Melanoma

Spitz nevi were first described in 1948.¹ Spitz¹ originally called these lesions benign juvenile melanoma. She was able to identify and describe a separate class of benign melanocytic neoplasms in children that were previously diagnosed and treated as melanoma.² Prior to this discovery, the standard of care was to remove all suspicious pigmented lesions in children prior to adulthood to prevent possible malignant transformation.^2,3 Today, Spitz nevus is the more commonly used term for benign juvenile melanoma because it is encountered occasionally in adults and the term melanoma carries a negative connotation.⁴ Other synonyms include juvenile melanoma, Spitz tumor, nevus of large spindle and/or epithelioid cells, and spindle cell and epithelioid nevus.^3,5 

Classic Spitz Nevus

Spitz nevi are uncommon. The approximate incidence is 7 per 100,000 people. Spitz nevi are more frequently found in children and adolescents but can occur in adults.^6,7 Spitz nevi occur predominantly in the white population and slightly more often in females.^4,8

A Spitz nevus can arise de novo or in association with an existing melanocytic nevus. The lesions can be asymptomatic or have a history of rapid but limited growth. Clinical features of Spitz nevi are well-circumscribed, symmetrical, small- to medium-sized firm papules with smooth discrete borders and a uniform color (typically pink or flesh colored).⁹ Spitz nevi can occur in various shapes. In a study of 211 cases of Spitz nevi, 19% were described as flat or uneven, 24% as polypoid, and 57% as plateau or elevated.⁷ Spitz nevi usually are found on the face, neck, or lower extremities but can occur anywhere on the body.^7,9 Size is typically less than 6 mm (Figures 1 and 2).

PLEASE REFER TO THE PDF TO VIEW THE FIGURES

The classic Spitz nevus histologically consists of large spindle and/or epithelioid melanocytes arrayed as epidermal nests grouped in a vertical orientation (called "bunches of bananas" or "raining down pattern"), with clefting artifact at the perimeter (Figure 3).^4,9,10 The nests are fairly uniform, nonconfluent, and evenly spaced. There is little or no pagetoid spread pattern. Epidermal changes include acanthosis, hypergranulosis, and hyperkeratosis. The intradermal pattern displays maturation, with single-file or single-unit arrays descending to the base. Eosinophilic Kamino bodies frequently are found along the dermoepidermal interface. Kamino bodies are globular clusters that represent apoptotic degenerative melanocytes (Figure 4). They stain positive with both periodic acid-Schiff and trichrome stains. At the dermal base, there is no mitosis, no pushing deep margins, and lack of significant pleomorphism. Little or no melanin is present.^4,9,10 The classic Spitz nevus behaves in a benign manner.¹ The differential diagnosis of the Spitz nevus includes pyogenic granuloma, mastocytoma, juvenile xanthogranuloma, and malignant melanoma.

PLEASE REFER TO THE PDF TO VIEW THE FIGURES

Atypical Spitz Nevus

The atypical Spitz nevus is difficult to formally define. Instead, it is loosely defined. An atypical Spitz nevus shares histologic features with the classic Spitz nevus, but it may have one or more atypical features, which can be characteristic of malignancy.^10-12 Gross atypical features may include irregular shape, nonuniform color, large size, or ulcerations. Histologically, there can be one or more of the following features: pleomorphism; increased cellularity; loss of cellular cohesion; epidermal pagetoid spread; minimal epidermal changes; absence of Kamino bodies; lack of maturation in the intradermal pattern; high-grade nuclear atypia; high basal mitotic rate; pushing deep margins into the dermal base or subcutis; and nests variable in size, shape, and orientation.^9,10,13

The behavior of any atypical Spitz nevus is unpredictable. There are case reports of metastasizing and malignant lesions with Spitz-like characteristics causing fatal outcomes.^11,13 However, there also are studies that show Spitz nevi acting in a benign manner, even with a history of metastases.^11,13-15 Some researchers try to explain this phenomenon by theorizing that Spitz nevi and melanoma exist along a continuum with the classic benign Spitz nevus at one end of the spectrum and the aggressive malignant melanoma at the opposite end, with a diverse range of atypical Spitz-like lesions with features of both in between.^4,10-12,14 Other researchers refute this claim and view the unequivocal Spitz nevus as benign and unrelated to melanoma. They point out that many of these case reports of melanomas with Spitz-like features do not fit the diagnosis of the Spitz nevus.¹⁶

In general, the more features an atypical Spitz nevus shares with melanoma, the greater the risk for malignant behavior. In 1999, Spatz et al¹² proposed formal and specific criteria for determining the risk for malignant behavior in atypical Spitz nevi in children. In the retrospective study, atypical features were used to define atypical Spitz nevi and grade their risk for metastasis. The 5 major factors were age, size, presence of ulceration, involvement of subcutaneous fat, and mitotic activity. Positive risk factors that increased the grade included age greater than 10 years, diameter greater than 10.0 mm, lesions with fat involvement, presence of ulceration, and dermal component mitotic activity greater than 5 mitoses/mm². The higher the grade, the higher the risk for malignancy and metastasis.¹² Since its publication, this grading system for categorizing atypical Spitz nevi has been put to use in a few case reports and studies.^17,18 Additional prospective studies using these criteria will be helpful in determining the true clinical nature of atypical Spitz nevi in children, the usefulness of this grading system, and the possible application of this grading system in adults. 

Problems Differentiating Classic and Atypical Spitz Nevi From Melanoma

Melanoma is a major part of the differential diagnosis of Spitz nevi. The classic Spitz nevus typically has a benign nature, while the atypical Spitz nevus displays unpredictable behavior that appears to be dependent on the degree of atypia.^1,3,16 In contrast, melanoma is potentially fatal. Fortunately, Spitz nevi typically occur in children and the risk for having childhood melanoma is rare.^6,8,19 Though risk is minimal, rare cases of melanoma have been reported in children.^{8,11,14,15,19-21} Therefore, making a correct diagnosis and ruling out melanoma is important.

Unfortunately, even with clinical and histologic guidelines, sometimes it is difficult to distinguish classic and atypical Spitz nevi from melanoma. The major problem is histologic overlap with Spitz nevi and melanoma. Many researchers have emphasized that there is no single discriminating factor for Spitz nevi and melanoma because virtually every trait of Spitz nevi has been described in melanoma.^{2,10,13,20,22,23} Results of multiple studies show variability among researchers on the analysis of melanocytic nevi and melanoma lesions, and the final diagnosis was subjective.^5,22 In one retrospective study where clinical outcome was already known, 30 melanocytic lesions were evaluated independently by a panel of 10 dermatopathologists and categorized as either a typical Spitz nevus, atypical Spitz nevus, melanoma, tumor with unknown biologic potential, or other melanocytic lesion.⁵ The dermatopathologists were blinded to the clinical data. Evaluation of 17 Spitzoid lesions yielded no clear diagnostic consensus and a few lethal lesions were identified by most dermatopathologists as either typical or atypical Spitz nevi. The authors maintain that these results show that current objective criteria are deficient and inadequate to permit the discrimination of Spitz nevi with atypical features from melanoma.⁵

Given these histologic analysis limitations, many investigators are researching other tools and techniques that may help enhance diagnostic accuracy. Promising genetic analysis techniques include comparative genomic hybridization and fluorescent in situ hybridization.²⁴ In one study,²⁴ researchers compared Spitz nevi with primary cutaneous melanomas using comparative genomic hybridization and fluorescent in situ hybridization and discovered differences. In the study, Spitz nevi were found to have no chromosomal aberrations or gains in chromosome 11p or 7q21qter. In comparison, primary cutaneous melanomas had frequent chromosome deletions of chromosomes 9p, 10q, 6q, and 8p, and gains of chromosomes 7, 8, 6p, and 1q.^24,25 Immunohistochemistry is another potential tool for improving diagnostic accuracy. Examples of promising immunohistochemical markers include antibody MIB-1,^26-28 BCL-2,²⁹ and anti-S100A6.³⁰ Studies have shown that most melanomas are immunoreactive to MIB-1 and BCL-2, whereas Spitz nevi are not.^26-29 Recently, anti-S100A6 protein also was shown to be a potential immunohistochemical marker to differentiate a Spitz nevus from melanoma.³⁰ Anti-S100A6 is different from anti-S100 because it is more specific to a subclass of normal cell types and certain cancer cell lines. Investigators found strong, uniform, and diffuse S100A6 protein expression in the junctional and dermal components of all 42 Spitz nevi they studied versus weak and patchy S100A6 protein expression found mainly in the dermal component of 35 of 105 melanoma specimens they studied.³⁰ Although these techniques show exceptional potential, further research will be required to prove their reliability. 

Management of Classic and Atypical Spitz Nevi

There is controversy regarding the treatment of a classic Spitz nevus. Some investigators recommend conservative treatment because a Spitz nevus is benign. They find that the Spitz nevus may be removed or left alone.³ Others agree but would add that complete excision with clinical follow-up is appropriate if there are atypical features found on the Spitz nevus.^16,23,31 Other investigators are more aggressive and recommend complete excision with clear margins of all Spitz nevi, unequivocal or not, because Spitz nevi have histologic overlap with melanoma, and recurrent lesions may present with pseudomelanomatous changes, which makes differentiation more difficult later.^4,32 They conclude that the benefits of complete excision outweigh the risks of partial treatment.⁴ Regardless of how a Spitz nevus case is managed, regular follow-up with a dermatologist is recommended to look for any changes or recurrences suggestive of malignancy.

Currently, there are no available evidence-based recommendations with predictive value for the specific management of atypical Spitz nevi because their clinical course is mostly unknown and unpredictable. Most articles that do address the management of atypical Spitz nevi state that they should be completely excised and followed periodically.^11,33 Murphy et al³⁴ suggest that an atypical Spitz nevus should be completely excised to avoid the rare possibility of a melanoma masquerading as an atypical Spitz nevus. Furthermore, if the physician is suspicious of malignancy, it is recommended that the lesion be managed like a melanoma and be removed in accordance with current melanoma margin guidelines or with comprehensive margin control via Mohs micrographic surgery.^34,35 Gurbuz et al¹⁷ stated that surgical margin excision, sentinel lymph node dissection, and clinical follow-up is recommended for atypical Spitz tumors. However, currently there are no prospective studies that have tested these various recommendations on atypical Spitz nevi management.

Within the last few years, sentinel lymph node biopsy (SLNB) has been proposed as a useful tool in the management of melanocytic neoplasms of uncertain behavior, such as the atypical Spitz nevus.³⁶ Researchers recommend SLNB in atypical Spitz nevi greater than 1.0-mm thick.^18,36,37 Supporters maintain that it increases the sensitivity of the diagnosis of melanoma (vs atypical Spitz nevus) and identifies patients who may potentially benefit from early lymph node dissection and/or adjuvant therapy. They state that a positive SLNB supports the diagnosis of malignancy and recommend that the lesion be treated aggressively. If the SLNB is negative, melanoma cannot be completely ruled out, but there is more reassurance that the lesion may be confined to the skin and can be completely removed by excision.^18,36,37 Other advantages of SLNB include minimal invasiveness and morbidity. Some researchers believe melanocytic neoplasms in which melanoma cannot be ruled out should undergo complete surgical excision with wide margins in accordance with current melanoma guidelines,^34,35 which can be as much as 3 cm.^36,38 A negative SLNB offers the advantage of planning a complete excision of an atypical Spitz nevus that preserves surrounding margins and is cosmetically more acceptable,³⁶ and avoiding the morbidity (ie, lymphedema, paresthesia) associated with regional or elective lymph node dissection.¹⁸

However, some researchers argue that a positive SLNB in an atypical Spitz nevus is not metastatic melanoma and point out articles that have shown classic and atypical Spitz nevi spreading to lymphatic vessels and lymph nodes but behaving in a benign manner.^{11,13,15,21,37} Therefore, more studies are needed to assess the prognostic significance of positive SLNB in atypical Spitz nevi.¹⁸

Spitz nevi were first described in 1948.¹ Spitz¹ originally called these lesions benign juvenile melanoma. She was able to identify and describe a separate class of benign melanocytic neoplasms in children that were previously diagnosed and treated as melanoma.² Prior to this discovery, the standard of care was to remove all suspicious pigmented lesions in children prior to adulthood to prevent possible malignant transformation.^2,3 Today, Spitz nevus is the more commonly used term for benign juvenile melanoma because it is encountered occasionally in adults and the term melanoma carries a negative connotation.⁴ Other synonyms include juvenile melanoma, Spitz tumor, nevus of large spindle and/or epithelioid cells, and spindle cell and epithelioid nevus.^3,5 

Classic Spitz Nevus

Spitz nevi are uncommon. The approximate incidence is 7 per 100,000 people. Spitz nevi are more frequently found in children and adolescents but can occur in adults.^6,7 Spitz nevi occur predominantly in the white population and slightly more often in females.^4,8

A Spitz nevus can arise de novo or in association with an existing melanocytic nevus. The lesions can be asymptomatic or have a history of rapid but limited growth. Clinical features of Spitz nevi are well-circumscribed, symmetrical, small- to medium-sized firm papules with smooth discrete borders and a uniform color (typically pink or flesh colored).⁹ Spitz nevi can occur in various shapes. In a study of 211 cases of Spitz nevi, 19% were described as flat or uneven, 24% as polypoid, and 57% as plateau or elevated.⁷ Spitz nevi usually are found on the face, neck, or lower extremities but can occur anywhere on the body.^7,9 Size is typically less than 6 mm (Figures 1 and 2).

PLEASE REFER TO THE PDF TO VIEW THE FIGURES

The classic Spitz nevus histologically consists of large spindle and/or epithelioid melanocytes arrayed as epidermal nests grouped in a vertical orientation (called "bunches of bananas" or "raining down pattern"), with clefting artifact at the perimeter (Figure 3).^4,9,10 The nests are fairly uniform, nonconfluent, and evenly spaced. There is little or no pagetoid spread pattern. Epidermal changes include acanthosis, hypergranulosis, and hyperkeratosis. The intradermal pattern displays maturation, with single-file or single-unit arrays descending to the base. Eosinophilic Kamino bodies frequently are found along the dermoepidermal interface. Kamino bodies are globular clusters that represent apoptotic degenerative melanocytes (Figure 4). They stain positive with both periodic acid-Schiff and trichrome stains. At the dermal base, there is no mitosis, no pushing deep margins, and lack of significant pleomorphism. Little or no melanin is present.^4,9,10 The classic Spitz nevus behaves in a benign manner.¹ The differential diagnosis of the Spitz nevus includes pyogenic granuloma, mastocytoma, juvenile xanthogranuloma, and malignant melanoma.

PLEASE REFER TO THE PDF TO VIEW THE FIGURES

Atypical Spitz Nevus

The atypical Spitz nevus is difficult to formally define. Instead, it is loosely defined. An atypical Spitz nevus shares histologic features with the classic Spitz nevus, but it may have one or more atypical features, which can be characteristic of malignancy.^10-12 Gross atypical features may include irregular shape, nonuniform color, large size, or ulcerations. Histologically, there can be one or more of the following features: pleomorphism; increased cellularity; loss of cellular cohesion; epidermal pagetoid spread; minimal epidermal changes; absence of Kamino bodies; lack of maturation in the intradermal pattern; high-grade nuclear atypia; high basal mitotic rate; pushing deep margins into the dermal base or subcutis; and nests variable in size, shape, and orientation.^9,10,13

The behavior of any atypical Spitz nevus is unpredictable. There are case reports of metastasizing and malignant lesions with Spitz-like characteristics causing fatal outcomes.^11,13 However, there also are studies that show Spitz nevi acting in a benign manner, even with a history of metastases.^11,13-15 Some researchers try to explain this phenomenon by theorizing that Spitz nevi and melanoma exist along a continuum with the classic benign Spitz nevus at one end of the spectrum and the aggressive malignant melanoma at the opposite end, with a diverse range of atypical Spitz-like lesions with features of both in between.^4,10-12,14 Other researchers refute this claim and view the unequivocal Spitz nevus as benign and unrelated to melanoma. They point out that many of these case reports of melanomas with Spitz-like features do not fit the diagnosis of the Spitz nevus.¹⁶

In general, the more features an atypical Spitz nevus shares with melanoma, the greater the risk for malignant behavior. In 1999, Spatz et al¹² proposed formal and specific criteria for determining the risk for malignant behavior in atypical Spitz nevi in children. In the retrospective study, atypical features were used to define atypical Spitz nevi and grade their risk for metastasis. The 5 major factors were age, size, presence of ulceration, involvement of subcutaneous fat, and mitotic activity. Positive risk factors that increased the grade included age greater than 10 years, diameter greater than 10.0 mm, lesions with fat involvement, presence of ulceration, and dermal component mitotic activity greater than 5 mitoses/mm². The higher the grade, the higher the risk for malignancy and metastasis.¹² Since its publication, this grading system for categorizing atypical Spitz nevi has been put to use in a few case reports and studies.^17,18 Additional prospective studies using these criteria will be helpful in determining the true clinical nature of atypical Spitz nevi in children, the usefulness of this grading system, and the possible application of this grading system in adults. 

Problems Differentiating Classic and Atypical Spitz Nevi From Melanoma

Melanoma is a major part of the differential diagnosis of Spitz nevi. The classic Spitz nevus typically has a benign nature, while the atypical Spitz nevus displays unpredictable behavior that appears to be dependent on the degree of atypia.^1,3,16 In contrast, melanoma is potentially fatal. Fortunately, Spitz nevi typically occur in children and the risk for having childhood melanoma is rare.^6,8,19 Though risk is minimal, rare cases of melanoma have been reported in children.^{8,11,14,15,19-21} Therefore, making a correct diagnosis and ruling out melanoma is important.

Unfortunately, even with clinical and histologic guidelines, sometimes it is difficult to distinguish classic and atypical Spitz nevi from melanoma. The major problem is histologic overlap with Spitz nevi and melanoma. Many researchers have emphasized that there is no single discriminating factor for Spitz nevi and melanoma because virtually every trait of Spitz nevi has been described in melanoma.^{2,10,13,20,22,23} Results of multiple studies show variability among researchers on the analysis of melanocytic nevi and melanoma lesions, and the final diagnosis was subjective.^5,22 In one retrospective study where clinical outcome was already known, 30 melanocytic lesions were evaluated independently by a panel of 10 dermatopathologists and categorized as either a typical Spitz nevus, atypical Spitz nevus, melanoma, tumor with unknown biologic potential, or other melanocytic lesion.⁵ The dermatopathologists were blinded to the clinical data. Evaluation of 17 Spitzoid lesions yielded no clear diagnostic consensus and a few lethal lesions were identified by most dermatopathologists as either typical or atypical Spitz nevi. The authors maintain that these results show that current objective criteria are deficient and inadequate to permit the discrimination of Spitz nevi with atypical features from melanoma.⁵

Given these histologic analysis limitations, many investigators are researching other tools and techniques that may help enhance diagnostic accuracy. Promising genetic analysis techniques include comparative genomic hybridization and fluorescent in situ hybridization.²⁴ In one study,²⁴ researchers compared Spitz nevi with primary cutaneous melanomas using comparative genomic hybridization and fluorescent in situ hybridization and discovered differences. In the study, Spitz nevi were found to have no chromosomal aberrations or gains in chromosome 11p or 7q21qter. In comparison, primary cutaneous melanomas had frequent chromosome deletions of chromosomes 9p, 10q, 6q, and 8p, and gains of chromosomes 7, 8, 6p, and 1q.^24,25 Immunohistochemistry is another potential tool for improving diagnostic accuracy. Examples of promising immunohistochemical markers include antibody MIB-1,^26-28 BCL-2,²⁹ and anti-S100A6.³⁰ Studies have shown that most melanomas are immunoreactive to MIB-1 and BCL-2, whereas Spitz nevi are not.^26-29 Recently, anti-S100A6 protein also was shown to be a potential immunohistochemical marker to differentiate a Spitz nevus from melanoma.³⁰ Anti-S100A6 is different from anti-S100 because it is more specific to a subclass of normal cell types and certain cancer cell lines. Investigators found strong, uniform, and diffuse S100A6 protein expression in the junctional and dermal components of all 42 Spitz nevi they studied versus weak and patchy S100A6 protein expression found mainly in the dermal component of 35 of 105 melanoma specimens they studied.³⁰ Although these techniques show exceptional potential, further research will be required to prove their reliability. 

Management of Classic and Atypical Spitz Nevi

There is controversy regarding the treatment of a classic Spitz nevus. Some investigators recommend conservative treatment because a Spitz nevus is benign. They find that the Spitz nevus may be removed or left alone.³ Others agree but would add that complete excision with clinical follow-up is appropriate if there are atypical features found on the Spitz nevus.^16,23,31 Other investigators are more aggressive and recommend complete excision with clear margins of all Spitz nevi, unequivocal or not, because Spitz nevi have histologic overlap with melanoma, and recurrent lesions may present with pseudomelanomatous changes, which makes differentiation more difficult later.^4,32 They conclude that the benefits of complete excision outweigh the risks of partial treatment.⁴ Regardless of how a Spitz nevus case is managed, regular follow-up with a dermatologist is recommended to look for any changes or recurrences suggestive of malignancy.

Currently, there are no available evidence-based recommendations with predictive value for the specific management of atypical Spitz nevi because their clinical course is mostly unknown and unpredictable. Most articles that do address the management of atypical Spitz nevi state that they should be completely excised and followed periodically.^11,33 Murphy et al³⁴ suggest that an atypical Spitz nevus should be completely excised to avoid the rare possibility of a melanoma masquerading as an atypical Spitz nevus. Furthermore, if the physician is suspicious of malignancy, it is recommended that the lesion be managed like a melanoma and be removed in accordance with current melanoma margin guidelines or with comprehensive margin control via Mohs micrographic surgery.^34,35 Gurbuz et al¹⁷ stated that surgical margin excision, sentinel lymph node dissection, and clinical follow-up is recommended for atypical Spitz tumors. However, currently there are no prospective studies that have tested these various recommendations on atypical Spitz nevi management.

Within the last few years, sentinel lymph node biopsy (SLNB) has been proposed as a useful tool in the management of melanocytic neoplasms of uncertain behavior, such as the atypical Spitz nevus.³⁶ Researchers recommend SLNB in atypical Spitz nevi greater than 1.0-mm thick.^18,36,37 Supporters maintain that it increases the sensitivity of the diagnosis of melanoma (vs atypical Spitz nevus) and identifies patients who may potentially benefit from early lymph node dissection and/or adjuvant therapy. They state that a positive SLNB supports the diagnosis of malignancy and recommend that the lesion be treated aggressively. If the SLNB is negative, melanoma cannot be completely ruled out, but there is more reassurance that the lesion may be confined to the skin and can be completely removed by excision.^18,36,37 Other advantages of SLNB include minimal invasiveness and morbidity. Some researchers believe melanocytic neoplasms in which melanoma cannot be ruled out should undergo complete surgical excision with wide margins in accordance with current melanoma guidelines,^34,35 which can be as much as 3 cm.^36,38 A negative SLNB offers the advantage of planning a complete excision of an atypical Spitz nevus that preserves surrounding margins and is cosmetically more acceptable,³⁶ and avoiding the morbidity (ie, lymphedema, paresthesia) associated with regional or elective lymph node dissection.¹⁸

However, some researchers argue that a positive SLNB in an atypical Spitz nevus is not metastatic melanoma and point out articles that have shown classic and atypical Spitz nevi spreading to lymphatic vessels and lymph nodes but behaving in a benign manner.^{11,13,15,21,37} Therefore, more studies are needed to assess the prognostic significance of positive SLNB in atypical Spitz nevi.¹⁸

Spitz nevi were first described in 1948.¹ Spitz¹ originally called these lesions benign juvenile melanoma. She was able to identify and describe a separate class of benign melanocytic neoplasms in children that were previously diagnosed and treated as melanoma.² Prior to this discovery, the standard of care was to remove all suspicious pigmented lesions in children prior to adulthood to prevent possible malignant transformation.^2,3 Today, Spitz nevus is the more commonly used term for benign juvenile melanoma because it is encountered occasionally in adults and the term melanoma carries a negative connotation.⁴ Other synonyms include juvenile melanoma, Spitz tumor, nevus of large spindle and/or epithelioid cells, and spindle cell and epithelioid nevus.^3,5 

Classic Spitz Nevus

Spitz nevi are uncommon. The approximate incidence is 7 per 100,000 people. Spitz nevi are more frequently found in children and adolescents but can occur in adults.^6,7 Spitz nevi occur predominantly in the white population and slightly more often in females.^4,8

A Spitz nevus can arise de novo or in association with an existing melanocytic nevus. The lesions can be asymptomatic or have a history of rapid but limited growth. Clinical features of Spitz nevi are well-circumscribed, symmetrical, small- to medium-sized firm papules with smooth discrete borders and a uniform color (typically pink or flesh colored).⁹ Spitz nevi can occur in various shapes. In a study of 211 cases of Spitz nevi, 19% were described as flat or uneven, 24% as polypoid, and 57% as plateau or elevated.⁷ Spitz nevi usually are found on the face, neck, or lower extremities but can occur anywhere on the body.^7,9 Size is typically less than 6 mm (Figures 1 and 2).

PLEASE REFER TO THE PDF TO VIEW THE FIGURES

The classic Spitz nevus histologically consists of large spindle and/or epithelioid melanocytes arrayed as epidermal nests grouped in a vertical orientation (called "bunches of bananas" or "raining down pattern"), with clefting artifact at the perimeter (Figure 3).^4,9,10 The nests are fairly uniform, nonconfluent, and evenly spaced. There is little or no pagetoid spread pattern. Epidermal changes include acanthosis, hypergranulosis, and hyperkeratosis. The intradermal pattern displays maturation, with single-file or single-unit arrays descending to the base. Eosinophilic Kamino bodies frequently are found along the dermoepidermal interface. Kamino bodies are globular clusters that represent apoptotic degenerative melanocytes (Figure 4). They stain positive with both periodic acid-Schiff and trichrome stains. At the dermal base, there is no mitosis, no pushing deep margins, and lack of significant pleomorphism. Little or no melanin is present.^4,9,10 The classic Spitz nevus behaves in a benign manner.¹ The differential diagnosis of the Spitz nevus includes pyogenic granuloma, mastocytoma, juvenile xanthogranuloma, and malignant melanoma.

PLEASE REFER TO THE PDF TO VIEW THE FIGURES

Atypical Spitz Nevus

The atypical Spitz nevus is difficult to formally define. Instead, it is loosely defined. An atypical Spitz nevus shares histologic features with the classic Spitz nevus, but it may have one or more atypical features, which can be characteristic of malignancy.^10-12 Gross atypical features may include irregular shape, nonuniform color, large size, or ulcerations. Histologically, there can be one or more of the following features: pleomorphism; increased cellularity; loss of cellular cohesion; epidermal pagetoid spread; minimal epidermal changes; absence of Kamino bodies; lack of maturation in the intradermal pattern; high-grade nuclear atypia; high basal mitotic rate; pushing deep margins into the dermal base or subcutis; and nests variable in size, shape, and orientation.^9,10,13

The behavior of any atypical Spitz nevus is unpredictable. There are case reports of metastasizing and malignant lesions with Spitz-like characteristics causing fatal outcomes.^11,13 However, there also are studies that show Spitz nevi acting in a benign manner, even with a history of metastases.^11,13-15 Some researchers try to explain this phenomenon by theorizing that Spitz nevi and melanoma exist along a continuum with the classic benign Spitz nevus at one end of the spectrum and the aggressive malignant melanoma at the opposite end, with a diverse range of atypical Spitz-like lesions with features of both in between.^4,10-12,14 Other researchers refute this claim and view the unequivocal Spitz nevus as benign and unrelated to melanoma. They point out that many of these case reports of melanomas with Spitz-like features do not fit the diagnosis of the Spitz nevus.¹⁶

In general, the more features an atypical Spitz nevus shares with melanoma, the greater the risk for malignant behavior. In 1999, Spatz et al¹² proposed formal and specific criteria for determining the risk for malignant behavior in atypical Spitz nevi in children. In the retrospective study, atypical features were used to define atypical Spitz nevi and grade their risk for metastasis. The 5 major factors were age, size, presence of ulceration, involvement of subcutaneous fat, and mitotic activity. Positive risk factors that increased the grade included age greater than 10 years, diameter greater than 10.0 mm, lesions with fat involvement, presence of ulceration, and dermal component mitotic activity greater than 5 mitoses/mm². The higher the grade, the higher the risk for malignancy and metastasis.¹² Since its publication, this grading system for categorizing atypical Spitz nevi has been put to use in a few case reports and studies.^17,18 Additional prospective studies using these criteria will be helpful in determining the true clinical nature of atypical Spitz nevi in children, the usefulness of this grading system, and the possible application of this grading system in adults. 

Problems Differentiating Classic and Atypical Spitz Nevi From Melanoma

Melanoma is a major part of the differential diagnosis of Spitz nevi. The classic Spitz nevus typically has a benign nature, while the atypical Spitz nevus displays unpredictable behavior that appears to be dependent on the degree of atypia.^1,3,16 In contrast, melanoma is potentially fatal. Fortunately, Spitz nevi typically occur in children and the risk for having childhood melanoma is rare.^6,8,19 Though risk is minimal, rare cases of melanoma have been reported in children.^{8,11,14,15,19-21} Therefore, making a correct diagnosis and ruling out melanoma is important.

Unfortunately, even with clinical and histologic guidelines, sometimes it is difficult to distinguish classic and atypical Spitz nevi from melanoma. The major problem is histologic overlap with Spitz nevi and melanoma. Many researchers have emphasized that there is no single discriminating factor for Spitz nevi and melanoma because virtually every trait of Spitz nevi has been described in melanoma.^{2,10,13,20,22,23} Results of multiple studies show variability among researchers on the analysis of melanocytic nevi and melanoma lesions, and the final diagnosis was subjective.^5,22 In one retrospective study where clinical outcome was already known, 30 melanocytic lesions were evaluated independently by a panel of 10 dermatopathologists and categorized as either a typical Spitz nevus, atypical Spitz nevus, melanoma, tumor with unknown biologic potential, or other melanocytic lesion.⁵ The dermatopathologists were blinded to the clinical data. Evaluation of 17 Spitzoid lesions yielded no clear diagnostic consensus and a few lethal lesions were identified by most dermatopathologists as either typical or atypical Spitz nevi. The authors maintain that these results show that current objective criteria are deficient and inadequate to permit the discrimination of Spitz nevi with atypical features from melanoma.⁵

Given these histologic analysis limitations, many investigators are researching other tools and techniques that may help enhance diagnostic accuracy. Promising genetic analysis techniques include comparative genomic hybridization and fluorescent in situ hybridization.²⁴ In one study,²⁴ researchers compared Spitz nevi with primary cutaneous melanomas using comparative genomic hybridization and fluorescent in situ hybridization and discovered differences. In the study, Spitz nevi were found to have no chromosomal aberrations or gains in chromosome 11p or 7q21qter. In comparison, primary cutaneous melanomas had frequent chromosome deletions of chromosomes 9p, 10q, 6q, and 8p, and gains of chromosomes 7, 8, 6p, and 1q.^24,25 Immunohistochemistry is another potential tool for improving diagnostic accuracy. Examples of promising immunohistochemical markers include antibody MIB-1,^26-28 BCL-2,²⁹ and anti-S100A6.³⁰ Studies have shown that most melanomas are immunoreactive to MIB-1 and BCL-2, whereas Spitz nevi are not.^26-29 Recently, anti-S100A6 protein also was shown to be a potential immunohistochemical marker to differentiate a Spitz nevus from melanoma.³⁰ Anti-S100A6 is different from anti-S100 because it is more specific to a subclass of normal cell types and certain cancer cell lines. Investigators found strong, uniform, and diffuse S100A6 protein expression in the junctional and dermal components of all 42 Spitz nevi they studied versus weak and patchy S100A6 protein expression found mainly in the dermal component of 35 of 105 melanoma specimens they studied.³⁰ Although these techniques show exceptional potential, further research will be required to prove their reliability. 

Management of Classic and Atypical Spitz Nevi

There is controversy regarding the treatment of a classic Spitz nevus. Some investigators recommend conservative treatment because a Spitz nevus is benign. They find that the Spitz nevus may be removed or left alone.³ Others agree but would add that complete excision with clinical follow-up is appropriate if there are atypical features found on the Spitz nevus.^16,23,31 Other investigators are more aggressive and recommend complete excision with clear margins of all Spitz nevi, unequivocal or not, because Spitz nevi have histologic overlap with melanoma, and recurrent lesions may present with pseudomelanomatous changes, which makes differentiation more difficult later.^4,32 They conclude that the benefits of complete excision outweigh the risks of partial treatment.⁴ Regardless of how a Spitz nevus case is managed, regular follow-up with a dermatologist is recommended to look for any changes or recurrences suggestive of malignancy.

Currently, there are no available evidence-based recommendations with predictive value for the specific management of atypical Spitz nevi because their clinical course is mostly unknown and unpredictable. Most articles that do address the management of atypical Spitz nevi state that they should be completely excised and followed periodically.^11,33 Murphy et al³⁴ suggest that an atypical Spitz nevus should be completely excised to avoid the rare possibility of a melanoma masquerading as an atypical Spitz nevus. Furthermore, if the physician is suspicious of malignancy, it is recommended that the lesion be managed like a melanoma and be removed in accordance with current melanoma margin guidelines or with comprehensive margin control via Mohs micrographic surgery.^34,35 Gurbuz et al¹⁷ stated that surgical margin excision, sentinel lymph node dissection, and clinical follow-up is recommended for atypical Spitz tumors. However, currently there are no prospective studies that have tested these various recommendations on atypical Spitz nevi management.

Within the last few years, sentinel lymph node biopsy (SLNB) has been proposed as a useful tool in the management of melanocytic neoplasms of uncertain behavior, such as the atypical Spitz nevus.³⁶ Researchers recommend SLNB in atypical Spitz nevi greater than 1.0-mm thick.^18,36,37 Supporters maintain that it increases the sensitivity of the diagnosis of melanoma (vs atypical Spitz nevus) and identifies patients who may potentially benefit from early lymph node dissection and/or adjuvant therapy. They state that a positive SLNB supports the diagnosis of malignancy and recommend that the lesion be treated aggressively. If the SLNB is negative, melanoma cannot be completely ruled out, but there is more reassurance that the lesion may be confined to the skin and can be completely removed by excision.^18,36,37 Other advantages of SLNB include minimal invasiveness and morbidity. Some researchers believe melanocytic neoplasms in which melanoma cannot be ruled out should undergo complete surgical excision with wide margins in accordance with current melanoma guidelines,^34,35 which can be as much as 3 cm.^36,38 A negative SLNB offers the advantage of planning a complete excision of an atypical Spitz nevus that preserves surrounding margins and is cosmetically more acceptable,³⁶ and avoiding the morbidity (ie, lymphedema, paresthesia) associated with regional or elective lymph node dissection.¹⁸

However, some researchers argue that a positive SLNB in an atypical Spitz nevus is not metastatic melanoma and point out articles that have shown classic and atypical Spitz nevi spreading to lymphatic vessels and lymph nodes but behaving in a benign manner.^{11,13,15,21,37} Therefore, more studies are needed to assess the prognostic significance of positive SLNB in atypical Spitz nevi.¹⁸

The method for skin grafting surgical defects of the nasal alar region known as the drumhead graft was invented and developed by Dr. J. Michael Wentzell of Billings, Mont. ('Drumhead' Technique May Spare Alar Graft Depressions, SKIN & ALLERGY NEWS, January 2007, p. 32). Dr. Bradley K. Draper of Billings presented Dr. Wentzell's technique at the annual meeting of the American Society for Dermatologic Surgery.

The method for skin grafting surgical defects of the nasal alar region known as the drumhead graft was invented and developed by Dr. J. Michael Wentzell of Billings, Mont. ('Drumhead' Technique May Spare Alar Graft Depressions, SKIN & ALLERGY NEWS, January 2007, p. 32). Dr. Bradley K. Draper of Billings presented Dr. Wentzell's technique at the annual meeting of the American Society for Dermatologic Surgery.

The method for skin grafting surgical defects of the nasal alar region known as the drumhead graft was invented and developed by Dr. J. Michael Wentzell of Billings, Mont. ('Drumhead' Technique May Spare Alar Graft Depressions, SKIN & ALLERGY NEWS, January 2007, p. 32). Dr. Bradley K. Draper of Billings presented Dr. Wentzell's technique at the annual meeting of the American Society for Dermatologic Surgery.

Syringomatous carcinoma (SC), considered by some to be a variant of microcystic adnexal carcinoma (MAC),1 is a rare malignant neoplasm of sweat gland origin. SC encompasses a range of neoplasms with different degrees of differentiation, and its nomenclature has varied over the years. SC also has been referred to as syringoid eccrine carcinoma,2 basal cell tumor with eccrine differentiation,3 malignant syringoma,4 and sclerosing sweat duct carcinoma.5 Its diagnosis has been a dilemma in a number of reported cases, probably due to the combination of its rarity and thus limited clinical and histopathologic information, microscopic similarities to other benign and malignant neoplasms, and characteristic histologic features that may only be apparent in surgical excisions containing deeper tissue. We report a case of SC that masqueraded as an epidermoid cyst in an unusually young patient.

Case Report
A 23-year-old Asian man, who was otherwise healthy, presented with an asymptomatic slowly enlarging nodule of one year's duration on the right medial eyebrow. Prior treatment with intralesional steroid injections resulted in minimal improvement. The patient had no personal or family history of skin cancers. Physical examination results demonstrated a well-demarcated, mobile, nontender subcutaneous nodule measuring 7 mm in diameter. The clinical presentation favored a diagnosis of an epidermal inclusion cyst, and the patient underwent surgical excision of the lesion. Results of the histopathologic examination revealed a neoplasm in the dermis consisting of bands and nests of pale staining basaloid cells extending between the collagen fibers (Figure 1). There were focal areas of ductal differentiation, scattered individual necrotic cells, moderate dermal fibrosis, and chronic inflammation with numerous eo-sinophils. Moderate nuclear atypia also was present (Figure 2). Perineural involvement was not seen. Results of immunohistochemical analysis revealed positive staining for high—and low—molecular-weight cytokeratins, as well as carcinoembryonic antigen (CEA)(Figure 3). There was scattered positivity with S-100 protein in occasional cells lining lumina and in dendritic cells (Figure 4). The histopathologic findings supported the diagnosis of SC. Because the neoplasm extended to the surgical margins of the specimen, repeat surgical excision with continuous microscopic control under the Mohs micrographic technique was performed to prevent local recurrence and spare normal tissue. At the 18-month follow-up visit, no local recurrence was seen.

Comment SC is a rare, malignant sweat gland neoplasm that usually occurs in the fourth and fifth decades of life.4-8 SC typically presents as a slow-growing, solitary, painless nodule or indurated plaque on the head or neck region.6-8 It has been frequently found on the upper and lower lips; however, it also has been reported to occur on the finger and breast.9,10 Predisposing factors for the development of SC are unclear11 but may include previous radiation to the face and history of receiving an organ transplant with immunosuppressive drug therapy.12-17 Histopathologically, SC is characterized by asymmetric and deep dermal invasion of tumor cells, perineural involvement, ductal formation, keratin-filled cysts, multiple nests of basaloid or squamous cells, and desmoplasia of the surrounding dermal stroma (Table 1).5,6 Some authors consider SC to be closely related to MAC but generally describe SC as more basaloid with larger tubules and a more sclerotic stroma than MAC.18-26 If histologic examination of SC is limited to the superficial dermis, SC demonstrates similarities to other neoplasms, including syringomas, trichoadenomas, trichoepitheliomas, basal cell carcinomas, or squamous cell carcinomas. In the reported cases in which SC was initially misdiagnosed as another benign or malignant neoplasm, many misdiagnoses were due to either a benign clinical appearance of the lesion or biopsy specimens that were too superficial to contain the deeper characteristic histologic features of SC.8,9,11,27-30

Immunohistochemical studies can facilitate the diagnosis of SC and differentiate it from other neoplasms. SC stains positively for CEA, S-100 protein, epithelial membrane antigen, cyto-keratin, and gross cystic disease fluid protein 15,31 all of which aid in the confirmation of a sweat gland neoplasm (Table 2).8,32,33,39 Positivity for CEA in the ductal lining cells and the luminal contents of tumor ducts confirms sweat gland differentiation.25,33,34 This ductal immunoreactivity to CEA appears to be one of the most reliable findings to differentiate SC and MAC from other adnexal tumors, especially desmoplastic trichoepithelioma, which may be one of the more challenging histo-pathologic differential diagnoses.35 In addition, epithelial membrane antigen positivity can be found in the areas showing glandular features.35 This can assist in distinguishing SC from a desmoplastic trichoepithelioma or sclerosing type basal cell carcinoma, both of which demonstrate negativity to epithelial membrane antigen.35 S-100 protein positivity in dendritic cells, as well as in some cords and ducts in SC, further verifies dendritic differentiation toward sweat gland structures and is useful as an adjunct in the confirmation of glandular differentiation.25,33,34,36

Without proper and timely diagnosis and management, SC can cause severe patient morbidity. Although SC rarely metastasizes and can have an indolent course, it can be locally de-structive and lead to potentially disfiguring outcomes.5-7 SC can invade deeply and infiltrate into the dermis, subcutaneous fat tissue, muscle, perichondrium, periosteum, and galea.8 Goto et al9 reported a case of an SC that was initially misdiagnosed as a basal cell carcinoma of the left middle finger. The deeper, characteristic features of SC were not recognized until after the affected finger required amputation due to erosion of the bone. Hoppenreijs et al11 described an aggressive case of an SC arising at a site of previously irradiated squamous cell carcinoma of the lower eyelid. Extensive involvement of the SC in the orbit led to the recommendation of an orbital exenter-ation; however, it was not performed because of the poor clinical condition of the patient. Treatments for SC have included wide local excision and Mohs micrographic surgery (MMS). SC treatment with wide local excision often resulted in incomplete excision of the neoplasm despite having taken an adequate margin around the clinically assessable tumor.5 Cases of SC treated with wide local excision had a recurrence rate of 47%.5 The positive surgical margins following wide local excision may be due to the deep infiltration of SC, which frequently exceeds the clinically predicted size of the tumor.5 Due to the close relationship of MAC and SC, we feel that MMS treatment of SC will reduce recurrences as it has for MAC. Currently, there is strong support for the treatment of MAC with MMS as a gold standard to ensure complete clearance of the neoplasm and to reduce the local recurrence rate.12,13,17,21,22,37,38 In a study of MAC by Chiller et al,37 the authors demonstrated a median 4-fold increase in defect size when they compared the clinically estimated pretreatment size of the lesion with the MMS-determined posttreatment size of the lesion. The authors therefore suggest that, similar to the MMS-treated lesions, the lesions completely treated with wide local excision also would produce a defect size that is at least 4 times greater than the predicted pretreatment size of the lesion. Because wide local excision relies on predicted margins of the lesion, which the authors have shown can be greatly underestimated, Chiller et al37 argue that the use of MMS, which does not rely on predicted margins, is a reasonable first-line therapeutic modality for effectively treating patients with MAC. Furthermore, MMS allows for the examination of the entire peripheral and deep margins of the lesion, which is critical when considering the deep infiltrative nature of MAC. The reported local recurrence rate of MAC treated with MMS is 0% to 5%,12,13,21,26,38 which is much lower than the reported local recurrence rate following treatment with wide local excision. This reduced recurrence rate found in MAC cases treated with MMS is probably due to the ability to confirm complete removal of the neoplasm with MMS. 

Conclusion To our knowledge, this case report describes the occurrence of SC, a rare sweat gland neoplasm, in the youngest reported patient and is only the second reported case of SC treated with MMS. Adequate sampling of tissue with an excisional biopsy allowed for appropriate evaluation with histologic and immunohistochemical studies to arrive at the diagnosis that could easily have been missed with a superficial biopsy. In our patient, histopathologic evaluation showed typical nests of basaloid cells, ductal differentiation, and ductal fibrosis seen in SC. However, perineural involvement that is particularly characteristic of SC was not present. This may portend a better prognosis for our patient whose tumor was completely excised after one stage of MMS and has not shown evidence of recurrence at the 18-month follow-up visit. MMS allowed for evaluation of the entire surgical margin and decreased risk of local recurrence resulting from an incomplete excision. In addition, it also allowed for sparing of normal tissue in a cosmetically sensitive area where SC commonly occurs. In summary, this case highlights the importance of including SC in the differential diagnosis of an enlarging cystic lesion in a younger patient and its successful treatment with MMS. 

Syringomatous carcinoma (SC), considered by some to be a variant of microcystic adnexal carcinoma (MAC),1 is a rare malignant neoplasm of sweat gland origin. SC encompasses a range of neoplasms with different degrees of differentiation, and its nomenclature has varied over the years. SC also has been referred to as syringoid eccrine carcinoma,2 basal cell tumor with eccrine differentiation,3 malignant syringoma,4 and sclerosing sweat duct carcinoma.5 Its diagnosis has been a dilemma in a number of reported cases, probably due to the combination of its rarity and thus limited clinical and histopathologic information, microscopic similarities to other benign and malignant neoplasms, and characteristic histologic features that may only be apparent in surgical excisions containing deeper tissue. We report a case of SC that masqueraded as an epidermoid cyst in an unusually young patient.

Case Report
A 23-year-old Asian man, who was otherwise healthy, presented with an asymptomatic slowly enlarging nodule of one year's duration on the right medial eyebrow. Prior treatment with intralesional steroid injections resulted in minimal improvement. The patient had no personal or family history of skin cancers. Physical examination results demonstrated a well-demarcated, mobile, nontender subcutaneous nodule measuring 7 mm in diameter. The clinical presentation favored a diagnosis of an epidermal inclusion cyst, and the patient underwent surgical excision of the lesion. Results of the histopathologic examination revealed a neoplasm in the dermis consisting of bands and nests of pale staining basaloid cells extending between the collagen fibers (Figure 1). There were focal areas of ductal differentiation, scattered individual necrotic cells, moderate dermal fibrosis, and chronic inflammation with numerous eo-sinophils. Moderate nuclear atypia also was present (Figure 2). Perineural involvement was not seen. Results of immunohistochemical analysis revealed positive staining for high—and low—molecular-weight cytokeratins, as well as carcinoembryonic antigen (CEA)(Figure 3). There was scattered positivity with S-100 protein in occasional cells lining lumina and in dendritic cells (Figure 4). The histopathologic findings supported the diagnosis of SC. Because the neoplasm extended to the surgical margins of the specimen, repeat surgical excision with continuous microscopic control under the Mohs micrographic technique was performed to prevent local recurrence and spare normal tissue. At the 18-month follow-up visit, no local recurrence was seen.

Comment SC is a rare, malignant sweat gland neoplasm that usually occurs in the fourth and fifth decades of life.4-8 SC typically presents as a slow-growing, solitary, painless nodule or indurated plaque on the head or neck region.6-8 It has been frequently found on the upper and lower lips; however, it also has been reported to occur on the finger and breast.9,10 Predisposing factors for the development of SC are unclear11 but may include previous radiation to the face and history of receiving an organ transplant with immunosuppressive drug therapy.12-17 Histopathologically, SC is characterized by asymmetric and deep dermal invasion of tumor cells, perineural involvement, ductal formation, keratin-filled cysts, multiple nests of basaloid or squamous cells, and desmoplasia of the surrounding dermal stroma (Table 1).5,6 Some authors consider SC to be closely related to MAC but generally describe SC as more basaloid with larger tubules and a more sclerotic stroma than MAC.18-26 If histologic examination of SC is limited to the superficial dermis, SC demonstrates similarities to other neoplasms, including syringomas, trichoadenomas, trichoepitheliomas, basal cell carcinomas, or squamous cell carcinomas. In the reported cases in which SC was initially misdiagnosed as another benign or malignant neoplasm, many misdiagnoses were due to either a benign clinical appearance of the lesion or biopsy specimens that were too superficial to contain the deeper characteristic histologic features of SC.8,9,11,27-30

Immunohistochemical studies can facilitate the diagnosis of SC and differentiate it from other neoplasms. SC stains positively for CEA, S-100 protein, epithelial membrane antigen, cyto-keratin, and gross cystic disease fluid protein 15,31 all of which aid in the confirmation of a sweat gland neoplasm (Table 2).8,32,33,39 Positivity for CEA in the ductal lining cells and the luminal contents of tumor ducts confirms sweat gland differentiation.25,33,34 This ductal immunoreactivity to CEA appears to be one of the most reliable findings to differentiate SC and MAC from other adnexal tumors, especially desmoplastic trichoepithelioma, which may be one of the more challenging histo-pathologic differential diagnoses.35 In addition, epithelial membrane antigen positivity can be found in the areas showing glandular features.35 This can assist in distinguishing SC from a desmoplastic trichoepithelioma or sclerosing type basal cell carcinoma, both of which demonstrate negativity to epithelial membrane antigen.35 S-100 protein positivity in dendritic cells, as well as in some cords and ducts in SC, further verifies dendritic differentiation toward sweat gland structures and is useful as an adjunct in the confirmation of glandular differentiation.25,33,34,36

Without proper and timely diagnosis and management, SC can cause severe patient morbidity. Although SC rarely metastasizes and can have an indolent course, it can be locally de-structive and lead to potentially disfiguring outcomes.5-7 SC can invade deeply and infiltrate into the dermis, subcutaneous fat tissue, muscle, perichondrium, periosteum, and galea.8 Goto et al9 reported a case of an SC that was initially misdiagnosed as a basal cell carcinoma of the left middle finger. The deeper, characteristic features of SC were not recognized until after the affected finger required amputation due to erosion of the bone. Hoppenreijs et al11 described an aggressive case of an SC arising at a site of previously irradiated squamous cell carcinoma of the lower eyelid. Extensive involvement of the SC in the orbit led to the recommendation of an orbital exenter-ation; however, it was not performed because of the poor clinical condition of the patient. Treatments for SC have included wide local excision and Mohs micrographic surgery (MMS). SC treatment with wide local excision often resulted in incomplete excision of the neoplasm despite having taken an adequate margin around the clinically assessable tumor.5 Cases of SC treated with wide local excision had a recurrence rate of 47%.5 The positive surgical margins following wide local excision may be due to the deep infiltration of SC, which frequently exceeds the clinically predicted size of the tumor.5 Due to the close relationship of MAC and SC, we feel that MMS treatment of SC will reduce recurrences as it has for MAC. Currently, there is strong support for the treatment of MAC with MMS as a gold standard to ensure complete clearance of the neoplasm and to reduce the local recurrence rate.12,13,17,21,22,37,38 In a study of MAC by Chiller et al,37 the authors demonstrated a median 4-fold increase in defect size when they compared the clinically estimated pretreatment size of the lesion with the MMS-determined posttreatment size of the lesion. The authors therefore suggest that, similar to the MMS-treated lesions, the lesions completely treated with wide local excision also would produce a defect size that is at least 4 times greater than the predicted pretreatment size of the lesion. Because wide local excision relies on predicted margins of the lesion, which the authors have shown can be greatly underestimated, Chiller et al37 argue that the use of MMS, which does not rely on predicted margins, is a reasonable first-line therapeutic modality for effectively treating patients with MAC. Furthermore, MMS allows for the examination of the entire peripheral and deep margins of the lesion, which is critical when considering the deep infiltrative nature of MAC. The reported local recurrence rate of MAC treated with MMS is 0% to 5%,12,13,21,26,38 which is much lower than the reported local recurrence rate following treatment with wide local excision. This reduced recurrence rate found in MAC cases treated with MMS is probably due to the ability to confirm complete removal of the neoplasm with MMS. 

Conclusion To our knowledge, this case report describes the occurrence of SC, a rare sweat gland neoplasm, in the youngest reported patient and is only the second reported case of SC treated with MMS. Adequate sampling of tissue with an excisional biopsy allowed for appropriate evaluation with histologic and immunohistochemical studies to arrive at the diagnosis that could easily have been missed with a superficial biopsy. In our patient, histopathologic evaluation showed typical nests of basaloid cells, ductal differentiation, and ductal fibrosis seen in SC. However, perineural involvement that is particularly characteristic of SC was not present. This may portend a better prognosis for our patient whose tumor was completely excised after one stage of MMS and has not shown evidence of recurrence at the 18-month follow-up visit. MMS allowed for evaluation of the entire surgical margin and decreased risk of local recurrence resulting from an incomplete excision. In addition, it also allowed for sparing of normal tissue in a cosmetically sensitive area where SC commonly occurs. In summary, this case highlights the importance of including SC in the differential diagnosis of an enlarging cystic lesion in a younger patient and its successful treatment with MMS. 

Syringomatous carcinoma (SC), considered by some to be a variant of microcystic adnexal carcinoma (MAC),1 is a rare malignant neoplasm of sweat gland origin. SC encompasses a range of neoplasms with different degrees of differentiation, and its nomenclature has varied over the years. SC also has been referred to as syringoid eccrine carcinoma,2 basal cell tumor with eccrine differentiation,3 malignant syringoma,4 and sclerosing sweat duct carcinoma.5 Its diagnosis has been a dilemma in a number of reported cases, probably due to the combination of its rarity and thus limited clinical and histopathologic information, microscopic similarities to other benign and malignant neoplasms, and characteristic histologic features that may only be apparent in surgical excisions containing deeper tissue. We report a case of SC that masqueraded as an epidermoid cyst in an unusually young patient.

Case Report
A 23-year-old Asian man, who was otherwise healthy, presented with an asymptomatic slowly enlarging nodule of one year's duration on the right medial eyebrow. Prior treatment with intralesional steroid injections resulted in minimal improvement. The patient had no personal or family history of skin cancers. Physical examination results demonstrated a well-demarcated, mobile, nontender subcutaneous nodule measuring 7 mm in diameter. The clinical presentation favored a diagnosis of an epidermal inclusion cyst, and the patient underwent surgical excision of the lesion. Results of the histopathologic examination revealed a neoplasm in the dermis consisting of bands and nests of pale staining basaloid cells extending between the collagen fibers (Figure 1). There were focal areas of ductal differentiation, scattered individual necrotic cells, moderate dermal fibrosis, and chronic inflammation with numerous eo-sinophils. Moderate nuclear atypia also was present (Figure 2). Perineural involvement was not seen. Results of immunohistochemical analysis revealed positive staining for high—and low—molecular-weight cytokeratins, as well as carcinoembryonic antigen (CEA)(Figure 3). There was scattered positivity with S-100 protein in occasional cells lining lumina and in dendritic cells (Figure 4). The histopathologic findings supported the diagnosis of SC. Because the neoplasm extended to the surgical margins of the specimen, repeat surgical excision with continuous microscopic control under the Mohs micrographic technique was performed to prevent local recurrence and spare normal tissue. At the 18-month follow-up visit, no local recurrence was seen.

Comment SC is a rare, malignant sweat gland neoplasm that usually occurs in the fourth and fifth decades of life.4-8 SC typically presents as a slow-growing, solitary, painless nodule or indurated plaque on the head or neck region.6-8 It has been frequently found on the upper and lower lips; however, it also has been reported to occur on the finger and breast.9,10 Predisposing factors for the development of SC are unclear11 but may include previous radiation to the face and history of receiving an organ transplant with immunosuppressive drug therapy.12-17 Histopathologically, SC is characterized by asymmetric and deep dermal invasion of tumor cells, perineural involvement, ductal formation, keratin-filled cysts, multiple nests of basaloid or squamous cells, and desmoplasia of the surrounding dermal stroma (Table 1).5,6 Some authors consider SC to be closely related to MAC but generally describe SC as more basaloid with larger tubules and a more sclerotic stroma than MAC.18-26 If histologic examination of SC is limited to the superficial dermis, SC demonstrates similarities to other neoplasms, including syringomas, trichoadenomas, trichoepitheliomas, basal cell carcinomas, or squamous cell carcinomas. In the reported cases in which SC was initially misdiagnosed as another benign or malignant neoplasm, many misdiagnoses were due to either a benign clinical appearance of the lesion or biopsy specimens that were too superficial to contain the deeper characteristic histologic features of SC.8,9,11,27-30

Immunohistochemical studies can facilitate the diagnosis of SC and differentiate it from other neoplasms. SC stains positively for CEA, S-100 protein, epithelial membrane antigen, cyto-keratin, and gross cystic disease fluid protein 15,31 all of which aid in the confirmation of a sweat gland neoplasm (Table 2).8,32,33,39 Positivity for CEA in the ductal lining cells and the luminal contents of tumor ducts confirms sweat gland differentiation.25,33,34 This ductal immunoreactivity to CEA appears to be one of the most reliable findings to differentiate SC and MAC from other adnexal tumors, especially desmoplastic trichoepithelioma, which may be one of the more challenging histo-pathologic differential diagnoses.35 In addition, epithelial membrane antigen positivity can be found in the areas showing glandular features.35 This can assist in distinguishing SC from a desmoplastic trichoepithelioma or sclerosing type basal cell carcinoma, both of which demonstrate negativity to epithelial membrane antigen.35 S-100 protein positivity in dendritic cells, as well as in some cords and ducts in SC, further verifies dendritic differentiation toward sweat gland structures and is useful as an adjunct in the confirmation of glandular differentiation.25,33,34,36

Without proper and timely diagnosis and management, SC can cause severe patient morbidity. Although SC rarely metastasizes and can have an indolent course, it can be locally de-structive and lead to potentially disfiguring outcomes.5-7 SC can invade deeply and infiltrate into the dermis, subcutaneous fat tissue, muscle, perichondrium, periosteum, and galea.8 Goto et al9 reported a case of an SC that was initially misdiagnosed as a basal cell carcinoma of the left middle finger. The deeper, characteristic features of SC were not recognized until after the affected finger required amputation due to erosion of the bone. Hoppenreijs et al11 described an aggressive case of an SC arising at a site of previously irradiated squamous cell carcinoma of the lower eyelid. Extensive involvement of the SC in the orbit led to the recommendation of an orbital exenter-ation; however, it was not performed because of the poor clinical condition of the patient. Treatments for SC have included wide local excision and Mohs micrographic surgery (MMS). SC treatment with wide local excision often resulted in incomplete excision of the neoplasm despite having taken an adequate margin around the clinically assessable tumor.5 Cases of SC treated with wide local excision had a recurrence rate of 47%.5 The positive surgical margins following wide local excision may be due to the deep infiltration of SC, which frequently exceeds the clinically predicted size of the tumor.5 Due to the close relationship of MAC and SC, we feel that MMS treatment of SC will reduce recurrences as it has for MAC. Currently, there is strong support for the treatment of MAC with MMS as a gold standard to ensure complete clearance of the neoplasm and to reduce the local recurrence rate.12,13,17,21,22,37,38 In a study of MAC by Chiller et al,37 the authors demonstrated a median 4-fold increase in defect size when they compared the clinically estimated pretreatment size of the lesion with the MMS-determined posttreatment size of the lesion. The authors therefore suggest that, similar to the MMS-treated lesions, the lesions completely treated with wide local excision also would produce a defect size that is at least 4 times greater than the predicted pretreatment size of the lesion. Because wide local excision relies on predicted margins of the lesion, which the authors have shown can be greatly underestimated, Chiller et al37 argue that the use of MMS, which does not rely on predicted margins, is a reasonable first-line therapeutic modality for effectively treating patients with MAC. Furthermore, MMS allows for the examination of the entire peripheral and deep margins of the lesion, which is critical when considering the deep infiltrative nature of MAC. The reported local recurrence rate of MAC treated with MMS is 0% to 5%,12,13,21,26,38 which is much lower than the reported local recurrence rate following treatment with wide local excision. This reduced recurrence rate found in MAC cases treated with MMS is probably due to the ability to confirm complete removal of the neoplasm with MMS. 

Conclusion To our knowledge, this case report describes the occurrence of SC, a rare sweat gland neoplasm, in the youngest reported patient and is only the second reported case of SC treated with MMS. Adequate sampling of tissue with an excisional biopsy allowed for appropriate evaluation with histologic and immunohistochemical studies to arrive at the diagnosis that could easily have been missed with a superficial biopsy. In our patient, histopathologic evaluation showed typical nests of basaloid cells, ductal differentiation, and ductal fibrosis seen in SC. However, perineural involvement that is particularly characteristic of SC was not present. This may portend a better prognosis for our patient whose tumor was completely excised after one stage of MMS and has not shown evidence of recurrence at the 18-month follow-up visit. MMS allowed for evaluation of the entire surgical margin and decreased risk of local recurrence resulting from an incomplete excision. In addition, it also allowed for sparing of normal tissue in a cosmetically sensitive area where SC commonly occurs. In summary, this case highlights the importance of including SC in the differential diagnosis of an enlarging cystic lesion in a younger patient and its successful treatment with MMS.