So-called “malignant blue nevus”

A clinicopathologic study of 23 patients

Authors

  • Richard C. W. Martin MBBS,

    1. Melanoma Institute Australia incorporating the Sydney Melanoma Unit, Royal Prince Alfred and Mater Hospitals, Sydney, New South Wales, Australia
    2. Discipline of Surgery, Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
    3. New Zealand Melanoma Unit, Takapuna, Auckland, New Zealand
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  • Rajmohan Murali MBBS,

    1. Melanoma Institute Australia incorporating the Sydney Melanoma Unit, Royal Prince Alfred and Mater Hospitals, Sydney, New South Wales, Australia
    2. Department of Anatomical Pathology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales, Australia
    3. Discipline of Pathology, Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
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  • Richard A. Scolyer MD,

    1. Melanoma Institute Australia incorporating the Sydney Melanoma Unit, Royal Prince Alfred and Mater Hospitals, Sydney, New South Wales, Australia
    2. Department of Anatomical Pathology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales, Australia
    3. Discipline of Pathology, Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
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  • Patrick Fitzgerald PhD,

    1. National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia
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  • Marjorie H. Colman BSc,

    1. Melanoma Institute Australia incorporating the Sydney Melanoma Unit, Royal Prince Alfred and Mater Hospitals, Sydney, New South Wales, Australia
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  • John F. Thompson MD

    Corresponding author
    1. Melanoma Institute Australia incorporating the Sydney Melanoma Unit, Royal Prince Alfred and Mater Hospitals, Sydney, New South Wales, Australia
    2. Discipline of Surgery, Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
    • Melanoma Institute Australia incorporating the Sydney Melanoma Unit, Royal Prince Alfred and Mater Hospitals, Sydney, NSW, 2050, Australia
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    • Fax: (011) 61 2 99549418


Abstract

BACKGROUND:

Melanomas that arise in association with or that resemble blue nevi are extremely rare and have been termed “malignant blue nevi.” The authors report on a single-institutional clinicopathologic study of “blue nevus-like melanomas” (BNLMs).

METHODS:

Twenty-six patients were identified with a “malignant blue nevus” over 29 years at the Sydney Melanoma Unit. Twenty-three patients were included in the current study after pathologic review. Clinical outcomes of those patients were compared with the outcomes in a matched control group of patients with melanoma (matched for age, sex, Breslow thickness, Clark level, ulceration, and anatomic site).

RESULTS:

The median patient age was 44 years, and men comprised 65% of the patients. The tumors were distributed evenly among skin sites, and their median Breslow thickness was 5.5 mm. After a median follow-up of 36.5 months, there was no difference in survival (P = .702) between patients with BNLM and patients in the control group.

CONCLUSIONS:

BNLMs tended to present at a more advanced stage, with thicker primary tumors, but had a metastatic pattern comparable to and was not more aggressive in behavior than other types of melanoma. The authors concluded that BNLMs should be treated in the same way as any other melanoma variants based on clinical staging and pathologic prognostic indices. Cancer 2009. © 2009 American Cancer Society.

The term “blue nevus” was introduced in 1906 by Tieche to describe the dermally based, common blue nevus composed of pigmented dendritic melanocytes.1 The name reflects the blue color that these tumors usually display clinically, which results from the Tyndall phenomenon (selective absorption of longer wavelength components of light by dermal melanin pigment with reflection of shorter wavelength [blue] components from the skin). Subsequently many variants of blue nevus have been described, such as common blue nevus, cellular blue nevus, epithelioid blue nevus and deep penetrating nevus. Tumors that resemble the blue nevus or its variants but exhibit atypical cytoarchitectural features have been identified as the spectrum of blue nevus has expanded.

“Malignant blue nevus” is a term that was coined first by Allen and Spitz2 to describe tumors that resembled blue nevi morphologically but resulted in metastasis and patient death in some patients. The term has been used to describe malignant change arising in a pre-existing cellular blue nevus,3-6 melanoma arising at the site of a (previously excised) blue nevus,3, 7-9 melanoma with architectural or cytologic features resembling cellular blue nevus but apparently arising de novo,10-12 or melanoma with an admixed, residual, benign cellular blue nevus component.3, 7, 13-15 The vast majority of blue nevus-like melanomas (BNLMs) are associated with a cellular blue nevus.

Given the varied definitions of the term “malignant blue nevus” and the relatively small numbers of patients reported in the literature, its natural history and prognosis are poorly understood.3-39 Nevertheless, it has been suggested that such tumors behave in a more aggressive manner than the more common conventional subtypes of melanoma.11 Therefore, tumors diagnosed as “malignant blue nevus” continue to cause diagnostic uncertainty and consequent difficulties in clinical management. In an effort to determine whether such lesions differ from conventional melanomas in their clinical behavior and to provide guidelines for their clinical management, we analyzed the clinicopathologic characteristics of a series of 23 patients with so-called “malignant blue nevus” who were managed at a single institution and compared their clinical outcomes with those in a matched series of conventional melanomas. To the best of our knowledge, this represents the largest series of patients reported in the English literature to date.

MATERIALS AND METHODS

Twenty-six patients with a diagnosis of “malignant blue nevus” who were treated at the Sydney Melanoma Unit (SMU) between 1978 and 2007 were identified from the SMU database. Clinical and follow-up data for these patients were retrieved from the database. All available histologic slides were reviewed by SMU pathologists (R.A.S., R.M.). Slides were diagnosed as BNLM if they had histologic features of melanoma (such as sheet-like expansile growth, cell crowding, nuclear enlargement and pleomorphism, and mitotic activity >2/mm2) associated with a histopathologically recognizable blue nevus or with areas that resembled a blue nevus (usually cellular blue nevus) (Fig. 1). The patients with BNLM were compared with a control group of patients with melanoma who were matched for patient age, sex, primary anatomic site, Breslow thickness, and ulceration. Data were analyzed using Microsoft Excel software (version 2003; Microsoft Corporation, Redmond, Wash) and STATA version 9.2 (Stata Statistical Software, release 9; StataCorp L.P., College Station, Tex).

Figure 1.

(Top Left) This photomicrograph of a cellular blue nevus shows fascicles of plump spindle cells with relatively uniform, oval nuclei and small nucleoli (hematoxylin and eosin [H&E] stain; original magnification, ×200). The other photomicrographs show a blue nevus-like melanoma arising in a cellular blue nevus: (Top Right) This low-power view of the lesion shows a cellular blue nevus that occupies much of the dermis and extends focally into the subcutaneous adipose tissue along with a rounded nodule that pushes deep into the subcutis (the box marked c and d are shown at higher magnification in the bottom left and right photomicrographs, respectively; H&E stain; original magnification, ×12.5). (Bottom Left) This view of a cellular blue nevus component from the box marked c in the previous view has features similar to those shown in the top left photomicrograph along with melanin pigment in some cells (H&E stain; original magnification, ×200). (Bottom Right) The deep subcutaneous nodule from the box marked d in the top right photomicrograph has a greater degree of cellularity, cytologic atypia, and an occasional mitotic figure (arrow) (H&E stain; original magnification, ×200).

RESULTS

After pathologic review, 3 patients did not meet the criteria for a diagnosis of BNLM, and they were excluded from further analysis. Of 23 patients, there were 15 men (65%) and 8 women (35%), and the median age was 44 years (age range, 22-73 years). The median follow-up was 36.5 months (range, 4-271 months) (Table 1). The primary tumors were located in skin of the head and neck region (8 patients; 34.8%), trunk (8 patients; 34.8%), upper limbs (4 patients; 17.4%), and lower limbs (3 patients; 13%).

Table 1. Details of Blue Nevus-like Melanoma Patients Versus Matched Control Melanoma Patients
VariableBNLMMatched Control
  1. BNLM indicates blue nevus-like melanoma.

Age44 (22-72)52 (27-75)
Sex  
 Men1515
 Women88
Site  
 Arm43
 Leg34
 Thorax88
 Scalp63
 Face25
Thickness (median in mm)5.555.25
Clark Level (median)VV
Ulceration26%26%
Loco Regional Recurrence43%43%
Distant Metastases43%56%
Median34 mo62 mo
Follow Up (range)(4-332)(8-271)

The median Breslow thickness was 5.5 mm (range, 1.1-15 mm), and the median Clark level was V. Ulceration was present in 6 patients (26%). All patients underwent wide excision of the primary tumor site, 6 patients underwent elective lymph node dissection (before the use of sentinel lymph node biopsy at the SMU), and 8 patients underwent sentinel lymph node biopsy. Eight patients (57%) who underwent lymph node sampling had positive lymph nodes.

Ten patients (43%) developed melanoma recurrence (locoregional or distant metastases) during follow-up, and 9 patients (39%) ultimately died of melanoma. In-transit metastasis occurred in 5 patients (22%), and 9 patients (39%) developed distant metastases (see Table 2). The median time to distant metastases was 18.5 months (range, 6-117 months), and the median time to death was 23.5 months (range, 4-271 months). There was a statistically significant difference (P = .002) in Breslow thickness between patients who developed a local recurrence (mean thickness, 9.4 mm) and those who did not (mean thickness, 4.2 mm). Other histologic features were not predictive of clinical outcome (lymph node involvement at diagnosis, regional recurrence or distant metastasis, or death).

Table 2. Sites of Distant Metastases*
Site of MetastasesNumber (%)
  • *

    Note: some patients developed metastases in multiple sites. Distant metastases occurred in 9 of 23 blue nevus-like melanoma patients.

Liver7 (37)
Lung5 (26)
Bone2 (10)
Brain1 (5)
Other4 (22)

Figure 2 shows Kaplan-Meier survival curves for patients who had BNLM versus the matched control group of patients with melanoma (matched for age, sex, Breslow thickness, ulceration, and anatomic site). There was no significant difference between the patients with BNLM and the melanoma control group when they were analyzed for melanoma-specific mortality (P = .702) or overall mortality. There was no significant difference in the risk of development of lymph node metastases between BNLM patients and the matched controls (P = .308).

Figure 2.

Kaplan-Meier survival curves for melanoma-specific mortality were calculated for patients with blue nevus-like melanoma (BNLM) versus a matched control group of patients with melanoma (P = .702).

DISCUSSION

The 23 cases of BNLM described herein were treated over a 29-year period at the SMU; they comprised a tiny subset of >25,000 cases of melanoma treated at the SMU during this period. In our series, BNLM was more common in men and had an even distribution among body sites, a finding contrary to previous reports17 in which a predilection for the scalp was suggested. The median age at diagnosis in the fourth decade was consistent with previous reports.37 The median thickness (5.5 mm) of the BNLMs in this series is greater than that of conventional melanomas, and indicates that they tend to present at a more advanced clinical stage than other subtypes of melanoma.38

The management of patients with BNLM has changed over the years in parallel with the changes in melanoma management that have occurred since the advent of the sentinel lymph node biopsy technique. Fourteen patients had pathologic assessment of excised lymph nodes, and 57% contained metastases, which is higher than the rate of positive sentinel lymph nodes reported for “conventional” melanomas in recent studies (overall, 16% of patients in the reported interim analysis of the Mulicenter Selective Lymphadenectomy Trial had positive sentinel lymph nodes39). However, the median tumor thickness in our series of BNLMs was much greater than that in most series reporting sentinel lymph node biopsy results in patients with melanoma, and it is well recognized that the frequency of sentinel lymph node metastases increases with increasing tumor thickness. The risk of in-transit metastases and the presence and sites of distant metastases were comparable to those reported in other melanomas of similar stage. The at-risk period for the development of metastases was in keeping with other patients with melanoma, in that the majority of recurrences occurred in the first 2 years. However, both BNLM and conventional melanomas also may exhibit late metastases >5 years after the primary diagnosis.7 The latest metastasis observed in our series was in the liver at 117 months after excision of the primary melanoma.

The general consensus in previously published reports has been that BNLMs are more aggressive than other melanomas.17, 29, 38 However, when we compared matched controls, we observed no difference in survival or in the risk of lymph node or distant metastases. Possible reasons for this include reporting or referral bias toward selectively reporting more aggressive cases, which may have affected the results from previous studies. The usual prognostic factors that are assessed in melanoma apply to BNLMs. Some studies have suggested that Breslow thickness may be predictive of outcome,11 and we have demonstrated that Breslow thickness is predictive of regional recurrence.

The histologic criteria for diagnosing BNLM are not well defined; and, along with other groups,2 we regard the term “malignant blue nevus” as descriptive only. Confusion can occur because this descriptive term can be used in 2 circumstances: The first is when a melanoma arises in association with a blue nevus (usually a cellular blue nevus), and the second is when a melanoma has architectural and morphologic features that resemble a cellular blue nevus.16 Furthermore, the juxtaposition of the adjective “malignant” with the noun “nevus” (the latter connoting a benign tumor) is inherently flawed and represents an oxymoron. The pathologic entity described by this term is a melanoma; therefore, and we prefer the term BNLM (“blue nevus-like or associated melanoma”).

Although rare, it has long been recognized that benign blue nevi may involve lymph nodes. Such involvement usually takes the form of banal (blue) nevus cells involving the lymph node capsule or intranodal fibrous trabeculae. In contrast, metastatic melanoma (including BNLM) usually involves the subcapsular sinus region of lymph nodes (frequently forming a large, expansile tumor mass effacing the lymph node architecture) and exhibits nuclear enlargement, pleomorphism, and mitotic activity. Occasional reports have documented cellular blue nevi involving the parenchymal region of lymph nodes. Comparison with the histology (including the cytologic features) of the primary cutaneous tumor (which invariably is present) may be necessary to distinguish such cases from metastatic BNLM.

At our institution, we report and classify all such tumors as melanomas, and we describe the standard morphologic and prognostic features (Breslow thickness, Clark level, ulceration, mitotic rate, margins, etc). We also describe the type of any adjacent or associated melanocytic tumor (such as a blue nevus), and we describe the morphologic nature of the malignant cells (spindled, epithelioid, dendritic, etc).

BNLM can generally be distinguished from cellular blue nevus by the presence of a frankly malignant component. BNLM is characterized by widespread necrosis in many cases, but the presence of necrosis is not invariable, and focal necrosis has been reported in typical cellular blue nevus.40 Other criteria supportive of a diagnosis of BNLM include high mitotic rate, abnormal mitotic figures, vascular invasion, expansile or destructive growth, marked cytologic atypia, and infiltrative margins.11, 23, 29 Cutaneous metastases from melanoma rarely may mimic BNLM, and when they lack atypical features, they may mimic blue nevus.41 The latter are composed of pigmented fusiform, dendritic, and epithelioid melanocytes between surrounding dermal collagen bundles. Melanophages, occasional atypical epithelioid melanocytes, and scattered mitotic figures may be observed, and an associated perivascular lymphocytic infiltrate may be present. However, correlation with the clinical features is critical to establishing the correct diagnosis.41

In conclusion, BNLM is a rare subtype of melanoma that occurs more commonly in men, typically occurs in the fourth decade, and can be located at any body site. The commonly used prognostic factors for melanoma apply to BNLMs; and, although they are not more aggressive than other melanomas, they do appear to be diagnosed at a later stage, which probably accounts for their reported adverse prognosis.

Suspected BNLMs should be biopsied with a 2-mm margin. Once a definite pathologic diagnosis has been established, the patient's subsequent management should be planned on the basis of the pathologic information and should follow appropriate melanoma management guidelines.42

Conflict of Interest Disclosures

Supported by the Cancer Institute NSW, the Australian National Health and Medical Research Council, and the Melanoma Foundation, University of Sydney. Drs. Murali and Scolyer are Cancer Institute New South Wales Clinical Research Fellows.