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.
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.
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.
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:© 2000 Lippincott Williams & Wilkins, Inc.
Blue nevus; Cellular blue nevus; Melanoma