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Large Plaque-Type Blue Nevus With Subcutaneous Cellular Nodules

Busam, Klaus J., M.D.; Woodruff, James M., M.D.; Erlandson, Robert A., Ph.D.; Brady, Mary S., M.D.

The American Journal of Surgical Pathology: January 2000 - Volume 24 - Issue 1 - p 92
Original Articles
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Unusual or atypical melanocytic nevi can be confused with malignant melanoma. The authors present two cases of an unusual variant of blue nevus that were misdiagnosed initially as malignancy. Both lesions were asymptomatic and characterized clinically by childhood onset, with slow enlargement during adolescence and subsequent nodule formation. One lesion, which measured 24 cm in greatest dimension, was located on the anterior chest wall of a 53-year-old woman. The other lesion, which measured approximately 15 cm in greatest dimension, was located on the lateral abdominal wall of a 20-year-old man. Both lesions were characterized by a multifocal dermal and subcutaneous proliferation of fusiform and dendritic pigmented melanocytes. The histologic appearance of individual foci ranged from dermal melanocytosis to common blue nevus and cellular blue nevus. The cellular foci were located in the subcutis and involved, in one patient, the stroma of the breast. The cells were immunoreactive for S-100 protein, gp100 (HMB-45), and Melan-A (A103). Ultrastructural analysis revealed melanocytes typical of blue nevus. The woman underwent complete excision of the lesion, and the man underwent only partial excision of the lesion. On clinical follow-up of 32 and 19 months, respectively, both patients are alive and well with no evidence of recurrence or progression. Because the lesions presented clinically as large plaques and were diagnosed histologically as blue nevi with subcutaneous foci of cellular blue nevus, we term this rare variant of blue nevus large plaque-type blue nevus with subcutaneous cellular nodules. Recognition of this lesion enhances our knowledge of the morphologic spectrum of melanocytic tumors and helps to avoid confusion with malignant melanoma.

From the Departments of Pathology (K.J.B., J.M.W., R.A.E.) and Surgery (M.S.B.), Memorial Sloan-Kettering Cancer Center, New York, NY, U.S.A.

Address correspondence and reprint requests to Dr. Klaus J. Busam, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, U.S.A.

The term blue nevus is used for a wide spectrum of melanocytic proliferations. 4 Typical blue nevi (BN) are usually confined to the dermis, and contain pigmented dendritic and fusiform melanocytes and melanophages in a usually sclerotic stroma. The proportion of the cellular components, the degree of pigmentation, the extent of stromal sclerosis, and the overall degree of cellularity may vary greatly from lesion to lesion. Since the first description of BN by Tieche in 1906, 50 several histologic types of BN have been described, including the common dermal blue nevus, 17,18,50 cellular blue nevus (CBN), 1,2,17,32,45 atypical cellular blue nevus, 3,21,51 desmoplastic cellular blue nevus, 37 combined blue nevus, 20 and compound blue nevus. 27 Unusual clinical variants have also been reported, such as eruptive BN, 23 congenital common blue nevus, 44 target blue nevus, 7 and plaque-type blue nevus. 24,42,43,52 One might also include Mongolian spot, 13,17,19,31 nevus of Ota, 28,38 nevus of Ito, 26 dermal melanocytic hamartoma, 8 and similar lesions in the spectrum of dermal melanocytoses. 12,25,40,47,53,54

In the vast majority of BN, their identification is straightforward clinically and histologically, and they rarely enter the differential diagnosis of malignant melanoma. However, unusual variants exist, in which distinction from malignant melanoma can be difficult. We present the clinical and pathologic features of two cases of such a rare variant.

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MATERIALS AND METHODS

Both patients were identified from the archives of the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY. Routine histologic sections from formalin-fixed and paraffin-embedded tissue were stained with hematoxylin–eosin stain and reviewed. Immunohistochemical studies were performed by the avidin–biotin–peroxidase complex technique (Vector, Burlingame, CA, USA). The antibodies used for immunohistochemistry included anti-S-100 protein (1:1,000; Dako), HMB-45 (1:250; Dako, Carpinteria, CA, USA), A103 (1 μg per milliliter; gift from Dr. Lloyd Old, Ludwig Institute for Cancer Research, New York Branch, New York, NY), CD34 (1:15,000; Immunotech, Westbrook, ME, USA), and MIB-1 (1:50; Dako). The proliferative index was measured as the number of MIB-1-positive cells per 10 high-power fields (HPFs; 40× objective). For ultrastructural analysis, fresh tissue was fixed immediately in 3% glutaraldehyde followed by routine processing. Clinical follow-up was obtained from the patients' physicians.

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RESULTS

Clinical and Pathologic Findings

Patient 1: Clinical Findings

A 53-year-old woman came to Memorial Sloan-Kettering Cancer Center for a second opinion. She had a pigmented lesion of her sternum and anterior chest. It was absent at birth and she remembered first noticing it at the age of 10. The lesion subsequently enlarged during puberty, but then remained stable in size and appearance. The lesion involved the skin overlying the sternum, the medial aspect of her right breast, and almost her entire left breast. It was completely asymptomatic. She reportedly had a biopsy of the lesion many years ago and was told to have a blue nevus.

At age 53, after she had not had a mammogram for several years, she underwent routine mammography at an outside hospital, which detected calcifications and nodular densities. Core needle biopsies were performed for additional evaluation, and the findings were first interpreted by a general surgical pathologist as metastatic melanoma and then subsequently by a dermatopathologist as a malignant primary tumor.

The lesion measured 24 × 17 cm in greatest horizontal dimension and appeared mottled and blue–black in color with a thin halo of more lightly pigmented skin around it (Fig. 1). The skin surface was smooth and no nodules were palpable in the skin. There was no cervical or axillary adenopathy. Her remaining examination was entirely normal. The patient had undergone radiologic evaluation of the chest, abdomen, and pelvis with no evidence of disease.

FIG. 1.

FIG. 1.

Although the mammographically detected and biopsied nodule was interpreted as CBN at Memorial Hospital, the patient elected to have the lesion removed completely because of her anxiety about the nature of the lesion and conflicting opinions that were rendered. She underwent full-thickness excision of the entire pigmented lesion with 1-cm margins and a left modified radical mastectomy. Thirty-two months later the patient is well with no evidence of recurrence.

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Patient 1: Histologic Findings

The lesion involved the reticular dermis, subcutis, and breast tissue. There was no melanocytic proliferation at the dermoepidermal junction or in the papillary dermis. The reticular dermal component was characterized by many individual foci, with the histologic appearance of common blue nevus (Fig. 2). Most of them were located in the deep dermis near the subcutis. Very rare clusters of small amelanotic or paucimelanocytic round or oval melanocytes were also present (Fig. 2). The foci of BN were separated by normal dermis or by Mongolian spot-like areas, in which pigmented, slender fusiform, or dendritic melanocytes and melanophages were spaced widely from each other as single cells without the formation of cellular aggregates (Fig. 3).

FIG. 2.

FIG. 2.

FIG. 3.

FIG. 3.

Variable cellular nodules were present in the subcutis. The largest nodule measured 1.5 cm in greatest diameter, and had histologic features of CBN (Fig. 4). Hypercellular areas contained nests and short fascicles of melanocytes with paucimelanotic eosinophilic or clear cytoplasm (Fig. 4). Their nuclei were oval in shape and had a slightly vesicular chromatin pattern and inconspicuous single nucleoli (Fig. 4). The cellular nests were surrounded by a population of slender spindle cells distributed loosely in a fibrous stroma with variable numbers of heavily pigmented dendritic melanocytes or melanophages. The highest mitotic index of the cellular nodules was one mitosis per 50 HPF (40× objective). No necrosis was seen in any nodule or anywhere else in the lesion. Although the majority of cells occupied expanded fibrous septae, some of them involved the adipose tissue of the fat lobules.

FIG. 4.

FIG. 4.

The lesion extended into the fibroadipose tissue of the left breast. The breast parenchyma itself showed nonproliferative fibrocystic changes. Ducts and lobules were surrounded by sheets of melanophages and by slender fusiform melanocytes (Fig. 5). In some foci of the breast, melanophages predominated over melanocytes. The melanocytes in the breast were benign cytologically and did not differ from the ones seen in the dermis or subcutis. No destruction of the breast parenchyma was seen.

FIG. 5.

FIG. 5.

In the reticular dermis, the subcutis, and the breast, pigmented melanocytes and melanophages focally surrounded peripheral nerves (Fig. 6) and blood vessels. Although the predominant cytologic appearance of individual melanocytes was that seen typically in common BN, focal clear and small epithelioid cell features (Fig. 7) were also noted.

FIG. 6.

FIG. 6.

FIG. 7.

FIG. 7.

Examination of the axillary lymph nodes failed to reveal metastatic disease in lymph node tissue. The capsule of one lymph node, however, was involved by many melanophages and cytologically bland pigmented melanocytes in a pattern typical of nodal blue nevus (Fig. 8).

FIG. 8.

FIG. 8.

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Patient 2: Clinical Findings

A 20-year-old man presented at Memorial Hospital for a second opinion. He had a pigmented lesion on his left flank, which was absent at birth but developed during childhood. It became darker during puberty. A precise measurement of the initial clinical lesion could not be obtained, but according to the patient's physician abroad, and on review of the pathology reports and slides, the lesion was estimated to measure approximately 15 × 10 cm. A dark bean-size nodule had formed in the more lightly pigmented background of the lesion between the ages of 15 and 16. Subsequently, additional smaller dark lesions developed around the nodule. A biopsy of the largest nodule performed abroad was interpreted initially as “pigmented neurosarcoma,” and the patient underwent partial excision and local electron beam therapy. When the patient arrived in New York, he was an athletic individual in excellent health without lymphadenopathy and had normal radiographic study results. A residual pigmented bluish black plaque was present surrounding and deep to a dermal scar. An additional partial excision was performed at Memorial Hospital, and the histologic material from the prior biopsy and excision abroad was reviewed. Although no evidence of malignancy was found, the uncertain biologic potential of the lesion was discussed with the patient. He decided not to undergo any additional surgical treatment, although the lesion extended focally to the margins of excision. Nineteen months later the patient is in excellent health with no evidence of recurrence or progression of the lesion.

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Patient 2: Histologic Findings

The lesion was multinodular and involved dermis, subcutis, and muscular fascia. Multiple foci, which corresponded histologically to common blue nevus, were present. The cellular nodules were present mainly in subcutaneous fibrous septae and in fascia. Each one of them had the characteristics of a CBN (Fig. 9). The largest individual nodule measured 0.9 cm. The highest mitotic index of the most cellular nodules was two mitoses per 50 HPF (40× objective). Occasional multinucleated cells were present. The nodules were separated and surrounded by loose aggregates of slender spindle cells, with focal clusters of heavily pigmented dendritic melanocytes and melanophages in a fibrous stroma (Fig. 10). Occasional small nests of epithelioid melanocytes were seen (Fig. 10). As in the tumor from the first patient, foci of neurotropism and angiotropism were identified. No necrosis or pleomorphism was found.

FIG. 9.

FIG. 9.

FIG. 10.

FIG. 10.

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Immunohistochemical Findings

The immunohistochemical findings are summarized in Table 1. In both patients, the tumor cells were positive with anti-S-100 protein, HMB-45, and A103. No immunoreactivity of the lesion for CD34 was seen. The highest proliferative index, as measured immunohistochemically with the antibody MIB-1, was 8 positive cells per 10 HPF (40× objective) in the tumor from the Patient 1, and 12 positive cells per 10 HPF in the tumor from Patient 2.

TABLE 1

TABLE 1

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Ultrastructural Findings

A representative sample of fresh tissue from the tumor of the second patient, which was excised at Memorial Hospital, was fixed in glutaraldehyde, which allowed ultrastructural analysis of the lesion. All tumor cells were melanocytes. Figure 11 demonstrates fusiform cells with variable numbers of melanosomes and numerous cellular processes. No basal lamina was identified at the periphery of any of the cells.

FIG. 11.

FIG. 11.

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DISCUSSION

Degos 16 described three clinical variants of BN: the common, solitary small BN; the rare occurrence of multiple BN; and the rare plaque-type BN. He referred to the latter as “naevus blue en nappe entendu.” The first case of a plaque-type BN published in the English literature is, to our knowledge, the one described by Upshaw et al. 54 In 1947, they reported a case of a large blue nevus, measuring 17 × 6 cm on the thorax of a 9-year-old boy, which was first noted when the child was 4 weeks of age. It was said to have a background of bluish discoloration, in which multiple, firm, slightly raised nodules arose. 54 Although the clinical description appears similar to our first patient, the histology of the lesion showed multiple foci of BN of the common type involving dermis, subcutis, and skeletal muscle, and no foci of CBN. However, because cellular foci developed in our patients only during adolescence and adulthood, it is possible that the lesion described by Upshaw et al. 54 represented the same entity. In 1954, Dorsey and Montgomery 17 reported their experience with 200 cases of BN (170 common type, 20 cellular type), including 2 patients who “exhibited large plaques containing many blue nevi with intervening zones of Mongolian-spot-like pigmentation between the blue nevi.”17,p.227 The histology of these BN was of the common type. No features were described, which would indicate the presence of CBN. Most other reports of large BN appear to be examples of nevus of Ota, nevus of Ito, or variants thereof, because their histologic features revealed predominantly widely spaced pigmented dermal fusiform and dendritic melanocytes with a variable number of admixed foci of common BN. 12,54 Thus, to our knowledge, a histologic description of large plaque-type BN with subcutaneous nodules of CBN has not been published previously.

The recognition of the spectrum of clinical and histologic appearances of BN, including the large plaque-type variant presented here, is important to avoid confusion with malignant melanoma. Although common BN rarely enter the differential diagnosis of malignant melanoma, large BN and CBN sometimes do. Before Allen and others 1,2,33,34 recognized the relationship of CBN to BN, CBN used to be considered a variant of malignant melanoma (so-called melanosarcoma). 15 Several cases of the largest and most thoroughly studied series of CBN to date published by Rodriguez and Ackerman 45 in 1968 were misdiagnosed initially as malignant melanoma, including the lesion of the thorax of a 58-year-old white woman that “had grown widely into the breast tissue.”45,p.394 Like our first patient, this patient with CBN of the breast underwent mastectomy because of an initial interpretation of malignancy. 45

The nodules, which arose in the subcutis of the two patients reported here, had features characteristic of CBN. 45 The nodules represented a well-demarcated lobular proliferation of cytologically benign melanocytes and contained a mixture of compact cellular nests and more loosely aggregated melanocytes (so-called “biphasic growth pattern”) as well as melanophages in a fibrous stroma. 4,45

Obvious features of malignancy, 45 such as tumoral necrosis, pleomorphism, or frequent mitoses, were absent in our patients. Other findings that favor malignant melanoma over CBN—like the presence of large epithelioid cells, 45 an infiltrative growth pattern, 45 or the presence of a “sarcomatoid” growth component, in which sheets of spindle cells replace small fascicular aggregates and nests of melanocytes—were also absent. Therefore, we concluded that the lesions presented by our patients were not malignant. Furthermore, the clinical findings were more in keeping with CBN. Malignant melanoma arising in BN, also termed malignant blue nevi (MBN), is said to be an aggressive type of melanoma with a high risk for metastatic disease, and it occurs typically on the scalp of elderly patients. 6,14,22,35,39,49

It has been suggested that measuring proliferative activity may be useful in recognizing MBN. 39,46 However, because only a small number of MBN and CBN were compared, the reliability of the results for diagnostic purposes remains uncertain. Nonetheless, we examined the cellular nodules in both patients immunohistochemically with the MIB-1 antibody. The greatest proliferative index we measured was 12 MIB-1-positive cells per 10 HPF (Table 1). This result is within the normal range of CBN and below the proliferative index reported for atypical CBN or MBN. 39,46,51

If the lesions are not malignant, should they be designated as atypical cellular blue nevus (ACBN)? The term ACBN has been applied to a rare variant of BN, which is said to be intermediate between typical CBN and MBN. 3,21,51 Lesions of ACBN may contain worrisome histologic features, such as asymmetry, infiltrative growth, hypercellular foci, focal cytologic atypia, and rare mitoses. Clinically, ACBN resemble more CBN than MBN. 14,45,51 Most MBN occur on the scalp of elderly patients, whereas most CBN and ACBN affect the buttocks or sacral region of young or middle-age adults. All lesions of ACBN reported so far have been solitary and mainly dermal nodules, some with extension into the superficial subcutis. None of the reported cases have metastasized to date.

The tumors described herein differ from reported cases of ACBN. They lack cytologic atypia, and their mitotic and proliferative index is still in keeping with CBN. What is unusual about them, and sets them apart from most CBN and ACBN, are their multinodularity; a dominant, deep growth component in the subcutis; even fascia or stroma of the breast; and the background setting of a large lesion with multiple foci of common BN and Mongolian spot-like areas. The clinical features of the large plaque-type blue nevus described herein—in other words, onset in childhood, location on the trunk, and large size—also differ from most CBN and ACBN.

What other entities enter the differential diagnosis? One pathologist reviewing the initial core biopsy of a breast nodule from Patient 1 considered metastatic melanoma. On a core biopsy alone, such a distinction can indeed be very difficult because metastatic melanoma can present with a blue nevuslike appearance. 9 None of our patients had a prior history of melanoma, and the previously outlined clinical and histologic findings clearly argue against metastases. Although one axillary lymph node of Patient 1 contained melanocytes, they were restricted to the capsule and were cytologically bland. Therefore, they represent nodal BN 29,30 and not metastatic melanoma.

Cutaneous malignant melanotic neurocristic tumor is another term that needs to be discussed during the differential diagnosis. It is said to represent a variant of malignant melanoma arising in cutaneous neurocristic hamartoma (CNH) 41 —a term that has been used rarely in the literature and is not well defined. Pearson et al. 41 defined CNH as “a pigmented lesion of the skin and superficial soft tissue composed of a complex proliferation of nevomelanocytes, Schwann cells, and pigmented spindle and dendritic blue nevus cells.”41,p.675 Others have reported cases as neurocristic hamartomas in which melanocytes were accompanied by tactoid bodies, CD34-positive stromal cells, and altered hair follicles. 36

The main problem related to the concept of neurocristic hamartomas is its distinction from melanocytic nevi, because it is well known that melanocytes can exhibit a wide spectrum of phenotypic heterogeneity in the same lesion. 5 The tumors presented in this report are, in our opinion, melanocytic nevi because they are only composed of melanocytes. No Schwann cells were found in the tumor by electron microscopy. Furthermore, all tumor cells were strongly immunoreactive with HMB-45 and A103, including nonpigmented or paucimelanotic spindle cells, which is typical of BN cells, 10,11,48 whereas amelanotic Schwann cells tend to be negative with these markers. Lastly, no immunoreactivity of stromal cells with CD34 was observed within the tumor.

Most solitary CBN are stable lesions. Malignant transformation to MBN is very rare. The clinical history in our patients with large plaque-type BN suggests that their subcutaneous nodules of CBN have been stable for many years. Nonetheless, due to the rarity of the lesions, the risk of malignant transformation of these nodules or the remainder of the lesion is unknown. Therefore, complete surgical excision seems a prudent treatment option. However, because of the large size of the lesion, the extent of surgery needs to be balanced with the consequences of large tissue loss for the patient. If a lesion is not excised completely, long-term clinical follow-up is recommended to monitor for recurrence or progression.

In conclusion, we present two cases of an unusual variant of plaque-type BN characterized by onset in childhood, large size, and development of subcutaneous nodules of CBN. We hope that by presenting these two patients we can enhance the knowledge of the morphologic spectrum of melanocytic nevi and in particular of BN, which should help to avoid confusion with malignant melanoma.

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Acknowledgment:

The authors thank the staff of the histology, immunohistochemistry, and electron microscopy laboratory for their excellent technical support. They are also very grateful to Dr. George Schaefer, Morton Plant Hospital, Clearwater, FL, for providing us with additional slides and tissue blocks for immunohistochemical study, and to Dr. Peter Blumencranz, Clearwater, FL, for clinical information.

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Keywords:

Blue nevus; Cellular blue nevus; Melanoma

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