A 62-year-old Caucasian male presented to the clinic with the complaint of nail changes (Figures 1 and 2, left to right) on his left third finger for the past 2 years. He describes a thickening and discoloration of his nail for one year that progressed over the last 12 months to the appearance demonstrated in the clinical photographs. He denied any associated pain, pruritus or bleeding. He reported that he had been evaluated by multiple other dermatologists, and none were concerned with the appearance of his nail.
What is your diagnosis?
Answer on page 2
{{pagebreak}}
DIAGNOSIS: SUBUNGUAL CUTANEOUS SQUAMOUS CELL CARCINOMA
Cutaneous squamous cell carcinoma (SCC) results from the growth of malignant keratinocytes within the epidermis and has the potential for aggressive behavior through local invasion, metastatic spread or recurrence of previously treated tumors.1 More than 250,000 cases of SCC are diagnosed in the United States each year, making it the second most common human cancer (after basal cell carcinoma).2,3 SCC may develop on any cutaneous surface, including the head, neck, extremities, trunk, lips, oral mucosa, anogenital areas and nails.2 Subungual SCC is a malignant process of the epithelium of the nail apparatus that may involve the nail bed, matrix, fold or groove.4 Diagnosis of subungual SCC can be challenging, and many cases are often invasive once the diagnosis is rendered.4,5 Subungual SCC is strongly associated with human papillomavirus (HPV). Treatment is surgical and often depends on the extent of the tumor.
Epidemiology
Subungual SCC is an uncommon tumor and the actual incidence is unknown. The incidence of subungual SCC is highest in the sixth decade and affects men more than women.4,6-8 Subungual SCC usually arises in the lateral nail folds or distal groove and extends to involve the nail unit.6 These tumors are the most common malignant subungual tumors and rarely affect more than one digit, with reports of 80%-90% involving the fingernails.4,7-9 Subungual SCC tends to involve the right hand as opposed to the left with a ratio reported in the literature of 3:1 to 2:1.7,10
Clinical Presentation
Subungual SCC is often a challenging diagnosis due to its unpredictable nail changes. A variety of nail findings have been associated with subungual SCC including hyperkeratosis, longitudinal melanonychia, chronic paronychia, pain, onycholysis, hemorrhage, dystrophy and erythronychia.4-8,10-12 Furthermore, subungual SCC can mimic other benign conditions including verruca and most commonly onychomycosis, which may lead to a delay in diagnosis.8 The average time period between symptom onset and diagnosis is 2 to 5.3 years, and subungual SCC often reaches advanced stages before it is properly diagnosed.5,6,8,13 In a review of 35 patients with subungual SCC, a correct diagnosis was suspected at the initial visit in only 29% of cases.8
Risk Factors
Chronic infection, trauma, radiation and chemical exposure have been listed as potential predisposing factors of subungual SCC.4,7,12,13 One article reports ultraviolet light exposure in nail salons as a cause of hand SCC in two healthy women.14 The most important carcinogenic factor in the development of digital SCC is HPV infection; 80%-90% of digital SCCs have been associated with HPV positivity.10,12
Immunosuppressed patients are at increased risk for developing cutaneous SCCs, including SCC of the nail, which may be partially due to the high prevalence of HPV in immunosuppressed patients, such as transplant recipients and HIV-infected individuals.15 SCCs are the most common skin cancer in transplant patients and are 65-250 times as likely to develop in transplant recipients when compared to the general population.16 SCCs have an aggressive nature in this unique group of high-risk patients, and the risk of SCC increases with the duration of immunosuppression.17 There is limited data regarding the efficacy of the quadrivalent HPV vaccine to prevent verruca or SCC in immunocompromised patients.13
The most common extra-genital HPV-associated cutaneous SCC is that of periungual skin.13 The presence of HPV DNA in subungual SCC may be as common as in cervical cancer.12 A majority of digital SCCs are associated with high-risk HPV subtypes, most commonly HPV 16.10,13,18 Alam et al summarized 23 of their own cases in addition to 51 reported digital SCC and SCC in situ cases and showed that a majority of the HPV-associated tumors (89% and 94%, respectively) were positive for HPV 16.10 However, several high-risk HPV types other than HPV 16 (ie, HPV 18, 26, 31, 33, 34, 35, 51, 56, 58 and 73) have also been reported to induce periungual SCCs.11,13 The same high-risk subtypes are also found in mucosal SCC, suggesting genital-digital-oral viral transmission as a mechanism of infection.13,18 Of 103 patients with HPV-associated digital SCC in one review, 27.4% had a personal history or a partner with a history of HPV-associated genital pathology.13 One patient with multiple SCCs of the hands happened to be a former gynecologist.13 The predilection of HPV-associated SCC for the fingers of the right hand also supports the idea of genital-digital transmission.10
Overall, the development of digital SCCs in patients with history of cervical dysplasia is rare (0.01%), and there is no evidence supporting a high risk of digital tumors in these women.18 However, physicians should be aware that nail bed tumors may harbor high-risk HPV subtypes with risk of transmission, and it remains appropriate to ask these patients and partners for a history of genital dysplasia and to examine perioral, digital and anogenital skin.10
Diagnosis and Histology
Nail plate removal with nail bed biopsy is the gold standard for diagnosing subungual SCC and should be employed when there is a suspicion for malignancy.4 Physicians should consider subungual SCC in nail lesions with atypical disease progression or chronic nail conditions that persist or recur despite standard treatment, especially in high-risk patients.4 In the literature, there is debate about whether it is cost-effective or necessary to routinely send digital SCC for HPV typing.10 HPV typing may be considered useful, given that HPV-associated subungual SCC has a higher expression of tumor markers (p16INK4a and Ki67) and tends to be more locally aggressive than non-HPV subungual SCC.10,11 However, a majority of digital SCCs are HPV positive, and HPV status does not currently effect management, as extensive treatment and close follow-up is recommended for all cases of subungual SCC.10
Despite varying clinical features, a majority of subungual SCC have similar histopathological changes.18 Biopsy specimens show sheets and islands of neoplastic primitive cells that lay in disarray throughout the epithelium.4 There is often proliferation of highly atypical keratinocytes with large, irregular nuclei, including “clumping cells.”19 The changes tend to extend into the nail bed, soft tissue, fascia and occasionally the bone.4,7 Many subungual SCC biopsy specimens show histologic changes consistent with HPV infection, such as keratinocytes with koilocytosis, acanthosis and polynucleation.12,20
Treatment Options
Diagnosis necessitates prompt surgical treatment, as digital SCC tends to be locally aggressive.13 Treatment choice relies on the extent of the disease and treatment modalities include digital amputation, wide local excision and Mohs micrographic surgery (MMS).8,20 Some recommend exclusion of bony involvement with X-ray imaging before surgical treatment is initiated.6,12,21
MMS is the treatment of choice for primary skin cancers located on anatomic sites that require maximal tissue conservation and is often considered the gold standard for treating subungual SCC without bony involvement.3,6,10,20-22 MMS maximally preserves surrounding healthy tissue and has a previously reported cure rate of 92%-96% in patients with subungual SCC.6,22 However, a 2011 literature review of 103 patients with digital SCC or SCC in situ reported a 20% recurrence rate after treatment with MMS,13 a much higher rate when compared to recurrence of non-subungual SCC after MMS treatment (3%).10 These recurrences may be related to persistence of oncogenic HPV at surgical margins, analogous to latent papillomavirus in recurring warts.8 Physicians may consider local adjuvant treatment such as curettage, imiquimod or carbon dixoide laser to decrease recurrence.10,20 Another factor that may contribute to recurrence rates is incomplete removal of the tumor due to the unique anatomic characteristics of the nail unit.5 If SCC is found at the last surgical stage and no tissue remains for clean excision, cryosurgery may be used as an adjuvant to improve cure rates while preserving digital function and bone integrity.5 In addition, radiation therapy has shown to be a successful treatment option, particularly for patients who are poor surgical candidates or have responded poorly to treatment.7 All patients require long-term follow-up (although the literature does not give an exact frequency) to monitor for recurrence, and those with known HPV positivity or tumor thicknesses >1mm should be followed even more closely.4,8,10
Patient Course
In our patient, a nail bed biopsy was performed. The nail was removed, demonstrating a pink, glistening papule involving the nail bed and plate (Figures 3 and 4, left and center). Pathology revealed invasive, well-differentiated squamous cell carcinoma with negative HPV stains. The patient was referred for Mohs micrographic surgery and his subungal SCC was cleared in two stages. The final defect after Mohs surgery measured 2.2 cm x 1.6 cm and extended to bone. The patient was referred to plastic surgery for reconstructive options, which included healing by second intent, graft placement or amputation/flap. Due to exposed bone, the patient decided to proceed with partial amputation with volar flap coverage. At his 6-month skin exam, the patient’s finger was well healed with no evidence of recurrence (Figure 5, right). His epitrochlear and axillary lymph node exam was negative. He will be followed closely with biannual skin exams.
Conclusion
Subungual SCC can be a challenging diagnosis, but careful examination of nail changes may lead to a correct and early diagnosis. Physicians should be aware of the association between subungual SCC, HPV and genital disease. A surgical biopsy is required for accurate diagnosis and should be performed in patients with chronic, atypical nail disease that is refractory to standard treatment. Subungual SCCs are treated surgically and require long-term follow-up.
Christina Kranc, MD, is an intern at Resurrection Medical Center in Chicago, IL.
Vanessa Lichon, MD is a procedural dermatology fellow at Fletcher Allen Health Care, University of Vermont, in Burlington, VT.
David Eilers, MD, is the section chief of dermatology at Edward Hines, Jr. Veterans Affairs Hospital in Hines, IL.
Disclosure: The authors have no conflicts of interest to report.
A 62-year-old Caucasian male presented to the clinic with the complaint of nail changes (Figures 1 and 2, left to right) on his left third finger for the past 2 years. He describes a thickening and discoloration of his nail for one year that progressed over the last 12 months to the appearance demonstrated in the clinical photographs. He denied any associated pain, pruritus or bleeding. He reported that he had been evaluated by multiple other dermatologists, and none were concerned with the appearance of his nail.
What is your diagnosis?
Hit "Next" for the answer!
Diagnosis: Subungual Cutaneous Squamous Cell Carcinoma
Cutaneous squamous cell carcinoma (SCC) results from the growth of malignant keratinocytes within the epidermis and has the potential for aggressive behavior through local invasion, metastatic spread or recurrence of previously treated tumors.1 More than 250,000 cases of SCC are diagnosed in the United States each year, making it the second most common human cancer (after basal cell carcinoma).2,3 SCC may develop on any cutaneous surface, including the head, neck, extremities, trunk, lips, oral mucosa, anogenital areas and nails.2 Subungual SCC is a malignant process of the epithelium of the nail apparatus that may involve the nail bed, matrix, fold or groove.4 Diagnosis of subungual SCC can be challenging, and many cases are often invasive once the diagnosis is rendered.4,5 Subungual SCC is strongly associated with human papillomavirus (HPV). Treatment is surgical and often depends on the extent of the tumor.
Epidemiology
Subungual SCC is an uncommon tumor and the actual incidence is unknown. The incidence of subungual SCC is highest in the sixth decade and affects men more than women.4,6-8 Subungual SCC usually arises in the lateral nail folds or distal groove and extends to involve the nail unit.6 These tumors are the most common malignant subungual tumors and rarely affect more than one digit, with reports of 80%-90% involving the fingernails.4,7-9 Subungual SCC tends to involve the right hand as opposed to the left with a ratio reported in the literature of 3:1 to 2:1.7,10
Clinical Presentation
Subungual SCC is often a challenging diagnosis due to its unpredictable nail changes. A variety of nail findings have been associated with subungual SCC including hyperkeratosis, longitudinal melanonychia, chronic paronychia, pain, onycholysis, hemorrhage, dystrophy and erythronychia.4-8,10-12 Furthermore, subungual SCC can mimic other benign conditions including verruca and most commonly onychomycosis, which may lead to a delay in diagnosis.8 The average time period between symptom onset and diagnosis is 2 to 5.3 years, and subungual SCC often reaches advanced stages before it is properly diagnosed.5,6,8,13 In a review of 35 patients with subungual SCC, a correct diagnosis was suspected at the initial visit in only 29% of cases.8
Risk Factors
Chronic infection, trauma, radiation and chemical exposure have been listed as potential predisposing factors of subungual SCC.4,7,12,13 One article reports ultraviolet light exposure in nail salons as a cause of hand SCC in two healthy women.14 The most important carcinogenic factor in the development of digital SCC is HPV infection; 80%-90% of digital SCCs have been associated with HPV positivity.10,12
Immunosuppressed patients are at increased risk for developing cutaneous SCCs, including SCC of the nail, which may be partially due to the high prevalence of HPV in immunosuppressed patients, such as transplant recipients and HIV-infected individuals.15 SCCs are the most common skin cancer in transplant patients and are 65-250 times as likely to develop in transplant recipients when compared to the general population.16 SCCs have an aggressive nature in this unique group of high-risk patients, and the risk of SCC increases with the duration of immunosuppression.17 There is limited data regarding the efficacy of the quadrivalent HPV vaccine to prevent verruca or SCC in immunocompromised patients.13
The most common extra-genital HPV-associated cutaneous SCC is that of periungual skin.13 The presence of HPV DNA in subungual SCC may be as common as in cervical cancer.12 A majority of digital SCCs are associated with high-risk HPV subtypes, most commonly HPV 16.10,13,18 Alam et al summarized 23 of their own cases in addition to 51 reported digital SCC and SCC in situ cases and showed that a majority of the HPV-associated tumors (89% and 94%, respectively) were positive for HPV 16.10 However, several high-risk HPV types other than HPV 16 (ie, HPV 18, 26, 31, 33, 34, 35, 51, 56, 58 and 73) have also been reported to induce periungual SCCs.11,13 The same high-risk subtypes are also found in mucosal SCC, suggesting genital-digital-oral viral transmission as a mechanism of infection.13,18 Of 103 patients with HPV-associated digital SCC in one review, 27.4% had a personal history or a partner with a history of HPV-associated genital pathology.13 One patient with multiple SCCs of the hands happened to be a former gynecologist.13 The predilection of HPV-associated SCC for the fingers of the right hand also supports the idea of genital-digital transmission.10
Overall, the development of digital SCCs in patients with history of cervical dysplasia is rare (0.01%), and there is no evidence supporting a high risk of digital tumors in these women.18 However, physicians should be aware that nail bed tumors may harbor high-risk HPV subtypes with risk of transmission, and it remains appropriate to ask these patients and partners for a history of genital dysplasia and to examine perioral, digital and anogenital skin.10
Diagnosis and Histology
Nail plate removal with nail bed biopsy is the gold standard for diagnosing subungual SCC and should be employed when there is a suspicion for malignancy.4 Physicians should consider subungual SCC in nail lesions with atypical disease progression or chronic nail conditions that persist or recur despite standard treatment, especially in high-risk patients.4 In the literature, there is debate about whether it is cost-effective or necessary to routinely send digital SCC for HPV typing.10 HPV typing may be considered useful, given that HPV-associated subungual SCC has a higher expression of tumor markers (p16INK4a and Ki67) and tends to be more locally aggressive than non-HPV subungual SCC.10,11 However, a majority of digital SCCs are HPV positive, and HPV status does not currently effect management, as extensive treatment and close follow-up is recommended for all cases of subungual SCC.10
Despite varying clinical features, a majority of subungual SCC have similar histopathological changes.18 Biopsy specimens show sheets and islands of neoplastic primitive cells that lay in disarray throughout the epithelium.4 There is often proliferation of highly atypical keratinocytes with large, irregular nuclei, including “clumping cells.”19 The changes tend to extend into the nail bed, soft tissue, fascia and occasionally the bone.4,7 Many subungual SCC biopsy specimens show histologic changes consistent with HPV infection, such as keratinocytes with koilocytosis, acanthosis and polynucleation.12,20
Treatment Options
Diagnosis necessitates prompt surgical treatment, as digital SCC tends to be locally aggressive.13 Treatment choice relies on the extent of the disease and treatment modalities include digital amputation, wide local excision and Mohs micrographic surgery (MMS).8,20 Some recommend exclusion of bony involvement with X-ray imaging before surgical treatment is initiated.6,12,21
MMS is the treatment of choice for primary skin cancers located on anatomic sites that require maximal tissue conservation and is often considered the gold standard for treating subungual SCC without bony involvement.3,6,10,20-22 MMS maximally preserves surrounding healthy tissue and has a previously reported cure rate of 92%-96% in patients with subungual SCC.6,22 However, a 2011 literature review of 103 patients with digital SCC or SCC in situ reported a 20% recurrence rate after treatment with MMS,13 a much higher rate when compared to recurrence of non-subungual SCC after MMS treatment (3%).10 These recurrences may be related to persistence of oncogenic HPV at surgical margins, analogous to latent papillomavirus in recurring warts.8 Physicians may consider local adjuvant treatment such as curettage, imiquimod or carbon dixoide laser to decrease recurrence.10,20 Another factor that may contribute to recurrence rates is incomplete removal of the tumor due to the unique anatomic characteristics of the nail unit.5 If SCC is found at the last surgical stage and no tissue remains for clean excision, cryosurgery may be used as an adjuvant to improve cure rates while preserving digital function and bone integrity.5 In addition, radiation therapy has shown to be a successful treatment option, particularly for patients who are poor surgical candidates or have responded poorly to treatment.7 All patients require long-term follow-up (although the literature does not give an exact frequency) to monitor for recurrence, and those with known HPV positivity or tumor thicknesses >1mm should be followed even more closely.4,8,10
Patient Course
In our patient, a nail bed biopsy was performed. The nail was removed, demonstrating a pink, glistening papule involving the nail bed and plate (Figures 3 and 4, left and center). Pathology revealed invasive, well-differentiated squamous cell carcinoma with negative HPV stains. The patient was referred for Mohs micrographic surgery and his subungal SCC was cleared in two stages. The final defect after Mohs surgery measured 2.2 cm x 1.6 cm and extended to bone. The patient was referred to plastic surgery for reconstructive options, which included healing by second intent, graft placement or amputation/flap. Due to exposed bone, the patient decided to proceed with partial amputation with volar flap coverage. At his 6-month skin exam, the patient’s finger was well healed with no evidence of recurrence (Figure 5, right). His epitrochlear and axillary lymph node exam was negative. He will be followed closely with biannual skin exams.
Conclusion
Subungual SCC can be a challenging diagnosis, but careful examination of nail changes may lead to a correct and early diagnosis. Physicians should be aware of the association between subungual SCC, HPV and genital disease. A surgical biopsy is required for accurate diagnosis and should be performed in patients with chronic, atypical nail disease that is refractory to standard treatment. Subungual SCCs are treated surgically and require long-term follow-up.
Christina Kranc, MD, is an intern at Resurrection Medical Center in Chicago, IL.
Vanessa Lichon, MD is a procedural dermatology fellow at Fletcher Allen Health Care, University of Vermont, in Burlington, VT.
David Eilers, MD, is the section chief of dermatology at Edward Hines, Jr. Veterans Affairs Hospital in Hines, IL.
Disclosure: The authors have no conflicts of interest to report.
A 62-year-old Caucasian male presented to the clinic with the complaint of nail changes (Figures 1 and 2, left to right) on his left third finger for the past 2 years. He describes a thickening and discoloration of his nail for one year that progressed over the last 12 months to the appearance demonstrated in the clinical photographs. He denied any associated pain, pruritus or bleeding. He reported that he had been evaluated by multiple other dermatologists, and none were concerned with the appearance of his nail.
What is your diagnosis?
Hit "Next" for the answer!
,
A 62-year-old Caucasian male presented to the clinic with the complaint of nail changes (Figures 1 and 2, left to right) on his left third finger for the past 2 years. He describes a thickening and discoloration of his nail for one year that progressed over the last 12 months to the appearance demonstrated in the clinical photographs. He denied any associated pain, pruritus or bleeding. He reported that he had been evaluated by multiple other dermatologists, and none were concerned with the appearance of his nail.
What is your diagnosis?
Answer on page 2
{{pagebreak}}
DIAGNOSIS: SUBUNGUAL CUTANEOUS SQUAMOUS CELL CARCINOMA
Cutaneous squamous cell carcinoma (SCC) results from the growth of malignant keratinocytes within the epidermis and has the potential for aggressive behavior through local invasion, metastatic spread or recurrence of previously treated tumors.1 More than 250,000 cases of SCC are diagnosed in the United States each year, making it the second most common human cancer (after basal cell carcinoma).2,3 SCC may develop on any cutaneous surface, including the head, neck, extremities, trunk, lips, oral mucosa, anogenital areas and nails.2 Subungual SCC is a malignant process of the epithelium of the nail apparatus that may involve the nail bed, matrix, fold or groove.4 Diagnosis of subungual SCC can be challenging, and many cases are often invasive once the diagnosis is rendered.4,5 Subungual SCC is strongly associated with human papillomavirus (HPV). Treatment is surgical and often depends on the extent of the tumor.
Epidemiology
Subungual SCC is an uncommon tumor and the actual incidence is unknown. The incidence of subungual SCC is highest in the sixth decade and affects men more than women.4,6-8 Subungual SCC usually arises in the lateral nail folds or distal groove and extends to involve the nail unit.6 These tumors are the most common malignant subungual tumors and rarely affect more than one digit, with reports of 80%-90% involving the fingernails.4,7-9 Subungual SCC tends to involve the right hand as opposed to the left with a ratio reported in the literature of 3:1 to 2:1.7,10
Clinical Presentation
Subungual SCC is often a challenging diagnosis due to its unpredictable nail changes. A variety of nail findings have been associated with subungual SCC including hyperkeratosis, longitudinal melanonychia, chronic paronychia, pain, onycholysis, hemorrhage, dystrophy and erythronychia.4-8,10-12 Furthermore, subungual SCC can mimic other benign conditions including verruca and most commonly onychomycosis, which may lead to a delay in diagnosis.8 The average time period between symptom onset and diagnosis is 2 to 5.3 years, and subungual SCC often reaches advanced stages before it is properly diagnosed.5,6,8,13 In a review of 35 patients with subungual SCC, a correct diagnosis was suspected at the initial visit in only 29% of cases.8
Risk Factors
Chronic infection, trauma, radiation and chemical exposure have been listed as potential predisposing factors of subungual SCC.4,7,12,13 One article reports ultraviolet light exposure in nail salons as a cause of hand SCC in two healthy women.14 The most important carcinogenic factor in the development of digital SCC is HPV infection; 80%-90% of digital SCCs have been associated with HPV positivity.10,12
Immunosuppressed patients are at increased risk for developing cutaneous SCCs, including SCC of the nail, which may be partially due to the high prevalence of HPV in immunosuppressed patients, such as transplant recipients and HIV-infected individuals.15 SCCs are the most common skin cancer in transplant patients and are 65-250 times as likely to develop in transplant recipients when compared to the general population.16 SCCs have an aggressive nature in this unique group of high-risk patients, and the risk of SCC increases with the duration of immunosuppression.17 There is limited data regarding the efficacy of the quadrivalent HPV vaccine to prevent verruca or SCC in immunocompromised patients.13
The most common extra-genital HPV-associated cutaneous SCC is that of periungual skin.13 The presence of HPV DNA in subungual SCC may be as common as in cervical cancer.12 A majority of digital SCCs are associated with high-risk HPV subtypes, most commonly HPV 16.10,13,18 Alam et al summarized 23 of their own cases in addition to 51 reported digital SCC and SCC in situ cases and showed that a majority of the HPV-associated tumors (89% and 94%, respectively) were positive for HPV 16.10 However, several high-risk HPV types other than HPV 16 (ie, HPV 18, 26, 31, 33, 34, 35, 51, 56, 58 and 73) have also been reported to induce periungual SCCs.11,13 The same high-risk subtypes are also found in mucosal SCC, suggesting genital-digital-oral viral transmission as a mechanism of infection.13,18 Of 103 patients with HPV-associated digital SCC in one review, 27.4% had a personal history or a partner with a history of HPV-associated genital pathology.13 One patient with multiple SCCs of the hands happened to be a former gynecologist.13 The predilection of HPV-associated SCC for the fingers of the right hand also supports the idea of genital-digital transmission.10
Overall, the development of digital SCCs in patients with history of cervical dysplasia is rare (0.01%), and there is no evidence supporting a high risk of digital tumors in these women.18 However, physicians should be aware that nail bed tumors may harbor high-risk HPV subtypes with risk of transmission, and it remains appropriate to ask these patients and partners for a history of genital dysplasia and to examine perioral, digital and anogenital skin.10
Diagnosis and Histology
Nail plate removal with nail bed biopsy is the gold standard for diagnosing subungual SCC and should be employed when there is a suspicion for malignancy.4 Physicians should consider subungual SCC in nail lesions with atypical disease progression or chronic nail conditions that persist or recur despite standard treatment, especially in high-risk patients.4 In the literature, there is debate about whether it is cost-effective or necessary to routinely send digital SCC for HPV typing.10 HPV typing may be considered useful, given that HPV-associated subungual SCC has a higher expression of tumor markers (p16INK4a and Ki67) and tends to be more locally aggressive than non-HPV subungual SCC.10,11 However, a majority of digital SCCs are HPV positive, and HPV status does not currently effect management, as extensive treatment and close follow-up is recommended for all cases of subungual SCC.10
Despite varying clinical features, a majority of subungual SCC have similar histopathological changes.18 Biopsy specimens show sheets and islands of neoplastic primitive cells that lay in disarray throughout the epithelium.4 There is often proliferation of highly atypical keratinocytes with large, irregular nuclei, including “clumping cells.”19 The changes tend to extend into the nail bed, soft tissue, fascia and occasionally the bone.4,7 Many subungual SCC biopsy specimens show histologic changes consistent with HPV infection, such as keratinocytes with koilocytosis, acanthosis and polynucleation.12,20
Treatment Options
Diagnosis necessitates prompt surgical treatment, as digital SCC tends to be locally aggressive.13 Treatment choice relies on the extent of the disease and treatment modalities include digital amputation, wide local excision and Mohs micrographic surgery (MMS).8,20 Some recommend exclusion of bony involvement with X-ray imaging before surgical treatment is initiated.6,12,21
MMS is the treatment of choice for primary skin cancers located on anatomic sites that require maximal tissue conservation and is often considered the gold standard for treating subungual SCC without bony involvement.3,6,10,20-22 MMS maximally preserves surrounding healthy tissue and has a previously reported cure rate of 92%-96% in patients with subungual SCC.6,22 However, a 2011 literature review of 103 patients with digital SCC or SCC in situ reported a 20% recurrence rate after treatment with MMS,13 a much higher rate when compared to recurrence of non-subungual SCC after MMS treatment (3%).10 These recurrences may be related to persistence of oncogenic HPV at surgical margins, analogous to latent papillomavirus in recurring warts.8 Physicians may consider local adjuvant treatment such as curettage, imiquimod or carbon dixoide laser to decrease recurrence.10,20 Another factor that may contribute to recurrence rates is incomplete removal of the tumor due to the unique anatomic characteristics of the nail unit.5 If SCC is found at the last surgical stage and no tissue remains for clean excision, cryosurgery may be used as an adjuvant to improve cure rates while preserving digital function and bone integrity.5 In addition, radiation therapy has shown to be a successful treatment option, particularly for patients who are poor surgical candidates or have responded poorly to treatment.7 All patients require long-term follow-up (although the literature does not give an exact frequency) to monitor for recurrence, and those with known HPV positivity or tumor thicknesses >1mm should be followed even more closely.4,8,10
Patient Course
In our patient, a nail bed biopsy was performed. The nail was removed, demonstrating a pink, glistening papule involving the nail bed and plate (Figures 3 and 4, left and center). Pathology revealed invasive, well-differentiated squamous cell carcinoma with negative HPV stains. The patient was referred for Mohs micrographic surgery and his subungal SCC was cleared in two stages. The final defect after Mohs surgery measured 2.2 cm x 1.6 cm and extended to bone. The patient was referred to plastic surgery for reconstructive options, which included healing by second intent, graft placement or amputation/flap. Due to exposed bone, the patient decided to proceed with partial amputation with volar flap coverage. At his 6-month skin exam, the patient’s finger was well healed with no evidence of recurrence (Figure 5, right). His epitrochlear and axillary lymph node exam was negative. He will be followed closely with biannual skin exams.
Conclusion
Subungual SCC can be a challenging diagnosis, but careful examination of nail changes may lead to a correct and early diagnosis. Physicians should be aware of the association between subungual SCC, HPV and genital disease. A surgical biopsy is required for accurate diagnosis and should be performed in patients with chronic, atypical nail disease that is refractory to standard treatment. Subungual SCCs are treated surgically and require long-term follow-up.
Christina Kranc, MD, is an intern at Resurrection Medical Center in Chicago, IL.
Vanessa Lichon, MD is a procedural dermatology fellow at Fletcher Allen Health Care, University of Vermont, in Burlington, VT.
David Eilers, MD, is the section chief of dermatology at Edward Hines, Jr. Veterans Affairs Hospital in Hines, IL.
Disclosure: The authors have no conflicts of interest to report.
A 62-year-old Caucasian male presented to the clinic with the complaint of nail changes (Figures 1 and 2, left to right) on his left third finger for the past 2 years. He describes a thickening and discoloration of his nail for one year that progressed over the last 12 months to the appearance demonstrated in the clinical photographs. He denied any associated pain, pruritus or bleeding. He reported that he had been evaluated by multiple other dermatologists, and none were concerned with the appearance of his nail.
What is your diagnosis?
Hit "Next" for the answer!
Diagnosis: Subungual Cutaneous Squamous Cell Carcinoma
Cutaneous squamous cell carcinoma (SCC) results from the growth of malignant keratinocytes within the epidermis and has the potential for aggressive behavior through local invasion, metastatic spread or recurrence of previously treated tumors.1 More than 250,000 cases of SCC are diagnosed in the United States each year, making it the second most common human cancer (after basal cell carcinoma).2,3 SCC may develop on any cutaneous surface, including the head, neck, extremities, trunk, lips, oral mucosa, anogenital areas and nails.2 Subungual SCC is a malignant process of the epithelium of the nail apparatus that may involve the nail bed, matrix, fold or groove.4 Diagnosis of subungual SCC can be challenging, and many cases are often invasive once the diagnosis is rendered.4,5 Subungual SCC is strongly associated with human papillomavirus (HPV). Treatment is surgical and often depends on the extent of the tumor.
Epidemiology
Subungual SCC is an uncommon tumor and the actual incidence is unknown. The incidence of subungual SCC is highest in the sixth decade and affects men more than women.4,6-8 Subungual SCC usually arises in the lateral nail folds or distal groove and extends to involve the nail unit.6 These tumors are the most common malignant subungual tumors and rarely affect more than one digit, with reports of 80%-90% involving the fingernails.4,7-9 Subungual SCC tends to involve the right hand as opposed to the left with a ratio reported in the literature of 3:1 to 2:1.7,10
Clinical Presentation
Subungual SCC is often a challenging diagnosis due to its unpredictable nail changes. A variety of nail findings have been associated with subungual SCC including hyperkeratosis, longitudinal melanonychia, chronic paronychia, pain, onycholysis, hemorrhage, dystrophy and erythronychia.4-8,10-12 Furthermore, subungual SCC can mimic other benign conditions including verruca and most commonly onychomycosis, which may lead to a delay in diagnosis.8 The average time period between symptom onset and diagnosis is 2 to 5.3 years, and subungual SCC often reaches advanced stages before it is properly diagnosed.5,6,8,13 In a review of 35 patients with subungual SCC, a correct diagnosis was suspected at the initial visit in only 29% of cases.8
Risk Factors
Chronic infection, trauma, radiation and chemical exposure have been listed as potential predisposing factors of subungual SCC.4,7,12,13 One article reports ultraviolet light exposure in nail salons as a cause of hand SCC in two healthy women.14 The most important carcinogenic factor in the development of digital SCC is HPV infection; 80%-90% of digital SCCs have been associated with HPV positivity.10,12
Immunosuppressed patients are at increased risk for developing cutaneous SCCs, including SCC of the nail, which may be partially due to the high prevalence of HPV in immunosuppressed patients, such as transplant recipients and HIV-infected individuals.15 SCCs are the most common skin cancer in transplant patients and are 65-250 times as likely to develop in transplant recipients when compared to the general population.16 SCCs have an aggressive nature in this unique group of high-risk patients, and the risk of SCC increases with the duration of immunosuppression.17 There is limited data regarding the efficacy of the quadrivalent HPV vaccine to prevent verruca or SCC in immunocompromised patients.13
The most common extra-genital HPV-associated cutaneous SCC is that of periungual skin.13 The presence of HPV DNA in subungual SCC may be as common as in cervical cancer.12 A majority of digital SCCs are associated with high-risk HPV subtypes, most commonly HPV 16.10,13,18 Alam et al summarized 23 of their own cases in addition to 51 reported digital SCC and SCC in situ cases and showed that a majority of the HPV-associated tumors (89% and 94%, respectively) were positive for HPV 16.10 However, several high-risk HPV types other than HPV 16 (ie, HPV 18, 26, 31, 33, 34, 35, 51, 56, 58 and 73) have also been reported to induce periungual SCCs.11,13 The same high-risk subtypes are also found in mucosal SCC, suggesting genital-digital-oral viral transmission as a mechanism of infection.13,18 Of 103 patients with HPV-associated digital SCC in one review, 27.4% had a personal history or a partner with a history of HPV-associated genital pathology.13 One patient with multiple SCCs of the hands happened to be a former gynecologist.13 The predilection of HPV-associated SCC for the fingers of the right hand also supports the idea of genital-digital transmission.10
Overall, the development of digital SCCs in patients with history of cervical dysplasia is rare (0.01%), and there is no evidence supporting a high risk of digital tumors in these women.18 However, physicians should be aware that nail bed tumors may harbor high-risk HPV subtypes with risk of transmission, and it remains appropriate to ask these patients and partners for a history of genital dysplasia and to examine perioral, digital and anogenital skin.10
Diagnosis and Histology
Nail plate removal with nail bed biopsy is the gold standard for diagnosing subungual SCC and should be employed when there is a suspicion for malignancy.4 Physicians should consider subungual SCC in nail lesions with atypical disease progression or chronic nail conditions that persist or recur despite standard treatment, especially in high-risk patients.4 In the literature, there is debate about whether it is cost-effective or necessary to routinely send digital SCC for HPV typing.10 HPV typing may be considered useful, given that HPV-associated subungual SCC has a higher expression of tumor markers (p16INK4a and Ki67) and tends to be more locally aggressive than non-HPV subungual SCC.10,11 However, a majority of digital SCCs are HPV positive, and HPV status does not currently effect management, as extensive treatment and close follow-up is recommended for all cases of subungual SCC.10
Despite varying clinical features, a majority of subungual SCC have similar histopathological changes.18 Biopsy specimens show sheets and islands of neoplastic primitive cells that lay in disarray throughout the epithelium.4 There is often proliferation of highly atypical keratinocytes with large, irregular nuclei, including “clumping cells.”19 The changes tend to extend into the nail bed, soft tissue, fascia and occasionally the bone.4,7 Many subungual SCC biopsy specimens show histologic changes consistent with HPV infection, such as keratinocytes with koilocytosis, acanthosis and polynucleation.12,20
Treatment Options
Diagnosis necessitates prompt surgical treatment, as digital SCC tends to be locally aggressive.13 Treatment choice relies on the extent of the disease and treatment modalities include digital amputation, wide local excision and Mohs micrographic surgery (MMS).8,20 Some recommend exclusion of bony involvement with X-ray imaging before surgical treatment is initiated.6,12,21
MMS is the treatment of choice for primary skin cancers located on anatomic sites that require maximal tissue conservation and is often considered the gold standard for treating subungual SCC without bony involvement.3,6,10,20-22 MMS maximally preserves surrounding healthy tissue and has a previously reported cure rate of 92%-96% in patients with subungual SCC.6,22 However, a 2011 literature review of 103 patients with digital SCC or SCC in situ reported a 20% recurrence rate after treatment with MMS,13 a much higher rate when compared to recurrence of non-subungual SCC after MMS treatment (3%).10 These recurrences may be related to persistence of oncogenic HPV at surgical margins, analogous to latent papillomavirus in recurring warts.8 Physicians may consider local adjuvant treatment such as curettage, imiquimod or carbon dixoide laser to decrease recurrence.10,20 Another factor that may contribute to recurrence rates is incomplete removal of the tumor due to the unique anatomic characteristics of the nail unit.5 If SCC is found at the last surgical stage and no tissue remains for clean excision, cryosurgery may be used as an adjuvant to improve cure rates while preserving digital function and bone integrity.5 In addition, radiation therapy has shown to be a successful treatment option, particularly for patients who are poor surgical candidates or have responded poorly to treatment.7 All patients require long-term follow-up (although the literature does not give an exact frequency) to monitor for recurrence, and those with known HPV positivity or tumor thicknesses >1mm should be followed even more closely.4,8,10
Patient Course
In our patient, a nail bed biopsy was performed. The nail was removed, demonstrating a pink, glistening papule involving the nail bed and plate (Figures 3 and 4, left and center). Pathology revealed invasive, well-differentiated squamous cell carcinoma with negative HPV stains. The patient was referred for Mohs micrographic surgery and his subungal SCC was cleared in two stages. The final defect after Mohs surgery measured 2.2 cm x 1.6 cm and extended to bone. The patient was referred to plastic surgery for reconstructive options, which included healing by second intent, graft placement or amputation/flap. Due to exposed bone, the patient decided to proceed with partial amputation with volar flap coverage. At his 6-month skin exam, the patient’s finger was well healed with no evidence of recurrence (Figure 5, right). His epitrochlear and axillary lymph node exam was negative. He will be followed closely with biannual skin exams.
Conclusion
Subungual SCC can be a challenging diagnosis, but careful examination of nail changes may lead to a correct and early diagnosis. Physicians should be aware of the association between subungual SCC, HPV and genital disease. A surgical biopsy is required for accurate diagnosis and should be performed in patients with chronic, atypical nail disease that is refractory to standard treatment. Subungual SCCs are treated surgically and require long-term follow-up.
Christina Kranc, MD, is an intern at Resurrection Medical Center in Chicago, IL.
Vanessa Lichon, MD is a procedural dermatology fellow at Fletcher Allen Health Care, University of Vermont, in Burlington, VT.
David Eilers, MD, is the section chief of dermatology at Edward Hines, Jr. Veterans Affairs Hospital in Hines, IL.
Disclosure: The authors have no conflicts of interest to report.
Diagnosis: Subungual Cutaneous Squamous Cell Carcinoma
Cutaneous squamous cell carcinoma (SCC) results from the growth of malignant keratinocytes within the epidermis and has the potential for aggressive behavior through local invasion, metastatic spread or recurrence of previously treated tumors.1 More than 250,000 cases of SCC are diagnosed in the United States each year, making it the second most common human cancer (after basal cell carcinoma).2,3 SCC may develop on any cutaneous surface, including the head, neck, extremities, trunk, lips, oral mucosa, anogenital areas and nails.2 Subungual SCC is a malignant process of the epithelium of the nail apparatus that may involve the nail bed, matrix, fold or groove.4 Diagnosis of subungual SCC can be challenging, and many cases are often invasive once the diagnosis is rendered.4,5 Subungual SCC is strongly associated with human papillomavirus (HPV). Treatment is surgical and often depends on the extent of the tumor.
Epidemiology
Subungual SCC is an uncommon tumor and the actual incidence is unknown. The incidence of subungual SCC is highest in the sixth decade and affects men more than women.4,6-8 Subungual SCC usually arises in the lateral nail folds or distal groove and extends to involve the nail unit.6 These tumors are the most common malignant subungual tumors and rarely affect more than one digit, with reports of 80%-90% involving the fingernails.4,7-9 Subungual SCC tends to involve the right hand as opposed to the left with a ratio reported in the literature of 3:1 to 2:1.7,10
Clinical Presentation
Subungual SCC is often a challenging diagnosis due to its unpredictable nail changes. A variety of nail findings have been associated with subungual SCC including hyperkeratosis, longitudinal melanonychia, chronic paronychia, pain, onycholysis, hemorrhage, dystrophy and erythronychia.4-8,10-12 Furthermore, subungual SCC can mimic other benign conditions including verruca and most commonly onychomycosis, which may lead to a delay in diagnosis.8 The average time period between symptom onset and diagnosis is 2 to 5.3 years, and subungual SCC often reaches advanced stages before it is properly diagnosed.5,6,8,13 In a review of 35 patients with subungual SCC, a correct diagnosis was suspected at the initial visit in only 29% of cases.8
Risk Factors
Chronic infection, trauma, radiation and chemical exposure have been listed as potential predisposing factors of subungual SCC.4,7,12,13 One article reports ultraviolet light exposure in nail salons as a cause of hand SCC in two healthy women.14 The most important carcinogenic factor in the development of digital SCC is HPV infection; 80%-90% of digital SCCs have been associated with HPV positivity.10,12
Immunosuppressed patients are at increased risk for developing cutaneous SCCs, including SCC of the nail, which may be partially due to the high prevalence of HPV in immunosuppressed patients, such as transplant recipients and HIV-infected individuals.15 SCCs are the most common skin cancer in transplant patients and are 65-250 times as likely to develop in transplant recipients when compared to the general population.16 SCCs have an aggressive nature in this unique group of high-risk patients, and the risk of SCC increases with the duration of immunosuppression.17 There is limited data regarding the efficacy of the quadrivalent HPV vaccine to prevent verruca or SCC in immunocompromised patients.13
The most common extra-genital HPV-associated cutaneous SCC is that of periungual skin.13 The presence of HPV DNA in subungual SCC may be as common as in cervical cancer.12 A majority of digital SCCs are associated with high-risk HPV subtypes, most commonly HPV 16.10,13,18 Alam et al summarized 23 of their own cases in addition to 51 reported digital SCC and SCC in situ cases and showed that a majority of the HPV-associated tumors (89% and 94%, respectively) were positive for HPV 16.10 However, several high-risk HPV types other than HPV 16 (ie, HPV 18, 26, 31, 33, 34, 35, 51, 56, 58 and 73) have also been reported to induce periungual SCCs.11,13 The same high-risk subtypes are also found in mucosal SCC, suggesting genital-digital-oral viral transmission as a mechanism of infection.13,18 Of 103 patients with HPV-associated digital SCC in one review, 27.4% had a personal history or a partner with a history of HPV-associated genital pathology.13 One patient with multiple SCCs of the hands happened to be a former gynecologist.13 The predilection of HPV-associated SCC for the fingers of the right hand also supports the idea of genital-digital transmission.10
Overall, the development of digital SCCs in patients with history of cervical dysplasia is rare (0.01%), and there is no evidence supporting a high risk of digital tumors in these women.18 However, physicians should be aware that nail bed tumors may harbor high-risk HPV subtypes with risk of transmission, and it remains appropriate to ask these patients and partners for a history of genital dysplasia and to examine perioral, digital and anogenital skin.10
Diagnosis and Histology
Nail plate removal with nail bed biopsy is the gold standard for diagnosing subungual SCC and should be employed when there is a suspicion for malignancy.4 Physicians should consider subungual SCC in nail lesions with atypical disease progression or chronic nail conditions that persist or recur despite standard treatment, especially in high-risk patients.4 In the literature, there is debate about whether it is cost-effective or necessary to routinely send digital SCC for HPV typing.10 HPV typing may be considered useful, given that HPV-associated subungual SCC has a higher expression of tumor markers (p16INK4a and Ki67) and tends to be more locally aggressive than non-HPV subungual SCC.10,11 However, a majority of digital SCCs are HPV positive, and HPV status does not currently effect management, as extensive treatment and close follow-up is recommended for all cases of subungual SCC.10
Despite varying clinical features, a majority of subungual SCC have similar histopathological changes.18 Biopsy specimens show sheets and islands of neoplastic primitive cells that lay in disarray throughout the epithelium.4 There is often proliferation of highly atypical keratinocytes with large, irregular nuclei, including “clumping cells.”19 The changes tend to extend into the nail bed, soft tissue, fascia and occasionally the bone.4,7 Many subungual SCC biopsy specimens show histologic changes consistent with HPV infection, such as keratinocytes with koilocytosis, acanthosis and polynucleation.12,20
Treatment Options
Diagnosis necessitates prompt surgical treatment, as digital SCC tends to be locally aggressive.13 Treatment choice relies on the extent of the disease and treatment modalities include digital amputation, wide local excision and Mohs micrographic surgery (MMS).8,20 Some recommend exclusion of bony involvement with X-ray imaging before surgical treatment is initiated.6,12,21
MMS is the treatment of choice for primary skin cancers located on anatomic sites that require maximal tissue conservation and is often considered the gold standard for treating subungual SCC without bony involvement.3,6,10,20-22 MMS maximally preserves surrounding healthy tissue and has a previously reported cure rate of 92%-96% in patients with subungual SCC.6,22 However, a 2011 literature review of 103 patients with digital SCC or SCC in situ reported a 20% recurrence rate after treatment with MMS,13 a much higher rate when compared to recurrence of non-subungual SCC after MMS treatment (3%).10 These recurrences may be related to persistence of oncogenic HPV at surgical margins, analogous to latent papillomavirus in recurring warts.8 Physicians may consider local adjuvant treatment such as curettage, imiquimod or carbon dixoide laser to decrease recurrence.10,20 Another factor that may contribute to recurrence rates is incomplete removal of the tumor due to the unique anatomic characteristics of the nail unit.5 If SCC is found at the last surgical stage and no tissue remains for clean excision, cryosurgery may be used as an adjuvant to improve cure rates while preserving digital function and bone integrity.5 In addition, radiation therapy has shown to be a successful treatment option, particularly for patients who are poor surgical candidates or have responded poorly to treatment.7 All patients require long-term follow-up (although the literature does not give an exact frequency) to monitor for recurrence, and those with known HPV positivity or tumor thicknesses >1mm should be followed even more closely.4,8,10
Patient Course
In our patient, a nail bed biopsy was performed. The nail was removed, demonstrating a pink, glistening papule involving the nail bed and plate (Figures 3 and 4, left and center). Pathology revealed invasive, well-differentiated squamous cell carcinoma with negative HPV stains. The patient was referred for Mohs micrographic surgery and his subungal SCC was cleared in two stages. The final defect after Mohs surgery measured 2.2 cm x 1.6 cm and extended to bone. The patient was referred to plastic surgery for reconstructive options, which included healing by second intent, graft placement or amputation/flap. Due to exposed bone, the patient decided to proceed with partial amputation with volar flap coverage. At his 6-month skin exam, the patient’s finger was well healed with no evidence of recurrence (Figure 5, right). His epitrochlear and axillary lymph node exam was negative. He will be followed closely with biannual skin exams.
Conclusion
Subungual SCC can be a challenging diagnosis, but careful examination of nail changes may lead to a correct and early diagnosis. Physicians should be aware of the association between subungual SCC, HPV and genital disease. A surgical biopsy is required for accurate diagnosis and should be performed in patients with chronic, atypical nail disease that is refractory to standard treatment. Subungual SCCs are treated surgically and require long-term follow-up.
Christina Kranc, MD, is an intern at Resurrection Medical Center in Chicago, IL.
Vanessa Lichon, MD is a procedural dermatology fellow at Fletcher Allen Health Care, University of Vermont, in Burlington, VT.
David Eilers, MD, is the section chief of dermatology at Edward Hines, Jr. Veterans Affairs Hospital in Hines, IL.
Disclosure: The authors have no conflicts of interest to report.
A 62-year-old Caucasian male presented to the clinic with the complaint of nail changes (Figures 1 and 2, left to right) on his left third finger for the past 2 years. He describes a thickening and discoloration of his nail for one year that progressed over the last 12 months to the appearance demonstrated in the clinical photographs. He denied any associated pain, pruritus or bleeding. He reported that he had been evaluated by multiple other dermatologists, and none were concerned with the appearance of his nail.
