Article

To the Editor:

Cryptococcus neoformans is an opportunistic fungus with a predilection for immunocompromised hosts, including solid organ transplant recipients (SOTRs). However, the rapid emergence of diffuse panniculitis only upon the start of therapy for extracutaneous disease is a rare phenomenon. We report the case of a liver transplant recipient who developed a paradoxical inflammatory reaction after initiating liposomal amphotericin B therapy for disseminated C neoformans, which manifested as progressive indurated plaques histologically consistent with cryptococcal panniculitis.

A 44-year-old man who received an orthotopic liver transplant 12 months prior and was on prednisone (20 mg daily) and tacrolimus (7 mg total daily) was admitted for multifocal pneumonia complicated by septic shock. Blood and respiratory cultures grew C neoformans, and lumbar puncture evaluation of cerebrospinal fluid revealed the presence of Cryptococcus antigen in 1:40 titers. Liposomal amphotericin B 5 mg/kg intravenous daily and fluconazole 400 mg intravenous daily were administered starting on the fourth day of admission; maintenance tacrolimus and steroids were stopped. Within 36 hours of treatment initiation, an erythematous papular rash was noted on the extremities, which initially was deemed an infusion reaction. Over the next 6 days, the rash became progressively confluent and hyperpigmented. A dermatologist was consulted on the fifteenth day of admission.

Physical examination by dermatology revealed diffuse, hyperpigmented to erythematous macules on the torso, back, arms, and legs that coalesced into dusky indurated plaques along the thighs, right side of the flank, and right upper arm (Figure 1). Laboratory analysis revealed thrombocytopenia but was otherwise unremarkable. Histoplasma antigen and Coccidioides IgG and IgM enzyme immunoassays were negative, as were cytomegalovirus, HIV, and rapid plasma reagin test results. Blood culture testing was repeated, and the findings were negative.

The emergence of the rash after amphotericin initiation prompted concern that the cause was due to a drug reaction rather than cutaneous involvement of cryptococcal infection. Punch biopsies were obtained from the thigh plaque. Hematoxylin and eosin and Grocott-Gomori methenamine-silver stains revealed cryptococcal organisms in the dermis and subcutaneous fat (Figure 2). Bacterial, acid-fast bacillus, and fungal cultures showed no growth.

The patient was diagnosed with cryptococcal panniculitis. Induction therapy with liposomal amphotericin B 5 mg/kg daily and flucytosine 25 mg/kg twice daily was pursued. During the treatment, cutaneous involvement evolved into superficial desquamation. The patient ultimately died from shock secondary to persistent cryptococcal fungemia.

Cryptococcus neoformans is an opportunistic fungal infection that represents a notable hazard to SOTR, inflicting 1.5% to 2.8% of this population and carrying a 19% to 42% mortality rate.^1,2 This infection occurs at a median of 1.6 to 2.3 years after transplantation,^1,3 though liver transplant recipients and those with immune reconstitution inflammatory syndrome (IRIS)–like complications may present sooner (8.8 and 10.5 months, respectively).⁴ Cutaneous involvement comprises 17% to 21% of cases and is associated with extensive dissemination, including the central nervous system, lung, and bloodstream (61.5%, 23.1%, and 38.5%, respectively).^1-3 When Cryptococcus infects the skin, it classically manifests as multiple nodules, umbilicated papules, ulcers, or cellulitis.³ Involvement of subcutaneous adipose tissue is uncommon and primarily is observed at initial presentation alongside disseminated disease.^5-8 Our case is unique because cutaneous involvement was absent until treatment initiation.

Similar patterns of worsened or unmasked disease following treatment initiation have been observed in SOTRs with extracutaneous cryptococcus and were attributed to IRIS-like phenomena that generate a hyperactive inflammatory response to infection.^4,9 Common immunosuppressive regimens, particularly tacrolimus, depress helper T cell (T_H1) cytokine release and promote a T_H2-dominant, anti-inflammatory state.¹⁰ In cryptococcosis, the fungus itself may stimulate a comparable cytokine milieu to promote immunologic evasion and dissemination. Cryptococcal IRIS-like responses in SOTRs are precipitated by rapid reduction or withdrawal of calcineurin inhibitors and corticosteroids, in combination with the inherent mitogenicity of the C neoformans polysaccharide capsule and antifungal agents.¹⁰ In our patient, cryptococcal yeasts may have invaded subcutaneous tissues when he became fungemic but remained subclinical due to minimal inflammatory recruitment. As treatment began and immunosuppressants diminished, fungal recognition and massive cytokine release resulted in frank panniculitis via precipitous immune dysregulation.

First-line therapy of cryptococcosis entails the use of liposomal amphotericin B and flucytosine for induction, followed by fluconazole for consolidation and maintenance. Use of corticosteroids is atypical to the antifungal regimen; however, a role for them has been suggested in severe IRIS involving individuals who are HIV positive, such as those with lesions demonstrating mass effect.¹¹ Rare case reports have described their utility as adjunctive therapies against cryptococcus in SOTRs when treatment with antifungal agents alone failed.¹² Given the paucity of prospective trials to support corticosteroid use in SOTRs as well as the worse global outcomes in cases of cryptococcal meningitis,¹³ therapeutic corticosteroids were not administered in our patient.

Although our case represents a rare event, cutaneous cryptococcosis and IRIS-like phenomena are clinically relevant complications in immunocompromised patients. In particular, they should be promptly considered in SOTRs receiving maintenance immunosuppressants who demonstrate symptom aggravation despite negative microbial culture results and uninterrupted antifungal therapy.

To the Editor:

Cryptococcus neoformans is an opportunistic fungus with a predilection for immunocompromised hosts, including solid organ transplant recipients (SOTRs). However, the rapid emergence of diffuse panniculitis only upon the start of therapy for extracutaneous disease is a rare phenomenon. We report the case of a liver transplant recipient who developed a paradoxical inflammatory reaction after initiating liposomal amphotericin B therapy for disseminated C neoformans, which manifested as progressive indurated plaques histologically consistent with cryptococcal panniculitis.

A 44-year-old man who received an orthotopic liver transplant 12 months prior and was on prednisone (20 mg daily) and tacrolimus (7 mg total daily) was admitted for multifocal pneumonia complicated by septic shock. Blood and respiratory cultures grew C neoformans, and lumbar puncture evaluation of cerebrospinal fluid revealed the presence of Cryptococcus antigen in 1:40 titers. Liposomal amphotericin B 5 mg/kg intravenous daily and fluconazole 400 mg intravenous daily were administered starting on the fourth day of admission; maintenance tacrolimus and steroids were stopped. Within 36 hours of treatment initiation, an erythematous papular rash was noted on the extremities, which initially was deemed an infusion reaction. Over the next 6 days, the rash became progressively confluent and hyperpigmented. A dermatologist was consulted on the fifteenth day of admission.

Physical examination by dermatology revealed diffuse, hyperpigmented to erythematous macules on the torso, back, arms, and legs that coalesced into dusky indurated plaques along the thighs, right side of the flank, and right upper arm (Figure 1). Laboratory analysis revealed thrombocytopenia but was otherwise unremarkable. Histoplasma antigen and Coccidioides IgG and IgM enzyme immunoassays were negative, as were cytomegalovirus, HIV, and rapid plasma reagin test results. Blood culture testing was repeated, and the findings were negative.

The emergence of the rash after amphotericin initiation prompted concern that the cause was due to a drug reaction rather than cutaneous involvement of cryptococcal infection. Punch biopsies were obtained from the thigh plaque. Hematoxylin and eosin and Grocott-Gomori methenamine-silver stains revealed cryptococcal organisms in the dermis and subcutaneous fat (Figure 2). Bacterial, acid-fast bacillus, and fungal cultures showed no growth.

The patient was diagnosed with cryptococcal panniculitis. Induction therapy with liposomal amphotericin B 5 mg/kg daily and flucytosine 25 mg/kg twice daily was pursued. During the treatment, cutaneous involvement evolved into superficial desquamation. The patient ultimately died from shock secondary to persistent cryptococcal fungemia.

Cryptococcus neoformans is an opportunistic fungal infection that represents a notable hazard to SOTR, inflicting 1.5% to 2.8% of this population and carrying a 19% to 42% mortality rate.^1,2 This infection occurs at a median of 1.6 to 2.3 years after transplantation,^1,3 though liver transplant recipients and those with immune reconstitution inflammatory syndrome (IRIS)–like complications may present sooner (8.8 and 10.5 months, respectively).⁴ Cutaneous involvement comprises 17% to 21% of cases and is associated with extensive dissemination, including the central nervous system, lung, and bloodstream (61.5%, 23.1%, and 38.5%, respectively).^1-3 When Cryptococcus infects the skin, it classically manifests as multiple nodules, umbilicated papules, ulcers, or cellulitis.³ Involvement of subcutaneous adipose tissue is uncommon and primarily is observed at initial presentation alongside disseminated disease.^5-8 Our case is unique because cutaneous involvement was absent until treatment initiation.

Similar patterns of worsened or unmasked disease following treatment initiation have been observed in SOTRs with extracutaneous cryptococcus and were attributed to IRIS-like phenomena that generate a hyperactive inflammatory response to infection.^4,9 Common immunosuppressive regimens, particularly tacrolimus, depress helper T cell (T_H1) cytokine release and promote a T_H2-dominant, anti-inflammatory state.¹⁰ In cryptococcosis, the fungus itself may stimulate a comparable cytokine milieu to promote immunologic evasion and dissemination. Cryptococcal IRIS-like responses in SOTRs are precipitated by rapid reduction or withdrawal of calcineurin inhibitors and corticosteroids, in combination with the inherent mitogenicity of the C neoformans polysaccharide capsule and antifungal agents.¹⁰ In our patient, cryptococcal yeasts may have invaded subcutaneous tissues when he became fungemic but remained subclinical due to minimal inflammatory recruitment. As treatment began and immunosuppressants diminished, fungal recognition and massive cytokine release resulted in frank panniculitis via precipitous immune dysregulation.

First-line therapy of cryptococcosis entails the use of liposomal amphotericin B and flucytosine for induction, followed by fluconazole for consolidation and maintenance. Use of corticosteroids is atypical to the antifungal regimen; however, a role for them has been suggested in severe IRIS involving individuals who are HIV positive, such as those with lesions demonstrating mass effect.¹¹ Rare case reports have described their utility as adjunctive therapies against cryptococcus in SOTRs when treatment with antifungal agents alone failed.¹² Given the paucity of prospective trials to support corticosteroid use in SOTRs as well as the worse global outcomes in cases of cryptococcal meningitis,¹³ therapeutic corticosteroids were not administered in our patient.

Although our case represents a rare event, cutaneous cryptococcosis and IRIS-like phenomena are clinically relevant complications in immunocompromised patients. In particular, they should be promptly considered in SOTRs receiving maintenance immunosuppressants who demonstrate symptom aggravation despite negative microbial culture results and uninterrupted antifungal therapy.

To the Editor:

Cryptococcus neoformans is an opportunistic fungus with a predilection for immunocompromised hosts, including solid organ transplant recipients (SOTRs). However, the rapid emergence of diffuse panniculitis only upon the start of therapy for extracutaneous disease is a rare phenomenon. We report the case of a liver transplant recipient who developed a paradoxical inflammatory reaction after initiating liposomal amphotericin B therapy for disseminated C neoformans, which manifested as progressive indurated plaques histologically consistent with cryptococcal panniculitis.

A 44-year-old man who received an orthotopic liver transplant 12 months prior and was on prednisone (20 mg daily) and tacrolimus (7 mg total daily) was admitted for multifocal pneumonia complicated by septic shock. Blood and respiratory cultures grew C neoformans, and lumbar puncture evaluation of cerebrospinal fluid revealed the presence of Cryptococcus antigen in 1:40 titers. Liposomal amphotericin B 5 mg/kg intravenous daily and fluconazole 400 mg intravenous daily were administered starting on the fourth day of admission; maintenance tacrolimus and steroids were stopped. Within 36 hours of treatment initiation, an erythematous papular rash was noted on the extremities, which initially was deemed an infusion reaction. Over the next 6 days, the rash became progressively confluent and hyperpigmented. A dermatologist was consulted on the fifteenth day of admission.

Physical examination by dermatology revealed diffuse, hyperpigmented to erythematous macules on the torso, back, arms, and legs that coalesced into dusky indurated plaques along the thighs, right side of the flank, and right upper arm (Figure 1). Laboratory analysis revealed thrombocytopenia but was otherwise unremarkable. Histoplasma antigen and Coccidioides IgG and IgM enzyme immunoassays were negative, as were cytomegalovirus, HIV, and rapid plasma reagin test results. Blood culture testing was repeated, and the findings were negative.

The emergence of the rash after amphotericin initiation prompted concern that the cause was due to a drug reaction rather than cutaneous involvement of cryptococcal infection. Punch biopsies were obtained from the thigh plaque. Hematoxylin and eosin and Grocott-Gomori methenamine-silver stains revealed cryptococcal organisms in the dermis and subcutaneous fat (Figure 2). Bacterial, acid-fast bacillus, and fungal cultures showed no growth.

The patient was diagnosed with cryptococcal panniculitis. Induction therapy with liposomal amphotericin B 5 mg/kg daily and flucytosine 25 mg/kg twice daily was pursued. During the treatment, cutaneous involvement evolved into superficial desquamation. The patient ultimately died from shock secondary to persistent cryptococcal fungemia.

Cryptococcus neoformans is an opportunistic fungal infection that represents a notable hazard to SOTR, inflicting 1.5% to 2.8% of this population and carrying a 19% to 42% mortality rate.^1,2 This infection occurs at a median of 1.6 to 2.3 years after transplantation,^1,3 though liver transplant recipients and those with immune reconstitution inflammatory syndrome (IRIS)–like complications may present sooner (8.8 and 10.5 months, respectively).⁴ Cutaneous involvement comprises 17% to 21% of cases and is associated with extensive dissemination, including the central nervous system, lung, and bloodstream (61.5%, 23.1%, and 38.5%, respectively).^1-3 When Cryptococcus infects the skin, it classically manifests as multiple nodules, umbilicated papules, ulcers, or cellulitis.³ Involvement of subcutaneous adipose tissue is uncommon and primarily is observed at initial presentation alongside disseminated disease.^5-8 Our case is unique because cutaneous involvement was absent until treatment initiation.

Similar patterns of worsened or unmasked disease following treatment initiation have been observed in SOTRs with extracutaneous cryptococcus and were attributed to IRIS-like phenomena that generate a hyperactive inflammatory response to infection.^4,9 Common immunosuppressive regimens, particularly tacrolimus, depress helper T cell (T_H1) cytokine release and promote a T_H2-dominant, anti-inflammatory state.¹⁰ In cryptococcosis, the fungus itself may stimulate a comparable cytokine milieu to promote immunologic evasion and dissemination. Cryptococcal IRIS-like responses in SOTRs are precipitated by rapid reduction or withdrawal of calcineurin inhibitors and corticosteroids, in combination with the inherent mitogenicity of the C neoformans polysaccharide capsule and antifungal agents.¹⁰ In our patient, cryptococcal yeasts may have invaded subcutaneous tissues when he became fungemic but remained subclinical due to minimal inflammatory recruitment. As treatment began and immunosuppressants diminished, fungal recognition and massive cytokine release resulted in frank panniculitis via precipitous immune dysregulation.

First-line therapy of cryptococcosis entails the use of liposomal amphotericin B and flucytosine for induction, followed by fluconazole for consolidation and maintenance. Use of corticosteroids is atypical to the antifungal regimen; however, a role for them has been suggested in severe IRIS involving individuals who are HIV positive, such as those with lesions demonstrating mass effect.¹¹ Rare case reports have described their utility as adjunctive therapies against cryptococcus in SOTRs when treatment with antifungal agents alone failed.¹² Given the paucity of prospective trials to support corticosteroid use in SOTRs as well as the worse global outcomes in cases of cryptococcal meningitis,¹³ therapeutic corticosteroids were not administered in our patient.

Although our case represents a rare event, cutaneous cryptococcosis and IRIS-like phenomena are clinically relevant complications in immunocompromised patients. In particular, they should be promptly considered in SOTRs receiving maintenance immunosuppressants who demonstrate symptom aggravation despite negative microbial culture results and uninterrupted antifungal therapy.

The Diagnosis: Scrotal Calcinosis

Scrotal calcinosis is a rare benign disease that results from the deposition of calcium, magnesium, phosphate, and carbonate within the dermis and subcutaneous layer of the skin in the absence of underlying systemic disease or serum calcium and phosphorus abnormalities.^1,2 Lesions usually are asymptomatic but can be mildly painful or pruritic. They usually present in childhood or early adulthood as yellow-white firm nodules ranging in size from a few millimeters to a few centimeters that increase in size and number over time. Additionally, lesions can ulcerate and discharge a chalklike exudative material. Although benign in nature, the quality-of-life impact in patients with this condition can be substantial, specifically regarding cosmesis, which may cause patients to feel embarrassed and even avoid sexual activity. This condition rarely has been associated with infection.¹

Our patient elected to undergo surgical excision under local anesthesia, and the lesions were sent for histopathologic examination. His postoperative course was unremarkable, and he was pleased with the cosmetic result of the surgery (Figure 1). Histopathology revealed calcified deposits that appeared as intradermal basophilic nodules lacking an epithelial lining (Figure 2), consistent with the diagnosis of scrotal calcinosis.² No recurrence of the lesions was documented over the course of 18 months.

The pathogenesis of this condition is not clear. Most research supports scrotal calcinosis resulting from dystrophic calcification of epidermal inclusion cysts.³ There have been cases of scrotal calcinosis coinciding with epidermal inclusion cysts of the scrotum in varying stages of inflammation (some intact and some ruptured).² Some research also suggests dystrophic calcification of eccrine epithelial cysts and degenerated dartos muscle as the origin of scrotal calcinosis.³

The differential diagnosis for this case included calcified steatocystoma multiplex, eruptive xanthomas, nodular scabies, and epidermal inclusion cysts. Steatocystoma multiplex can be inherited in an autosomal-dominant fashion or can develop sporadically with mutations in the KRT17 gene.⁴ It is characterized by multiple sebum-filled, cystic lesions of the pilosebaceous unit that may become calcified. Calcified lesions appear as yellow, firm, irregularly shaped papules or nodules ranging from a few millimeters to centimeters in size. Cysts can develop anywhere on the body with a predilection for the chest, upper extremities, axillae, trunk, groin, and scrotum.⁴ Histologically, our patient’s lesions were not associated with the pilosebaceous unit. Additionally, our patient denied a family history of similar skin lesions, which made calcified steatocystoma multiplex an unlikely diagnosis.

Eruptive xanthomas result from localized deposition of lipids within the dermis, typically in the setting of dyslipidemia or poorly controlled diabetes mellitus. They commonly appear on the extremities or buttocks as pruritic crops of yellow-red papules or nodules that are a few millimeters in size. Although our patient has a history of hyperlipidemia, his lesions differed substantially from eruptive xanthomas in clinical presentation.

Nodular scabies is a manifestation of classic scabies that presents with intensely pruritic erythematous papules and nodules that are a few millimeters in size and commonly occur on the axillae, groin, and genitalia. Our patient’s skin lesions were not pruritic and differed in appearance from nodular scabies.

Although research indicates scrotal calcinosis may result from dystrophic calcification of epidermal inclusion cysts,² the latter present as dome-shaped, flesh-colored nodules with central pores representing the opening of hair follicles. Our patient lacked characteristic findings of epidermal inclusion cysts on histology.

The preferred treatment for scrotal calcinosis is surgical excision, which improves the aesthetic appearance, relieves itch, and removes ulcerative lesions.⁵ Additionally, surgical excision provides histological diagnostic confirmation. Recurrence with incomplete excision is possible; therefore, all lesions should be completely excised to reduce the risk for recurrence.³

The Diagnosis: Scrotal Calcinosis

Scrotal calcinosis is a rare benign disease that results from the deposition of calcium, magnesium, phosphate, and carbonate within the dermis and subcutaneous layer of the skin in the absence of underlying systemic disease or serum calcium and phosphorus abnormalities.^1,2 Lesions usually are asymptomatic but can be mildly painful or pruritic. They usually present in childhood or early adulthood as yellow-white firm nodules ranging in size from a few millimeters to a few centimeters that increase in size and number over time. Additionally, lesions can ulcerate and discharge a chalklike exudative material. Although benign in nature, the quality-of-life impact in patients with this condition can be substantial, specifically regarding cosmesis, which may cause patients to feel embarrassed and even avoid sexual activity. This condition rarely has been associated with infection.¹

Our patient elected to undergo surgical excision under local anesthesia, and the lesions were sent for histopathologic examination. His postoperative course was unremarkable, and he was pleased with the cosmetic result of the surgery (Figure 1). Histopathology revealed calcified deposits that appeared as intradermal basophilic nodules lacking an epithelial lining (Figure 2), consistent with the diagnosis of scrotal calcinosis.² No recurrence of the lesions was documented over the course of 18 months.

The pathogenesis of this condition is not clear. Most research supports scrotal calcinosis resulting from dystrophic calcification of epidermal inclusion cysts.³ There have been cases of scrotal calcinosis coinciding with epidermal inclusion cysts of the scrotum in varying stages of inflammation (some intact and some ruptured).² Some research also suggests dystrophic calcification of eccrine epithelial cysts and degenerated dartos muscle as the origin of scrotal calcinosis.³

The differential diagnosis for this case included calcified steatocystoma multiplex, eruptive xanthomas, nodular scabies, and epidermal inclusion cysts. Steatocystoma multiplex can be inherited in an autosomal-dominant fashion or can develop sporadically with mutations in the KRT17 gene.⁴ It is characterized by multiple sebum-filled, cystic lesions of the pilosebaceous unit that may become calcified. Calcified lesions appear as yellow, firm, irregularly shaped papules or nodules ranging from a few millimeters to centimeters in size. Cysts can develop anywhere on the body with a predilection for the chest, upper extremities, axillae, trunk, groin, and scrotum.⁴ Histologically, our patient’s lesions were not associated with the pilosebaceous unit. Additionally, our patient denied a family history of similar skin lesions, which made calcified steatocystoma multiplex an unlikely diagnosis.

Eruptive xanthomas result from localized deposition of lipids within the dermis, typically in the setting of dyslipidemia or poorly controlled diabetes mellitus. They commonly appear on the extremities or buttocks as pruritic crops of yellow-red papules or nodules that are a few millimeters in size. Although our patient has a history of hyperlipidemia, his lesions differed substantially from eruptive xanthomas in clinical presentation.

Nodular scabies is a manifestation of classic scabies that presents with intensely pruritic erythematous papules and nodules that are a few millimeters in size and commonly occur on the axillae, groin, and genitalia. Our patient’s skin lesions were not pruritic and differed in appearance from nodular scabies.

Although research indicates scrotal calcinosis may result from dystrophic calcification of epidermal inclusion cysts,² the latter present as dome-shaped, flesh-colored nodules with central pores representing the opening of hair follicles. Our patient lacked characteristic findings of epidermal inclusion cysts on histology.

The preferred treatment for scrotal calcinosis is surgical excision, which improves the aesthetic appearance, relieves itch, and removes ulcerative lesions.⁵ Additionally, surgical excision provides histological diagnostic confirmation. Recurrence with incomplete excision is possible; therefore, all lesions should be completely excised to reduce the risk for recurrence.³

The Diagnosis: Scrotal Calcinosis

Scrotal calcinosis is a rare benign disease that results from the deposition of calcium, magnesium, phosphate, and carbonate within the dermis and subcutaneous layer of the skin in the absence of underlying systemic disease or serum calcium and phosphorus abnormalities.^1,2 Lesions usually are asymptomatic but can be mildly painful or pruritic. They usually present in childhood or early adulthood as yellow-white firm nodules ranging in size from a few millimeters to a few centimeters that increase in size and number over time. Additionally, lesions can ulcerate and discharge a chalklike exudative material. Although benign in nature, the quality-of-life impact in patients with this condition can be substantial, specifically regarding cosmesis, which may cause patients to feel embarrassed and even avoid sexual activity. This condition rarely has been associated with infection.¹

Our patient elected to undergo surgical excision under local anesthesia, and the lesions were sent for histopathologic examination. His postoperative course was unremarkable, and he was pleased with the cosmetic result of the surgery (Figure 1). Histopathology revealed calcified deposits that appeared as intradermal basophilic nodules lacking an epithelial lining (Figure 2), consistent with the diagnosis of scrotal calcinosis.² No recurrence of the lesions was documented over the course of 18 months.

The pathogenesis of this condition is not clear. Most research supports scrotal calcinosis resulting from dystrophic calcification of epidermal inclusion cysts.³ There have been cases of scrotal calcinosis coinciding with epidermal inclusion cysts of the scrotum in varying stages of inflammation (some intact and some ruptured).² Some research also suggests dystrophic calcification of eccrine epithelial cysts and degenerated dartos muscle as the origin of scrotal calcinosis.³

The differential diagnosis for this case included calcified steatocystoma multiplex, eruptive xanthomas, nodular scabies, and epidermal inclusion cysts. Steatocystoma multiplex can be inherited in an autosomal-dominant fashion or can develop sporadically with mutations in the KRT17 gene.⁴ It is characterized by multiple sebum-filled, cystic lesions of the pilosebaceous unit that may become calcified. Calcified lesions appear as yellow, firm, irregularly shaped papules or nodules ranging from a few millimeters to centimeters in size. Cysts can develop anywhere on the body with a predilection for the chest, upper extremities, axillae, trunk, groin, and scrotum.⁴ Histologically, our patient’s lesions were not associated with the pilosebaceous unit. Additionally, our patient denied a family history of similar skin lesions, which made calcified steatocystoma multiplex an unlikely diagnosis.

Eruptive xanthomas result from localized deposition of lipids within the dermis, typically in the setting of dyslipidemia or poorly controlled diabetes mellitus. They commonly appear on the extremities or buttocks as pruritic crops of yellow-red papules or nodules that are a few millimeters in size. Although our patient has a history of hyperlipidemia, his lesions differed substantially from eruptive xanthomas in clinical presentation.

Nodular scabies is a manifestation of classic scabies that presents with intensely pruritic erythematous papules and nodules that are a few millimeters in size and commonly occur on the axillae, groin, and genitalia. Our patient’s skin lesions were not pruritic and differed in appearance from nodular scabies.

Although research indicates scrotal calcinosis may result from dystrophic calcification of epidermal inclusion cysts,² the latter present as dome-shaped, flesh-colored nodules with central pores representing the opening of hair follicles. Our patient lacked characteristic findings of epidermal inclusion cysts on histology.

The preferred treatment for scrotal calcinosis is surgical excision, which improves the aesthetic appearance, relieves itch, and removes ulcerative lesions.⁵ Additionally, surgical excision provides histological diagnostic confirmation. Recurrence with incomplete excision is possible; therefore, all lesions should be completely excised to reduce the risk for recurrence.³

To the Editor:

Methemoglobinemia (MetHb) is a condition caused by elevated levels of methemoglobin in the blood, which leads to an overall reduced ability of red blood cells to release oxygen to tissues, causing tissue hypoxia. Methemoglobinemia may be congenital or acquired. Various antibiotics and local anesthetics have been reported to induce acquired MetHb.¹ We describe an adult who presented with MetHb resulting from excessive topical application of local anesthetics for painful scrotal ulcers.

A 54-year-old man presented with multiple scrotal and penile shaft ulcers of a few weeks’ duration with no systemic concerns. His medical history included chronic hepatitis C virus (HCV) and lumbar disc disease. Physical examination revealed multiple erosions and ulcers on an erythematous base involving the scrotal skin and distal penile shaft (Figure). Histopathology revealed acute leukocytoclastic vasculitis, and a laboratory workup was positive for mixed cryoglobulinemia that was thought to be HCV related. The patient was started on a systemic corticosteroid treatment in addition to sofosbuvir-velpatasvir for the treatment of HCV-related mixed cryoglobulinemic vasculitis. Concomitantly, the patient self-treated for pain with a local anesthetic cream containing lidocaine 2.5% and prilocaine 2.5%, applying it excessively every few hours daily for 2 weeks. He also intermittently used occlusive dressings.

After 2 weeks of application, the patient developed lightheadedness and shortness of breath. He returned and was admitted for further evaluation. He had dyspnea and tachypnea of 22 breaths per minute. He also had mild tachycardia (109 beats per minute). He did not have a fever, and his blood pressure was normal. The oxygen saturation measured in ambient room air by pulse oximetry was 82%. A neurologic examination was normal except for mild drowsiness. The lungs were clear, and heart sounds were normal. A 12-lead electrocardiogram also was normal. A complete blood cell count showed severe macrocytic anemia with a hemoglobin level of 7 g/dL, which was a severe decline from the patient’s baseline level of 14 g/dL (reference range, 13–17 g/dL). A MetHb blood level of 11% was reported on co-oximetry. An arterial blood gas analysis revealed a pH of 7.46; partial pressure of carbon dioxide of 41 mm Hg; and partial pressure of oxygen of 63 mm Hg. The haptoglobin level was low at 2.6 mg/dL (reference range, 30–200 mg/dL). An absolute reticulocyte count was markedly elevated at 0.4×10⁶/mL (reference range, 0.03–0.08×10⁶/mL), lactate dehydrogenase was elevated at 430 U/L (reference range, 125–220 U/L), and indirect billirubin was high at 0.9 mg/dL (reference range, 0–0.5 mg/dL), consistent with hemolytic anemia. Electrolyte serum levels and renal function tests were within reference range. A diagnosis of MetHb induced by the lidocaine-prilocaine cream was rendered, and intravenous methylene blue 72 mg (1 mg/kg) was administered over 10 minutes. Within the next 60 minutes, the patient’s drowsiness and arterial desaturation resolved. A subsequent MetHb measurement taken several hours later was reduced to 4%. The patient remained asymptomatic and was eventually discharged.

Methemoglobinemia is an altered state of hemoglobin where the ferrous (Fe2⁺) ions of heme are oxidized to the ferric (Fe3⁺) state. These ferric ions are unable to bind oxygen, resulting in impaired oxygen delivery to tissues.¹ Local anesthetics, which are strong oxidizers, have been reported to induce MetHb.² In our patient, the extensive use of lidocaine 2.5%–prilocaine 2.5% cream resulted in severe life-threatening MetHb. The oxidizing properties of local anesthetics can be attributed to their chemical structure. Benzocaine is metabolized to potent oxidizers such as aniline, phenylhydroxylamine, and nitrobenzene.³ Prilocaine and another potent oxidizer, ortho-toluidine, which is a metabolite of prilocaine, can oxidize the iron in hemoglobin from ferrous (Fe2⁺) to ferric (Fe3⁺), leading to MetHb.^2,3

Cases of anesthetic-induced MetHb primarily are associated with overuse of the product by applying it to large surface areas or using it for prolonged periods of time. In one case report, the occlusive dressing of the lidocaine-prilocaine cream applied to skin of the legs that was already abraded by laser epilation therapy resulted in MetHb.⁴ In our patient, applying the topical anesthetic to the eroded high-absorptive mucosal surface of the scrotal skin and the use of occlusive dressings increased the risk for toxicity. Absorption from scrotal skin is 40-times higher than the forearm.⁵ The face, axillae, and scalp also exhibit increased absorption compared to the forearm—10-, 4-, and 3-times higher, respectively.

In recent years, the use of topical anesthetics has greatly expanded due to the popularity of aesthetic and cosmetic procedures. These procedures often are performed in an outpatient setting.⁶ Dermatologists should be well aware of MetHb as a serious adverse effect and guide patients accordingly, as patients do not tend to consider a local anesthetic to be a drug. Drug interactions also may affect free lidocaine concentrations by liver cytochrome P450 metabolism; although this was not the case with our patient, special attention should be given to potential interactions that may exacerbate this serious adverse effect. Consideration should be given to patients applying the anesthetic to areas with high absorption capacity.

To the Editor:

Methemoglobinemia (MetHb) is a condition caused by elevated levels of methemoglobin in the blood, which leads to an overall reduced ability of red blood cells to release oxygen to tissues, causing tissue hypoxia. Methemoglobinemia may be congenital or acquired. Various antibiotics and local anesthetics have been reported to induce acquired MetHb.¹ We describe an adult who presented with MetHb resulting from excessive topical application of local anesthetics for painful scrotal ulcers.

A 54-year-old man presented with multiple scrotal and penile shaft ulcers of a few weeks’ duration with no systemic concerns. His medical history included chronic hepatitis C virus (HCV) and lumbar disc disease. Physical examination revealed multiple erosions and ulcers on an erythematous base involving the scrotal skin and distal penile shaft (Figure). Histopathology revealed acute leukocytoclastic vasculitis, and a laboratory workup was positive for mixed cryoglobulinemia that was thought to be HCV related. The patient was started on a systemic corticosteroid treatment in addition to sofosbuvir-velpatasvir for the treatment of HCV-related mixed cryoglobulinemic vasculitis. Concomitantly, the patient self-treated for pain with a local anesthetic cream containing lidocaine 2.5% and prilocaine 2.5%, applying it excessively every few hours daily for 2 weeks. He also intermittently used occlusive dressings.

After 2 weeks of application, the patient developed lightheadedness and shortness of breath. He returned and was admitted for further evaluation. He had dyspnea and tachypnea of 22 breaths per minute. He also had mild tachycardia (109 beats per minute). He did not have a fever, and his blood pressure was normal. The oxygen saturation measured in ambient room air by pulse oximetry was 82%. A neurologic examination was normal except for mild drowsiness. The lungs were clear, and heart sounds were normal. A 12-lead electrocardiogram also was normal. A complete blood cell count showed severe macrocytic anemia with a hemoglobin level of 7 g/dL, which was a severe decline from the patient’s baseline level of 14 g/dL (reference range, 13–17 g/dL). A MetHb blood level of 11% was reported on co-oximetry. An arterial blood gas analysis revealed a pH of 7.46; partial pressure of carbon dioxide of 41 mm Hg; and partial pressure of oxygen of 63 mm Hg. The haptoglobin level was low at 2.6 mg/dL (reference range, 30–200 mg/dL). An absolute reticulocyte count was markedly elevated at 0.4×10⁶/mL (reference range, 0.03–0.08×10⁶/mL), lactate dehydrogenase was elevated at 430 U/L (reference range, 125–220 U/L), and indirect billirubin was high at 0.9 mg/dL (reference range, 0–0.5 mg/dL), consistent with hemolytic anemia. Electrolyte serum levels and renal function tests were within reference range. A diagnosis of MetHb induced by the lidocaine-prilocaine cream was rendered, and intravenous methylene blue 72 mg (1 mg/kg) was administered over 10 minutes. Within the next 60 minutes, the patient’s drowsiness and arterial desaturation resolved. A subsequent MetHb measurement taken several hours later was reduced to 4%. The patient remained asymptomatic and was eventually discharged.

Methemoglobinemia is an altered state of hemoglobin where the ferrous (Fe2⁺) ions of heme are oxidized to the ferric (Fe3⁺) state. These ferric ions are unable to bind oxygen, resulting in impaired oxygen delivery to tissues.¹ Local anesthetics, which are strong oxidizers, have been reported to induce MetHb.² In our patient, the extensive use of lidocaine 2.5%–prilocaine 2.5% cream resulted in severe life-threatening MetHb. The oxidizing properties of local anesthetics can be attributed to their chemical structure. Benzocaine is metabolized to potent oxidizers such as aniline, phenylhydroxylamine, and nitrobenzene.³ Prilocaine and another potent oxidizer, ortho-toluidine, which is a metabolite of prilocaine, can oxidize the iron in hemoglobin from ferrous (Fe2⁺) to ferric (Fe3⁺), leading to MetHb.^2,3

Cases of anesthetic-induced MetHb primarily are associated with overuse of the product by applying it to large surface areas or using it for prolonged periods of time. In one case report, the occlusive dressing of the lidocaine-prilocaine cream applied to skin of the legs that was already abraded by laser epilation therapy resulted in MetHb.⁴ In our patient, applying the topical anesthetic to the eroded high-absorptive mucosal surface of the scrotal skin and the use of occlusive dressings increased the risk for toxicity. Absorption from scrotal skin is 40-times higher than the forearm.⁵ The face, axillae, and scalp also exhibit increased absorption compared to the forearm—10-, 4-, and 3-times higher, respectively.

In recent years, the use of topical anesthetics has greatly expanded due to the popularity of aesthetic and cosmetic procedures. These procedures often are performed in an outpatient setting.⁶ Dermatologists should be well aware of MetHb as a serious adverse effect and guide patients accordingly, as patients do not tend to consider a local anesthetic to be a drug. Drug interactions also may affect free lidocaine concentrations by liver cytochrome P450 metabolism; although this was not the case with our patient, special attention should be given to potential interactions that may exacerbate this serious adverse effect. Consideration should be given to patients applying the anesthetic to areas with high absorption capacity.

To the Editor:

Methemoglobinemia (MetHb) is a condition caused by elevated levels of methemoglobin in the blood, which leads to an overall reduced ability of red blood cells to release oxygen to tissues, causing tissue hypoxia. Methemoglobinemia may be congenital or acquired. Various antibiotics and local anesthetics have been reported to induce acquired MetHb.¹ We describe an adult who presented with MetHb resulting from excessive topical application of local anesthetics for painful scrotal ulcers.

A 54-year-old man presented with multiple scrotal and penile shaft ulcers of a few weeks’ duration with no systemic concerns. His medical history included chronic hepatitis C virus (HCV) and lumbar disc disease. Physical examination revealed multiple erosions and ulcers on an erythematous base involving the scrotal skin and distal penile shaft (Figure). Histopathology revealed acute leukocytoclastic vasculitis, and a laboratory workup was positive for mixed cryoglobulinemia that was thought to be HCV related. The patient was started on a systemic corticosteroid treatment in addition to sofosbuvir-velpatasvir for the treatment of HCV-related mixed cryoglobulinemic vasculitis. Concomitantly, the patient self-treated for pain with a local anesthetic cream containing lidocaine 2.5% and prilocaine 2.5%, applying it excessively every few hours daily for 2 weeks. He also intermittently used occlusive dressings.

After 2 weeks of application, the patient developed lightheadedness and shortness of breath. He returned and was admitted for further evaluation. He had dyspnea and tachypnea of 22 breaths per minute. He also had mild tachycardia (109 beats per minute). He did not have a fever, and his blood pressure was normal. The oxygen saturation measured in ambient room air by pulse oximetry was 82%. A neurologic examination was normal except for mild drowsiness. The lungs were clear, and heart sounds were normal. A 12-lead electrocardiogram also was normal. A complete blood cell count showed severe macrocytic anemia with a hemoglobin level of 7 g/dL, which was a severe decline from the patient’s baseline level of 14 g/dL (reference range, 13–17 g/dL). A MetHb blood level of 11% was reported on co-oximetry. An arterial blood gas analysis revealed a pH of 7.46; partial pressure of carbon dioxide of 41 mm Hg; and partial pressure of oxygen of 63 mm Hg. The haptoglobin level was low at 2.6 mg/dL (reference range, 30–200 mg/dL). An absolute reticulocyte count was markedly elevated at 0.4×10⁶/mL (reference range, 0.03–0.08×10⁶/mL), lactate dehydrogenase was elevated at 430 U/L (reference range, 125–220 U/L), and indirect billirubin was high at 0.9 mg/dL (reference range, 0–0.5 mg/dL), consistent with hemolytic anemia. Electrolyte serum levels and renal function tests were within reference range. A diagnosis of MetHb induced by the lidocaine-prilocaine cream was rendered, and intravenous methylene blue 72 mg (1 mg/kg) was administered over 10 minutes. Within the next 60 minutes, the patient’s drowsiness and arterial desaturation resolved. A subsequent MetHb measurement taken several hours later was reduced to 4%. The patient remained asymptomatic and was eventually discharged.

Methemoglobinemia is an altered state of hemoglobin where the ferrous (Fe2⁺) ions of heme are oxidized to the ferric (Fe3⁺) state. These ferric ions are unable to bind oxygen, resulting in impaired oxygen delivery to tissues.¹ Local anesthetics, which are strong oxidizers, have been reported to induce MetHb.² In our patient, the extensive use of lidocaine 2.5%–prilocaine 2.5% cream resulted in severe life-threatening MetHb. The oxidizing properties of local anesthetics can be attributed to their chemical structure. Benzocaine is metabolized to potent oxidizers such as aniline, phenylhydroxylamine, and nitrobenzene.³ Prilocaine and another potent oxidizer, ortho-toluidine, which is a metabolite of prilocaine, can oxidize the iron in hemoglobin from ferrous (Fe2⁺) to ferric (Fe3⁺), leading to MetHb.^2,3

Cases of anesthetic-induced MetHb primarily are associated with overuse of the product by applying it to large surface areas or using it for prolonged periods of time. In one case report, the occlusive dressing of the lidocaine-prilocaine cream applied to skin of the legs that was already abraded by laser epilation therapy resulted in MetHb.⁴ In our patient, applying the topical anesthetic to the eroded high-absorptive mucosal surface of the scrotal skin and the use of occlusive dressings increased the risk for toxicity. Absorption from scrotal skin is 40-times higher than the forearm.⁵ The face, axillae, and scalp also exhibit increased absorption compared to the forearm—10-, 4-, and 3-times higher, respectively.

In recent years, the use of topical anesthetics has greatly expanded due to the popularity of aesthetic and cosmetic procedures. These procedures often are performed in an outpatient setting.⁶ Dermatologists should be well aware of MetHb as a serious adverse effect and guide patients accordingly, as patients do not tend to consider a local anesthetic to be a drug. Drug interactions also may affect free lidocaine concentrations by liver cytochrome P450 metabolism; although this was not the case with our patient, special attention should be given to potential interactions that may exacerbate this serious adverse effect. Consideration should be given to patients applying the anesthetic to areas with high absorption capacity.

Data are limited regarding the effect of interrupting radiation therapy for patients with BC. A retrospective study by Chow and colleagues looked at 35,845 patients with nonmetastatic triple-negative BC from the National Cancer Database who had received external beam radiation therapy as part of the management of their BC. The analysis showed inferior overall survival in patients with a longer duration of radiation treatment (hazard ratio 1.023; 95% CI 1.015-1.031) The more days of interruption, the higher the likelihood of mortality seen. In reference to 0-1 days of interruption, patients with 2-5 interrupted days (hazard ratio 1.069; 95% CI 1.002-1.140), 6-10 interrupted days (hazard ratio 1.239; 95% CI 1.140-1.348), and 11-15 interrupted days (hazard ratio 1.265; 95% CI 1.126-1.431) did worse. These findings should encourage further studies to explore ways to minimize treatment interruptions among patients with BC.

A lack of adherence to adjuvant endocrine therapy has been associated with increased mortality among women with BC. The retrospective study by Zheng and Thomas  included 25,796 older women (> 65 years old) diagnosed with stage I-III hormone receptor–positive BC and looked at associations between adherence to and persistence with adjuvant endocrine therapy and mortality in this cohort. Their findings showed that the risk for all-cause mortality was reduced by 25% in patients with vs without cumulative adherence to endocrine therapy (hazard ratio 0.75; P < .001), although no association was seen with BC-specific mortality. Persistence with endocrine therapy, which was defined as having taken the treatment for ≥ 180 continuous days, was associated with 11% reduction in all-cause mortality and 37% reduction in BC-specific mortality. This study supports prior studies in highlighting the importance of endocrine therapy adherence among women with hormone-positive BC.

Tumor-infiltrating lymphocytes (TIL) are considered significant prognostic markers in patients with BC, although the prognostic effect of TIL in human epidermal growth factor reception 2 (HER2)–low BC has not been identified. A large-cohort, single-institution retrospective analysis by Sun and colleagues investigated the prognostic role of TIL in HER2-low early-stage BC. The analysis included 1763 patients with early-stage BC who underwent surgery, of whom 429 patients were HER2+, 739 were HER2-low, and 595 were HER2-0. No differences in disease-free survival (DFS) were seen between the three cohorts. However, in patients with HER2-low BC, high (>10%) vs low (≤10%) TIL levels were associated with a 53% improvement in DFS overall (hazard ratio 0.47; P = .035), and a 58% improvement in DFS was seen for the hormone receptor–positive/HER2-low cohort (hazard ratio 0.42; P = .032).

Data are limited regarding the effect of interrupting radiation therapy for patients with BC. A retrospective study by Chow and colleagues looked at 35,845 patients with nonmetastatic triple-negative BC from the National Cancer Database who had received external beam radiation therapy as part of the management of their BC. The analysis showed inferior overall survival in patients with a longer duration of radiation treatment (hazard ratio 1.023; 95% CI 1.015-1.031) The more days of interruption, the higher the likelihood of mortality seen. In reference to 0-1 days of interruption, patients with 2-5 interrupted days (hazard ratio 1.069; 95% CI 1.002-1.140), 6-10 interrupted days (hazard ratio 1.239; 95% CI 1.140-1.348), and 11-15 interrupted days (hazard ratio 1.265; 95% CI 1.126-1.431) did worse. These findings should encourage further studies to explore ways to minimize treatment interruptions among patients with BC.

A lack of adherence to adjuvant endocrine therapy has been associated with increased mortality among women with BC. The retrospective study by Zheng and Thomas  included 25,796 older women (> 65 years old) diagnosed with stage I-III hormone receptor–positive BC and looked at associations between adherence to and persistence with adjuvant endocrine therapy and mortality in this cohort. Their findings showed that the risk for all-cause mortality was reduced by 25% in patients with vs without cumulative adherence to endocrine therapy (hazard ratio 0.75; P < .001), although no association was seen with BC-specific mortality. Persistence with endocrine therapy, which was defined as having taken the treatment for ≥ 180 continuous days, was associated with 11% reduction in all-cause mortality and 37% reduction in BC-specific mortality. This study supports prior studies in highlighting the importance of endocrine therapy adherence among women with hormone-positive BC.

Tumor-infiltrating lymphocytes (TIL) are considered significant prognostic markers in patients with BC, although the prognostic effect of TIL in human epidermal growth factor reception 2 (HER2)–low BC has not been identified. A large-cohort, single-institution retrospective analysis by Sun and colleagues investigated the prognostic role of TIL in HER2-low early-stage BC. The analysis included 1763 patients with early-stage BC who underwent surgery, of whom 429 patients were HER2+, 739 were HER2-low, and 595 were HER2-0. No differences in disease-free survival (DFS) were seen between the three cohorts. However, in patients with HER2-low BC, high (>10%) vs low (≤10%) TIL levels were associated with a 53% improvement in DFS overall (hazard ratio 0.47; P = .035), and a 58% improvement in DFS was seen for the hormone receptor–positive/HER2-low cohort (hazard ratio 0.42; P = .032).

Data are limited regarding the effect of interrupting radiation therapy for patients with BC. A retrospective study by Chow and colleagues looked at 35,845 patients with nonmetastatic triple-negative BC from the National Cancer Database who had received external beam radiation therapy as part of the management of their BC. The analysis showed inferior overall survival in patients with a longer duration of radiation treatment (hazard ratio 1.023; 95% CI 1.015-1.031) The more days of interruption, the higher the likelihood of mortality seen. In reference to 0-1 days of interruption, patients with 2-5 interrupted days (hazard ratio 1.069; 95% CI 1.002-1.140), 6-10 interrupted days (hazard ratio 1.239; 95% CI 1.140-1.348), and 11-15 interrupted days (hazard ratio 1.265; 95% CI 1.126-1.431) did worse. These findings should encourage further studies to explore ways to minimize treatment interruptions among patients with BC.

A lack of adherence to adjuvant endocrine therapy has been associated with increased mortality among women with BC. The retrospective study by Zheng and Thomas  included 25,796 older women (> 65 years old) diagnosed with stage I-III hormone receptor–positive BC and looked at associations between adherence to and persistence with adjuvant endocrine therapy and mortality in this cohort. Their findings showed that the risk for all-cause mortality was reduced by 25% in patients with vs without cumulative adherence to endocrine therapy (hazard ratio 0.75; P < .001), although no association was seen with BC-specific mortality. Persistence with endocrine therapy, which was defined as having taken the treatment for ≥ 180 continuous days, was associated with 11% reduction in all-cause mortality and 37% reduction in BC-specific mortality. This study supports prior studies in highlighting the importance of endocrine therapy adherence among women with hormone-positive BC.

Tumor-infiltrating lymphocytes (TIL) are considered significant prognostic markers in patients with BC, although the prognostic effect of TIL in human epidermal growth factor reception 2 (HER2)–low BC has not been identified. A large-cohort, single-institution retrospective analysis by Sun and colleagues investigated the prognostic role of TIL in HER2-low early-stage BC. The analysis included 1763 patients with early-stage BC who underwent surgery, of whom 429 patients were HER2+, 739 were HER2-low, and 595 were HER2-0. No differences in disease-free survival (DFS) were seen between the three cohorts. However, in patients with HER2-low BC, high (>10%) vs low (≤10%) TIL levels were associated with a 53% improvement in DFS overall (hazard ratio 0.47; P = .035), and a 58% improvement in DFS was seen for the hormone receptor–positive/HER2-low cohort (hazard ratio 0.42; P = .032).

The addition of pertuzumab to trastuzumab plus chemotherapy has demonstrated improvement in pathologic complete response (pCR) rates compared with trastuzumab plus chemotherapy in early-stage HER2-positive breast cancer.³ The framework of oncology is built on clinical trials through their rigorous design, enrollment, and synthesis of data; however, real-world studies are an integral component of cancer research because they provide a more representative sample of the general population treated in routine clinical practice. Neopearl was a retrospective, observational, real-world study that evaluated the efficacy and safety of trastuzumab plus chemotherapy with or without pertuzumab among 271 patients with stage II-III HER2-positive breast cancer (Fabbri et al). The addition of pertuzumab led to an increase in pCR rate (49% vs 62%; odds ratio 1.74; P = .032) and improvement in 5-year event-free survival (81% vs 93%; hazard ratio 2.22; P = .041), and the benefit on univariate analysis was restricted to patients with positive axillary nodes. Furthermore, there were no significant differences in adverse events, including cardiac, between the two groups. These results serve to strengthen the available data regarding the clinical efficacy and favorable safety profile of dual HER2-targeted therapy combined with neoadjuvant chemotherapy.

Lifestyle factors, including physical activity and diet, are becoming increasingly recognized as important determinants of various cancer-specific outcomes and overall health. Furthermore, because these are modifiable, there is often motivation on behalf of an individual to change behaviors that can affect their outcome. Adherence to the Mediterranean diet (MD) has been associated with reduced risk for breast cancer development and lower mortality among women with breast cancer.^4,5 Data from a prospective multicenter European cohort including 13,270 breast cancer survivors demonstrated that low compared with medium adherence to a MD before a breast cancer diagnosis was associated with a 13% higher risk for all-cause mortality (hazard ratio 1.13; 95% CI 1.01-1.26). A three-unit increase in the adapted relative MD score was associated with an 8% reduced risk for overall mortality (hazard ratio_3-unit 0.92; 95% CI 0.87-0.97); this result was sustained in the postmenopausal population and strengthened in metastatic disease (Castro-Espin et al). The connection between diet and cancer outcomes is complex, and future research evaluating specific dietary interventions and the underlying biologic pathways by which nutrition exerts its effects will be important to inform our counseling for patients with breast cancer in the survivorship setting.

Additional References

1. Whelan TJ, Olivotto IA, Parulekar WR, et al, for the MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373:307-16. doi:10.1056/NEJMoa1415340
2. ClinicalTrials.gov. Regional radiotherapy in biomarker low-risk node positive and T3N0 breast cancer (TAILOR RT). National Library of Medicine. Last updated November 23, 2022. https://www.clinicaltrials.gov/study/NCT03488693
3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32. doi:10.1016/S1470-2045(11)70336-9
4. Buckland G, Travier N, Cottet V, et al. Adherence to the mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study. Int J Cancer. 2013;132:2918-27. doi:10.1002/ijc.27958
5. Haslam DE, John EM, Knight JA, et al. Diet quality and all-cause mortality in women with breast cancer from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2023;32:678-686. doi:10.1158/1055-9965.EPI-22-1198

The addition of pertuzumab to trastuzumab plus chemotherapy has demonstrated improvement in pathologic complete response (pCR) rates compared with trastuzumab plus chemotherapy in early-stage HER2-positive breast cancer.³ The framework of oncology is built on clinical trials through their rigorous design, enrollment, and synthesis of data; however, real-world studies are an integral component of cancer research because they provide a more representative sample of the general population treated in routine clinical practice. Neopearl was a retrospective, observational, real-world study that evaluated the efficacy and safety of trastuzumab plus chemotherapy with or without pertuzumab among 271 patients with stage II-III HER2-positive breast cancer (Fabbri et al). The addition of pertuzumab led to an increase in pCR rate (49% vs 62%; odds ratio 1.74; P = .032) and improvement in 5-year event-free survival (81% vs 93%; hazard ratio 2.22; P = .041), and the benefit on univariate analysis was restricted to patients with positive axillary nodes. Furthermore, there were no significant differences in adverse events, including cardiac, between the two groups. These results serve to strengthen the available data regarding the clinical efficacy and favorable safety profile of dual HER2-targeted therapy combined with neoadjuvant chemotherapy.

Lifestyle factors, including physical activity and diet, are becoming increasingly recognized as important determinants of various cancer-specific outcomes and overall health. Furthermore, because these are modifiable, there is often motivation on behalf of an individual to change behaviors that can affect their outcome. Adherence to the Mediterranean diet (MD) has been associated with reduced risk for breast cancer development and lower mortality among women with breast cancer.^4,5 Data from a prospective multicenter European cohort including 13,270 breast cancer survivors demonstrated that low compared with medium adherence to a MD before a breast cancer diagnosis was associated with a 13% higher risk for all-cause mortality (hazard ratio 1.13; 95% CI 1.01-1.26). A three-unit increase in the adapted relative MD score was associated with an 8% reduced risk for overall mortality (hazard ratio_3-unit 0.92; 95% CI 0.87-0.97); this result was sustained in the postmenopausal population and strengthened in metastatic disease (Castro-Espin et al). The connection between diet and cancer outcomes is complex, and future research evaluating specific dietary interventions and the underlying biologic pathways by which nutrition exerts its effects will be important to inform our counseling for patients with breast cancer in the survivorship setting.

Additional References

1. Whelan TJ, Olivotto IA, Parulekar WR, et al, for the MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373:307-16. doi:10.1056/NEJMoa1415340
2. ClinicalTrials.gov. Regional radiotherapy in biomarker low-risk node positive and T3N0 breast cancer (TAILOR RT). National Library of Medicine. Last updated November 23, 2022. https://www.clinicaltrials.gov/study/NCT03488693
3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32. doi:10.1016/S1470-2045(11)70336-9
4. Buckland G, Travier N, Cottet V, et al. Adherence to the mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study. Int J Cancer. 2013;132:2918-27. doi:10.1002/ijc.27958
5. Haslam DE, John EM, Knight JA, et al. Diet quality and all-cause mortality in women with breast cancer from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2023;32:678-686. doi:10.1158/1055-9965.EPI-22-1198

The addition of pertuzumab to trastuzumab plus chemotherapy has demonstrated improvement in pathologic complete response (pCR) rates compared with trastuzumab plus chemotherapy in early-stage HER2-positive breast cancer.³ The framework of oncology is built on clinical trials through their rigorous design, enrollment, and synthesis of data; however, real-world studies are an integral component of cancer research because they provide a more representative sample of the general population treated in routine clinical practice. Neopearl was a retrospective, observational, real-world study that evaluated the efficacy and safety of trastuzumab plus chemotherapy with or without pertuzumab among 271 patients with stage II-III HER2-positive breast cancer (Fabbri et al). The addition of pertuzumab led to an increase in pCR rate (49% vs 62%; odds ratio 1.74; P = .032) and improvement in 5-year event-free survival (81% vs 93%; hazard ratio 2.22; P = .041), and the benefit on univariate analysis was restricted to patients with positive axillary nodes. Furthermore, there were no significant differences in adverse events, including cardiac, between the two groups. These results serve to strengthen the available data regarding the clinical efficacy and favorable safety profile of dual HER2-targeted therapy combined with neoadjuvant chemotherapy.

Lifestyle factors, including physical activity and diet, are becoming increasingly recognized as important determinants of various cancer-specific outcomes and overall health. Furthermore, because these are modifiable, there is often motivation on behalf of an individual to change behaviors that can affect their outcome. Adherence to the Mediterranean diet (MD) has been associated with reduced risk for breast cancer development and lower mortality among women with breast cancer.^4,5 Data from a prospective multicenter European cohort including 13,270 breast cancer survivors demonstrated that low compared with medium adherence to a MD before a breast cancer diagnosis was associated with a 13% higher risk for all-cause mortality (hazard ratio 1.13; 95% CI 1.01-1.26). A three-unit increase in the adapted relative MD score was associated with an 8% reduced risk for overall mortality (hazard ratio_3-unit 0.92; 95% CI 0.87-0.97); this result was sustained in the postmenopausal population and strengthened in metastatic disease (Castro-Espin et al). The connection between diet and cancer outcomes is complex, and future research evaluating specific dietary interventions and the underlying biologic pathways by which nutrition exerts its effects will be important to inform our counseling for patients with breast cancer in the survivorship setting.

Additional References

1. Whelan TJ, Olivotto IA, Parulekar WR, et al, for the MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373:307-16. doi:10.1056/NEJMoa1415340
2. ClinicalTrials.gov. Regional radiotherapy in biomarker low-risk node positive and T3N0 breast cancer (TAILOR RT). National Library of Medicine. Last updated November 23, 2022. https://www.clinicaltrials.gov/study/NCT03488693
3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32. doi:10.1016/S1470-2045(11)70336-9
4. Buckland G, Travier N, Cottet V, et al. Adherence to the mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study. Int J Cancer. 2013;132:2918-27. doi:10.1002/ijc.27958
5. Haslam DE, John EM, Knight JA, et al. Diet quality and all-cause mortality in women with breast cancer from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2023;32:678-686. doi:10.1158/1055-9965.EPI-22-1198

THE COMPARISON

A A 51-year-old Hispanic man with a squamous cell carcinoma (SCC) of the keratoacanthoma type on the arm.

B A 75-year-old Black man with an SCC of the keratoacanthoma type on the abdomen.

C An African woman with an SCC on the lower lip decades after a large facial burn, which is known as a Marjolin ulcer.

Cutaneous squamous cell carcinoma (SCC) develops from a malignant tumor of the keratinocytes, eccrine glands, or pilosebaceous units that invades the dermis. Risk factors include lighter skin tone, higher cumulative sun exposure, human papillomavirus (HPV) infection, hidradenitis suppurativa (HS), lichen sclerosus, family history of skin cancer,¹ and immunosuppression.² It typically affects sun-exposed areas of the body such as the face, scalp, neck, and extensor surfaces of the arms (FIGURE A).^3,4 However, in those with darker skin tones, the most common anatomic sites are those that are not exposed to the sun (FIGURE B). SCC is diagnosed via skin biopsy. Treatment options include surgical excision, destructive methods such as electrodesiccation and curettage, and Mohs micrographic surgery. Cutaneous SCC has a cure rate of more than 95% and a mortality rate of 1.5% to 2% in the United States.³

Epidemiology

SCC is the most common skin cancer occurring in Black individuals, manifesting primarily in the fifth decade of life.^5-7 It is the second most common skin cancer in White, Hispanic, and Asian individuals and is more common in males.⁸ In a study of organ transplant recipients (N = 413), Pritchett et al⁹ reported that HPV infection was a major risk factor in Hispanic patients because 66.7% of those with SCC had a history of HPV. However, HPV is a risk factor for SCC in all ethnic groups.¹⁰

Key clinical features in people with darker skin tones

Anatomic location

• The lower legs and anogenital areas are the most common sites for SCC in patients with skin of color.^4,11
• In Black women, SCC occurs more often on sun-exposed areas such as the arms and legs compared to Black men.^7,12-14
• The genitalia, perianal area, ocular mucosa, and oral mucosa are the least likely areas to be routinely examined, even in skin cancer clinics that see highrisk patients, despite the SCC risk in the anogenital area.^15,16
• Squamous cell carcinoma of the lips and scalp is more likely to occur in Black women vs Black men.^4,7,17

Clinical appearance

• In those with darker skin tones, SCCs may appear hyperpigmented4 or hyperkeratotic with a lack of erythema and an inconsistent appearance.^6,7,18
• A nonhealing ulceration of the skin should prompt a biopsy to rule out SCC.^3,19

Worth noting

In patients with darker skin tones, the risk for SCC increases in areas with chronic inflammation and scarring of the skin.^{4,6,7,11,18,20-22} In Black patients, 20% to 40% of cases of SCC occur in the setting of chronic inflammation and scarring.^6,7,18 Chronic inflammatory conditions include ulcers, lupus vulgaris, discoid lupus erythematosus, and HPV. In patients with discoid lupus erythematosus, there is an additive effect of sun exposure on the scars, which may play a role in the pathogenesis and metastasis risk for skin cancer in Black patients.⁴ Other scarring conditions include thermal or chemical burn scars, areas of physical trauma, and prior sites of radiation treatment.^14,23 SCC arising in a burn scar is called a Marjolin ulcer or malignant degeneration of a scar (FIGURE C). It is reported more often in lower-income, underresourced countries, which may suggest the need for early detection in populations with skin of color.²⁴

SCC is more aggressive in sites that are not exposed to sun compared to sun-exposed areas.^17,25

Continue to: The risk for SCC...

The risk for SCC is increased in immunocompromised patients,2 especially those with HPV.¹⁰

The prevalence of SCC in those with HS is approximately 4.6%. The chronic inflammation and irritation from HS in association with other risk factors such as tobacco use may contribute to the malignant transformation to SCC.²⁶

Health disparity highlight

• The risk for metastasis from SCC is 20% to 40% in Black patients vs 1% to 4% in White patients.^4,6,27
• Penile SCC was associated with a lower overall survival rate in patients of African descent.^20,21
• The increased morbidity and mortality from SCC in patients with skin of color may be attributed to delays in diagnosis and treatment as well as an incomplete understanding of tumor genetics.^4,6,18

ACKNOWLEDGMENT
The authors thank Elyse Gadra (Philadelphia, Pennsylvania) for assistance in the preparation of this manuscript.

THE COMPARISON

A A 51-year-old Hispanic man with a squamous cell carcinoma (SCC) of the keratoacanthoma type on the arm.

B A 75-year-old Black man with an SCC of the keratoacanthoma type on the abdomen.

C An African woman with an SCC on the lower lip decades after a large facial burn, which is known as a Marjolin ulcer.

Cutaneous squamous cell carcinoma (SCC) develops from a malignant tumor of the keratinocytes, eccrine glands, or pilosebaceous units that invades the dermis. Risk factors include lighter skin tone, higher cumulative sun exposure, human papillomavirus (HPV) infection, hidradenitis suppurativa (HS), lichen sclerosus, family history of skin cancer,¹ and immunosuppression.² It typically affects sun-exposed areas of the body such as the face, scalp, neck, and extensor surfaces of the arms (FIGURE A).^3,4 However, in those with darker skin tones, the most common anatomic sites are those that are not exposed to the sun (FIGURE B). SCC is diagnosed via skin biopsy. Treatment options include surgical excision, destructive methods such as electrodesiccation and curettage, and Mohs micrographic surgery. Cutaneous SCC has a cure rate of more than 95% and a mortality rate of 1.5% to 2% in the United States.³

Epidemiology

SCC is the most common skin cancer occurring in Black individuals, manifesting primarily in the fifth decade of life.^5-7 It is the second most common skin cancer in White, Hispanic, and Asian individuals and is more common in males.⁸ In a study of organ transplant recipients (N = 413), Pritchett et al⁹ reported that HPV infection was a major risk factor in Hispanic patients because 66.7% of those with SCC had a history of HPV. However, HPV is a risk factor for SCC in all ethnic groups.¹⁰

Key clinical features in people with darker skin tones

Anatomic location

• The lower legs and anogenital areas are the most common sites for SCC in patients with skin of color.^4,11
• In Black women, SCC occurs more often on sun-exposed areas such as the arms and legs compared to Black men.^7,12-14
• The genitalia, perianal area, ocular mucosa, and oral mucosa are the least likely areas to be routinely examined, even in skin cancer clinics that see highrisk patients, despite the SCC risk in the anogenital area.^15,16
• Squamous cell carcinoma of the lips and scalp is more likely to occur in Black women vs Black men.^4,7,17

Clinical appearance

• In those with darker skin tones, SCCs may appear hyperpigmented4 or hyperkeratotic with a lack of erythema and an inconsistent appearance.^6,7,18
• A nonhealing ulceration of the skin should prompt a biopsy to rule out SCC.^3,19

Worth noting

In patients with darker skin tones, the risk for SCC increases in areas with chronic inflammation and scarring of the skin.^{4,6,7,11,18,20-22} In Black patients, 20% to 40% of cases of SCC occur in the setting of chronic inflammation and scarring.^6,7,18 Chronic inflammatory conditions include ulcers, lupus vulgaris, discoid lupus erythematosus, and HPV. In patients with discoid lupus erythematosus, there is an additive effect of sun exposure on the scars, which may play a role in the pathogenesis and metastasis risk for skin cancer in Black patients.⁴ Other scarring conditions include thermal or chemical burn scars, areas of physical trauma, and prior sites of radiation treatment.^14,23 SCC arising in a burn scar is called a Marjolin ulcer or malignant degeneration of a scar (FIGURE C). It is reported more often in lower-income, underresourced countries, which may suggest the need for early detection in populations with skin of color.²⁴

SCC is more aggressive in sites that are not exposed to sun compared to sun-exposed areas.^17,25

Continue to: The risk for SCC...

The risk for SCC is increased in immunocompromised patients,2 especially those with HPV.¹⁰

The prevalence of SCC in those with HS is approximately 4.6%. The chronic inflammation and irritation from HS in association with other risk factors such as tobacco use may contribute to the malignant transformation to SCC.²⁶

Health disparity highlight

• The risk for metastasis from SCC is 20% to 40% in Black patients vs 1% to 4% in White patients.^4,6,27
• Penile SCC was associated with a lower overall survival rate in patients of African descent.^20,21
• The increased morbidity and mortality from SCC in patients with skin of color may be attributed to delays in diagnosis and treatment as well as an incomplete understanding of tumor genetics.^4,6,18

ACKNOWLEDGMENT
The authors thank Elyse Gadra (Philadelphia, Pennsylvania) for assistance in the preparation of this manuscript.

THE COMPARISON

A A 51-year-old Hispanic man with a squamous cell carcinoma (SCC) of the keratoacanthoma type on the arm.

B A 75-year-old Black man with an SCC of the keratoacanthoma type on the abdomen.

C An African woman with an SCC on the lower lip decades after a large facial burn, which is known as a Marjolin ulcer.

Cutaneous squamous cell carcinoma (SCC) develops from a malignant tumor of the keratinocytes, eccrine glands, or pilosebaceous units that invades the dermis. Risk factors include lighter skin tone, higher cumulative sun exposure, human papillomavirus (HPV) infection, hidradenitis suppurativa (HS), lichen sclerosus, family history of skin cancer,¹ and immunosuppression.² It typically affects sun-exposed areas of the body such as the face, scalp, neck, and extensor surfaces of the arms (FIGURE A).^3,4 However, in those with darker skin tones, the most common anatomic sites are those that are not exposed to the sun (FIGURE B). SCC is diagnosed via skin biopsy. Treatment options include surgical excision, destructive methods such as electrodesiccation and curettage, and Mohs micrographic surgery. Cutaneous SCC has a cure rate of more than 95% and a mortality rate of 1.5% to 2% in the United States.³

Epidemiology

SCC is the most common skin cancer occurring in Black individuals, manifesting primarily in the fifth decade of life.^5-7 It is the second most common skin cancer in White, Hispanic, and Asian individuals and is more common in males.⁸ In a study of organ transplant recipients (N = 413), Pritchett et al⁹ reported that HPV infection was a major risk factor in Hispanic patients because 66.7% of those with SCC had a history of HPV. However, HPV is a risk factor for SCC in all ethnic groups.¹⁰

Key clinical features in people with darker skin tones

Anatomic location

• The lower legs and anogenital areas are the most common sites for SCC in patients with skin of color.^4,11
• In Black women, SCC occurs more often on sun-exposed areas such as the arms and legs compared to Black men.^7,12-14
• The genitalia, perianal area, ocular mucosa, and oral mucosa are the least likely areas to be routinely examined, even in skin cancer clinics that see highrisk patients, despite the SCC risk in the anogenital area.^15,16
• Squamous cell carcinoma of the lips and scalp is more likely to occur in Black women vs Black men.^4,7,17

Clinical appearance

• In those with darker skin tones, SCCs may appear hyperpigmented4 or hyperkeratotic with a lack of erythema and an inconsistent appearance.^6,7,18
• A nonhealing ulceration of the skin should prompt a biopsy to rule out SCC.^3,19

Worth noting

In patients with darker skin tones, the risk for SCC increases in areas with chronic inflammation and scarring of the skin.^{4,6,7,11,18,20-22} In Black patients, 20% to 40% of cases of SCC occur in the setting of chronic inflammation and scarring.^6,7,18 Chronic inflammatory conditions include ulcers, lupus vulgaris, discoid lupus erythematosus, and HPV. In patients with discoid lupus erythematosus, there is an additive effect of sun exposure on the scars, which may play a role in the pathogenesis and metastasis risk for skin cancer in Black patients.⁴ Other scarring conditions include thermal or chemical burn scars, areas of physical trauma, and prior sites of radiation treatment.^14,23 SCC arising in a burn scar is called a Marjolin ulcer or malignant degeneration of a scar (FIGURE C). It is reported more often in lower-income, underresourced countries, which may suggest the need for early detection in populations with skin of color.²⁴

SCC is more aggressive in sites that are not exposed to sun compared to sun-exposed areas.^17,25

Continue to: The risk for SCC...

The risk for SCC is increased in immunocompromised patients,2 especially those with HPV.¹⁰

The prevalence of SCC in those with HS is approximately 4.6%. The chronic inflammation and irritation from HS in association with other risk factors such as tobacco use may contribute to the malignant transformation to SCC.²⁶

Health disparity highlight

• The risk for metastasis from SCC is 20% to 40% in Black patients vs 1% to 4% in White patients.^4,6,27
• Penile SCC was associated with a lower overall survival rate in patients of African descent.^20,21
• The increased morbidity and mortality from SCC in patients with skin of color may be attributed to delays in diagnosis and treatment as well as an incomplete understanding of tumor genetics.^4,6,18

ACKNOWLEDGMENT
The authors thank Elyse Gadra (Philadelphia, Pennsylvania) for assistance in the preparation of this manuscript.