are now both acute and preventive CGRP antagonists, both as small molecule agents and monoclonal antibodies (mAb). Menstrual migraines specifically can be a more difficult-to-treat subtype, and often when other triggers are negated, hormonal fluctuation can still be a significant problem for many patients. Verhagen and colleagues set out to determine whether CGRP mAb are more or less effective for menstrually associated migraine.

This analysis was post hoc, using data from a single-arm study investigating the efficacy of two of the CGRP mAb medications: erenumab and fremanezumab. Patients were included if they had a history of migraine with > 8 monthly migraine days and at least one antihypertensive or antiepileptic preventive treatment for migraine had previously failed. Any other prophylactic medications were tapered before starting this trial; patients were given a validated electronic diary, and adherence to this diary had to be > 80%. Women were also excluded if they did not have regular menses (for instance, if they were on continuous hormonal contraception) or they were postmenopausal. Logistic regression was used to compare the preventive effect of these medications on perimenstrual and non-perimenstrual migraine attacks.

A total of 45 women were included in this observation. The relative reduction in total monthly migraine days was 31.4%; 28% were noted during and around menses, 32% were during other times of the menstrual cycle. Sensitivity analysis showed no significant difference between these two periods of time, and the ratio remained statistically similar as well.

It appears that the relative reduction in monthly migraine days did not fluctuate when the patient was treated with a CGRP antagonist mAb. Although other classes of preventive medication, specifically onabotulinumtoxinA (Botox), may affect menstrually associated migraine less potently, it appears that the CGRP antagonist class may be just as effective regardless of the underlying migraine trigger. It would definitely be worth considering a CGRP antagonist trial, or the addition of a CGRP mAb, if menstrual migraine remains significant despite otherwise effective preventive treatment.

Migraine is strongly affected by fluctuations in estrogen, and women with endometriosis often experience headaches associated with their severe attacks. Pasquini and colleagues specifically looked to see if the headache associated with endometriosis could be better diagnosed. Specifically, were these women experiencing migraine or another headache disorder?

This was a consecutive case-control series of 131 women admitted to a specialty endometriosis clinic. They were given a validated headache questionnaire that was reviewed by a neurologist to determine a diagnosis of migraine vs a diagnosis of another headache disorder. The case group included women with a history of endometriosis who were previously diagnosed with migraine, while the control group consisted of women with endometriosis only who did not have a history of headache.

Diagnosis of migraine was made in 53.4% of all patients: 18.6% of those experienced pure menstrual migraine (defined as migraine only occurring perimenstrually), 46% had some menstrually associated migraine symptoms, and 36% had purely non-menstrual migraine. Painful periods and dysuria were more frequent in patients with endometriosis and migraine compared with those without migraine. Other menstrually related conditions, including the duration of endometriosis, the phenotype of endometriosis, the presence of other systemic comorbidities, or heavy menstrual bleeding did not seem to differ significantly between the migraine and non-migraine groups.

Women of reproductive age consistently are seen most often for migraine and other headache conditions. Much of this is related to menstrual migraine and the effect that hormonal fluctuation has on migraine frequency and severity. Most practitioners work closely with their patient's gynecologist to determine which hormonal treatments and migraine treatments are most appropriate and safe for each individual situation. This study in particular sheds light on the particular phenotypes of headache pain and the specific headache diagnosis that most women with endometriosis experience.

The theme of this month's round-up is women's health, specifically as it relates to migraine. Three recent studies have highlighted the connection between estrogen and migraine, in terms of the potential increase in risk for certain conditions, such as gestational hypertension and endometriosis, and the use of potential therapies, such as calcitonin gene-related peptide (CGRP) antagonist medications to treat menstrual migraine.

Although most practitioners know that there is a deep connection between vascular risk and migraine, most are unfamiliar with the specific interplay between these two conditions. Antihypertensive medications are common preventive treatments for migraine, and migraine itself has been associated with an increased risk for specific vascular issues in pregnancy, most notably venous sinus thrombosis. Crowe and colleagues specifically looked at whether women with migraine experience a higher risk for hypertensive disorders of pregnancy.

This was a UK-based prospective cohort study using a large longitudinal database called the Clinical Practice Research Datalink. Over 1 million live-born or stillborn deliveries were analyzed from 1993 through 2020. The data were linked to diagnosis and prescription codes for migraine that were filled or documented before 20 weeks of gestation and compared with diagnosis codes for hypertensive disorders that occurred from week 20 through the pregnancy and delivery. Regression models were then used to estimate risk ratios and CI. Only single pregnancies were counted because multiple pregnancies already are associated with a higher risk for most other vascular conditions.

Any history of migraine prior to pregnancy was associated with an increased risk for gestational hypertension, eclampsia, and preeclampsia (relative risk 1.17). The greatest risk was higher frequency. Migraine that persisted into the first trimester led to a relative risk of 1.84. The use of migraine medications, especially vasoconstrictive-type medications, was also associated with a higher risk compared with women without migraine.

Women with migraine frequently present before family planning to discuss the potential risks and options of migraine treatment during pregnancy. In addition to discussing the most appropriate preventive and acute medications, it would be appropriate also to discuss any potential red flag symptoms that may occur during pregnancy. This discussion should include hypertensive disorders of pregnancy as per this study.

Since the advent of CGRP antagonist treatments for migraine, many practitioners and patients have been curious to know whether specific features of migraine are better treated with this class of medication. There are now both acute and preventive CGRP antagonists, both as small molecule agents and monoclonal antibodies (mAb). Menstrual migraines specifically can be a more difficult-to-treat subtype, and often when other triggers are negated, hormonal fluctuation can still be a significant problem for many patients. Verhagen and colleagues set out to determine whether CGRP mAb are more or less effective for menstrually associated migraine.

This analysis was post hoc, using data from a single-arm study investigating the efficacy of two of the CGRP mAb medications: erenumab and fremanezumab. Patients were included if they had a history of migraine with > 8 monthly migraine days and at least one antihypertensive or antiepileptic preventive treatment for migraine had previously failed. Any other prophylactic medications were tapered before starting this trial; patients were given a validated electronic diary, and adherence to this diary had to be > 80%. Women were also excluded if they did not have regular menses (for instance, if they were on continuous hormonal contraception) or they were postmenopausal. Logistic regression was used to compare the preventive effect of these medications on perimenstrual and non-perimenstrual migraine attacks.

A total of 45 women were included in this observation. The relative reduction in total monthly migraine days was 31.4%; 28% were noted during and around menses, 32% were during other times of the menstrual cycle. Sensitivity analysis showed no significant difference between these two periods of time, and the ratio remained statistically similar as well.

It appears that the relative reduction in monthly migraine days did not fluctuate when the patient was treated with a CGRP antagonist mAb. Although other classes of preventive medication, specifically onabotulinumtoxinA (Botox), may affect menstrually associated migraine less potently, it appears that the CGRP antagonist class may be just as effective regardless of the underlying migraine trigger. It would definitely be worth considering a CGRP antagonist trial, or the addition of a CGRP mAb, if menstrual migraine remains significant despite otherwise effective preventive treatment.

Migraine is strongly affected by fluctuations in estrogen, and women with endometriosis often experience headaches associated with their severe attacks. Pasquini and colleagues specifically looked to see if the headache associated with endometriosis could be better diagnosed. Specifically, were these women experiencing migraine or another headache disorder?

This was a consecutive case-control series of 131 women admitted to a specialty endometriosis clinic. They were given a validated headache questionnaire that was reviewed by a neurologist to determine a diagnosis of migraine vs a diagnosis of another headache disorder. The case group included women with a history of endometriosis who were previously diagnosed with migraine, while the control group consisted of women with endometriosis only who did not have a history of headache.

Diagnosis of migraine was made in 53.4% of all patients: 18.6% of those experienced pure menstrual migraine (defined as migraine only occurring perimenstrually), 46% had some menstrually associated migraine symptoms, and 36% had purely non-menstrual migraine. Painful periods and dysuria were more frequent in patients with endometriosis and migraine compared with those without migraine. Other menstrually related conditions, including the duration of endometriosis, the phenotype of endometriosis, the presence of other systemic comorbidities, or heavy menstrual bleeding did not seem to differ significantly between the migraine and non-migraine groups.

Women of reproductive age consistently are seen most often for migraine and other headache conditions. Much of this is related to menstrual migraine and the effect that hormonal fluctuation has on migraine frequency and severity. Most practitioners work closely with their patient's gynecologist to determine which hormonal treatments and migraine treatments are most appropriate and safe for each individual situation. This study in particular sheds light on the particular phenotypes of headache pain and the specific headache diagnosis that most women with endometriosis experience.

Diffuse large B-cell lymphoma (DLBCL) is both a clinically and molecularly heterogenous disease. The International Prognostic Index (IPI), which is based on clinical and laboratory variables, is still currently used to delineate risk at the time of diagnosis. Diffuse large B-cell lymphoma can also further be classified into either germinal center B-cell (GCB) or activated B-cell (ABC) subtype, also known as the cell-of-origin classification (COO), which has been prognostic in prior studies.¹ COO is based on gene expression profiling (GEP), though it can be estimated by immunohistochemistry.

Although these classifications are available, treatment of DLBCL has largely remained uniform over the past few decades. Despite encouraging preclinical data and early trials, large randomized studies had not demonstrated an advantage of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) plus X over R-CHOP alone.^2,3 The REMoDL-B trial, which included 801 adult patients with DLBCL, including patients with ABC, GCB, or molecular high grade (MHG) classification by GEP. Patients received one cycle of R-CHOP and were randomly assigned to R-CHOP (n = 407) alone or bortezomib–R-CHOP (n = 394) for cycles 2-6. Initial reports did not demonstrate any clear benefit of the addition of bortezomib.⁴ More recently, however, 5-year follow-up data demonstrate that the addition of bortezomib confers an advantage over R-CHOP in patients with ABC and MHG DLBCL (Davies et al). Bortezomib–R-CHOP vs R-CHOP significantly improved 60-month progression-free survival (PFS) in the ABC (adjusted hazard ratio [aHR] 0.65; P = .041) and MHG (aHR 0.46; P = .011) groups and overall survival (OS) in the ABC group (aHR 0.58; P = .032). The GCB group showed no significant difference in PFS or OS.

Despite the results of REMoDL-B, it is unlikely that this study will change practice. GEP is not readily available and with the approval of polatuzumab (pola)–R-CHP, based on the results of POLARIX trial, there is new option available for patients with newly diagnosed DLBCL with a high IPI. A recent meta-analysis of 12 randomized controlled trials (Sheng et al) involving 8376 patients with previously untreated ABC- or GCB-type DLBCL who received pola–R-CHP or other regimens was also recently performed. This study showed that pola–R-CHP prolonged PFS in patients with ABC-type DLBCL compared with bortezomib–R-CHOP (hazard ratio [HR] 0.52; P = .02); ibrutinib–R-CHOP (HR 0.43; P = .001); lenalidomide–R-CHOP (HR 0.51; P = .009); Obinutuzumab–CHOP (HR 0.46; P = .008); R-CHOP (HR 0.40; P < .001); and bortezomib, rituximab, and cyclophosphamide (HR 0.44; P = .07). Pola–R-CHP had no PFS benefit in patients with GCB-type DLBCL. Although it is difficult to directly compare trials, these data suggest that pola–R-CHP is active in ABC subtype DLBCL.

Together, these trials suggest that there still may be a role for more personalized therapy in DLBCL, though there may be room for improvement. Recent studies have suggested more complex genomic underpinnings in DLBCL beyond COO, which will hopefully be studied in the context of DLBCL trials.⁵

In the second line, patients with primary refractory or early relapse of DLBCL now have the option of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, based on the results of the ZUMA-7 and TRANSFORM studies.^6,7 Lisocabtagene maraleucel (liso-cel) was also found to have a manageable safety profile in older patients with large B-cell lymphoma who were not transplant candidates in the PILOT study, leading to approval in this setting.⁸ More recently, axicabtagene ciloleucel (axi-cel) was found to be an effective second-line therapy with a manageable safety profile for patients aged ≥ 65 years as well (Westin et al). These findings are from a preplanned analysis of 109 patients aged ≥ 65 years from ZUMA-7 who were randomly assigned to receive second-line axi-cel (n = 51) or standard of care (SOC) (n = 58; two or three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation). At a median follow-up of 24.3 months, the median event-free survival was significantly longer with axi-cel vs SOC; 21.5 vs 2.5 months; HR, 0.276; descriptive P < .0001). Rates of grade 3 or higher treatment-emergent adverse events were 94% and 82% with axi-cel and SOC, respectively. Although these patients were considered transplant eligible, this study demonstrates that axi-cel can be safely administered to older patients.

Additional References

1.         Rosenwald A, Wright G, Chan WC, et al; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947. doi: 10.1056/NEJMoa012914

2.         Younes A, Sehn LH, Johnson P, et al; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37:1285-1295. doi: 10.1200/JCO.18.02403

3.         Nowakowski GS, Chiappella A, Gascoyne RD, et al; ROBUST Trial Investigators. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021;39:1317-1328. doi: 10.1200/JCO.20.01366

4.         Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:649-662. doi: 10.1016/S1470-2045(18)30935-5

5.         Crombie JL, Armand P. Diffuse large B-cell lymphoma's new genomics: the bridge and the chasm. J Clin Oncol. 2020;38:3565-3574. doi: 10.1200/JCO.20.01501

6.         Locke FL, Miklos DB, Jacobson CA, et al for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133

7.         Abramson JS, Solomon SR, Arnason JE, et al; TRANSFORM Investigators. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood. 2023:141:1675-1684. doi: 10.1182/blood.2022018730

8.         Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23:1066-1077. doi: 10.1016/S1470-2045(22)00339-4

Diffuse large B-cell lymphoma (DLBCL) is both a clinically and molecularly heterogenous disease. The International Prognostic Index (IPI), which is based on clinical and laboratory variables, is still currently used to delineate risk at the time of diagnosis. Diffuse large B-cell lymphoma can also further be classified into either germinal center B-cell (GCB) or activated B-cell (ABC) subtype, also known as the cell-of-origin classification (COO), which has been prognostic in prior studies.¹ COO is based on gene expression profiling (GEP), though it can be estimated by immunohistochemistry.

Although these classifications are available, treatment of DLBCL has largely remained uniform over the past few decades. Despite encouraging preclinical data and early trials, large randomized studies had not demonstrated an advantage of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) plus X over R-CHOP alone.^2,3 The REMoDL-B trial, which included 801 adult patients with DLBCL, including patients with ABC, GCB, or molecular high grade (MHG) classification by GEP. Patients received one cycle of R-CHOP and were randomly assigned to R-CHOP (n = 407) alone or bortezomib–R-CHOP (n = 394) for cycles 2-6. Initial reports did not demonstrate any clear benefit of the addition of bortezomib.⁴ More recently, however, 5-year follow-up data demonstrate that the addition of bortezomib confers an advantage over R-CHOP in patients with ABC and MHG DLBCL (Davies et al). Bortezomib–R-CHOP vs R-CHOP significantly improved 60-month progression-free survival (PFS) in the ABC (adjusted hazard ratio [aHR] 0.65; P = .041) and MHG (aHR 0.46; P = .011) groups and overall survival (OS) in the ABC group (aHR 0.58; P = .032). The GCB group showed no significant difference in PFS or OS.

Despite the results of REMoDL-B, it is unlikely that this study will change practice. GEP is not readily available and with the approval of polatuzumab (pola)–R-CHP, based on the results of POLARIX trial, there is new option available for patients with newly diagnosed DLBCL with a high IPI. A recent meta-analysis of 12 randomized controlled trials (Sheng et al) involving 8376 patients with previously untreated ABC- or GCB-type DLBCL who received pola–R-CHP or other regimens was also recently performed. This study showed that pola–R-CHP prolonged PFS in patients with ABC-type DLBCL compared with bortezomib–R-CHOP (hazard ratio [HR] 0.52; P = .02); ibrutinib–R-CHOP (HR 0.43; P = .001); lenalidomide–R-CHOP (HR 0.51; P = .009); Obinutuzumab–CHOP (HR 0.46; P = .008); R-CHOP (HR 0.40; P < .001); and bortezomib, rituximab, and cyclophosphamide (HR 0.44; P = .07). Pola–R-CHP had no PFS benefit in patients with GCB-type DLBCL. Although it is difficult to directly compare trials, these data suggest that pola–R-CHP is active in ABC subtype DLBCL.

Together, these trials suggest that there still may be a role for more personalized therapy in DLBCL, though there may be room for improvement. Recent studies have suggested more complex genomic underpinnings in DLBCL beyond COO, which will hopefully be studied in the context of DLBCL trials.⁵

In the second line, patients with primary refractory or early relapse of DLBCL now have the option of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, based on the results of the ZUMA-7 and TRANSFORM studies.^6,7 Lisocabtagene maraleucel (liso-cel) was also found to have a manageable safety profile in older patients with large B-cell lymphoma who were not transplant candidates in the PILOT study, leading to approval in this setting.⁸ More recently, axicabtagene ciloleucel (axi-cel) was found to be an effective second-line therapy with a manageable safety profile for patients aged ≥ 65 years as well (Westin et al). These findings are from a preplanned analysis of 109 patients aged ≥ 65 years from ZUMA-7 who were randomly assigned to receive second-line axi-cel (n = 51) or standard of care (SOC) (n = 58; two or three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation). At a median follow-up of 24.3 months, the median event-free survival was significantly longer with axi-cel vs SOC; 21.5 vs 2.5 months; HR, 0.276; descriptive P < .0001). Rates of grade 3 or higher treatment-emergent adverse events were 94% and 82% with axi-cel and SOC, respectively. Although these patients were considered transplant eligible, this study demonstrates that axi-cel can be safely administered to older patients.

Additional References

1.         Rosenwald A, Wright G, Chan WC, et al; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947. doi: 10.1056/NEJMoa012914

2.         Younes A, Sehn LH, Johnson P, et al; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37:1285-1295. doi: 10.1200/JCO.18.02403

3.         Nowakowski GS, Chiappella A, Gascoyne RD, et al; ROBUST Trial Investigators. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021;39:1317-1328. doi: 10.1200/JCO.20.01366

4.         Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:649-662. doi: 10.1016/S1470-2045(18)30935-5

5.         Crombie JL, Armand P. Diffuse large B-cell lymphoma's new genomics: the bridge and the chasm. J Clin Oncol. 2020;38:3565-3574. doi: 10.1200/JCO.20.01501

6.         Locke FL, Miklos DB, Jacobson CA, et al for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133

7.         Abramson JS, Solomon SR, Arnason JE, et al; TRANSFORM Investigators. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood. 2023:141:1675-1684. doi: 10.1182/blood.2022018730

8.         Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23:1066-1077. doi: 10.1016/S1470-2045(22)00339-4

Diffuse large B-cell lymphoma (DLBCL) is both a clinically and molecularly heterogenous disease. The International Prognostic Index (IPI), which is based on clinical and laboratory variables, is still currently used to delineate risk at the time of diagnosis. Diffuse large B-cell lymphoma can also further be classified into either germinal center B-cell (GCB) or activated B-cell (ABC) subtype, also known as the cell-of-origin classification (COO), which has been prognostic in prior studies.¹ COO is based on gene expression profiling (GEP), though it can be estimated by immunohistochemistry.

Although these classifications are available, treatment of DLBCL has largely remained uniform over the past few decades. Despite encouraging preclinical data and early trials, large randomized studies had not demonstrated an advantage of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) plus X over R-CHOP alone.^2,3 The REMoDL-B trial, which included 801 adult patients with DLBCL, including patients with ABC, GCB, or molecular high grade (MHG) classification by GEP. Patients received one cycle of R-CHOP and were randomly assigned to R-CHOP (n = 407) alone or bortezomib–R-CHOP (n = 394) for cycles 2-6. Initial reports did not demonstrate any clear benefit of the addition of bortezomib.⁴ More recently, however, 5-year follow-up data demonstrate that the addition of bortezomib confers an advantage over R-CHOP in patients with ABC and MHG DLBCL (Davies et al). Bortezomib–R-CHOP vs R-CHOP significantly improved 60-month progression-free survival (PFS) in the ABC (adjusted hazard ratio [aHR] 0.65; P = .041) and MHG (aHR 0.46; P = .011) groups and overall survival (OS) in the ABC group (aHR 0.58; P = .032). The GCB group showed no significant difference in PFS or OS.

Despite the results of REMoDL-B, it is unlikely that this study will change practice. GEP is not readily available and with the approval of polatuzumab (pola)–R-CHP, based on the results of POLARIX trial, there is new option available for patients with newly diagnosed DLBCL with a high IPI. A recent meta-analysis of 12 randomized controlled trials (Sheng et al) involving 8376 patients with previously untreated ABC- or GCB-type DLBCL who received pola–R-CHP or other regimens was also recently performed. This study showed that pola–R-CHP prolonged PFS in patients with ABC-type DLBCL compared with bortezomib–R-CHOP (hazard ratio [HR] 0.52; P = .02); ibrutinib–R-CHOP (HR 0.43; P = .001); lenalidomide–R-CHOP (HR 0.51; P = .009); Obinutuzumab–CHOP (HR 0.46; P = .008); R-CHOP (HR 0.40; P < .001); and bortezomib, rituximab, and cyclophosphamide (HR 0.44; P = .07). Pola–R-CHP had no PFS benefit in patients with GCB-type DLBCL. Although it is difficult to directly compare trials, these data suggest that pola–R-CHP is active in ABC subtype DLBCL.

Together, these trials suggest that there still may be a role for more personalized therapy in DLBCL, though there may be room for improvement. Recent studies have suggested more complex genomic underpinnings in DLBCL beyond COO, which will hopefully be studied in the context of DLBCL trials.⁵

In the second line, patients with primary refractory or early relapse of DLBCL now have the option of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, based on the results of the ZUMA-7 and TRANSFORM studies.^6,7 Lisocabtagene maraleucel (liso-cel) was also found to have a manageable safety profile in older patients with large B-cell lymphoma who were not transplant candidates in the PILOT study, leading to approval in this setting.⁸ More recently, axicabtagene ciloleucel (axi-cel) was found to be an effective second-line therapy with a manageable safety profile for patients aged ≥ 65 years as well (Westin et al). These findings are from a preplanned analysis of 109 patients aged ≥ 65 years from ZUMA-7 who were randomly assigned to receive second-line axi-cel (n = 51) or standard of care (SOC) (n = 58; two or three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation). At a median follow-up of 24.3 months, the median event-free survival was significantly longer with axi-cel vs SOC; 21.5 vs 2.5 months; HR, 0.276; descriptive P < .0001). Rates of grade 3 or higher treatment-emergent adverse events were 94% and 82% with axi-cel and SOC, respectively. Although these patients were considered transplant eligible, this study demonstrates that axi-cel can be safely administered to older patients.

Additional References

1.         Rosenwald A, Wright G, Chan WC, et al; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947. doi: 10.1056/NEJMoa012914

2.         Younes A, Sehn LH, Johnson P, et al; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37:1285-1295. doi: 10.1200/JCO.18.02403

3.         Nowakowski GS, Chiappella A, Gascoyne RD, et al; ROBUST Trial Investigators. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021;39:1317-1328. doi: 10.1200/JCO.20.01366

4.         Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:649-662. doi: 10.1016/S1470-2045(18)30935-5

5.         Crombie JL, Armand P. Diffuse large B-cell lymphoma's new genomics: the bridge and the chasm. J Clin Oncol. 2020;38:3565-3574. doi: 10.1200/JCO.20.01501

6.         Locke FL, Miklos DB, Jacobson CA, et al for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133

7.         Abramson JS, Solomon SR, Arnason JE, et al; TRANSFORM Investigators. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood. 2023:141:1675-1684. doi: 10.1182/blood.2022018730

8.         Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23:1066-1077. doi: 10.1016/S1470-2045(22)00339-4

What is the significance of the recent TRIANGLE study on mantle cell lymphoma (MCL)?

Dr. LaCasce: The TRIANGLE study is extremely important in previously untreated, transplant-eligible patients with MCL. The cutoff age for transplants varies by center and is between 60 and 75 years. In the absence of a TP53 mutation, we have typically used induction chemotherapy followed by autologous stem-cell transplant (ASCT), followed by 3 years of maintenance rituximab. Obviously, this is a lot of therapy.

The TRIANGLE study was a 3-arm study in which ibrutinib-containing therapy was compared with standard RCHOP/RDHAP followed by ASCT. Maintenance rituximab became standard of care midway through the trial and was added. In the first experimental arm, ibrutinib was combined with RCHOP and then given as maintenance for 2 years following ASCT. The second experimental arm included the same schedule of ibrutinib and omitted the ASCT.

The results are early, but what has been presented thus far, ibrutinib induction and maintenance with ASCT is clearly superior to the standard arm with ASCT. Although the data are not statistically mature, the failure-free survival of the 2 ibrutinib arms was similar, suggesting that transplant may not be necessary. Longer follow-up is necessary to confirm this conclusion and assess overall survival in all 3 arms.

If the results hold, ASCT could become a thing of the past or perhaps used in the second line. With the favorable activity of chimeric antigen receptor (CAR) T-cell therapy, however, it is unclear whether ASCT would be used in second line. Avoiding the sequential use of ASCT and CAR T-cell therapy is appealing given the stem-cell damage that can result. It is appealing to think about not using ASCT upfront, because ASCT increases the risk of myelodysplastic syndrome.

The TRIANGLE data are likely to change the frontline management of MCL. Although ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor approved in MCL and has obviously changed the field dramatically, it is significantly less well-tolerated than the next generation of drugs—acalabrutinib and zanubrutinib. I suspect these will be substituted for ibrutinib and we will see even more tolerable upfront regimens for patients with newly diagnosed MCL.

Have there been any disparities that you found in patients newly diagnosed with MCL regarding age, sex, or ethnicity?

Dr. LaCasce: MCL typically affects patients in their 60s. It is rare in young patients, and approximately 75% of the cases are male. If you look at the demographics, it is more common in White patients and less common in Hispanic and African American patients. In addition, there is an association with farming, which likely contribute to the demographics of patients with MCL.

What is your recommended approach to managing patients newly diagnosed with MCL in your day-to-day practice?

Dr. LaCasce: Management is a bit tricky right now because the TRIANGLE study is not part of any guidelines thus far. Therefore, most would argue the standard treatment continues to include ASCT upfront. There is an important, large randomized  study (NCT03267433) going on in the United States that is assessing the role of ASCT in patients who are in MRD-negative complete remission at the end of induction therapy. These patients are randomized to ASCT plus maintenance rituximab versus maintenance rituximab alone.

We are still enrolling patients to participate in this study, which is addressing a different question than TRIANGLE. I think we will learn a lot from this study. For patients who are not interested in participating in this study, we talk about the risks and benefits of ASCT.

One or 2 years ago, I would have strongly encouraged patients who were appropriate candidates to consider transplant in first remission. With the TRIANGLE data, however, and now that we have CAR T-cell therapy, I think it is more important to tailor the recommendation to the individual patient. If a patient is reluctant about ASCT and the associated risks, I do not push it.

If patients want the most aggressive approach associated with the longest remissions, at this moment, before TRIANGLE findings have been adopted into guidelines, I continue to recommend ASCT. For patients who have TP53 mutation, however, we treat with typically less aggressive therapy, as this patient population does not benefit from ASCT. We look forward to more data incorporating BTK inhibitors upfront, particularly for this group of patients, who tend to have a more adverse prognosis.

Do you feel MCL data and clinical trials are important areas of focus for your colleagues?

Dr. LaCasce: Yes. I think it is a rapidly evolving field, which is really exciting. We are seeing data now from the bispecific antibodies in the relapsed/refractory setting. We also need more data using pirtobrutinib for patients who have had BTK inhibitors and compare pirtobrutinib (a non-covalent BTK inhibitor) with the covalent BTK inhibitors.

I would strongly encourage patients to participate in clinical trials so that we can better answer these important questions. When patients go online and read about MCL, they often see a median survival of 3 to 4 years, which is completely outdated. The overall prognosis of MCL has changed dramatically since I have been in the field. Hopefully, survival will continue to improve, and therapies will become more tolerable, as well.

What is the significance of the recent TRIANGLE study on mantle cell lymphoma (MCL)?

Dr. LaCasce: The TRIANGLE study is extremely important in previously untreated, transplant-eligible patients with MCL. The cutoff age for transplants varies by center and is between 60 and 75 years. In the absence of a TP53 mutation, we have typically used induction chemotherapy followed by autologous stem-cell transplant (ASCT), followed by 3 years of maintenance rituximab. Obviously, this is a lot of therapy.

The TRIANGLE study was a 3-arm study in which ibrutinib-containing therapy was compared with standard RCHOP/RDHAP followed by ASCT. Maintenance rituximab became standard of care midway through the trial and was added. In the first experimental arm, ibrutinib was combined with RCHOP and then given as maintenance for 2 years following ASCT. The second experimental arm included the same schedule of ibrutinib and omitted the ASCT.

The results are early, but what has been presented thus far, ibrutinib induction and maintenance with ASCT is clearly superior to the standard arm with ASCT. Although the data are not statistically mature, the failure-free survival of the 2 ibrutinib arms was similar, suggesting that transplant may not be necessary. Longer follow-up is necessary to confirm this conclusion and assess overall survival in all 3 arms.

If the results hold, ASCT could become a thing of the past or perhaps used in the second line. With the favorable activity of chimeric antigen receptor (CAR) T-cell therapy, however, it is unclear whether ASCT would be used in second line. Avoiding the sequential use of ASCT and CAR T-cell therapy is appealing given the stem-cell damage that can result. It is appealing to think about not using ASCT upfront, because ASCT increases the risk of myelodysplastic syndrome.

The TRIANGLE data are likely to change the frontline management of MCL. Although ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor approved in MCL and has obviously changed the field dramatically, it is significantly less well-tolerated than the next generation of drugs—acalabrutinib and zanubrutinib. I suspect these will be substituted for ibrutinib and we will see even more tolerable upfront regimens for patients with newly diagnosed MCL.

Have there been any disparities that you found in patients newly diagnosed with MCL regarding age, sex, or ethnicity?

Dr. LaCasce: MCL typically affects patients in their 60s. It is rare in young patients, and approximately 75% of the cases are male. If you look at the demographics, it is more common in White patients and less common in Hispanic and African American patients. In addition, there is an association with farming, which likely contribute to the demographics of patients with MCL.

What is your recommended approach to managing patients newly diagnosed with MCL in your day-to-day practice?

Dr. LaCasce: Management is a bit tricky right now because the TRIANGLE study is not part of any guidelines thus far. Therefore, most would argue the standard treatment continues to include ASCT upfront. There is an important, large randomized  study (NCT03267433) going on in the United States that is assessing the role of ASCT in patients who are in MRD-negative complete remission at the end of induction therapy. These patients are randomized to ASCT plus maintenance rituximab versus maintenance rituximab alone.

We are still enrolling patients to participate in this study, which is addressing a different question than TRIANGLE. I think we will learn a lot from this study. For patients who are not interested in participating in this study, we talk about the risks and benefits of ASCT.

One or 2 years ago, I would have strongly encouraged patients who were appropriate candidates to consider transplant in first remission. With the TRIANGLE data, however, and now that we have CAR T-cell therapy, I think it is more important to tailor the recommendation to the individual patient. If a patient is reluctant about ASCT and the associated risks, I do not push it.

If patients want the most aggressive approach associated with the longest remissions, at this moment, before TRIANGLE findings have been adopted into guidelines, I continue to recommend ASCT. For patients who have TP53 mutation, however, we treat with typically less aggressive therapy, as this patient population does not benefit from ASCT. We look forward to more data incorporating BTK inhibitors upfront, particularly for this group of patients, who tend to have a more adverse prognosis.

Do you feel MCL data and clinical trials are important areas of focus for your colleagues?

Dr. LaCasce: Yes. I think it is a rapidly evolving field, which is really exciting. We are seeing data now from the bispecific antibodies in the relapsed/refractory setting. We also need more data using pirtobrutinib for patients who have had BTK inhibitors and compare pirtobrutinib (a non-covalent BTK inhibitor) with the covalent BTK inhibitors.

I would strongly encourage patients to participate in clinical trials so that we can better answer these important questions. When patients go online and read about MCL, they often see a median survival of 3 to 4 years, which is completely outdated. The overall prognosis of MCL has changed dramatically since I have been in the field. Hopefully, survival will continue to improve, and therapies will become more tolerable, as well.

What is the significance of the recent TRIANGLE study on mantle cell lymphoma (MCL)?

Dr. LaCasce: The TRIANGLE study is extremely important in previously untreated, transplant-eligible patients with MCL. The cutoff age for transplants varies by center and is between 60 and 75 years. In the absence of a TP53 mutation, we have typically used induction chemotherapy followed by autologous stem-cell transplant (ASCT), followed by 3 years of maintenance rituximab. Obviously, this is a lot of therapy.

The TRIANGLE study was a 3-arm study in which ibrutinib-containing therapy was compared with standard RCHOP/RDHAP followed by ASCT. Maintenance rituximab became standard of care midway through the trial and was added. In the first experimental arm, ibrutinib was combined with RCHOP and then given as maintenance for 2 years following ASCT. The second experimental arm included the same schedule of ibrutinib and omitted the ASCT.

The results are early, but what has been presented thus far, ibrutinib induction and maintenance with ASCT is clearly superior to the standard arm with ASCT. Although the data are not statistically mature, the failure-free survival of the 2 ibrutinib arms was similar, suggesting that transplant may not be necessary. Longer follow-up is necessary to confirm this conclusion and assess overall survival in all 3 arms.

If the results hold, ASCT could become a thing of the past or perhaps used in the second line. With the favorable activity of chimeric antigen receptor (CAR) T-cell therapy, however, it is unclear whether ASCT would be used in second line. Avoiding the sequential use of ASCT and CAR T-cell therapy is appealing given the stem-cell damage that can result. It is appealing to think about not using ASCT upfront, because ASCT increases the risk of myelodysplastic syndrome.

The TRIANGLE data are likely to change the frontline management of MCL. Although ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor approved in MCL and has obviously changed the field dramatically, it is significantly less well-tolerated than the next generation of drugs—acalabrutinib and zanubrutinib. I suspect these will be substituted for ibrutinib and we will see even more tolerable upfront regimens for patients with newly diagnosed MCL.

Have there been any disparities that you found in patients newly diagnosed with MCL regarding age, sex, or ethnicity?

Dr. LaCasce: MCL typically affects patients in their 60s. It is rare in young patients, and approximately 75% of the cases are male. If you look at the demographics, it is more common in White patients and less common in Hispanic and African American patients. In addition, there is an association with farming, which likely contribute to the demographics of patients with MCL.

What is your recommended approach to managing patients newly diagnosed with MCL in your day-to-day practice?

Dr. LaCasce: Management is a bit tricky right now because the TRIANGLE study is not part of any guidelines thus far. Therefore, most would argue the standard treatment continues to include ASCT upfront. There is an important, large randomized  study (NCT03267433) going on in the United States that is assessing the role of ASCT in patients who are in MRD-negative complete remission at the end of induction therapy. These patients are randomized to ASCT plus maintenance rituximab versus maintenance rituximab alone.

We are still enrolling patients to participate in this study, which is addressing a different question than TRIANGLE. I think we will learn a lot from this study. For patients who are not interested in participating in this study, we talk about the risks and benefits of ASCT.

One or 2 years ago, I would have strongly encouraged patients who were appropriate candidates to consider transplant in first remission. With the TRIANGLE data, however, and now that we have CAR T-cell therapy, I think it is more important to tailor the recommendation to the individual patient. If a patient is reluctant about ASCT and the associated risks, I do not push it.

If patients want the most aggressive approach associated with the longest remissions, at this moment, before TRIANGLE findings have been adopted into guidelines, I continue to recommend ASCT. For patients who have TP53 mutation, however, we treat with typically less aggressive therapy, as this patient population does not benefit from ASCT. We look forward to more data incorporating BTK inhibitors upfront, particularly for this group of patients, who tend to have a more adverse prognosis.

Do you feel MCL data and clinical trials are important areas of focus for your colleagues?

Dr. LaCasce: Yes. I think it is a rapidly evolving field, which is really exciting. We are seeing data now from the bispecific antibodies in the relapsed/refractory setting. We also need more data using pirtobrutinib for patients who have had BTK inhibitors and compare pirtobrutinib (a non-covalent BTK inhibitor) with the covalent BTK inhibitors.

I would strongly encourage patients to participate in clinical trials so that we can better answer these important questions. When patients go online and read about MCL, they often see a median survival of 3 to 4 years, which is completely outdated. The overall prognosis of MCL has changed dramatically since I have been in the field. Hopefully, survival will continue to improve, and therapies will become more tolerable, as well.

A review of the patient’s chemotherapy medications revealed that 4 weeks earlier, panitumumab had been added to her folinic acid, fluorouracil, and irinotecan (FOLFIRI) regimen. The physician diagnosed this acneiform eruption as an adverse effect of the panitumumab.

Panitumumab is a monoclonal antibody that works to inhibit epidermal growth factor receptor (EGFR) proteins that are overexpressed on some solid tumors and responsible for cancer cell proliferation. EGFR inhibitor–induced acneiform eruptions are common in patients receiving panitumumab.

EGFR proteins have been a target of chemotherapy since the approval of the small molecule erlotinib in 2004. Panitumumab and cetuximab are monoclonal antibodies targeting EGFR and improve long-term survival in patients with metastatic colorectal cancer when added to other standard chemotherapy regimens. EGFR is found throughout the epidermis and all EGFR inhibitors may cause unique skin toxicity not seen with other chemotherapy agents. In 1 study of 229 patients, 59% of patients exhibited skin toxicity at Day 15; the most common examples included widespread acne-like papules and pustules or an eczema-like manifestation.¹ Eruptions may be worsened by significant sun exposure while on panitumumab. In this case, the acneiform eruption occurred more intensely along visible facial telangiectasias.

When EGFR inhibitor–induced acneiform eruption occurs, patients commonly develop skin toxicity within the first 2 to 4 weeks of therapy. Pre-therapy doxycycline or minocycline and/or topical steroids may help prevent toxicities from occurring. These same therapies may be used to treat symptoms after they have occurred. More severe cases with systemic symptoms or failure to improve with the above measures may need prednisone or cessation of therapy.

This patient was started on topical hydrocortisone 2.5% ointment twice daily and oral doxycycline 100 mg bid for 6 weeks. She had dramatic improvement within 3 weeks. Doxycycline was subsequently continued at a dose of 100 mg/d and the patient was able to continue with her chemotherapy combination for several more months. Unfortunately, her colon cancer progressed despite therapy and she ultimately died from cancer-related complications.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

A review of the patient’s chemotherapy medications revealed that 4 weeks earlier, panitumumab had been added to her folinic acid, fluorouracil, and irinotecan (FOLFIRI) regimen. The physician diagnosed this acneiform eruption as an adverse effect of the panitumumab.

Panitumumab is a monoclonal antibody that works to inhibit epidermal growth factor receptor (EGFR) proteins that are overexpressed on some solid tumors and responsible for cancer cell proliferation. EGFR inhibitor–induced acneiform eruptions are common in patients receiving panitumumab.

EGFR proteins have been a target of chemotherapy since the approval of the small molecule erlotinib in 2004. Panitumumab and cetuximab are monoclonal antibodies targeting EGFR and improve long-term survival in patients with metastatic colorectal cancer when added to other standard chemotherapy regimens. EGFR is found throughout the epidermis and all EGFR inhibitors may cause unique skin toxicity not seen with other chemotherapy agents. In 1 study of 229 patients, 59% of patients exhibited skin toxicity at Day 15; the most common examples included widespread acne-like papules and pustules or an eczema-like manifestation.¹ Eruptions may be worsened by significant sun exposure while on panitumumab. In this case, the acneiform eruption occurred more intensely along visible facial telangiectasias.

When EGFR inhibitor–induced acneiform eruption occurs, patients commonly develop skin toxicity within the first 2 to 4 weeks of therapy. Pre-therapy doxycycline or minocycline and/or topical steroids may help prevent toxicities from occurring. These same therapies may be used to treat symptoms after they have occurred. More severe cases with systemic symptoms or failure to improve with the above measures may need prednisone or cessation of therapy.

This patient was started on topical hydrocortisone 2.5% ointment twice daily and oral doxycycline 100 mg bid for 6 weeks. She had dramatic improvement within 3 weeks. Doxycycline was subsequently continued at a dose of 100 mg/d and the patient was able to continue with her chemotherapy combination for several more months. Unfortunately, her colon cancer progressed despite therapy and she ultimately died from cancer-related complications.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

A review of the patient’s chemotherapy medications revealed that 4 weeks earlier, panitumumab had been added to her folinic acid, fluorouracil, and irinotecan (FOLFIRI) regimen. The physician diagnosed this acneiform eruption as an adverse effect of the panitumumab.

Panitumumab is a monoclonal antibody that works to inhibit epidermal growth factor receptor (EGFR) proteins that are overexpressed on some solid tumors and responsible for cancer cell proliferation. EGFR inhibitor–induced acneiform eruptions are common in patients receiving panitumumab.

EGFR proteins have been a target of chemotherapy since the approval of the small molecule erlotinib in 2004. Panitumumab and cetuximab are monoclonal antibodies targeting EGFR and improve long-term survival in patients with metastatic colorectal cancer when added to other standard chemotherapy regimens. EGFR is found throughout the epidermis and all EGFR inhibitors may cause unique skin toxicity not seen with other chemotherapy agents. In 1 study of 229 patients, 59% of patients exhibited skin toxicity at Day 15; the most common examples included widespread acne-like papules and pustules or an eczema-like manifestation.¹ Eruptions may be worsened by significant sun exposure while on panitumumab. In this case, the acneiform eruption occurred more intensely along visible facial telangiectasias.

When EGFR inhibitor–induced acneiform eruption occurs, patients commonly develop skin toxicity within the first 2 to 4 weeks of therapy. Pre-therapy doxycycline or minocycline and/or topical steroids may help prevent toxicities from occurring. These same therapies may be used to treat symptoms after they have occurred. More severe cases with systemic symptoms or failure to improve with the above measures may need prednisone or cessation of therapy.

This patient was started on topical hydrocortisone 2.5% ointment twice daily and oral doxycycline 100 mg bid for 6 weeks. She had dramatic improvement within 3 weeks. Doxycycline was subsequently continued at a dose of 100 mg/d and the patient was able to continue with her chemotherapy combination for several more months. Unfortunately, her colon cancer progressed despite therapy and she ultimately died from cancer-related complications.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

The Diagnosis: Pleomorphic Lipoma

Pleomorphic lipoma is a rare, benign, adipocytic neoplasm that presents in the subcutaneous tissues of the upper shoulder, back, or neck. It predominantly affects men aged 50 to 70 years. Most lesions are situated in the subcutaneous tissues; few cases of intramuscular and retroperitoneal tumors have been reported.¹ Clinically, pleomorphic lipomas present as painless, well-circumscribed lesions of the subcutaneous tissue that often resemble a lipoma or occasionally may be mistaken for liposarcoma. Histopathologic examination of ordinary lipomas reveals uniform mature adipocytes. However, pleomorphic lipomas consist of a mixture of multinucleated floretlike giant cells, variable-sized adipocytes, and fibrous tissue (ropy collagen bundles) with some myxoid and spindled areas.^1,2 The most characteristic histologic feature of pleomorphic lipoma is multinucleated floretlike giant cells. The nuclei of these giant cells appear hyperchromatic, enlarged, and disposed to the periphery of the cell in a circular pattern. Additionally, tumors frequently contain excess mature dense collagen bundles that are strongly refractile in polarized light. Numerous mast cells are present. Atypical lipoblasts and capillary networks commonly are not visible in pleomorphic lipoma.³ The spindle cells express CD34 on immunohistochemistry. Loss of Rb-1 expression is typical.⁴

Dermatofibrosarcoma protuberans is a slow-growing soft tissue sarcoma that commonly begins as a pink or violet plaque on the trunk or upper limbs. Involvement of the head or neck accounts for only 10% to 15% of cases.⁵ This tumor has low metastatic potential but is highly infiltrative of surrounding tissues. It is associated with a translocation between chromosomes 22 and 17, leading to the fusion of the platelet-derived growth factor subunit β, PDGFB, and collagen type 1α1, COL1A1, genes.⁵ Clinically, patients often report that the lesion was present for several years prior to presentation with general stability in size and shape. Eventually, untreated lesions progress to become nodules or tumors and may even bleed or ulcerate. Histology reveals a storiform spindle cell proliferation throughout the dermis with infiltration into subcutaneous fat, commonly appearing in a honeycomblike pattern (Figure 1). Numerous histologic variants exist, including myxoid, sclerosing, pigmented (Bednar tumor), myoid, atrophic, or fibrosarcomatous dermatofibrosarcoma protuberans, as well as a giant cell fibroblastoma variant.⁶ These tumor subtypes can exist independently or in association with one another, creating hybrid lesions that can closely mimic other entities such as pleomorphic lipoma. The spindle cells stain positively for CD34. Treatment of these tumors involves complete surgical excision or Mohs micrographic surgery; however, recurrence is common for tumors involving the head or neck.⁵

Superficial angiomyxoma is a slow-growing papule that most commonly appears on the trunk, head, or neck in middle-aged adults. Occasionally, patients with Carney complex also can develop lesions on the external ear or breast.⁷ Histologically, superficial angiomyxoma is a hypocellular tumor characterized by abundant myxoid stroma, thin blood vessels, and small spindled and stellate cells with minimal cytoplasm (Figure 2).⁸ Superficial angiomyxoma and pleomorphic lipoma present differently on histology; superficial angiomyxoma is not associated with nuclear atypia or pleomorphism, whereas pleomorphic lipoma characteristically contains multinucleated floretlike giant cells and pleomorphism. Frequently, there also is loss of normal PRKAR1A gene expression, which is responsible for protein kinase A regulatory subunit 1-alpha expression.⁸

Multinucleate cell angiohistiocytoma is a rare benign proliferation that presents with numerous red-violet asymptomatic papules that commonly appear on the upper and lower extremities of women aged 40 to 70 years. Lesions feature both a fibrohistiocytic and vascular component.9 Histologic examination commonly shows multinucleated cells with angular outlining in the superficial dermis accompanied by fibrosis and ectatic small-caliber vessels (Figure 3). Although both pleomorphic lipoma and multinucleate cell angiohistiocytoma have similar-appearing multinucleated giant cells, the latter has a proliferation of narrow vessels in thick collagen bundles and lacks an adipocytic component, which distinguishes it from the former.¹⁰ Multinucleate cell angiohistiocytoma also is characterized by a substantial number of factor XIIIa–positive fibrohistiocytic interstitial cells and vascular hyperplasia.⁹

Nodular fasciitis is a benign lesion involving the rapid proliferation of myofibroblasts and fibroblasts in the subcutaneous tissue and most commonly is encountered on the extremities or head and neck regions. Many cases appear at sites of prior trauma, especially in patients aged 20 to 40 years. However, in infants and children the lesions typically are found in the head and neck regions.¹¹ Clinically, lesions present as subcutaneous nodules. Histology reveals an infiltrative and poorly circumscribed proliferation of spindled myofibroblasts associated with myxoid stroma and dense collagen depositions. The spindled cells are loosely associated, rendering a tissue culture–like appearance (Figure 4). It also is common to see erythrocyte extravasation adjacent to myxoid stroma.¹¹ Positive stains include vimentin, smooth muscle actin, and CD68, though immunohistochemistry often is not necessary for diagnosis.¹² There often is abundant mitotic activity in nodular fasciitis, especially in early lesions, and the differential diagnosis includes sarcoma. Although nodular fasciitis is mitotically active, it does not show atypical mitotic figures. Nodular fasciitis commonly harbors a gene translocation of the MYH9 gene’s promoter region to the USP6 gene’s coding region.¹³

The Diagnosis: Pleomorphic Lipoma

Pleomorphic lipoma is a rare, benign, adipocytic neoplasm that presents in the subcutaneous tissues of the upper shoulder, back, or neck. It predominantly affects men aged 50 to 70 years. Most lesions are situated in the subcutaneous tissues; few cases of intramuscular and retroperitoneal tumors have been reported.¹ Clinically, pleomorphic lipomas present as painless, well-circumscribed lesions of the subcutaneous tissue that often resemble a lipoma or occasionally may be mistaken for liposarcoma. Histopathologic examination of ordinary lipomas reveals uniform mature adipocytes. However, pleomorphic lipomas consist of a mixture of multinucleated floretlike giant cells, variable-sized adipocytes, and fibrous tissue (ropy collagen bundles) with some myxoid and spindled areas.^1,2 The most characteristic histologic feature of pleomorphic lipoma is multinucleated floretlike giant cells. The nuclei of these giant cells appear hyperchromatic, enlarged, and disposed to the periphery of the cell in a circular pattern. Additionally, tumors frequently contain excess mature dense collagen bundles that are strongly refractile in polarized light. Numerous mast cells are present. Atypical lipoblasts and capillary networks commonly are not visible in pleomorphic lipoma.³ The spindle cells express CD34 on immunohistochemistry. Loss of Rb-1 expression is typical.⁴

Dermatofibrosarcoma protuberans is a slow-growing soft tissue sarcoma that commonly begins as a pink or violet plaque on the trunk or upper limbs. Involvement of the head or neck accounts for only 10% to 15% of cases.⁵ This tumor has low metastatic potential but is highly infiltrative of surrounding tissues. It is associated with a translocation between chromosomes 22 and 17, leading to the fusion of the platelet-derived growth factor subunit β, PDGFB, and collagen type 1α1, COL1A1, genes.⁵ Clinically, patients often report that the lesion was present for several years prior to presentation with general stability in size and shape. Eventually, untreated lesions progress to become nodules or tumors and may even bleed or ulcerate. Histology reveals a storiform spindle cell proliferation throughout the dermis with infiltration into subcutaneous fat, commonly appearing in a honeycomblike pattern (Figure 1). Numerous histologic variants exist, including myxoid, sclerosing, pigmented (Bednar tumor), myoid, atrophic, or fibrosarcomatous dermatofibrosarcoma protuberans, as well as a giant cell fibroblastoma variant.⁶ These tumor subtypes can exist independently or in association with one another, creating hybrid lesions that can closely mimic other entities such as pleomorphic lipoma. The spindle cells stain positively for CD34. Treatment of these tumors involves complete surgical excision or Mohs micrographic surgery; however, recurrence is common for tumors involving the head or neck.⁵

Superficial angiomyxoma is a slow-growing papule that most commonly appears on the trunk, head, or neck in middle-aged adults. Occasionally, patients with Carney complex also can develop lesions on the external ear or breast.⁷ Histologically, superficial angiomyxoma is a hypocellular tumor characterized by abundant myxoid stroma, thin blood vessels, and small spindled and stellate cells with minimal cytoplasm (Figure 2).⁸ Superficial angiomyxoma and pleomorphic lipoma present differently on histology; superficial angiomyxoma is not associated with nuclear atypia or pleomorphism, whereas pleomorphic lipoma characteristically contains multinucleated floretlike giant cells and pleomorphism. Frequently, there also is loss of normal PRKAR1A gene expression, which is responsible for protein kinase A regulatory subunit 1-alpha expression.⁸

Multinucleate cell angiohistiocytoma is a rare benign proliferation that presents with numerous red-violet asymptomatic papules that commonly appear on the upper and lower extremities of women aged 40 to 70 years. Lesions feature both a fibrohistiocytic and vascular component.9 Histologic examination commonly shows multinucleated cells with angular outlining in the superficial dermis accompanied by fibrosis and ectatic small-caliber vessels (Figure 3). Although both pleomorphic lipoma and multinucleate cell angiohistiocytoma have similar-appearing multinucleated giant cells, the latter has a proliferation of narrow vessels in thick collagen bundles and lacks an adipocytic component, which distinguishes it from the former.¹⁰ Multinucleate cell angiohistiocytoma also is characterized by a substantial number of factor XIIIa–positive fibrohistiocytic interstitial cells and vascular hyperplasia.⁹

Nodular fasciitis is a benign lesion involving the rapid proliferation of myofibroblasts and fibroblasts in the subcutaneous tissue and most commonly is encountered on the extremities or head and neck regions. Many cases appear at sites of prior trauma, especially in patients aged 20 to 40 years. However, in infants and children the lesions typically are found in the head and neck regions.¹¹ Clinically, lesions present as subcutaneous nodules. Histology reveals an infiltrative and poorly circumscribed proliferation of spindled myofibroblasts associated with myxoid stroma and dense collagen depositions. The spindled cells are loosely associated, rendering a tissue culture–like appearance (Figure 4). It also is common to see erythrocyte extravasation adjacent to myxoid stroma.¹¹ Positive stains include vimentin, smooth muscle actin, and CD68, though immunohistochemistry often is not necessary for diagnosis.¹² There often is abundant mitotic activity in nodular fasciitis, especially in early lesions, and the differential diagnosis includes sarcoma. Although nodular fasciitis is mitotically active, it does not show atypical mitotic figures. Nodular fasciitis commonly harbors a gene translocation of the MYH9 gene’s promoter region to the USP6 gene’s coding region.¹³

The Diagnosis: Pleomorphic Lipoma

Pleomorphic lipoma is a rare, benign, adipocytic neoplasm that presents in the subcutaneous tissues of the upper shoulder, back, or neck. It predominantly affects men aged 50 to 70 years. Most lesions are situated in the subcutaneous tissues; few cases of intramuscular and retroperitoneal tumors have been reported.¹ Clinically, pleomorphic lipomas present as painless, well-circumscribed lesions of the subcutaneous tissue that often resemble a lipoma or occasionally may be mistaken for liposarcoma. Histopathologic examination of ordinary lipomas reveals uniform mature adipocytes. However, pleomorphic lipomas consist of a mixture of multinucleated floretlike giant cells, variable-sized adipocytes, and fibrous tissue (ropy collagen bundles) with some myxoid and spindled areas.^1,2 The most characteristic histologic feature of pleomorphic lipoma is multinucleated floretlike giant cells. The nuclei of these giant cells appear hyperchromatic, enlarged, and disposed to the periphery of the cell in a circular pattern. Additionally, tumors frequently contain excess mature dense collagen bundles that are strongly refractile in polarized light. Numerous mast cells are present. Atypical lipoblasts and capillary networks commonly are not visible in pleomorphic lipoma.³ The spindle cells express CD34 on immunohistochemistry. Loss of Rb-1 expression is typical.⁴

Dermatofibrosarcoma protuberans is a slow-growing soft tissue sarcoma that commonly begins as a pink or violet plaque on the trunk or upper limbs. Involvement of the head or neck accounts for only 10% to 15% of cases.⁵ This tumor has low metastatic potential but is highly infiltrative of surrounding tissues. It is associated with a translocation between chromosomes 22 and 17, leading to the fusion of the platelet-derived growth factor subunit β, PDGFB, and collagen type 1α1, COL1A1, genes.⁵ Clinically, patients often report that the lesion was present for several years prior to presentation with general stability in size and shape. Eventually, untreated lesions progress to become nodules or tumors and may even bleed or ulcerate. Histology reveals a storiform spindle cell proliferation throughout the dermis with infiltration into subcutaneous fat, commonly appearing in a honeycomblike pattern (Figure 1). Numerous histologic variants exist, including myxoid, sclerosing, pigmented (Bednar tumor), myoid, atrophic, or fibrosarcomatous dermatofibrosarcoma protuberans, as well as a giant cell fibroblastoma variant.⁶ These tumor subtypes can exist independently or in association with one another, creating hybrid lesions that can closely mimic other entities such as pleomorphic lipoma. The spindle cells stain positively for CD34. Treatment of these tumors involves complete surgical excision or Mohs micrographic surgery; however, recurrence is common for tumors involving the head or neck.⁵

Superficial angiomyxoma is a slow-growing papule that most commonly appears on the trunk, head, or neck in middle-aged adults. Occasionally, patients with Carney complex also can develop lesions on the external ear or breast.⁷ Histologically, superficial angiomyxoma is a hypocellular tumor characterized by abundant myxoid stroma, thin blood vessels, and small spindled and stellate cells with minimal cytoplasm (Figure 2).⁸ Superficial angiomyxoma and pleomorphic lipoma present differently on histology; superficial angiomyxoma is not associated with nuclear atypia or pleomorphism, whereas pleomorphic lipoma characteristically contains multinucleated floretlike giant cells and pleomorphism. Frequently, there also is loss of normal PRKAR1A gene expression, which is responsible for protein kinase A regulatory subunit 1-alpha expression.⁸

Multinucleate cell angiohistiocytoma is a rare benign proliferation that presents with numerous red-violet asymptomatic papules that commonly appear on the upper and lower extremities of women aged 40 to 70 years. Lesions feature both a fibrohistiocytic and vascular component.9 Histologic examination commonly shows multinucleated cells with angular outlining in the superficial dermis accompanied by fibrosis and ectatic small-caliber vessels (Figure 3). Although both pleomorphic lipoma and multinucleate cell angiohistiocytoma have similar-appearing multinucleated giant cells, the latter has a proliferation of narrow vessels in thick collagen bundles and lacks an adipocytic component, which distinguishes it from the former.¹⁰ Multinucleate cell angiohistiocytoma also is characterized by a substantial number of factor XIIIa–positive fibrohistiocytic interstitial cells and vascular hyperplasia.⁹

Nodular fasciitis is a benign lesion involving the rapid proliferation of myofibroblasts and fibroblasts in the subcutaneous tissue and most commonly is encountered on the extremities or head and neck regions. Many cases appear at sites of prior trauma, especially in patients aged 20 to 40 years. However, in infants and children the lesions typically are found in the head and neck regions.¹¹ Clinically, lesions present as subcutaneous nodules. Histology reveals an infiltrative and poorly circumscribed proliferation of spindled myofibroblasts associated with myxoid stroma and dense collagen depositions. The spindled cells are loosely associated, rendering a tissue culture–like appearance (Figure 4). It also is common to see erythrocyte extravasation adjacent to myxoid stroma.¹¹ Positive stains include vimentin, smooth muscle actin, and CD68, though immunohistochemistry often is not necessary for diagnosis.¹² There often is abundant mitotic activity in nodular fasciitis, especially in early lesions, and the differential diagnosis includes sarcoma. Although nodular fasciitis is mitotically active, it does not show atypical mitotic figures. Nodular fasciitis commonly harbors a gene translocation of the MYH9 gene’s promoter region to the USP6 gene’s coding region.¹³

To the Editor:

Melanoma is an aggressive form of skin cancer with a high rate of metastasis and poor prognosis.¹ Historically, Hispanic and/or Latino patients have presented with more advanced-stage melanomas and have lower survival rates compared with non-Hispanic and/or non-Latino White patients.² In this study, we evaluated recent data from the last decade to investigate if disparities in melanoma tumor stage at diagnosis and risk for metastases continue to exist in the Hispanic and/or Latino population.

We conducted a retrospective review of melanoma patients at 2 major medical centers in Los Angeles, California—Keck Medicine of USC and Los Angeles County-USC Medical Center—from January 2010 to January 2020. The data collected from electronic medical records included age at melanoma diagnosis, sex, race and ethnicity, insurance type, Breslow depth of lesion, presence of ulceration, and presence of lymph node or distant metastases. Melanoma tumor stage was determined using the American Joint Committee on Cancer classification. Patients who self-reported their ethnicity as not Hispanic and/or Latino were designated to this group regardless of their reported race. Those patients who reported their ethnicity as not Hispanic and/or Latino and reported their race as White were designated as non-Hispanic and/or non-Latino White. This study was approved by the institutional review board of the University of Southern California (Los Angeles). Data analysis was performed using the Pearson χ² test, Fisher exact test, and Wilcoxon rank sum test. Statistical significance was determined at P<.05.

The final cohort of patients included 79 Hispanic and/or Latino patients and 402 non-Hispanic and/or non-Latino White patients. The median age for the Hispanic and/or Latino group was 54 years and 64 years for the non-Hispanic and/or non-Latino White group (P<.001). There was a greater percentage of females in the Hispanic and/or Latino group compared with the non-Hispanic and/or non-Latino White group (53.2% vs 34.6%)(P=.002). Hispanic and/or Latino patients presented with more advanced tumor stage melanomas (T3: 15.2%; T4: 21.5%) compared with non-Hispanic and/or non-Latino White patients (T3: 8.0%; T4: 10.7%)(P=.004). Furthermore, Hispanic and/or Latino patients had higher rates of lymph node metastases compared with non-Hispanic and/or non-Latino White patients (20.3% vs 7.7% [P<.001]) and higher rates of distant metastases (12.7% vs 5.2% [P=.014])(Table 1). The majority of Hispanic and/or Latino patients had Medicaid (39.2%), while most non-Hispanic and/or non-Latino White patients had a preferred provider organization insurance plan (37.3%) or Medicare (34.3%)(P<.001)(Table 2).

This retrospective study analyzing nearly 10 years of recent melanoma data found that disparities in melanoma diagnosis and treatment continue to exist among Hispanic and/or Latino patients. Compared to non-Hispanic and/or non-Latino White patients, Hispanic and/or Latino patients were diagnosed with melanoma at a younger age and the proportion of females with melanoma was higher. Cormier et al² also reported that Hispanic patients were younger at melanoma diagnosis, and females represented a larger majority of patients in the Hispanic population compared with the White population. Hispanic and/or Latino patients in our study had more advanced melanoma tumor stage at diagnosis and a higher risk of lymph node and distant metastases, similar to findings reported by Koblinksi et al.³

Our retrospective cohort study demonstrated that the demographics of Hispanic and/or Latino patients with melanoma differ from non-Hispanic and/or non-Latino White patients, specifically with a greater proportion of younger and female patients in the Hispanic and/or Latino population. We also found that Hispanic and/or Latino patients continue to experience worse melanoma outcomes compared with non-Hispanic and/or non-Latino White patients. Further studies are needed to investigate the etiologies behind these health care disparities and potential interventions to address them. In addition, there needs to be increased awareness of the risk for melanoma in Hispanic and/or Latino patients among both health care providers and patients.

Limitations of this study included a smaller sample size of patients from one geographic region. The retrospective design of this study also increased the risk for selection bias, as some of the patients may have had incomplete records or were lost to follow-up. Therefore, the study cohort may not be representative of the general population. Additionally, patients’ skin types could not be determined using standardized tools such as the Fitzpatrick scale, thus we could not assess how patient skin type may have affected melanoma outcomes.

To the Editor:

Melanoma is an aggressive form of skin cancer with a high rate of metastasis and poor prognosis.¹ Historically, Hispanic and/or Latino patients have presented with more advanced-stage melanomas and have lower survival rates compared with non-Hispanic and/or non-Latino White patients.² In this study, we evaluated recent data from the last decade to investigate if disparities in melanoma tumor stage at diagnosis and risk for metastases continue to exist in the Hispanic and/or Latino population.

We conducted a retrospective review of melanoma patients at 2 major medical centers in Los Angeles, California—Keck Medicine of USC and Los Angeles County-USC Medical Center—from January 2010 to January 2020. The data collected from electronic medical records included age at melanoma diagnosis, sex, race and ethnicity, insurance type, Breslow depth of lesion, presence of ulceration, and presence of lymph node or distant metastases. Melanoma tumor stage was determined using the American Joint Committee on Cancer classification. Patients who self-reported their ethnicity as not Hispanic and/or Latino were designated to this group regardless of their reported race. Those patients who reported their ethnicity as not Hispanic and/or Latino and reported their race as White were designated as non-Hispanic and/or non-Latino White. This study was approved by the institutional review board of the University of Southern California (Los Angeles). Data analysis was performed using the Pearson χ² test, Fisher exact test, and Wilcoxon rank sum test. Statistical significance was determined at P<.05.

The final cohort of patients included 79 Hispanic and/or Latino patients and 402 non-Hispanic and/or non-Latino White patients. The median age for the Hispanic and/or Latino group was 54 years and 64 years for the non-Hispanic and/or non-Latino White group (P<.001). There was a greater percentage of females in the Hispanic and/or Latino group compared with the non-Hispanic and/or non-Latino White group (53.2% vs 34.6%)(P=.002). Hispanic and/or Latino patients presented with more advanced tumor stage melanomas (T3: 15.2%; T4: 21.5%) compared with non-Hispanic and/or non-Latino White patients (T3: 8.0%; T4: 10.7%)(P=.004). Furthermore, Hispanic and/or Latino patients had higher rates of lymph node metastases compared with non-Hispanic and/or non-Latino White patients (20.3% vs 7.7% [P<.001]) and higher rates of distant metastases (12.7% vs 5.2% [P=.014])(Table 1). The majority of Hispanic and/or Latino patients had Medicaid (39.2%), while most non-Hispanic and/or non-Latino White patients had a preferred provider organization insurance plan (37.3%) or Medicare (34.3%)(P<.001)(Table 2).

This retrospective study analyzing nearly 10 years of recent melanoma data found that disparities in melanoma diagnosis and treatment continue to exist among Hispanic and/or Latino patients. Compared to non-Hispanic and/or non-Latino White patients, Hispanic and/or Latino patients were diagnosed with melanoma at a younger age and the proportion of females with melanoma was higher. Cormier et al² also reported that Hispanic patients were younger at melanoma diagnosis, and females represented a larger majority of patients in the Hispanic population compared with the White population. Hispanic and/or Latino patients in our study had more advanced melanoma tumor stage at diagnosis and a higher risk of lymph node and distant metastases, similar to findings reported by Koblinksi et al.³

Our retrospective cohort study demonstrated that the demographics of Hispanic and/or Latino patients with melanoma differ from non-Hispanic and/or non-Latino White patients, specifically with a greater proportion of younger and female patients in the Hispanic and/or Latino population. We also found that Hispanic and/or Latino patients continue to experience worse melanoma outcomes compared with non-Hispanic and/or non-Latino White patients. Further studies are needed to investigate the etiologies behind these health care disparities and potential interventions to address them. In addition, there needs to be increased awareness of the risk for melanoma in Hispanic and/or Latino patients among both health care providers and patients.

Limitations of this study included a smaller sample size of patients from one geographic region. The retrospective design of this study also increased the risk for selection bias, as some of the patients may have had incomplete records or were lost to follow-up. Therefore, the study cohort may not be representative of the general population. Additionally, patients’ skin types could not be determined using standardized tools such as the Fitzpatrick scale, thus we could not assess how patient skin type may have affected melanoma outcomes.

To the Editor:

Melanoma is an aggressive form of skin cancer with a high rate of metastasis and poor prognosis.¹ Historically, Hispanic and/or Latino patients have presented with more advanced-stage melanomas and have lower survival rates compared with non-Hispanic and/or non-Latino White patients.² In this study, we evaluated recent data from the last decade to investigate if disparities in melanoma tumor stage at diagnosis and risk for metastases continue to exist in the Hispanic and/or Latino population.

We conducted a retrospective review of melanoma patients at 2 major medical centers in Los Angeles, California—Keck Medicine of USC and Los Angeles County-USC Medical Center—from January 2010 to January 2020. The data collected from electronic medical records included age at melanoma diagnosis, sex, race and ethnicity, insurance type, Breslow depth of lesion, presence of ulceration, and presence of lymph node or distant metastases. Melanoma tumor stage was determined using the American Joint Committee on Cancer classification. Patients who self-reported their ethnicity as not Hispanic and/or Latino were designated to this group regardless of their reported race. Those patients who reported their ethnicity as not Hispanic and/or Latino and reported their race as White were designated as non-Hispanic and/or non-Latino White. This study was approved by the institutional review board of the University of Southern California (Los Angeles). Data analysis was performed using the Pearson χ² test, Fisher exact test, and Wilcoxon rank sum test. Statistical significance was determined at P<.05.

The final cohort of patients included 79 Hispanic and/or Latino patients and 402 non-Hispanic and/or non-Latino White patients. The median age for the Hispanic and/or Latino group was 54 years and 64 years for the non-Hispanic and/or non-Latino White group (P<.001). There was a greater percentage of females in the Hispanic and/or Latino group compared with the non-Hispanic and/or non-Latino White group (53.2% vs 34.6%)(P=.002). Hispanic and/or Latino patients presented with more advanced tumor stage melanomas (T3: 15.2%; T4: 21.5%) compared with non-Hispanic and/or non-Latino White patients (T3: 8.0%; T4: 10.7%)(P=.004). Furthermore, Hispanic and/or Latino patients had higher rates of lymph node metastases compared with non-Hispanic and/or non-Latino White patients (20.3% vs 7.7% [P<.001]) and higher rates of distant metastases (12.7% vs 5.2% [P=.014])(Table 1). The majority of Hispanic and/or Latino patients had Medicaid (39.2%), while most non-Hispanic and/or non-Latino White patients had a preferred provider organization insurance plan (37.3%) or Medicare (34.3%)(P<.001)(Table 2).

This retrospective study analyzing nearly 10 years of recent melanoma data found that disparities in melanoma diagnosis and treatment continue to exist among Hispanic and/or Latino patients. Compared to non-Hispanic and/or non-Latino White patients, Hispanic and/or Latino patients were diagnosed with melanoma at a younger age and the proportion of females with melanoma was higher. Cormier et al² also reported that Hispanic patients were younger at melanoma diagnosis, and females represented a larger majority of patients in the Hispanic population compared with the White population. Hispanic and/or Latino patients in our study had more advanced melanoma tumor stage at diagnosis and a higher risk of lymph node and distant metastases, similar to findings reported by Koblinksi et al.³

Our retrospective cohort study demonstrated that the demographics of Hispanic and/or Latino patients with melanoma differ from non-Hispanic and/or non-Latino White patients, specifically with a greater proportion of younger and female patients in the Hispanic and/or Latino population. We also found that Hispanic and/or Latino patients continue to experience worse melanoma outcomes compared with non-Hispanic and/or non-Latino White patients. Further studies are needed to investigate the etiologies behind these health care disparities and potential interventions to address them. In addition, there needs to be increased awareness of the risk for melanoma in Hispanic and/or Latino patients among both health care providers and patients.

Limitations of this study included a smaller sample size of patients from one geographic region. The retrospective design of this study also increased the risk for selection bias, as some of the patients may have had incomplete records or were lost to follow-up. Therefore, the study cohort may not be representative of the general population. Additionally, patients’ skin types could not be determined using standardized tools such as the Fitzpatrick scale, thus we could not assess how patient skin type may have affected melanoma outcomes.

Cutaneous Manifestations

Capsicum peppers are used worldwide in preparing spicy dishes. Their active ingredient—capsaicin—is used as a topical medicine to treat localized pain. Capsicum peppers can cause irritant contact dermatitis with symptoms of erythema, cutaneous burning, and itch.¹

Irritant contact dermatitis is a common occupational skin disorder. Many cooks have experienced the sting of a chili pepper after contact with the hands or eyes. Cases of chronic exposure to Capsicum peppers with persistent burning and pain have been called Hunan hand syndrome.² Capsicum peppers also have induced allergic contact dermatitis in a food production worker.³

Capsicum peppers also are used in pepper spray, tear gas, and animal repellents because of their stinging properties. These agents usually cause cutaneous tingling and burning that soon resolves; however, a review of 31 studies showed that crowd-control methods with Capsicum-containing tear gas and pepper spray can cause moderate to severe skin damage such as a persistent skin rash or erythema, or even first-, second-, or third-degree burns.⁴

Topical application of capsaicin isolate is meant to cause burning and deplete local neuropeptides, with a cutaneous reaction that ranges from mild to intolerable.^5,6 Capsaicin also is found in other products. In one published case report, a 3-year-old boy broke out in facial urticaria when his mother kissed him on the cheek after she applied lip plumper containing capsaicin to her lips.⁷ Dermatologists should consider capsaicin an active ingredient that can irritate the skin in the garden, in the kitchen, and in topical products.

Obtaining Relief

Capsaicin-induced dermatitis can be relieved by washing the area with soap, detergent, baking soda, or oily compounds that act as solvents for the nonpolar capsaicin.⁸ Application of ice water or a high-potency topical steroid also may help. If the reaction is severe and persistent, a continuous stellate ganglion block may alleviate the pain of capsaicin-induced contact dermatitis.⁹

Identifying Features and Plant Facts

The Capsicum genus includes chili peppers, paprika, and red peppers. Capsicum peppers are native to tropical regions of the Americas (Figure). The use of Capsicum peppers in food can be traced to Indigenous peoples of Mexico as early as 7000 bc.¹⁰ On the Scoville scale, which was developed to quantify the hotness of foods and spices, Capsicum peppers are rated at approximately 2 million units; by comparison, jalapeño peppers have a Scoville score of 4500¹¹ and capsaicin isolate has a score of 16 million units. Capsicum species rank among the hottest peppers in the world.

Capsicum belongs to the family Solanaceae, which includes tobacco, tomatoes, potatoes, and nightshade plants. There are many varieties of peppers in the Capsicum genus, with 5 domesticated species: Capsicum annuum, Capsicum baccatum, Capsicum chinense, Capsicum frutescens, and Capsicum pubescens. These include bell, poblano, cayenne, tabasco, habanero, and ají peppers, among others. Capsicum species grow as a shrub with flowers that rotate to stellate corollas and rounded berries of different sizes and colors.¹² Capsaicin and other alkaloids are concentrated in the fruit; therefore, Capsicum dermatitis is most commonly induced by contact with the flesh of peppers.

 

 

Irritant Chemicals

Capsaicin (8-methyl-6-nonanoyl vanillylamide) is a nonpolar phenol, which is why washing skin that has come in contact with capsaicin with water or vinegar alone is insufficient to solubilize it.¹³ Capsaicin binds to the transient receptor potential vanilloid 1 (TRPV1), a calcium channel on neurons that opens in response to heat. When bound, the channel opens at a lower temperature threshold and depolarizes nerve endings, leading to vasodilation and activation of sensory nerves.¹⁴ Substance P is released and the individual experiences a painful burning sensation. When purified capsaicin is frequently applied at an appropriate dose, synthesis of substance P is diminished, resulting in reduced local pain overall.¹⁵

Capsaicin does not affect neurons without TRPV1, and administration of capsaicin is not painful if given with anesthesia. An inappropriately high dose of capsaicin destroys cells in the epidermal barrier, resulting in water loss and inducing release of vasoactive peptides and inflammatory cytokines.¹ Careful handling of Capsicum peppers and capsaicin products can reduce the risk for irritation.

Medicinal Use

On-/Off-Label and Potential Uses—Capsaicin is US Food and Drug Administration approved for use in arthritis and musculoskeletal pain. It also is used to treat diabetic neuropathy,⁵ postherpetic neuralgia,⁶ psoriasis,¹⁶ and other conditions. Studies have shown that capsaicin might be useful in treating trigeminal neuralgia,¹⁷ fibromyalgia,¹⁸ migraines,¹⁴ cluster headaches,⁹ and HIV-associated distal sensory neuropathy.⁵

Delivery of Capsaicin—Capsaicin preferentially acts on C-fibers, which transmit dull, aching, chronic pain.¹⁹ The compound is available as a cream, lotion, and large bandage (for the lower back), as well as low- and high-dose patches. Capsaicin creams, lotions, and the low-dose patch are uncomfortable and must be applied for 4 to 6 weeks to take effect, which may impact patient adherence. The high-dose patch, which requires administration under local anesthesia by a health care worker, brings pain relief with a single use and improves adherence.¹¹ Synthetic TRPV1-agonist injectables based on capsaicin have undergone clinical trials for localized pain (eg, postoperative musculoskeletal pain); many patients experience pain relief, though benefit fades over weeks to months.^20,21

Use in Traditional Medicine—Capsicum peppers have been used to aid digestion and promote healing in gastrointestinal conditions, such as dyspepsia.²² The peppers are a source of important vitamins and minerals, including vitamins A, C, and E; many of the B complex vitamins; and magnesium, calcium, and iron.²³

Use as Cancer Therapy—Studies of the use of capsaicin in treating cancer have produced controversial results. In cell and animal models, capsaicin induces apoptosis through downregulation of the Bcl-2 protein; upregulation of oxidative stress, tribbles-related protein 3 (TRIB3), and caspase-3; and other pathways.^19,24-26 On the other hand, consumption of Capsicum peppers has been associated with cancer of the stomach and gallbladder.²⁷ Capsaicin might have anticarcinogenic properties, but its mechanism of action varies, depending on variables not fully understood.

Final Thoughts

Capsaicin is a neuropeptide-active compound found in Capsicum peppers that has many promising applications for use. However, dermatologists should be aware of the possibility of a skin reaction to this compound from handling peppers and using topical medicines. Exposure to capsaicin can cause irritant contact dermatitis that may require clinical care.

Cutaneous Manifestations

Capsicum peppers are used worldwide in preparing spicy dishes. Their active ingredient—capsaicin—is used as a topical medicine to treat localized pain. Capsicum peppers can cause irritant contact dermatitis with symptoms of erythema, cutaneous burning, and itch.¹

Irritant contact dermatitis is a common occupational skin disorder. Many cooks have experienced the sting of a chili pepper after contact with the hands or eyes. Cases of chronic exposure to Capsicum peppers with persistent burning and pain have been called Hunan hand syndrome.² Capsicum peppers also have induced allergic contact dermatitis in a food production worker.³

Capsicum peppers also are used in pepper spray, tear gas, and animal repellents because of their stinging properties. These agents usually cause cutaneous tingling and burning that soon resolves; however, a review of 31 studies showed that crowd-control methods with Capsicum-containing tear gas and pepper spray can cause moderate to severe skin damage such as a persistent skin rash or erythema, or even first-, second-, or third-degree burns.⁴

Topical application of capsaicin isolate is meant to cause burning and deplete local neuropeptides, with a cutaneous reaction that ranges from mild to intolerable.^5,6 Capsaicin also is found in other products. In one published case report, a 3-year-old boy broke out in facial urticaria when his mother kissed him on the cheek after she applied lip plumper containing capsaicin to her lips.⁷ Dermatologists should consider capsaicin an active ingredient that can irritate the skin in the garden, in the kitchen, and in topical products.

Obtaining Relief

Capsaicin-induced dermatitis can be relieved by washing the area with soap, detergent, baking soda, or oily compounds that act as solvents for the nonpolar capsaicin.⁸ Application of ice water or a high-potency topical steroid also may help. If the reaction is severe and persistent, a continuous stellate ganglion block may alleviate the pain of capsaicin-induced contact dermatitis.⁹

Identifying Features and Plant Facts

The Capsicum genus includes chili peppers, paprika, and red peppers. Capsicum peppers are native to tropical regions of the Americas (Figure). The use of Capsicum peppers in food can be traced to Indigenous peoples of Mexico as early as 7000 bc.¹⁰ On the Scoville scale, which was developed to quantify the hotness of foods and spices, Capsicum peppers are rated at approximately 2 million units; by comparison, jalapeño peppers have a Scoville score of 4500¹¹ and capsaicin isolate has a score of 16 million units. Capsicum species rank among the hottest peppers in the world.

Capsicum belongs to the family Solanaceae, which includes tobacco, tomatoes, potatoes, and nightshade plants. There are many varieties of peppers in the Capsicum genus, with 5 domesticated species: Capsicum annuum, Capsicum baccatum, Capsicum chinense, Capsicum frutescens, and Capsicum pubescens. These include bell, poblano, cayenne, tabasco, habanero, and ají peppers, among others. Capsicum species grow as a shrub with flowers that rotate to stellate corollas and rounded berries of different sizes and colors.¹² Capsaicin and other alkaloids are concentrated in the fruit; therefore, Capsicum dermatitis is most commonly induced by contact with the flesh of peppers.

 

 

Irritant Chemicals

Capsaicin (8-methyl-6-nonanoyl vanillylamide) is a nonpolar phenol, which is why washing skin that has come in contact with capsaicin with water or vinegar alone is insufficient to solubilize it.¹³ Capsaicin binds to the transient receptor potential vanilloid 1 (TRPV1), a calcium channel on neurons that opens in response to heat. When bound, the channel opens at a lower temperature threshold and depolarizes nerve endings, leading to vasodilation and activation of sensory nerves.¹⁴ Substance P is released and the individual experiences a painful burning sensation. When purified capsaicin is frequently applied at an appropriate dose, synthesis of substance P is diminished, resulting in reduced local pain overall.¹⁵

Capsaicin does not affect neurons without TRPV1, and administration of capsaicin is not painful if given with anesthesia. An inappropriately high dose of capsaicin destroys cells in the epidermal barrier, resulting in water loss and inducing release of vasoactive peptides and inflammatory cytokines.¹ Careful handling of Capsicum peppers and capsaicin products can reduce the risk for irritation.

Medicinal Use

On-/Off-Label and Potential Uses—Capsaicin is US Food and Drug Administration approved for use in arthritis and musculoskeletal pain. It also is used to treat diabetic neuropathy,⁵ postherpetic neuralgia,⁶ psoriasis,¹⁶ and other conditions. Studies have shown that capsaicin might be useful in treating trigeminal neuralgia,¹⁷ fibromyalgia,¹⁸ migraines,¹⁴ cluster headaches,⁹ and HIV-associated distal sensory neuropathy.⁵

Delivery of Capsaicin—Capsaicin preferentially acts on C-fibers, which transmit dull, aching, chronic pain.¹⁹ The compound is available as a cream, lotion, and large bandage (for the lower back), as well as low- and high-dose patches. Capsaicin creams, lotions, and the low-dose patch are uncomfortable and must be applied for 4 to 6 weeks to take effect, which may impact patient adherence. The high-dose patch, which requires administration under local anesthesia by a health care worker, brings pain relief with a single use and improves adherence.¹¹ Synthetic TRPV1-agonist injectables based on capsaicin have undergone clinical trials for localized pain (eg, postoperative musculoskeletal pain); many patients experience pain relief, though benefit fades over weeks to months.^20,21

Use in Traditional Medicine—Capsicum peppers have been used to aid digestion and promote healing in gastrointestinal conditions, such as dyspepsia.²² The peppers are a source of important vitamins and minerals, including vitamins A, C, and E; many of the B complex vitamins; and magnesium, calcium, and iron.²³

Use as Cancer Therapy—Studies of the use of capsaicin in treating cancer have produced controversial results. In cell and animal models, capsaicin induces apoptosis through downregulation of the Bcl-2 protein; upregulation of oxidative stress, tribbles-related protein 3 (TRIB3), and caspase-3; and other pathways.^19,24-26 On the other hand, consumption of Capsicum peppers has been associated with cancer of the stomach and gallbladder.²⁷ Capsaicin might have anticarcinogenic properties, but its mechanism of action varies, depending on variables not fully understood.

Final Thoughts

Capsaicin is a neuropeptide-active compound found in Capsicum peppers that has many promising applications for use. However, dermatologists should be aware of the possibility of a skin reaction to this compound from handling peppers and using topical medicines. Exposure to capsaicin can cause irritant contact dermatitis that may require clinical care.

Cutaneous Manifestations

Capsicum peppers are used worldwide in preparing spicy dishes. Their active ingredient—capsaicin—is used as a topical medicine to treat localized pain. Capsicum peppers can cause irritant contact dermatitis with symptoms of erythema, cutaneous burning, and itch.¹

Irritant contact dermatitis is a common occupational skin disorder. Many cooks have experienced the sting of a chili pepper after contact with the hands or eyes. Cases of chronic exposure to Capsicum peppers with persistent burning and pain have been called Hunan hand syndrome.² Capsicum peppers also have induced allergic contact dermatitis in a food production worker.³

Capsicum peppers also are used in pepper spray, tear gas, and animal repellents because of their stinging properties. These agents usually cause cutaneous tingling and burning that soon resolves; however, a review of 31 studies showed that crowd-control methods with Capsicum-containing tear gas and pepper spray can cause moderate to severe skin damage such as a persistent skin rash or erythema, or even first-, second-, or third-degree burns.⁴

Topical application of capsaicin isolate is meant to cause burning and deplete local neuropeptides, with a cutaneous reaction that ranges from mild to intolerable.^5,6 Capsaicin also is found in other products. In one published case report, a 3-year-old boy broke out in facial urticaria when his mother kissed him on the cheek after she applied lip plumper containing capsaicin to her lips.⁷ Dermatologists should consider capsaicin an active ingredient that can irritate the skin in the garden, in the kitchen, and in topical products.

Obtaining Relief

Capsaicin-induced dermatitis can be relieved by washing the area with soap, detergent, baking soda, or oily compounds that act as solvents for the nonpolar capsaicin.⁸ Application of ice water or a high-potency topical steroid also may help. If the reaction is severe and persistent, a continuous stellate ganglion block may alleviate the pain of capsaicin-induced contact dermatitis.⁹

Identifying Features and Plant Facts

The Capsicum genus includes chili peppers, paprika, and red peppers. Capsicum peppers are native to tropical regions of the Americas (Figure). The use of Capsicum peppers in food can be traced to Indigenous peoples of Mexico as early as 7000 bc.¹⁰ On the Scoville scale, which was developed to quantify the hotness of foods and spices, Capsicum peppers are rated at approximately 2 million units; by comparison, jalapeño peppers have a Scoville score of 4500¹¹ and capsaicin isolate has a score of 16 million units. Capsicum species rank among the hottest peppers in the world.

Capsicum belongs to the family Solanaceae, which includes tobacco, tomatoes, potatoes, and nightshade plants. There are many varieties of peppers in the Capsicum genus, with 5 domesticated species: Capsicum annuum, Capsicum baccatum, Capsicum chinense, Capsicum frutescens, and Capsicum pubescens. These include bell, poblano, cayenne, tabasco, habanero, and ají peppers, among others. Capsicum species grow as a shrub with flowers that rotate to stellate corollas and rounded berries of different sizes and colors.¹² Capsaicin and other alkaloids are concentrated in the fruit; therefore, Capsicum dermatitis is most commonly induced by contact with the flesh of peppers.

 

 

Irritant Chemicals

Capsaicin (8-methyl-6-nonanoyl vanillylamide) is a nonpolar phenol, which is why washing skin that has come in contact with capsaicin with water or vinegar alone is insufficient to solubilize it.¹³ Capsaicin binds to the transient receptor potential vanilloid 1 (TRPV1), a calcium channel on neurons that opens in response to heat. When bound, the channel opens at a lower temperature threshold and depolarizes nerve endings, leading to vasodilation and activation of sensory nerves.¹⁴ Substance P is released and the individual experiences a painful burning sensation. When purified capsaicin is frequently applied at an appropriate dose, synthesis of substance P is diminished, resulting in reduced local pain overall.¹⁵

Capsaicin does not affect neurons without TRPV1, and administration of capsaicin is not painful if given with anesthesia. An inappropriately high dose of capsaicin destroys cells in the epidermal barrier, resulting in water loss and inducing release of vasoactive peptides and inflammatory cytokines.¹ Careful handling of Capsicum peppers and capsaicin products can reduce the risk for irritation.

Medicinal Use

On-/Off-Label and Potential Uses—Capsaicin is US Food and Drug Administration approved for use in arthritis and musculoskeletal pain. It also is used to treat diabetic neuropathy,⁵ postherpetic neuralgia,⁶ psoriasis,¹⁶ and other conditions. Studies have shown that capsaicin might be useful in treating trigeminal neuralgia,¹⁷ fibromyalgia,¹⁸ migraines,¹⁴ cluster headaches,⁹ and HIV-associated distal sensory neuropathy.⁵

Delivery of Capsaicin—Capsaicin preferentially acts on C-fibers, which transmit dull, aching, chronic pain.¹⁹ The compound is available as a cream, lotion, and large bandage (for the lower back), as well as low- and high-dose patches. Capsaicin creams, lotions, and the low-dose patch are uncomfortable and must be applied for 4 to 6 weeks to take effect, which may impact patient adherence. The high-dose patch, which requires administration under local anesthesia by a health care worker, brings pain relief with a single use and improves adherence.¹¹ Synthetic TRPV1-agonist injectables based on capsaicin have undergone clinical trials for localized pain (eg, postoperative musculoskeletal pain); many patients experience pain relief, though benefit fades over weeks to months.^20,21

Use in Traditional Medicine—Capsicum peppers have been used to aid digestion and promote healing in gastrointestinal conditions, such as dyspepsia.²² The peppers are a source of important vitamins and minerals, including vitamins A, C, and E; many of the B complex vitamins; and magnesium, calcium, and iron.²³

Use as Cancer Therapy—Studies of the use of capsaicin in treating cancer have produced controversial results. In cell and animal models, capsaicin induces apoptosis through downregulation of the Bcl-2 protein; upregulation of oxidative stress, tribbles-related protein 3 (TRIB3), and caspase-3; and other pathways.^19,24-26 On the other hand, consumption of Capsicum peppers has been associated with cancer of the stomach and gallbladder.²⁷ Capsaicin might have anticarcinogenic properties, but its mechanism of action varies, depending on variables not fully understood.

Final Thoughts

Capsaicin is a neuropeptide-active compound found in Capsicum peppers that has many promising applications for use. However, dermatologists should be aware of the possibility of a skin reaction to this compound from handling peppers and using topical medicines. Exposure to capsaicin can cause irritant contact dermatitis that may require clinical care.

Eating disorders (EDs) and feeding disorders refer to a wide spectrum of complex biopsychosocial illnesses. The spectrum of EDs encompasses anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder, and other specified feeding or eating disorders. Feeding disorders, distinguished from EDs based on the absence of body image disturbance, include pica, rumination syndrome, and avoidant/restrictive food intake disorder (ARFID).¹

This spectrum of illnesses predominantly affect young females aged 15 to 45 years, with recent increases in the rates of EDs among males, patients with skin of color, and adolescent females.^2-5 Patients with EDs are at an elevated lifetime risk of suicidal ideation, suicide attempts, and other psychiatric comorbidities compared to the general population.⁶ Specifically, AN and BN are associated with high psychiatric morbidity and mortality. A meta-analysis by Arcelus et al⁷ demonstrated the weighted annual mortality for AN was 5.10 deaths per 1000 person-years (95% CI, 3.57-7.59) among patients with EDs and 4.55 deaths for studies that selected inpatients (95% CI, 3.09-6.28); for BN, the weighted mortality was 1.74 deaths per 1000 person-years (95% CI, 1.09-2.44). Unfortunately, ED diagnoses often are delayed or missed in clinical settings. Patients may lack insight into the severity of their illness, experience embarrassment about their eating behaviors, or actively avoid treatment for their ED.⁸

Pica—compulsive eating of nonnutritive substances outside the cultural norm—and rumination syndrome—regurgitation of undigested food—are feeding disorders more commonly recognized in childhood.^9-11 Pregnancy, intellectual disability, iron deficiency, and lead poisoning are other conditions associated with pica.^6,9,10 Avoidant/restrictive food intake disorder, a new diagnosis added to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)¹ in 2013, is an eating or feeding disturbance resulting in persistent failure to meet nutritional or energy needs. Etiologies of ARFID may include sensory sensitivities and/or a traumatic event related to eating, leading to avoidance of associated foods.¹²

Patients with an ED or a feeding disorder frequently experience malnutrition, including deficiencies, excesses, or imbalances in nutritional intake, which may lead to nutritional dermatoses.¹³ As a result, the skin may present the first visible clues to an ED diagnosis.^8,14-19 Gupta et al¹⁸ organized the skin signs of EDs into 4 categories: (1) those secondary to starvation or malnutrition; (2) cutaneous injury related to self-induced vomiting; (3) dermatoses due to laxative, diuretic, or emetic use; and (4) other concomitant psychiatric illnesses (eg, hand dermatitis from compulsive handwashing, dermatodaxia, onychophagia, trichotillomania). This review will focus on the effects of malnutrition and starvation on the skin.

Skin findings in patients with EDs offer the treating dermatologist a special opportunity for early diagnosis and appropriate consultation with specialists trained in ED treatment. It is important for dermatologists to be vigilant in looking for skin findings of nutritional dermatoses, especially in populations at an increased risk for developing an ED, such as young female patients. The approach to therapy and treatment must occur through a collaborative multidisciplinary effort in a thoughtful and nonjudgmental environment.

Xerosis

Xerosis, or dry skin, is the most common dermatologic finding in both adult and pediatric patients with AN and BN.^14,19 It presents as skin roughness, tightness, flaking, and scaling, which may be complicated by fissuring, itching, and bleeding.²⁰ In healthy skin, moisture is maintained by the stratum corneum and its lipids such as ceramides, cholesterol, and free fatty acids.²¹ Natural moisturizing factor (NMF) within the skin is composed of amino acids, ammonia, urea, uric acid, inorganic salts, lactic acid derivatives, and pyrrolidine-3-carboxylic acid.^20-22 Disruptions to this system result in increased transepidermal water loss and impaired barrier function.²³

In patients with ED, xerosis arises through several mechanisms. Chronic illness or starvation can lead to euthyroid sick syndrome with decreased peripheral conversion of thyroxine (T₄) to triiodothyronine (T₃).^24,25 In the context of functional hypothyroidism, xerosis can arise from decreased eccrine gland secretion.²⁶ Secretions of water, lactate, urea, sodium, and potassium from eccrine glands help to maintain NMF for skin hydration.²⁷ Persistent laxative or diuretic abuse and fluid intake restriction, which are common behaviors across the spectrum of EDs, lead to dehydration and electrolyte imbalances that can manifest as skin dryness.²⁰ Disrupted keratinocyte differentiation due to insufficient stores of vitamins and minerals involved in keratinocyte differentiation, such as vitamins A and C, selenium, and zinc, also may contribute to xerosis.^25,28,29

Severely restrictive eating patterns may lead to development of protein energy malnutrition (PEM). Cutaneous findings in PEM occur due to dysmaturation of epidermal keratinocytes and epidermal atrophy.³⁰ Patients with severe persistent depletion of macronutrients—carbohydrates, fat, and protein—may experience marasmus, resulting in loss of subcutaneous fat that causes the appearance of dry loose skin.^29,31

Xerosis is exceedingly common in the general population and has no predictive value in ED diagnosis; however, this finding should be noted in the context of other signs suggestive of an ED. Treatment of xerosis in the setting of an ED should focus on correction of the underlying malnutrition. Symptomatic alleviation requires improving skin hydration and repairing barrier function. Mild xerosis may not need treatment or can be ameliorated with over-the-counter moisturizers and emollients. Scaling secondary to dry skin can be improved by ingredients such as glycerol, urea, lactic acid, and dexpanthenol.^20,32 Glycerol and urea are small hydrophilic molecules that penetrate the stratum corneum and help to bind moisture within the skin to reduce transepidermal water loss. Urea and lactic acid are keratolytics of NMF commonly found in moisturizers and emollients.^33,34 Dexpanthenol may be used for soothing fissures and pruritus; in vitro and in vivo studies have demonstrated its ability to upregulate dermal fibroblast proliferation and epidermal re-epithelization to promote faster wound healing.³⁵

Lanugo

Lanugo is clinically apparent as a layer of fine, minimally pigmented hair. It is physiologically present on the skin surface of fetuses and newborns. In utero, lanugo plays an essential role in fetal skin protection from amniotic fluid, as well as promotion of proper hydration, thermoregulation, and innate immune development.^36-38 Although it may be found on approximately 30% of newborns as normal variation, its presence beyond the neonatal period signals underlying systemic disease and severe undernutrition.^16,36,39 Rarely, hypertrichosis lanuginosa acquisita has been reported in association with malignancy.^40,41 The finding of lanugo beyond the neonatal period should prompt exclusion of other medical disorders, including neoplasms, chronic infections, hyperthyroidism, malabsorption syndromes, and inflammatory bowel disease.^41-47

There is a limited understanding of the pathomechanism behind lanugo development in the context of malnutrition. Intentional starvation leads to loss of subcutaneous fat and a state of functional hypothyroidism.⁴⁸ Studies hypothesize that lanugo develops as a response to hypothermia, regulated by dermal papillae cell–derived exosomes that may stimulate hair growth via paracrine signaling to outer root sheath cells.^36,49 Molecular studies have found that T₃ impacts skin and hair differentiation and proliferation by modulating thyroid hormone receptor regulation of keratin expression in epithelial cells.^50,51 Lanugo may be a clinical indicator of severe malnutrition among ED patients, especially children and adolescents. A study of 30 patients aged 8 to 17 years with AN and BN who underwent a standard dermatologic examination found significant positive correlation between the presence of lanugo hair growth and concomitant amenorrhea (P<.01) as well as between lanugo hair and body mass index lower than 16 kg/m² (P<.05).¹⁹ Discovery of lanugo in the dermatology clinical setting should prompt a thorough history, including screening questions about eating patterns; attitudes on eating, exercise, and appearance; personal and family history of EDs or other psychiatric disorders; and screening for depression and anxiety. Given its association with other signs of severe malnutrition, a clinical finding of lanugo should prompt close physical examination for other potential signs of an ED and laboratory evaluation for electrolyte levels and blood counts.⁵² Resolution of lanugo secondary to an ED is achieved with restoration of normal total body fat.¹⁸ Treatment should be focused on appropriate weight gain with the guidance of an ED specialist.

Pruritus

The prevalence and pathomechanism of pruritus secondary to EDs remains unclear.^16,53,54 There have been limited reports of pruritus secondary to ED, with Gupta et al⁵³ providing a case series of 6 patients with generalized pruritus in association with starvation and/or rapid weight loss. The study reported remission of pruritus with nutritional rehabilitation and/or weight gain of 5 to 10 pounds. Laboratory evaluation ruled out other causes of pruritus such as cholestasis and uremia.⁵³ Other case reports have associated pruritus with iron deficiency, with anecdotal evidence of pruritus resolution following iron supplementation.^55-59 Although we found no studies specifically relating iron deficiency, EDs, and pruritus, iron deficiency routinely is seen in ED patients and has a known association with pica.^9,10,60 As such, iron deficiency may be a contributing factor in pruritus in ED patients. A UK study of 19 women with AN and a body mass index lower than 16 kg/m² found that more than half of the patients (11/19 [57.9%]) described pruritus on the St. Thomas’ Itch Questionnaire, postulating that pruritus may be a clinical feature of AN.⁶¹ Limited studies with small samples make it difficult to conclude whether pruritus arises as a direct consequence of malnutrition.

Treatment of pruritus should address the underlying ED, as the pathophysiology of itch as it relates to malnutrition is poorly understood. Correction of existing nutritional imbalances by iron supplementation and appropriate weight gain may lead to symptom resolution. Because xerosis may be a contributing factor to pruritus, correction of the xerosis also may be therapeutic. More studies are needed on the connection between pruritus and the nutritional imbalances encountered in patients with EDs.

Acrocyanosis

Acrocyanosis is clinically seen as bluish-dusky discoloration most commonly affecting the hands and feet but also may affect the nose, ears, and nipples. Acrocyanosis typically is a sign of cold intolerance, hypothesized to occur in the context of AN due to shunting of blood centrally in response to hypothermia.^39,62 The diminished oxyhemoglobin delivery to extremity sites leads to the characteristic blue color.⁶³ In a study of 211 adolescent females (age range, 13–17 years) with AN, physical examination revealed peripheral hypothermia and peripheral cyanosis in 80% and 43% of patients, respectively.⁴⁸ Cold intolerance seen in EDs may be secondary to a functional hypothyroid state similar to euthyroid sick syndrome seen in conditions of severe caloric deficit.²⁵

It is possible that anemia and dehydration can worsen acrocyanosis due to impaired delivery of oxyhemoglobin to the body’s periphery.⁶³ In a study of 14 ED patients requiring inpatient care, 6 were found to have underlying anemia following intravenous fluid supplementation.⁶⁴ On admission, the mean (SD) hemoglobin and hematocrit across 14 patients was 12.74 (2.19) and 37.42 (5.99), respectively. Following intravenous fluid supplementation, the mean (SD) hemoglobin and hematocrit decreased to 9.88 (1.79)(P<.001) and 29.56 (4.91)(P=.008), respectively. Most cases reported intentional restriction of dietary sodium and fluid intake, with 2 patients reporting a history of diuretic misuse.⁶⁴ These findings demonstrate that hemoglobin and hematocrit may be falsely normal in patients with AN due to hemoconcentration, suggesting that anemia may be underdiagnosed in inpatients with AN.

Beyond treatment of the underlying ED, acrocyanosis therapy is focused on improvement of circulation and avoidance of exacerbating factors. Pharmacologic intervention rarely is needed. Patients should be reassured that acrocyanosis is a benign condition and often can be improved by dressing warmly and avoiding exposure to cold. Severe cases may warrant trial treatment with nicotinic acid derivatives, α-adrenergic blockade, and topical minoxidil, which have demonstrated limited benefit in treating primary idiopathic acrocyanosis.⁶³

Carotenoderma

Carotenoderma—the presence of a yellow discoloration to skin secondary to hypercarotenemia—has been described in patients with EDs since the 1960s.^65,66 Beyond its clinical appearance, carotenoderma is asymptomatic. Carotenoids are lipid-soluble compounds present in the diet that are metabolized by the intestinal mucosa and liver to the primary conversion product, retinaldehyde, which is further converted to retinol, retinyl esters, and other retinoid metabolites.^67,68 Retinol is bound by lipoproteins and transported in the plasma, then deposited in peripheral tissues,⁶⁹ including in intercellular lipids in the stratum corneum, resulting in an orange hue that is most apparent in sites of increased skin thickness and sweating (eg, palms, soles, nasolabial folds).⁷⁰ In an observational study of ED patients, Glorio et al¹⁴ found that carotenoderma was present in 23.77% (29/122) and 25% (4/16) of patients with BN and other specified feeding or eating disorder, respectively; it was not noted among patients with AN. Prior case reports have provided anecdotal evidence of carotenoderma in AN patients.^66,71 In the setting of an ED, increased serum carotenoids likely are due to increased ingestion of carotene-rich foods, leading to increased levels of carotenoid-bound lipoproteins in the serum.⁷⁰ Resolution of xanthoderma requires restriction of carotenoid intake and may take 2 to 3 months to be clinically apparent. The lipophilic nature of carotenoids allows storage in body fat, prolonging resolution.⁷¹

Hair Changes

Telogen effluvium (TE) and hair pigmentary changes are clinical findings that have been reported in association with EDs.^14,16,19,72 Telogen effluvium occurs when physiologic stress causes a large portion of hairs in the anagen phase of growth to prematurely shift into the catagen then telogen phase. Approximately 2 to 3 months following the initial insult, there is clinically apparent excessive hair shedding compared to baseline.⁷³ Studies have demonstrated that patients with EDs commonly have psychiatric comorbidities such as mood and anxiety disorders, obsessive compulsive disorder, posttraumatic stress disorder, and panic disorder compared to the general population.^6,74-76 As such, stress experienced by ED patients may contribute to TE. Despite TE being commonly reported in ED patients,^16-18 there is a lack of controlled studies of TE in human subjects with ED. An animal model for TE demonstrated that stressed mice exhibited further progression in the hair cycle compared with nonstressed mice (P<.01); the majority of hair follicles in stressed mice were in the catagen phase, while the majority of hair follicles in nonstressed mice were in the anagen phase.⁷⁷ Stressed mice demonstrated an increased number of major histocompatibility complex class II⁺ cell clusters, composed mostly of activated macrophages, per 12.5-mm epidermal length compared to nonstressed mice (mean [SEM], 7.0 [1.1] vs 2.0 [0.3][P<.05]). This study illustrated that stress can lead to inflammatory cell recruitment and activation in the hair follicle microenvironment with growth-inhibitory effects.⁷⁷

The flag sign, or alternating bands of lesser and greater pigmentation in the hair, has been reported in cases of severe PEM.³¹ In addition, PEM may lead to scalp alopecia, dry and brittle hair, and/or hypopigmentation with periods of inadequate nutrition.^29,78 Scalp hair hypopigmentation, brittleness, and alopecia have been reported in pediatric patients with highly selective eating and/or ARFID.^79,80 Maruo et al⁸⁰ described a 3-year-old boy with ASD who consumed only potato chips for more than a year. Physical examination revealed reduced skin turgor overall and sparse red-brown hair on the scalp; laboratory testing showed deficiencies of protein, vitamin A, vitamin D, copper, and zinc. The patient was admitted for nutritional rehabilitation via nasogastric tube feeding, leading to resolution of laboratory abnormalities and growth of thicker black scalp hair over the course of several months.⁸⁰

Neuroendocrine control of keratin expression by thyroid-stimulating hormone (TSH) and thyroid hormones likely plays a role in the regulation of hair follicle activities, including hair growth, structure, and stem cell differentiation.^81,82 Altered thyroid hormone activity, which commonly is seen in patients with EDs,^24,25 may contribute to impaired hair growth and pigmentation.^26,51,83-85 Using tissue cultures of human anagen hair follicles, van Beek et al⁸⁵ provided in vitro evidence that T₃ and T₄ modulate scalp hair follicle growth and pigmentation. Both T₃- and T₄-treated tissue exhibited increased numbers of anagen and decreased numbers of catagen hair follicles in organ cultures compared with control (P<.01); on quantitative Fontana-Masson histochemistry, T₃ and T₄ significantly stimulated hair follicle melanin synthesis compared with control (P<.001 and P<.01, respectively).⁸⁵ Molecular studies by Bodó et al⁸³ have shown that the human scalp epidermis expresses TSH at the messenger RNA and protein levels. Both studies showed that intraepidermal TSH expression is downregulated by thyroid hormones.^83,85 Further studies are needed to examine the impact of malnutrition on local thyroid hormone signaling and action at the level of the dermis, epidermis, and hair follicle.

Discovery of TE, hair loss, and/or hair hypopigmentation should prompt close investigation for other signs of thyroid dysfunction, specifically secondary to malnutrition. Imbalances in TSH, T₃, and T₄ should be corrected. Nutritional deficiencies and dietary habits should be addressed through careful nutritional rehabilitation and targeted ED treatment.

Oral and Mucosal Symptoms

Symptoms of the oral cavity that may arise secondary to EDs and feeding disorders include glossitis, stomatitis, cheilitis, and dental erosions. Mucosal symptoms have been observed in patients with vitamin B deficiencies, inflammatory bowel disease, and other malabsorptive disorders, including patients with EDs.^86-88 Patients following restrictive diets, specifically strict vegan diets, without additional supplementation are at risk for developing vitamin B₁₂ deficiency. Because vitamin B₁₂ is stored in the liver, symptoms of deficiency appear when hepatic stores are depleted over the course of several years.⁸⁹ Insufficient vitamin B₁₂ prevents the proper functioning of methionine synthase, which is required for the conversion of homocysteine to methionine and for the conversion of methyl-tetrahydrofolate to tetrahydrofolate.⁸⁹ Impairment of this process impedes the synthesis of pyrimidine bases of DNA, disrupting the production of rapidly proliferating cells such as myeloid cells or mucosal lining cells. In cases of glossitis and/or stomatitis due to vitamin B₁₂ deficiency, resolution of lesions was achieved within 4 weeks of daily oral supplementation with vitamin B₁₂ at 2 μg daily.^90,91 Iron deficiency, a common finding in EDs, also may contribute to glossitis and angular cheilitis.²⁹ If uncovered, iron deficiency should be corrected by supplementation based on total deficit, age, and sex. Oral supplementation may be done with oral ferrous sulfate (325 mg provides 65 mg elemental iron) or with other iron salts such as ferrous gluconate (325 mg provides 38 mg elemental iron).²⁹ Mucosal symptoms of cheilitis and labial erythema may arise from irritation due to self-induced vomiting.⁸⁸

Dental erosion refers to loss of tooth structure via a chemical process that does not involve bacteria; in contrast, dental caries refer to tooth damage secondary to bacterial acid production. Patients with EDs who repeatedly self-induce vomiting have persistent introduction of gastric acids into the oral cavity, resulting in dissolution of the tooth enamel, which occurs when teeth are persistently exposed to a pH less than 5.5.⁹² Feeding disorders also may predispose patients to dental pathology. In a study of 60 pediatric patients, those with rumination syndrome were significantly more likely to have dental erosions than age- and sex-matched healthy controls (23/30 [77%] vs 4/30 [13%][P<.001]). The same study found no difference in the frequency of dental caries between children with and without rumination syndrome.⁹² These findings suggest that rumination syndrome increases the risk for dental erosions but not dental caries. The distribution of teeth affected by dental erosions may differ between EDs and feeding disorders. Patients with BN are more likely to experience involvement of the palatal surfaces of maxillary teeth, while patients with rumination syndrome had equal involvement of maxillary and mandibular teeth.⁹²

There is limited literature on the role of dentists in the care of patients with EDs and feeding disorders, though existing studies suggest inclusion of a dental care professional in multidisciplinary treatment along with emphasis on education around a home dental care regimen and frequent dental follow-up.^76,93,94 Prevention of further damage requires correction of the underlying behaviors and ED.

Other Dermatologic Findings

Russell sign refers to the development of calluses on the dorsal metacarpophalangeal joints of the dominant hand due to self-induced vomiting. Due to its specificity in purging-type EDs, the discovery of Russell sign should greatly increase suspicion for an ED.¹⁷ Patients with EDs also are at an increased risk for self-harming and body-focused repetitive behaviors, including skin cutting, superficial burning, onychophagia, and trichotillomania.¹⁹ It is important to recognize these signs in patients for whom an ED is suspected. The role of the dermatologist should include careful examination of the skin and documentation of findings that may aid in the diagnosis of an underlying ED.

Final Thoughts

A major limitation of this review is the reliance on small case reports and case series reporting cutaneous manifestations of ED. Controlled studies with larger cohorts are challenging in this population but are needed to substantiate the dermatologic signs commonly associated with EDs. Translational studies may help elucidate the pathomechanisms underlying dermatologic diseases such as lanugo, pruritus, and alopecia in the context of EDs and malnutrition. The known association between thyroid dysfunction and skin disease has been substantiated by clinical and basic science investigation, suggesting a notable role of thyroid hormone and TSH signaling in the skin local environment. Further investigation into nutritional and neuroendocrine regulation of skin health will aid in the diagnosis and treatment of patients impacted by EDs.

The treatment of the underlying ED is key in correcting associated skin disease, which requires interdisciplinary collaboration that addresses the psychological, behavioral, and social components of the condition. Following a diagnosis of ED, assessment should be made of the nutritional rehabilitation required to restore weight and nutritional status. Inpatient treatment may be indicated for patients requiring close monitoring to avoid refeeding syndrome, or those who meet the criteria for extreme AN in the DSM-5 (ie, body mass index <15 kg/m²),¹ or demonstrate signs of medical instability or organ failure secondary to malnutrition.⁶² Long-term recovery for ED patients should focus on behavioral therapy with a multidisciplinary team consisting of a psychiatrist, therapist, dietitian, and primary care provider. Comparative studies in large-scale trials of cognitive behavioral therapy, focal psychodynamic psychotherapy, and specialist supportive clinical management have shown little to no difference in efficacy in treating EDs.^75,95,96

Dermatologists may be the first providers to observe sequelae of nutritional and behavioral derangement in patients with EDs. Existing literature on the dermatologic findings of EDs report great heterogeneity of skin signs, with a very limited number of controlled studies available. Each cutaneous symptom described in this review should not be interpreted as an isolated pathology but should be placed in the context of patient predisposing risk factors and the constellation of other skin findings that may be suggestive of disordered eating behavior or other psychiatric illness. The observation of multiple signs and symptoms at the same time, especially of symptoms uncommonly encountered or suggestive of a severe and prolonged imbalance (eg, xanthoderma with vitamin A excess, aphthous stomatitis with vitamin B deficiency), should heighten clinical suspicion for an underlying ED. A clinician’s highest priority should be to resolve life-threatening medical emergencies and address nutritional derangements with the assistance of experts who are well versed in EDs. The patient should undergo workup to rule out organic causes of their nutritional dermatoses. Given the high psychiatric morbidity and mortality of patients with an ED and the demonstrated benefit of early intervention, recognition of cutaneous manifestations of malnutrition and EDs may be paramount to improving outcomes.

Eating disorders (EDs) and feeding disorders refer to a wide spectrum of complex biopsychosocial illnesses. The spectrum of EDs encompasses anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder, and other specified feeding or eating disorders. Feeding disorders, distinguished from EDs based on the absence of body image disturbance, include pica, rumination syndrome, and avoidant/restrictive food intake disorder (ARFID).¹

This spectrum of illnesses predominantly affect young females aged 15 to 45 years, with recent increases in the rates of EDs among males, patients with skin of color, and adolescent females.^2-5 Patients with EDs are at an elevated lifetime risk of suicidal ideation, suicide attempts, and other psychiatric comorbidities compared to the general population.⁶ Specifically, AN and BN are associated with high psychiatric morbidity and mortality. A meta-analysis by Arcelus et al⁷ demonstrated the weighted annual mortality for AN was 5.10 deaths per 1000 person-years (95% CI, 3.57-7.59) among patients with EDs and 4.55 deaths for studies that selected inpatients (95% CI, 3.09-6.28); for BN, the weighted mortality was 1.74 deaths per 1000 person-years (95% CI, 1.09-2.44). Unfortunately, ED diagnoses often are delayed or missed in clinical settings. Patients may lack insight into the severity of their illness, experience embarrassment about their eating behaviors, or actively avoid treatment for their ED.⁸

Pica—compulsive eating of nonnutritive substances outside the cultural norm—and rumination syndrome—regurgitation of undigested food—are feeding disorders more commonly recognized in childhood.^9-11 Pregnancy, intellectual disability, iron deficiency, and lead poisoning are other conditions associated with pica.^6,9,10 Avoidant/restrictive food intake disorder, a new diagnosis added to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)¹ in 2013, is an eating or feeding disturbance resulting in persistent failure to meet nutritional or energy needs. Etiologies of ARFID may include sensory sensitivities and/or a traumatic event related to eating, leading to avoidance of associated foods.¹²

Patients with an ED or a feeding disorder frequently experience malnutrition, including deficiencies, excesses, or imbalances in nutritional intake, which may lead to nutritional dermatoses.¹³ As a result, the skin may present the first visible clues to an ED diagnosis.^8,14-19 Gupta et al¹⁸ organized the skin signs of EDs into 4 categories: (1) those secondary to starvation or malnutrition; (2) cutaneous injury related to self-induced vomiting; (3) dermatoses due to laxative, diuretic, or emetic use; and (4) other concomitant psychiatric illnesses (eg, hand dermatitis from compulsive handwashing, dermatodaxia, onychophagia, trichotillomania). This review will focus on the effects of malnutrition and starvation on the skin.

Skin findings in patients with EDs offer the treating dermatologist a special opportunity for early diagnosis and appropriate consultation with specialists trained in ED treatment. It is important for dermatologists to be vigilant in looking for skin findings of nutritional dermatoses, especially in populations at an increased risk for developing an ED, such as young female patients. The approach to therapy and treatment must occur through a collaborative multidisciplinary effort in a thoughtful and nonjudgmental environment.

Xerosis

Xerosis, or dry skin, is the most common dermatologic finding in both adult and pediatric patients with AN and BN.^14,19 It presents as skin roughness, tightness, flaking, and scaling, which may be complicated by fissuring, itching, and bleeding.²⁰ In healthy skin, moisture is maintained by the stratum corneum and its lipids such as ceramides, cholesterol, and free fatty acids.²¹ Natural moisturizing factor (NMF) within the skin is composed of amino acids, ammonia, urea, uric acid, inorganic salts, lactic acid derivatives, and pyrrolidine-3-carboxylic acid.^20-22 Disruptions to this system result in increased transepidermal water loss and impaired barrier function.²³

In patients with ED, xerosis arises through several mechanisms. Chronic illness or starvation can lead to euthyroid sick syndrome with decreased peripheral conversion of thyroxine (T₄) to triiodothyronine (T₃).^24,25 In the context of functional hypothyroidism, xerosis can arise from decreased eccrine gland secretion.²⁶ Secretions of water, lactate, urea, sodium, and potassium from eccrine glands help to maintain NMF for skin hydration.²⁷ Persistent laxative or diuretic abuse and fluid intake restriction, which are common behaviors across the spectrum of EDs, lead to dehydration and electrolyte imbalances that can manifest as skin dryness.²⁰ Disrupted keratinocyte differentiation due to insufficient stores of vitamins and minerals involved in keratinocyte differentiation, such as vitamins A and C, selenium, and zinc, also may contribute to xerosis.^25,28,29

Severely restrictive eating patterns may lead to development of protein energy malnutrition (PEM). Cutaneous findings in PEM occur due to dysmaturation of epidermal keratinocytes and epidermal atrophy.³⁰ Patients with severe persistent depletion of macronutrients—carbohydrates, fat, and protein—may experience marasmus, resulting in loss of subcutaneous fat that causes the appearance of dry loose skin.^29,31

Xerosis is exceedingly common in the general population and has no predictive value in ED diagnosis; however, this finding should be noted in the context of other signs suggestive of an ED. Treatment of xerosis in the setting of an ED should focus on correction of the underlying malnutrition. Symptomatic alleviation requires improving skin hydration and repairing barrier function. Mild xerosis may not need treatment or can be ameliorated with over-the-counter moisturizers and emollients. Scaling secondary to dry skin can be improved by ingredients such as glycerol, urea, lactic acid, and dexpanthenol.^20,32 Glycerol and urea are small hydrophilic molecules that penetrate the stratum corneum and help to bind moisture within the skin to reduce transepidermal water loss. Urea and lactic acid are keratolytics of NMF commonly found in moisturizers and emollients.^33,34 Dexpanthenol may be used for soothing fissures and pruritus; in vitro and in vivo studies have demonstrated its ability to upregulate dermal fibroblast proliferation and epidermal re-epithelization to promote faster wound healing.³⁵

Lanugo

Lanugo is clinically apparent as a layer of fine, minimally pigmented hair. It is physiologically present on the skin surface of fetuses and newborns. In utero, lanugo plays an essential role in fetal skin protection from amniotic fluid, as well as promotion of proper hydration, thermoregulation, and innate immune development.^36-38 Although it may be found on approximately 30% of newborns as normal variation, its presence beyond the neonatal period signals underlying systemic disease and severe undernutrition.^16,36,39 Rarely, hypertrichosis lanuginosa acquisita has been reported in association with malignancy.^40,41 The finding of lanugo beyond the neonatal period should prompt exclusion of other medical disorders, including neoplasms, chronic infections, hyperthyroidism, malabsorption syndromes, and inflammatory bowel disease.^41-47

There is a limited understanding of the pathomechanism behind lanugo development in the context of malnutrition. Intentional starvation leads to loss of subcutaneous fat and a state of functional hypothyroidism.⁴⁸ Studies hypothesize that lanugo develops as a response to hypothermia, regulated by dermal papillae cell–derived exosomes that may stimulate hair growth via paracrine signaling to outer root sheath cells.^36,49 Molecular studies have found that T₃ impacts skin and hair differentiation and proliferation by modulating thyroid hormone receptor regulation of keratin expression in epithelial cells.^50,51 Lanugo may be a clinical indicator of severe malnutrition among ED patients, especially children and adolescents. A study of 30 patients aged 8 to 17 years with AN and BN who underwent a standard dermatologic examination found significant positive correlation between the presence of lanugo hair growth and concomitant amenorrhea (P<.01) as well as between lanugo hair and body mass index lower than 16 kg/m² (P<.05).¹⁹ Discovery of lanugo in the dermatology clinical setting should prompt a thorough history, including screening questions about eating patterns; attitudes on eating, exercise, and appearance; personal and family history of EDs or other psychiatric disorders; and screening for depression and anxiety. Given its association with other signs of severe malnutrition, a clinical finding of lanugo should prompt close physical examination for other potential signs of an ED and laboratory evaluation for electrolyte levels and blood counts.⁵² Resolution of lanugo secondary to an ED is achieved with restoration of normal total body fat.¹⁸ Treatment should be focused on appropriate weight gain with the guidance of an ED specialist.

Pruritus

The prevalence and pathomechanism of pruritus secondary to EDs remains unclear.^16,53,54 There have been limited reports of pruritus secondary to ED, with Gupta et al⁵³ providing a case series of 6 patients with generalized pruritus in association with starvation and/or rapid weight loss. The study reported remission of pruritus with nutritional rehabilitation and/or weight gain of 5 to 10 pounds. Laboratory evaluation ruled out other causes of pruritus such as cholestasis and uremia.⁵³ Other case reports have associated pruritus with iron deficiency, with anecdotal evidence of pruritus resolution following iron supplementation.^55-59 Although we found no studies specifically relating iron deficiency, EDs, and pruritus, iron deficiency routinely is seen in ED patients and has a known association with pica.^9,10,60 As such, iron deficiency may be a contributing factor in pruritus in ED patients. A UK study of 19 women with AN and a body mass index lower than 16 kg/m² found that more than half of the patients (11/19 [57.9%]) described pruritus on the St. Thomas’ Itch Questionnaire, postulating that pruritus may be a clinical feature of AN.⁶¹ Limited studies with small samples make it difficult to conclude whether pruritus arises as a direct consequence of malnutrition.

Treatment of pruritus should address the underlying ED, as the pathophysiology of itch as it relates to malnutrition is poorly understood. Correction of existing nutritional imbalances by iron supplementation and appropriate weight gain may lead to symptom resolution. Because xerosis may be a contributing factor to pruritus, correction of the xerosis also may be therapeutic. More studies are needed on the connection between pruritus and the nutritional imbalances encountered in patients with EDs.

Acrocyanosis

Acrocyanosis is clinically seen as bluish-dusky discoloration most commonly affecting the hands and feet but also may affect the nose, ears, and nipples. Acrocyanosis typically is a sign of cold intolerance, hypothesized to occur in the context of AN due to shunting of blood centrally in response to hypothermia.^39,62 The diminished oxyhemoglobin delivery to extremity sites leads to the characteristic blue color.⁶³ In a study of 211 adolescent females (age range, 13–17 years) with AN, physical examination revealed peripheral hypothermia and peripheral cyanosis in 80% and 43% of patients, respectively.⁴⁸ Cold intolerance seen in EDs may be secondary to a functional hypothyroid state similar to euthyroid sick syndrome seen in conditions of severe caloric deficit.²⁵

It is possible that anemia and dehydration can worsen acrocyanosis due to impaired delivery of oxyhemoglobin to the body’s periphery.⁶³ In a study of 14 ED patients requiring inpatient care, 6 were found to have underlying anemia following intravenous fluid supplementation.⁶⁴ On admission, the mean (SD) hemoglobin and hematocrit across 14 patients was 12.74 (2.19) and 37.42 (5.99), respectively. Following intravenous fluid supplementation, the mean (SD) hemoglobin and hematocrit decreased to 9.88 (1.79)(P<.001) and 29.56 (4.91)(P=.008), respectively. Most cases reported intentional restriction of dietary sodium and fluid intake, with 2 patients reporting a history of diuretic misuse.⁶⁴ These findings demonstrate that hemoglobin and hematocrit may be falsely normal in patients with AN due to hemoconcentration, suggesting that anemia may be underdiagnosed in inpatients with AN.

Beyond treatment of the underlying ED, acrocyanosis therapy is focused on improvement of circulation and avoidance of exacerbating factors. Pharmacologic intervention rarely is needed. Patients should be reassured that acrocyanosis is a benign condition and often can be improved by dressing warmly and avoiding exposure to cold. Severe cases may warrant trial treatment with nicotinic acid derivatives, α-adrenergic blockade, and topical minoxidil, which have demonstrated limited benefit in treating primary idiopathic acrocyanosis.⁶³

Carotenoderma

Carotenoderma—the presence of a yellow discoloration to skin secondary to hypercarotenemia—has been described in patients with EDs since the 1960s.^65,66 Beyond its clinical appearance, carotenoderma is asymptomatic. Carotenoids are lipid-soluble compounds present in the diet that are metabolized by the intestinal mucosa and liver to the primary conversion product, retinaldehyde, which is further converted to retinol, retinyl esters, and other retinoid metabolites.^67,68 Retinol is bound by lipoproteins and transported in the plasma, then deposited in peripheral tissues,⁶⁹ including in intercellular lipids in the stratum corneum, resulting in an orange hue that is most apparent in sites of increased skin thickness and sweating (eg, palms, soles, nasolabial folds).⁷⁰ In an observational study of ED patients, Glorio et al¹⁴ found that carotenoderma was present in 23.77% (29/122) and 25% (4/16) of patients with BN and other specified feeding or eating disorder, respectively; it was not noted among patients with AN. Prior case reports have provided anecdotal evidence of carotenoderma in AN patients.^66,71 In the setting of an ED, increased serum carotenoids likely are due to increased ingestion of carotene-rich foods, leading to increased levels of carotenoid-bound lipoproteins in the serum.⁷⁰ Resolution of xanthoderma requires restriction of carotenoid intake and may take 2 to 3 months to be clinically apparent. The lipophilic nature of carotenoids allows storage in body fat, prolonging resolution.⁷¹

Hair Changes

Telogen effluvium (TE) and hair pigmentary changes are clinical findings that have been reported in association with EDs.^14,16,19,72 Telogen effluvium occurs when physiologic stress causes a large portion of hairs in the anagen phase of growth to prematurely shift into the catagen then telogen phase. Approximately 2 to 3 months following the initial insult, there is clinically apparent excessive hair shedding compared to baseline.⁷³ Studies have demonstrated that patients with EDs commonly have psychiatric comorbidities such as mood and anxiety disorders, obsessive compulsive disorder, posttraumatic stress disorder, and panic disorder compared to the general population.^6,74-76 As such, stress experienced by ED patients may contribute to TE. Despite TE being commonly reported in ED patients,^16-18 there is a lack of controlled studies of TE in human subjects with ED. An animal model for TE demonstrated that stressed mice exhibited further progression in the hair cycle compared with nonstressed mice (P<.01); the majority of hair follicles in stressed mice were in the catagen phase, while the majority of hair follicles in nonstressed mice were in the anagen phase.⁷⁷ Stressed mice demonstrated an increased number of major histocompatibility complex class II⁺ cell clusters, composed mostly of activated macrophages, per 12.5-mm epidermal length compared to nonstressed mice (mean [SEM], 7.0 [1.1] vs 2.0 [0.3][P<.05]). This study illustrated that stress can lead to inflammatory cell recruitment and activation in the hair follicle microenvironment with growth-inhibitory effects.⁷⁷

The flag sign, or alternating bands of lesser and greater pigmentation in the hair, has been reported in cases of severe PEM.³¹ In addition, PEM may lead to scalp alopecia, dry and brittle hair, and/or hypopigmentation with periods of inadequate nutrition.^29,78 Scalp hair hypopigmentation, brittleness, and alopecia have been reported in pediatric patients with highly selective eating and/or ARFID.^79,80 Maruo et al⁸⁰ described a 3-year-old boy with ASD who consumed only potato chips for more than a year. Physical examination revealed reduced skin turgor overall and sparse red-brown hair on the scalp; laboratory testing showed deficiencies of protein, vitamin A, vitamin D, copper, and zinc. The patient was admitted for nutritional rehabilitation via nasogastric tube feeding, leading to resolution of laboratory abnormalities and growth of thicker black scalp hair over the course of several months.⁸⁰

Neuroendocrine control of keratin expression by thyroid-stimulating hormone (TSH) and thyroid hormones likely plays a role in the regulation of hair follicle activities, including hair growth, structure, and stem cell differentiation.^81,82 Altered thyroid hormone activity, which commonly is seen in patients with EDs,^24,25 may contribute to impaired hair growth and pigmentation.^26,51,83-85 Using tissue cultures of human anagen hair follicles, van Beek et al⁸⁵ provided in vitro evidence that T₃ and T₄ modulate scalp hair follicle growth and pigmentation. Both T₃- and T₄-treated tissue exhibited increased numbers of anagen and decreased numbers of catagen hair follicles in organ cultures compared with control (P<.01); on quantitative Fontana-Masson histochemistry, T₃ and T₄ significantly stimulated hair follicle melanin synthesis compared with control (P<.001 and P<.01, respectively).⁸⁵ Molecular studies by Bodó et al⁸³ have shown that the human scalp epidermis expresses TSH at the messenger RNA and protein levels. Both studies showed that intraepidermal TSH expression is downregulated by thyroid hormones.^83,85 Further studies are needed to examine the impact of malnutrition on local thyroid hormone signaling and action at the level of the dermis, epidermis, and hair follicle.

Discovery of TE, hair loss, and/or hair hypopigmentation should prompt close investigation for other signs of thyroid dysfunction, specifically secondary to malnutrition. Imbalances in TSH, T₃, and T₄ should be corrected. Nutritional deficiencies and dietary habits should be addressed through careful nutritional rehabilitation and targeted ED treatment.

Oral and Mucosal Symptoms

Symptoms of the oral cavity that may arise secondary to EDs and feeding disorders include glossitis, stomatitis, cheilitis, and dental erosions. Mucosal symptoms have been observed in patients with vitamin B deficiencies, inflammatory bowel disease, and other malabsorptive disorders, including patients with EDs.^86-88 Patients following restrictive diets, specifically strict vegan diets, without additional supplementation are at risk for developing vitamin B₁₂ deficiency. Because vitamin B₁₂ is stored in the liver, symptoms of deficiency appear when hepatic stores are depleted over the course of several years.⁸⁹ Insufficient vitamin B₁₂ prevents the proper functioning of methionine synthase, which is required for the conversion of homocysteine to methionine and for the conversion of methyl-tetrahydrofolate to tetrahydrofolate.⁸⁹ Impairment of this process impedes the synthesis of pyrimidine bases of DNA, disrupting the production of rapidly proliferating cells such as myeloid cells or mucosal lining cells. In cases of glossitis and/or stomatitis due to vitamin B₁₂ deficiency, resolution of lesions was achieved within 4 weeks of daily oral supplementation with vitamin B₁₂ at 2 μg daily.^90,91 Iron deficiency, a common finding in EDs, also may contribute to glossitis and angular cheilitis.²⁹ If uncovered, iron deficiency should be corrected by supplementation based on total deficit, age, and sex. Oral supplementation may be done with oral ferrous sulfate (325 mg provides 65 mg elemental iron) or with other iron salts such as ferrous gluconate (325 mg provides 38 mg elemental iron).²⁹ Mucosal symptoms of cheilitis and labial erythema may arise from irritation due to self-induced vomiting.⁸⁸

Dental erosion refers to loss of tooth structure via a chemical process that does not involve bacteria; in contrast, dental caries refer to tooth damage secondary to bacterial acid production. Patients with EDs who repeatedly self-induce vomiting have persistent introduction of gastric acids into the oral cavity, resulting in dissolution of the tooth enamel, which occurs when teeth are persistently exposed to a pH less than 5.5.⁹² Feeding disorders also may predispose patients to dental pathology. In a study of 60 pediatric patients, those with rumination syndrome were significantly more likely to have dental erosions than age- and sex-matched healthy controls (23/30 [77%] vs 4/30 [13%][P<.001]). The same study found no difference in the frequency of dental caries between children with and without rumination syndrome.⁹² These findings suggest that rumination syndrome increases the risk for dental erosions but not dental caries. The distribution of teeth affected by dental erosions may differ between EDs and feeding disorders. Patients with BN are more likely to experience involvement of the palatal surfaces of maxillary teeth, while patients with rumination syndrome had equal involvement of maxillary and mandibular teeth.⁹²

There is limited literature on the role of dentists in the care of patients with EDs and feeding disorders, though existing studies suggest inclusion of a dental care professional in multidisciplinary treatment along with emphasis on education around a home dental care regimen and frequent dental follow-up.^76,93,94 Prevention of further damage requires correction of the underlying behaviors and ED.

Other Dermatologic Findings

Russell sign refers to the development of calluses on the dorsal metacarpophalangeal joints of the dominant hand due to self-induced vomiting. Due to its specificity in purging-type EDs, the discovery of Russell sign should greatly increase suspicion for an ED.¹⁷ Patients with EDs also are at an increased risk for self-harming and body-focused repetitive behaviors, including skin cutting, superficial burning, onychophagia, and trichotillomania.¹⁹ It is important to recognize these signs in patients for whom an ED is suspected. The role of the dermatologist should include careful examination of the skin and documentation of findings that may aid in the diagnosis of an underlying ED.

Final Thoughts

A major limitation of this review is the reliance on small case reports and case series reporting cutaneous manifestations of ED. Controlled studies with larger cohorts are challenging in this population but are needed to substantiate the dermatologic signs commonly associated with EDs. Translational studies may help elucidate the pathomechanisms underlying dermatologic diseases such as lanugo, pruritus, and alopecia in the context of EDs and malnutrition. The known association between thyroid dysfunction and skin disease has been substantiated by clinical and basic science investigation, suggesting a notable role of thyroid hormone and TSH signaling in the skin local environment. Further investigation into nutritional and neuroendocrine regulation of skin health will aid in the diagnosis and treatment of patients impacted by EDs.

The treatment of the underlying ED is key in correcting associated skin disease, which requires interdisciplinary collaboration that addresses the psychological, behavioral, and social components of the condition. Following a diagnosis of ED, assessment should be made of the nutritional rehabilitation required to restore weight and nutritional status. Inpatient treatment may be indicated for patients requiring close monitoring to avoid refeeding syndrome, or those who meet the criteria for extreme AN in the DSM-5 (ie, body mass index <15 kg/m²),¹ or demonstrate signs of medical instability or organ failure secondary to malnutrition.⁶² Long-term recovery for ED patients should focus on behavioral therapy with a multidisciplinary team consisting of a psychiatrist, therapist, dietitian, and primary care provider. Comparative studies in large-scale trials of cognitive behavioral therapy, focal psychodynamic psychotherapy, and specialist supportive clinical management have shown little to no difference in efficacy in treating EDs.^75,95,96

Dermatologists may be the first providers to observe sequelae of nutritional and behavioral derangement in patients with EDs. Existing literature on the dermatologic findings of EDs report great heterogeneity of skin signs, with a very limited number of controlled studies available. Each cutaneous symptom described in this review should not be interpreted as an isolated pathology but should be placed in the context of patient predisposing risk factors and the constellation of other skin findings that may be suggestive of disordered eating behavior or other psychiatric illness. The observation of multiple signs and symptoms at the same time, especially of symptoms uncommonly encountered or suggestive of a severe and prolonged imbalance (eg, xanthoderma with vitamin A excess, aphthous stomatitis with vitamin B deficiency), should heighten clinical suspicion for an underlying ED. A clinician’s highest priority should be to resolve life-threatening medical emergencies and address nutritional derangements with the assistance of experts who are well versed in EDs. The patient should undergo workup to rule out organic causes of their nutritional dermatoses. Given the high psychiatric morbidity and mortality of patients with an ED and the demonstrated benefit of early intervention, recognition of cutaneous manifestations of malnutrition and EDs may be paramount to improving outcomes.

Eating disorders (EDs) and feeding disorders refer to a wide spectrum of complex biopsychosocial illnesses. The spectrum of EDs encompasses anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder, and other specified feeding or eating disorders. Feeding disorders, distinguished from EDs based on the absence of body image disturbance, include pica, rumination syndrome, and avoidant/restrictive food intake disorder (ARFID).¹

This spectrum of illnesses predominantly affect young females aged 15 to 45 years, with recent increases in the rates of EDs among males, patients with skin of color, and adolescent females.^2-5 Patients with EDs are at an elevated lifetime risk of suicidal ideation, suicide attempts, and other psychiatric comorbidities compared to the general population.⁶ Specifically, AN and BN are associated with high psychiatric morbidity and mortality. A meta-analysis by Arcelus et al⁷ demonstrated the weighted annual mortality for AN was 5.10 deaths per 1000 person-years (95% CI, 3.57-7.59) among patients with EDs and 4.55 deaths for studies that selected inpatients (95% CI, 3.09-6.28); for BN, the weighted mortality was 1.74 deaths per 1000 person-years (95% CI, 1.09-2.44). Unfortunately, ED diagnoses often are delayed or missed in clinical settings. Patients may lack insight into the severity of their illness, experience embarrassment about their eating behaviors, or actively avoid treatment for their ED.⁸

Pica—compulsive eating of nonnutritive substances outside the cultural norm—and rumination syndrome—regurgitation of undigested food—are feeding disorders more commonly recognized in childhood.^9-11 Pregnancy, intellectual disability, iron deficiency, and lead poisoning are other conditions associated with pica.^6,9,10 Avoidant/restrictive food intake disorder, a new diagnosis added to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)¹ in 2013, is an eating or feeding disturbance resulting in persistent failure to meet nutritional or energy needs. Etiologies of ARFID may include sensory sensitivities and/or a traumatic event related to eating, leading to avoidance of associated foods.¹²

Patients with an ED or a feeding disorder frequently experience malnutrition, including deficiencies, excesses, or imbalances in nutritional intake, which may lead to nutritional dermatoses.¹³ As a result, the skin may present the first visible clues to an ED diagnosis.^8,14-19 Gupta et al¹⁸ organized the skin signs of EDs into 4 categories: (1) those secondary to starvation or malnutrition; (2) cutaneous injury related to self-induced vomiting; (3) dermatoses due to laxative, diuretic, or emetic use; and (4) other concomitant psychiatric illnesses (eg, hand dermatitis from compulsive handwashing, dermatodaxia, onychophagia, trichotillomania). This review will focus on the effects of malnutrition and starvation on the skin.

Skin findings in patients with EDs offer the treating dermatologist a special opportunity for early diagnosis and appropriate consultation with specialists trained in ED treatment. It is important for dermatologists to be vigilant in looking for skin findings of nutritional dermatoses, especially in populations at an increased risk for developing an ED, such as young female patients. The approach to therapy and treatment must occur through a collaborative multidisciplinary effort in a thoughtful and nonjudgmental environment.

Xerosis

Xerosis, or dry skin, is the most common dermatologic finding in both adult and pediatric patients with AN and BN.^14,19 It presents as skin roughness, tightness, flaking, and scaling, which may be complicated by fissuring, itching, and bleeding.²⁰ In healthy skin, moisture is maintained by the stratum corneum and its lipids such as ceramides, cholesterol, and free fatty acids.²¹ Natural moisturizing factor (NMF) within the skin is composed of amino acids, ammonia, urea, uric acid, inorganic salts, lactic acid derivatives, and pyrrolidine-3-carboxylic acid.^20-22 Disruptions to this system result in increased transepidermal water loss and impaired barrier function.²³

In patients with ED, xerosis arises through several mechanisms. Chronic illness or starvation can lead to euthyroid sick syndrome with decreased peripheral conversion of thyroxine (T₄) to triiodothyronine (T₃).^24,25 In the context of functional hypothyroidism, xerosis can arise from decreased eccrine gland secretion.²⁶ Secretions of water, lactate, urea, sodium, and potassium from eccrine glands help to maintain NMF for skin hydration.²⁷ Persistent laxative or diuretic abuse and fluid intake restriction, which are common behaviors across the spectrum of EDs, lead to dehydration and electrolyte imbalances that can manifest as skin dryness.²⁰ Disrupted keratinocyte differentiation due to insufficient stores of vitamins and minerals involved in keratinocyte differentiation, such as vitamins A and C, selenium, and zinc, also may contribute to xerosis.^25,28,29

Severely restrictive eating patterns may lead to development of protein energy malnutrition (PEM). Cutaneous findings in PEM occur due to dysmaturation of epidermal keratinocytes and epidermal atrophy.³⁰ Patients with severe persistent depletion of macronutrients—carbohydrates, fat, and protein—may experience marasmus, resulting in loss of subcutaneous fat that causes the appearance of dry loose skin.^29,31

Xerosis is exceedingly common in the general population and has no predictive value in ED diagnosis; however, this finding should be noted in the context of other signs suggestive of an ED. Treatment of xerosis in the setting of an ED should focus on correction of the underlying malnutrition. Symptomatic alleviation requires improving skin hydration and repairing barrier function. Mild xerosis may not need treatment or can be ameliorated with over-the-counter moisturizers and emollients. Scaling secondary to dry skin can be improved by ingredients such as glycerol, urea, lactic acid, and dexpanthenol.^20,32 Glycerol and urea are small hydrophilic molecules that penetrate the stratum corneum and help to bind moisture within the skin to reduce transepidermal water loss. Urea and lactic acid are keratolytics of NMF commonly found in moisturizers and emollients.^33,34 Dexpanthenol may be used for soothing fissures and pruritus; in vitro and in vivo studies have demonstrated its ability to upregulate dermal fibroblast proliferation and epidermal re-epithelization to promote faster wound healing.³⁵

Lanugo

Lanugo is clinically apparent as a layer of fine, minimally pigmented hair. It is physiologically present on the skin surface of fetuses and newborns. In utero, lanugo plays an essential role in fetal skin protection from amniotic fluid, as well as promotion of proper hydration, thermoregulation, and innate immune development.^36-38 Although it may be found on approximately 30% of newborns as normal variation, its presence beyond the neonatal period signals underlying systemic disease and severe undernutrition.^16,36,39 Rarely, hypertrichosis lanuginosa acquisita has been reported in association with malignancy.^40,41 The finding of lanugo beyond the neonatal period should prompt exclusion of other medical disorders, including neoplasms, chronic infections, hyperthyroidism, malabsorption syndromes, and inflammatory bowel disease.^41-47

There is a limited understanding of the pathomechanism behind lanugo development in the context of malnutrition. Intentional starvation leads to loss of subcutaneous fat and a state of functional hypothyroidism.⁴⁸ Studies hypothesize that lanugo develops as a response to hypothermia, regulated by dermal papillae cell–derived exosomes that may stimulate hair growth via paracrine signaling to outer root sheath cells.^36,49 Molecular studies have found that T₃ impacts skin and hair differentiation and proliferation by modulating thyroid hormone receptor regulation of keratin expression in epithelial cells.^50,51 Lanugo may be a clinical indicator of severe malnutrition among ED patients, especially children and adolescents. A study of 30 patients aged 8 to 17 years with AN and BN who underwent a standard dermatologic examination found significant positive correlation between the presence of lanugo hair growth and concomitant amenorrhea (P<.01) as well as between lanugo hair and body mass index lower than 16 kg/m² (P<.05).¹⁹ Discovery of lanugo in the dermatology clinical setting should prompt a thorough history, including screening questions about eating patterns; attitudes on eating, exercise, and appearance; personal and family history of EDs or other psychiatric disorders; and screening for depression and anxiety. Given its association with other signs of severe malnutrition, a clinical finding of lanugo should prompt close physical examination for other potential signs of an ED and laboratory evaluation for electrolyte levels and blood counts.⁵² Resolution of lanugo secondary to an ED is achieved with restoration of normal total body fat.¹⁸ Treatment should be focused on appropriate weight gain with the guidance of an ED specialist.

Pruritus

The prevalence and pathomechanism of pruritus secondary to EDs remains unclear.^16,53,54 There have been limited reports of pruritus secondary to ED, with Gupta et al⁵³ providing a case series of 6 patients with generalized pruritus in association with starvation and/or rapid weight loss. The study reported remission of pruritus with nutritional rehabilitation and/or weight gain of 5 to 10 pounds. Laboratory evaluation ruled out other causes of pruritus such as cholestasis and uremia.⁵³ Other case reports have associated pruritus with iron deficiency, with anecdotal evidence of pruritus resolution following iron supplementation.^55-59 Although we found no studies specifically relating iron deficiency, EDs, and pruritus, iron deficiency routinely is seen in ED patients and has a known association with pica.^9,10,60 As such, iron deficiency may be a contributing factor in pruritus in ED patients. A UK study of 19 women with AN and a body mass index lower than 16 kg/m² found that more than half of the patients (11/19 [57.9%]) described pruritus on the St. Thomas’ Itch Questionnaire, postulating that pruritus may be a clinical feature of AN.⁶¹ Limited studies with small samples make it difficult to conclude whether pruritus arises as a direct consequence of malnutrition.

Treatment of pruritus should address the underlying ED, as the pathophysiology of itch as it relates to malnutrition is poorly understood. Correction of existing nutritional imbalances by iron supplementation and appropriate weight gain may lead to symptom resolution. Because xerosis may be a contributing factor to pruritus, correction of the xerosis also may be therapeutic. More studies are needed on the connection between pruritus and the nutritional imbalances encountered in patients with EDs.

Acrocyanosis

Acrocyanosis is clinically seen as bluish-dusky discoloration most commonly affecting the hands and feet but also may affect the nose, ears, and nipples. Acrocyanosis typically is a sign of cold intolerance, hypothesized to occur in the context of AN due to shunting of blood centrally in response to hypothermia.^39,62 The diminished oxyhemoglobin delivery to extremity sites leads to the characteristic blue color.⁶³ In a study of 211 adolescent females (age range, 13–17 years) with AN, physical examination revealed peripheral hypothermia and peripheral cyanosis in 80% and 43% of patients, respectively.⁴⁸ Cold intolerance seen in EDs may be secondary to a functional hypothyroid state similar to euthyroid sick syndrome seen in conditions of severe caloric deficit.²⁵

It is possible that anemia and dehydration can worsen acrocyanosis due to impaired delivery of oxyhemoglobin to the body’s periphery.⁶³ In a study of 14 ED patients requiring inpatient care, 6 were found to have underlying anemia following intravenous fluid supplementation.⁶⁴ On admission, the mean (SD) hemoglobin and hematocrit across 14 patients was 12.74 (2.19) and 37.42 (5.99), respectively. Following intravenous fluid supplementation, the mean (SD) hemoglobin and hematocrit decreased to 9.88 (1.79)(P<.001) and 29.56 (4.91)(P=.008), respectively. Most cases reported intentional restriction of dietary sodium and fluid intake, with 2 patients reporting a history of diuretic misuse.⁶⁴ These findings demonstrate that hemoglobin and hematocrit may be falsely normal in patients with AN due to hemoconcentration, suggesting that anemia may be underdiagnosed in inpatients with AN.

Beyond treatment of the underlying ED, acrocyanosis therapy is focused on improvement of circulation and avoidance of exacerbating factors. Pharmacologic intervention rarely is needed. Patients should be reassured that acrocyanosis is a benign condition and often can be improved by dressing warmly and avoiding exposure to cold. Severe cases may warrant trial treatment with nicotinic acid derivatives, α-adrenergic blockade, and topical minoxidil, which have demonstrated limited benefit in treating primary idiopathic acrocyanosis.⁶³

Carotenoderma

Carotenoderma—the presence of a yellow discoloration to skin secondary to hypercarotenemia—has been described in patients with EDs since the 1960s.^65,66 Beyond its clinical appearance, carotenoderma is asymptomatic. Carotenoids are lipid-soluble compounds present in the diet that are metabolized by the intestinal mucosa and liver to the primary conversion product, retinaldehyde, which is further converted to retinol, retinyl esters, and other retinoid metabolites.^67,68 Retinol is bound by lipoproteins and transported in the plasma, then deposited in peripheral tissues,⁶⁹ including in intercellular lipids in the stratum corneum, resulting in an orange hue that is most apparent in sites of increased skin thickness and sweating (eg, palms, soles, nasolabial folds).⁷⁰ In an observational study of ED patients, Glorio et al¹⁴ found that carotenoderma was present in 23.77% (29/122) and 25% (4/16) of patients with BN and other specified feeding or eating disorder, respectively; it was not noted among patients with AN. Prior case reports have provided anecdotal evidence of carotenoderma in AN patients.^66,71 In the setting of an ED, increased serum carotenoids likely are due to increased ingestion of carotene-rich foods, leading to increased levels of carotenoid-bound lipoproteins in the serum.⁷⁰ Resolution of xanthoderma requires restriction of carotenoid intake and may take 2 to 3 months to be clinically apparent. The lipophilic nature of carotenoids allows storage in body fat, prolonging resolution.⁷¹

Hair Changes

Telogen effluvium (TE) and hair pigmentary changes are clinical findings that have been reported in association with EDs.^14,16,19,72 Telogen effluvium occurs when physiologic stress causes a large portion of hairs in the anagen phase of growth to prematurely shift into the catagen then telogen phase. Approximately 2 to 3 months following the initial insult, there is clinically apparent excessive hair shedding compared to baseline.⁷³ Studies have demonstrated that patients with EDs commonly have psychiatric comorbidities such as mood and anxiety disorders, obsessive compulsive disorder, posttraumatic stress disorder, and panic disorder compared to the general population.^6,74-76 As such, stress experienced by ED patients may contribute to TE. Despite TE being commonly reported in ED patients,^16-18 there is a lack of controlled studies of TE in human subjects with ED. An animal model for TE demonstrated that stressed mice exhibited further progression in the hair cycle compared with nonstressed mice (P<.01); the majority of hair follicles in stressed mice were in the catagen phase, while the majority of hair follicles in nonstressed mice were in the anagen phase.⁷⁷ Stressed mice demonstrated an increased number of major histocompatibility complex class II⁺ cell clusters, composed mostly of activated macrophages, per 12.5-mm epidermal length compared to nonstressed mice (mean [SEM], 7.0 [1.1] vs 2.0 [0.3][P<.05]). This study illustrated that stress can lead to inflammatory cell recruitment and activation in the hair follicle microenvironment with growth-inhibitory effects.⁷⁷

The flag sign, or alternating bands of lesser and greater pigmentation in the hair, has been reported in cases of severe PEM.³¹ In addition, PEM may lead to scalp alopecia, dry and brittle hair, and/or hypopigmentation with periods of inadequate nutrition.^29,78 Scalp hair hypopigmentation, brittleness, and alopecia have been reported in pediatric patients with highly selective eating and/or ARFID.^79,80 Maruo et al⁸⁰ described a 3-year-old boy with ASD who consumed only potato chips for more than a year. Physical examination revealed reduced skin turgor overall and sparse red-brown hair on the scalp; laboratory testing showed deficiencies of protein, vitamin A, vitamin D, copper, and zinc. The patient was admitted for nutritional rehabilitation via nasogastric tube feeding, leading to resolution of laboratory abnormalities and growth of thicker black scalp hair over the course of several months.⁸⁰

Neuroendocrine control of keratin expression by thyroid-stimulating hormone (TSH) and thyroid hormones likely plays a role in the regulation of hair follicle activities, including hair growth, structure, and stem cell differentiation.^81,82 Altered thyroid hormone activity, which commonly is seen in patients with EDs,^24,25 may contribute to impaired hair growth and pigmentation.^26,51,83-85 Using tissue cultures of human anagen hair follicles, van Beek et al⁸⁵ provided in vitro evidence that T₃ and T₄ modulate scalp hair follicle growth and pigmentation. Both T₃- and T₄-treated tissue exhibited increased numbers of anagen and decreased numbers of catagen hair follicles in organ cultures compared with control (P<.01); on quantitative Fontana-Masson histochemistry, T₃ and T₄ significantly stimulated hair follicle melanin synthesis compared with control (P<.001 and P<.01, respectively).⁸⁵ Molecular studies by Bodó et al⁸³ have shown that the human scalp epidermis expresses TSH at the messenger RNA and protein levels. Both studies showed that intraepidermal TSH expression is downregulated by thyroid hormones.^83,85 Further studies are needed to examine the impact of malnutrition on local thyroid hormone signaling and action at the level of the dermis, epidermis, and hair follicle.

Discovery of TE, hair loss, and/or hair hypopigmentation should prompt close investigation for other signs of thyroid dysfunction, specifically secondary to malnutrition. Imbalances in TSH, T₃, and T₄ should be corrected. Nutritional deficiencies and dietary habits should be addressed through careful nutritional rehabilitation and targeted ED treatment.

Oral and Mucosal Symptoms

Symptoms of the oral cavity that may arise secondary to EDs and feeding disorders include glossitis, stomatitis, cheilitis, and dental erosions. Mucosal symptoms have been observed in patients with vitamin B deficiencies, inflammatory bowel disease, and other malabsorptive disorders, including patients with EDs.^86-88 Patients following restrictive diets, specifically strict vegan diets, without additional supplementation are at risk for developing vitamin B₁₂ deficiency. Because vitamin B₁₂ is stored in the liver, symptoms of deficiency appear when hepatic stores are depleted over the course of several years.⁸⁹ Insufficient vitamin B₁₂ prevents the proper functioning of methionine synthase, which is required for the conversion of homocysteine to methionine and for the conversion of methyl-tetrahydrofolate to tetrahydrofolate.⁸⁹ Impairment of this process impedes the synthesis of pyrimidine bases of DNA, disrupting the production of rapidly proliferating cells such as myeloid cells or mucosal lining cells. In cases of glossitis and/or stomatitis due to vitamin B₁₂ deficiency, resolution of lesions was achieved within 4 weeks of daily oral supplementation with vitamin B₁₂ at 2 μg daily.^90,91 Iron deficiency, a common finding in EDs, also may contribute to glossitis and angular cheilitis.²⁹ If uncovered, iron deficiency should be corrected by supplementation based on total deficit, age, and sex. Oral supplementation may be done with oral ferrous sulfate (325 mg provides 65 mg elemental iron) or with other iron salts such as ferrous gluconate (325 mg provides 38 mg elemental iron).²⁹ Mucosal symptoms of cheilitis and labial erythema may arise from irritation due to self-induced vomiting.⁸⁸

Dental erosion refers to loss of tooth structure via a chemical process that does not involve bacteria; in contrast, dental caries refer to tooth damage secondary to bacterial acid production. Patients with EDs who repeatedly self-induce vomiting have persistent introduction of gastric acids into the oral cavity, resulting in dissolution of the tooth enamel, which occurs when teeth are persistently exposed to a pH less than 5.5.⁹² Feeding disorders also may predispose patients to dental pathology. In a study of 60 pediatric patients, those with rumination syndrome were significantly more likely to have dental erosions than age- and sex-matched healthy controls (23/30 [77%] vs 4/30 [13%][P<.001]). The same study found no difference in the frequency of dental caries between children with and without rumination syndrome.⁹² These findings suggest that rumination syndrome increases the risk for dental erosions but not dental caries. The distribution of teeth affected by dental erosions may differ between EDs and feeding disorders. Patients with BN are more likely to experience involvement of the palatal surfaces of maxillary teeth, while patients with rumination syndrome had equal involvement of maxillary and mandibular teeth.⁹²

There is limited literature on the role of dentists in the care of patients with EDs and feeding disorders, though existing studies suggest inclusion of a dental care professional in multidisciplinary treatment along with emphasis on education around a home dental care regimen and frequent dental follow-up.^76,93,94 Prevention of further damage requires correction of the underlying behaviors and ED.

Other Dermatologic Findings

Russell sign refers to the development of calluses on the dorsal metacarpophalangeal joints of the dominant hand due to self-induced vomiting. Due to its specificity in purging-type EDs, the discovery of Russell sign should greatly increase suspicion for an ED.¹⁷ Patients with EDs also are at an increased risk for self-harming and body-focused repetitive behaviors, including skin cutting, superficial burning, onychophagia, and trichotillomania.¹⁹ It is important to recognize these signs in patients for whom an ED is suspected. The role of the dermatologist should include careful examination of the skin and documentation of findings that may aid in the diagnosis of an underlying ED.

Final Thoughts

A major limitation of this review is the reliance on small case reports and case series reporting cutaneous manifestations of ED. Controlled studies with larger cohorts are challenging in this population but are needed to substantiate the dermatologic signs commonly associated with EDs. Translational studies may help elucidate the pathomechanisms underlying dermatologic diseases such as lanugo, pruritus, and alopecia in the context of EDs and malnutrition. The known association between thyroid dysfunction and skin disease has been substantiated by clinical and basic science investigation, suggesting a notable role of thyroid hormone and TSH signaling in the skin local environment. Further investigation into nutritional and neuroendocrine regulation of skin health will aid in the diagnosis and treatment of patients impacted by EDs.

The treatment of the underlying ED is key in correcting associated skin disease, which requires interdisciplinary collaboration that addresses the psychological, behavioral, and social components of the condition. Following a diagnosis of ED, assessment should be made of the nutritional rehabilitation required to restore weight and nutritional status. Inpatient treatment may be indicated for patients requiring close monitoring to avoid refeeding syndrome, or those who meet the criteria for extreme AN in the DSM-5 (ie, body mass index <15 kg/m²),¹ or demonstrate signs of medical instability or organ failure secondary to malnutrition.⁶² Long-term recovery for ED patients should focus on behavioral therapy with a multidisciplinary team consisting of a psychiatrist, therapist, dietitian, and primary care provider. Comparative studies in large-scale trials of cognitive behavioral therapy, focal psychodynamic psychotherapy, and specialist supportive clinical management have shown little to no difference in efficacy in treating EDs.^75,95,96

Dermatologists may be the first providers to observe sequelae of nutritional and behavioral derangement in patients with EDs. Existing literature on the dermatologic findings of EDs report great heterogeneity of skin signs, with a very limited number of controlled studies available. Each cutaneous symptom described in this review should not be interpreted as an isolated pathology but should be placed in the context of patient predisposing risk factors and the constellation of other skin findings that may be suggestive of disordered eating behavior or other psychiatric illness. The observation of multiple signs and symptoms at the same time, especially of symptoms uncommonly encountered or suggestive of a severe and prolonged imbalance (eg, xanthoderma with vitamin A excess, aphthous stomatitis with vitamin B deficiency), should heighten clinical suspicion for an underlying ED. A clinician’s highest priority should be to resolve life-threatening medical emergencies and address nutritional derangements with the assistance of experts who are well versed in EDs. The patient should undergo workup to rule out organic causes of their nutritional dermatoses. Given the high psychiatric morbidity and mortality of patients with an ED and the demonstrated benefit of early intervention, recognition of cutaneous manifestations of malnutrition and EDs may be paramount to improving outcomes.