黑素痣与SPITZ痣管理区别
The Laryngoscope
V C2010The American Laryngological,
Rhinological and Otological Society,Inc.
Melanocytic Nevi with Spitz Differentiation: Diagnosis and Management
Neda Ahmadi,MD;Steven P.Davison,DDS,MD;Catharine L.Kauffman,MD
Objectives:Melanocytic proliferations with Spitz differentiation present a difficult clinicopatho-logic dilemma,as their spectrum ranges from benign to malignant.Distinct entities include Spitz nevus, atypical Spitz nevus,and Spitzoid melanoma.Their histopathologic differentiation can be challenging, and cases of Spitzoid melanoma initially diagnosed as benign Spitz nevi are reported in the literature.The goal of this article is to discuss the diagnostic tools (including comparative genomic hybridization),which may be helpful in differentiating benign Spitz nevi from malignant melanoma with Spitzoid features, and to propose an appropriate management strategy for each entity.
Study Design:Retrospective case reports.
Methods:Medical records of patients referred for suspicious nevi were reviewed.Data regarding demographics,site,pathology reports,and treatment were reviewed.
Results:Four patients with three distinct diag-noses involving Spitz differentiation were identified. The pathologic interpretation of these biopsies was difficult and multiple dermatopathologists were involved.All four patients underwent excision with or without sentinel node biopsy.
Conclusions:Otolaryngologists,plastic surgeons and dermatopathologists will encounter patients who have melanocytic lesions with Spitz differentiation at some point in their career.The management of these patients is significantly impacted by the histopatho-logic diagnosis,and should not be undertaken until it is confirmed,possibly with comparative genomic hybrid-
ization.In our experience,it is not unusual to have multiple independent pathologic examinations.We believe that a team approach between the surgeon and the dermatopathologist is crucial when diagnosing and managing patients with Spitz lesions.
Key Words:Spitz nevi,Spitzoid melanoma, atypical Spitz nevi,atypical Spitz tumor,Spitz lesions,malignant melanoma with Spitz features.
Level of Evidence:4.
Laryngoscope,120:2385–2390,2010
INTRODUCTION
Spitz nevi are benign proliferations of melanocytes with histopathologic features usually distinct from ma-lignant melanoma.They commonly occur in Caucasians.1,2Clinically,Spitz nevi present as a single symmetric pink/brown papule or nodule that is usually less than1cm.2,3In a small number of cases,they can be moderately or markedly pigmented.The cheeks and ears are the favored sites in children,and in adults,the limbs and trunk are most commonly involved.2
Historically,until the late1940s,Spitz nevi were not recognized as a separate entity and were often mis-diagnosed as melanomas.2This changed after Sophie Spitz,4published the seminal article entitled‘‘Melano-mas of Childhood.’’In this article,Spitz did not consider the then-called‘‘juvenile melanomas’’as benign nevi of childhood nor malignant melanomas of adulthood. Although,she pointed out detailed features distinguish-ing Spitz nevi from malignant melanomas,Spitz concluded that histologic differentiation between the ju-venile and adult melanomas was nearly impossible,and could not be made with certainty.2,4,5This was evident when one of the13cases of benign Spitz nevus reported by Spitz,developed fatal metastases.1,3,4
The term‘‘juvenile melanoma’’has since been dis-carded and replaced with Spitz nevus not only because these lesions occur in adults as well as children,but also because the term‘‘melanoma’’automatically implies malignancy.2
The clinicopathologic spectrum of melanocytic nevi with Spitz differentiation ranges from benign to malig-nant.1,5These entities include the benign Spitz nevus, atypical Spitz nevus,and malignant melanoma with Spitz features(Spitzoid melanoma).5Spitz lesions
From the Department of Otolaryngology-Head and Neck Surgery,
Georgetown University Hospital(N.A.),Washington,DC,U.S.A.;
Department of Plastic Surgery(S.P.D.),Georgetown University Hospital,
Washington,DC,U.S.A.;Department of Dermatopathology(C.L.K.),
Georgetown University Hospital,Washington,DC,U.S.A.
Editor’s Note:This Manuscript was accepted for publication July
1,2010.
Poster presented at the Combined Otolaryngology Spring Meeting
(Triologic section)on April2010,Las Vegas,Nevada.The poster was
awarded first place in the Plastics–Aesthetics category.
The authors have no financial disclosures to this article.
The authors have no conflicts of interest to declare.
Send correspondence to Neda Ahmadi,MD,Department of Otolar-
yngology-Head and Neck Surgery,First Floor,Gorman Building,George-
town University Hospital,3800Reservoir Road,NW,Washington DC,
20007.E-mail:Neda.Ahmadi56@https://www.360docs.net/doc/1713790802.html,
DOI:10.1002/lary.21149
Laryngoscope120:December2010Ahmadi et al.:Melanocytic Nevi with Spitz Differentiation
present a difficult dilemma because histopathologic dif-ferentiation among these lesions can be challenging,and reports of Spitzoid melanomas initially diagnosed as be-nign Spitz nevi exist.6,7As surgeons,we are likely to encounter patients with melanocytic lesions with Spitz differentiation.Surgical management of these patients is significantly impacted by the pathologic analysis,and should not be undertaken until there is consensus.In our experience,it is not unusual to have multiple inde-pendent pathologic examinations before initiating management.We believe that a team approach between the surgeon and the dermatopathologist is crucial when diagnosing and managing patients with Spitz lesions.
In this article,the clinicopathologic spectrum of Spitzoid differentiation is presented with four represen-tative cases.The objective is to discuss the diagnostic tools used to differentiate between benign and malignant lesions and to propose an appropriate management for each entity.The use of comparative genomic hybridiza-tion (CGH)as an evolving technology in distinguishing benign and malignant Spitz lesions is also discussed.
MATERIALS AND METHODS
The medical records of four patients referred to our insti-tution for suspicious nevi were reviewed.Data regarding demographics,lesion site,pathology reports,and treatment were collected retrospectively.
RESULTS Case 1
A 3-year-old otherwise healthy boy presented with a pink symmetric papule measuring less than 5mm in diameter on the left arm (Fig.1).He underwent excision with 3-mm margins.The pathologic examination demon-strated nests and strands of nevus cells at the dermoepidermal junction and in the dermis (Fig.2A).Kamino bodies were noted at the dermoepidermal junc-tion (Fig.2B).There was normal maturation (diminution of the size of the melanocytes as they descend into the dermis)(Fig.2C).Pagetoid spread (upward epidermal spread of single rather than nests of melanocytes)and mitoses were absent.These pathologic findings are con-sistent with a benign Spitz nevus.Patient did not require further excision or sentinel lymph node biopsy
(SLNB).
Fig.1.Pink papule on the left arm of a 3-year old boy (case 1)consistent with a benign Spitz nevus.Note the symmetric borders.[Color figure can be viewed in the online issue,which is available at
https://www.360docs.net/doc/1713790802.html,.]
Fig.2.Spitz nevus on the left arm of 3year old boy (case 1).(A)This section demonstrates a symmetric well-circumscribed proliferation of nests of melanocytes (H&E 50?).(B)Kamino bodies (aggregates of basement membrane)can be seen as eosinophilic globules at the dermoepidermal junction (H&E 400?).(C)Nests of melanocytes with good uniform appearance and maturation.Occasional kamino bodies are also noted (H&E 200?).[Color figure can be viewed in the online issue,which is available at https://www.360docs.net/doc/1713790802.html,.]
Case 2
A 30-year-old Caucasian man presented with a pig-mented nodule measuring 1.4?1.0?0.2cm on the left upper back.He underwent biopsy and the pathologic ex-amination revealed an asymmetrical nodule consisting of nests and strands of mild to moderate atypical melano-cytes at the dermoepidermal junction and in the dermis (Fig.3A and B).Pagetoid intraepidermal spread and mitoses were not seen (Fig.3C).Because the nevus cells extended to the lateral margin,reexcision was recom-mended.The patient underwent reexcision and the final pathologic examination was consistent with an atypical Spitz nevus.He also underwent SLNB,which was nega-tive.Currently,he is without evidence of disease at 10months follow-up.
Case 3
A 9-year-old Caucasian girl presented with a salmon-pink colored papule on the upper back.Even though,the biopsy results from the outside institution revealed an atypical melanocytic lesion,the preliminary diagnosis was that of a benign Spitz nevus.Reexamina-tion of the slides was recommended.The pathology slides were reviewed at multiple institutions.According to one of the pathology reports,‘‘This was a
difficult
Fig.3.Atypical Spitz nevus on the upper back of 30-year old man (case 2).(A)Asymmetrical but well-circumscribed proliferation of variably sized nests of epithelioid melanocytes (H&E 50?).(B)The epithelioid nests show good maturation but moderate cytologic atypia characterized by large hyperchromatic melanocytes closer to the epidermal surface (H&E 100?).(C)Within a dermal nest,the melanocytes appear fairly uniform.Mitotic activity is not seen (H&E 400?).[Color figure can be viewed in the online issue,which is available at
https://www.360docs.net/doc/1713790802.html,.]
Fig.4.Melanoma with Spitz features on the upper back of 9-year-old girl (case 3).(A)Large pleomorphic hyperchromatic epithelioid tumor cells with occasional deep and atypical dermal mitoses are present (H&E 400?).(B)Low-power magnification showing irregularly sized and shaped dermal melanocytic nests.Focal intraepidermal pagetoid spread is seen (H&E 100?).[Color figure can be viewed in the online issue,which is available at https://www.360docs.net/doc/1713790802.html,.]
Laryngoscope 120:December 2010
Ahmadi et al.:Melanocytic Nevi with Spitz Differentiation
lesion.’’Deep mitotic figures were noted(Fig.4A)and the Ki-67(proliferative marker)proliferation index was 30%.There was also focal absence of maturation(Fig. 4B).Given the diagnostic dilemma,CGH analysis was also performed,which demonstrated gain of chromosome 7q.This confirmed the diagnosis of Spitzoid melanoma with a Breslow depth of 2.9mm.Patient underwent wide local excision with an additional 1.5-cm margins and an SLNB.The margins were clear and the SLNB was negative for metastasis.She was staged as IIB (based on the American Joint Committee on Cancer [AJCC]Melanoma Staging).An oncologic work up was negative and no further treatment was recommended. Currently,she is without evidence of disease at8 months follow-up.
Case4
A3-year-old Caucasian girl presented with a pig-mented lesion of the anterior chin.Patient initially had a shave biopsy demonstrating severely atypical spindle and epithelioid melanocytes forming nests that appeared as sheets of single cells within the dermis.The Ki-67im-munostain stained nuclei of several cells.Given these features,an excisional biopsy was recommended.Patient underwent reexcision demonstrating severely atypical spindle and epithelioid cells.Atypical cells with mitotic activity were also noted to be present within the muscle. The pathology was consistent with Spitzoid melanoma. Positive margins necessitated re-excision with1-cm mar-gins and SLNB.Lymphoscintography identified the sentinel node in the right neck,which was excised through a planned flap incision.This node was positive; demonstrating nests of highly atypical cells consistent with metastatic melanoma.Postoperatively,the patient received interferon a-2b treatment.She has remained disease free for approximately3years.
DISCUSSION
Spitz lesions comprise a diverse group on the histo-logic continuum ranging from benign Spitz nevus to malignant melanoma with Spitz features.5They may display overlapping histopathologic features,making the important diagnostic and management decisions one of the most challenging for the surgeons and the dermatopathologist.8
A key distinguishing histopathologic feature and an absolute prerequisite for diagnosis of Spitz lesions are the large size of melanocytes,which can be round/polyg-onal(epithelioid)or oval/spindled.2,9In contrast to the benign Spitz nevi of childhood,which are mainly com-posed of epithelioid cells,the benign Spitz nevi seen in adults are mainly composed of spindle cells,which may be pigmented.2Regardless of the proportion of spindle or epithelioid cells,the most characteristic feature of be-nign Spitz nevi is the uniformity in the appearance and size of the cells.9Some histologic features that assist in diagnosing benign Spitz nevi include maturation,lack of deep extension,lack of pagetoid spread,and the absence or rarity of deep dermal mitoses.2,9,10Solitary or clus-tered eosinophilic globules(Kamino bodies)at the dermoepidermal junction also occur more frequently in benign Spitz nevi.2,9,10
At the opposite end of the histologic continuum lies Spitzoid melanoma.Clinically,Spitzoid melanoma is characterized by architectural asymmetry,irregular bor-ders,and occasional ulceration.The growth pattern is solid without interspersed collagen fibers,which is in contrast to benign Spitz nevi(contain collagen fibers in the dermal component).10,11High-grade nuclear atypia, high mitotic rate with deep dermal mitoses,deep pene-tration into the lower dermis or subcutis are also features of Spitzoid melanoma.
Even though the majority of melanocytic prolifera-tions with Spitzoid differentiation can be readily classified as benign Spitz nevus or Spitzoid melanoma, there is a subset in the central portion of the continuum that challenge even the most experienced dermatopa-thologists.Terms to describe this category include atypical Spitz nevus,atypical Spitz tumor,or Spitz tu-mor of uncertain malignant potential.10Although these problematic nevi display architectural and cytologic atypia to a degree beyond benign Spitz nevus,the atypia is not sufficient for a diagnosis of Spitzoid melanoma.10 Table I compares certain key histopathologic and clinical aspects of Spitz nevi,atypical Spitz nevi,and Spitzoid melanoma.
Given the difficulties in distinguishing benign from malignant lesions,in1999Spatz et al.12described a grading system for risk stratification of atypical Spitz nevi in children and adolescents.The article provided a grading system for atypical Spitz nevi based on five pa-rameters including patient age,lesion diameter,fat involvement(indicative of tumor thickness),presence or absence of ulceration,and the degree of mitotic activity. Patients were placed in low-,intermediate-,or high-risk categories.However,the only patient in this study that developed widespread metastases and died after a 3-year follow-up was initially categorized as low risk. This further emphasizes the unpredictability of these lesions and the importance of accurate diagnosis and management.
Due to the challenge in distinguishing atypical Spitz nevi from Spitzoid melanoma using light micros-copy,other diagnostic techniques have been investigated including immunohistochemistry and CGH.4
TABLE I.
Histologic Characteriscits of Benign Spitz Nevi,
Atypical Spitz Nevi,and Spitzoid Melanoma.
Benign
Spitz Nevus
Atypical
Spitz Nevus
Spitzoid
Melanoma Size Usually<1cm Often>1cm Usually>1cm Ulceration Uncommon Rare Occasional Kamino
bodies
Common Common Uncommon Maturation Present Variable Lacking
Deep mitoses Uncommon Rare Frequent Atypical
mitoses
Uncommon Absent Present
A variety of immunohistochemical markers have been used to evaluate and to assist in diagnosis.One of these markers is HMB-45,and although it is positive in both benign Spitz nevi and Spitzoid melanoma,deeper tissue expression of HMB-45is more in favor of Spitzoid melanoma.7Benign Spitz nevi also have lower rates of bcl-2(antiapoptotic protein)and fatty acid synthetase (key enzyme responsible for synthesis of fatty acids) expression compared to Spitzoid melanoma.4Ki-67stain-ing,a protein expressed by cells that have entered the cell cycle is also found to increase significantly from be-nign Spitz nevi to melanoma.5,7Although,these markers can sometimes assist in the diagnosis of Spitz lesions, determining their predictive value requires long-term follow-up and a greater number of cases,which are cur-rently lacking.4
Comparative genomic hybridization is an evolving technology that is playing a pivotal role in distinguishing benign from malignant Spitz lesions.As a molecular–cyto-genetic method,CGH analyzes copy number changes in the DNA content of Spitz lesions.It is capable of detecting loss,gain,and amplification of the DNA copy number at the chromosomal level.13Based on CGH analysis,Spitzoid melanomas have higher overall number of chromosomal abnormalities compared to benign Spitz nevi.1On the other hand,CGH analysis has also demonstrated copy number increase in chromosome11p in a subset of Spitz nevi.This copy number increase is associated with muta-tions of HRAS.4HRAS is an isoform of the RAS family of genes,which are protooncogenes involved in cellular sig-nal transduction.13HRAS activation could explain several of the histologic features that overlap with Spitzoid mela-noma.Copy number increase of chromosome11p and the associated HRAS mutation do not occur in Spitzoid mela-noma.Therefore,chromosomal gains of11p and the absence of other chromosomal aberrations in most Spitz nevi can aid in the distinction of certain Spitz nevi whose atypical features may make histopathologic distinction from Spitzoid melanoma difficult.
Although these diagnostic tools are promising,cur-rently there is no technique that unequivocally identifies between the borderline Spitz lesions and Spitzoid mela-noma.In these situations,we believe that sentinel lymph node biopsy plays an important role in making the final decision regarding management.According to Mones and Ackerman,8the presence of atypical cells within the sentinel node prove malignancy.Therefore, melanocytic nevi with atypical cells within the sentinel node should be reclassified and managed as Spitzoid melanoma.
Recommendations for the management of melano-cytic nevi with Spitz differentiation reported in the literature include observation,subtotal excision,or com-plete excision.14However,we believe that all lesions with Spitz differentiation must be excised completely.10,4 Because Spitzoid melanoma can arise within benign Spitz nevi,15we recommend wide local excision with5-mm margins of benign Spitz nevi.Sentinel lymph node biopsy is not recommended in these cases.
The management of Spitzoid melanoma is contro-versial.Pol-Rodriquez et al.,16in a retrospective study involving82patients,demonstrated that patients aged0 to10years had a better5-year survival compared to patients aged11to17years(88%vs.49%).Younger chil-dren also had thicker average tumor sizes(4.67mm vs.
3.93mm),and a greater proportion of regional metasta-ses(86%vs.59%);however,the older group had a higher rate of widespread metastasis(41%vs.14%). They concluded that younger age may be associated with longer survival.
Paradela et al.17retrospectively analyzed38 patients(<18years)with Spitzoid melanoma.They staged their patients based on the AJCC for melanoma system.In their group,54.8%of the patients were stage III or higher,and therefore had regional or distant me-tastases.Patients were treated based on the National Comprehensive Cancer Network(NCCN)management guidelines for melanoma.The mortality rate in this study was0.1%,which is much lower than the40%mor-tality rate reported by other series of childhood melanomas.18,19However,despite this improved sur-vival,Paradela et al.17concluded that patients with Spitzoid melanoma can develop metastasis and die from disease,and therefore,recommended using the same treatment in children as in adults.Therefore,the stag-ing and management of Spitzoid melanoma should follow the NCCN guidelines in children and adults.
The management of atypical Spitz nevi is also con-troversial.Only one article has thus far formulated an algorithm for the treatment of these lesions.Ludgate et al.20studied the largest reported series of patients with atypical Spitz nevi.In their study group,the inci-dence of sentinel lymph node positivity was47%.SLNB-positive cases had a significantly lower mean age com-pared to SLNB-negative cases.However,despite this, the SLNB-positive cases had favorable prognoses.Ludg-ate et al.20recommended an excisional margin of1cm for all atypical Spitz nevi.They also recommended that SLNB be performed in lesions that are!1mm in depth. In lesions that are0.75–0.99mm in depth,SLNB is advised if adverse features such as ulceration and high mitotic rate are present.20
Whether or not atypical Spitz lesions are reclassi-fied as Spitzoid melanoma based on positive SLNB is controversial.However,we agree with Ackerman that ‘‘the notion of metastasizing Spitz’s naevus is illogical and without foundation,’’and therefore,the presence of atypia within the sentinel lymph node confirms the diagnosis of Spitzoid melanoma,and the management should follow the NCCN management guidelines for melanoma.10
CONCLUSION
In this article,we have attempted to portray the current state of the art involving melanocytic prolifera-tions with Spitz differentiation.Distinguishing among the three categories can be challenging.Misdiagnosis, and therefore mismanagement,in these cases have been reported and can have devastating consequences.The management of these patients should not be undertaken until it is confirmed potentially with comparative
Laryngoscope120:December2010Ahmadi et al.:Melanocytic Nevi with Spitz Differentiation
genomic hybridization.In our experience,it is not un-usual to have multiple independent dermatopathologic consultations before initiating management.Therefore, we believe that a team approach and good communication between the surgeons and dermatopathologists is critical in diagnosing and managing patients with melanocytic nevi with Spitz differentiation.
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