LT Daryl J. Sulit

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