Material and Method: Hematoxylin-eosin and MIB-1 stained slides of 21 cases diagnosed between 2000-2014 were re-evaluated. In order to attract attention to this rare lesion, 21 cases are presented with the clinical and above-mentioned histopathological findings.

Results: Thirteen (61.9%) cases were females and eight (38.1%) were male. The mean age was 25.4 (2-73). The most frequent localization was the sacral and gluteal region (11 cases). The mean diameter was 14.4 mm (4-60 mm). From the parameters defined to assess the atypia, ulceration was identified in four cases. Prominent cellularity and subcutaneous infiltration were seen in three and 16 cases, respectively. Mitosis was seen in six tumors. Immunohistochemically, MIB-1 was present in two cases as 3% and 2% respectively, while in others it was 1% or less. Although there is no precise definition for the “atypical cellular blue nevus”, five patients were assessed as atypical cellular blue nevus (a case with infiltrative development of six cm tumor diameter, two cases with two mitosis and a MIB-1 index 3% and 2%, a case with one mitosis and confluent development and a case with one mitosis in addition to focal necrosis areas). No lymph node and/or distant metastasis was observed during follow-up.

Conclusion: We think it is more important to rule out the possibility of conventional melanoma in cellular blue nevus with exaggerated morphological findings alongside low proliferative activity rather than to determine the atypia.

The blue nevus term was first used by Jadassohn for dark blue lesions of the skin but the lesion was first described in the literature by Max Tiéche in 1906^10,11. Blue nevi are commonly classified among dermal hamartomatous dendritic melanocytic lesions such as nevus of Ota and Ito^1,11. The blue nevus group includes dendritic (classic) blue nevus, cellular blue nevus (CBN), and deep penetrating nevus¹¹. They can be blue or grey in the clinic according to the depth of the lesion and melanin content¹¹.

Cellular blue nevus differs from classic blue nevus with a cellular appearance, subcutaneous infiltration, intensive pigmentation and large size. It can be confused with melanoma due to the atypia criteria that may be present. The term was first used by Allen¹² in 1949 and it was described as a benign variant of blue nevus that could be confused with melanosarcoma due to its cellularity and intense melanin content. Other authors have reported that CBN is a benign neoplasm related to blue nevus but is not similar to melanoma^1,11,13.

The atypical cellular blue nevus (ACBN) term is used for CBN that has atypical features and requires differentiation from malignant blue nevus. However, there is no consensus regarding the classification or definite diagnostic criteria of the CBN, ACBN, malignant CBN and malignant melanoma spectrum¹.

We aimed to present the clinical and histopathological data of our cellular blue nevus cases as they are less common blue nevi lesions and to reveal the common and different aspects when compared with our few atypical cellular blue nevus cases.

The demographic characteristics of the cases and histopathological features of the lesions are presented in Table I.

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Table I: The clinical and histopathological features of cases

Histopathological evaluation revealed surface ulceration in four cases. The lesion was in the form of dermal nodular lesion and bulges into the subcutaneous fat in all but one case. Expansive development and subcutaneous fat tissue invasion in the tumor was seen in 15 (71.4%) cases while infiltrative development to surrounding tissues was found in one case (Figure 1A-D). Intensive cellularity was observed in three cases. The lesions consisted of ovalspindle cells, dendritic melanocytic cells and macrophages in various rates. The pigmentation, mostly observed in the macrophages, was quite intense (more than 75%) in two cases and mild (less than 25%) in six cases. Sclerosis areas were observed in addition to dendritic melanocyte clusters and melanophage groups constituting an alveolar pattern in some of the lesion. A markedly edematous stroma (n=5), cystic areas (n=1) and rosette-like multinucleated giant cells (n=1) were observed in a small number of cases.

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Figure 1: A) Dermal localized cellular blue nevus (H&E; x40), B) Intensive pigment content (H&E; x100), C) Ulcer on the surface (H&E; x100), D) Expansive growth pattern into subcutaneous tissue (H&E; x100).

Focal necrosis and one mitosis per square millimeter were found in a lesion on the gluteal area. Other atypia criteria were not observed. None of the case had marked cytological atypia or nuclear pleomorphism.

No mitosis was observed in 16 (72%) cases, while there was one mitosis per square millimeter in four cases and two mitoses per square millimeter in two cases (Figure 2A-D). MIB-1 proliferating index were 3% and 2% in two cases and 1% or lower in the others on immunohistochemical investigation.

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Figure 2: A) Nevus cells of epithelioid appearance in cellular blue nevus (H&E; x200), B) Presence of focal necrosis (H&E; x 200), C) Two mitoses in one field (H&E; x400), D) MIB-1 positivity (MIB-1; x400).

The mean follow-up period was 58.38±48.00 (9-179 months). No recurrence and/or metastasis were observed during follow-up.

Clinically, there is a pigmented nodular lesion with a size from a few millimeters to centimeters. Giant CBN cases larger than 10 cm have been reported in addition to the usual 1-2 cm lesions. The pigmentation may be blue-black^1,7,11,14.

Our CBN lesions were mostly gluteal and sacral, as reported in the literature. The 6 cm vulvar lesion in a 15-year-old patient and the CBN together with a pilonidal sinus were examples of rare presentations among our patients.

Microscopically, the lesions are generally located in the superficial and mid dermis and can show invasion to the deep dermis and subcutaneous tissue. Most lesions have an expansive and regular border¹. Dendritic melanocytic cells and melanophages in various rates are observed among the oval-spindle cells. Sclerosis is frequently present and other findings such as myxoid change, hemorrhage and stromal hyalinization can be seen^1,7,8,11. Mitosis is usually not seen or less than one per square millimeter^8,r11>.

Cytologically, oval-spindle melanocytes are seen in cellular areas. The cells have a large and lightly pigmented-clear cytoplasm with vesicular nuclei. Multinucleated giant cells can be seen¹.

CBNs can exhibit very different histological appearances and can therefore be confused with melanomas. A small number of melanoma cases on a CBN background have been reported in the literatüre^11,16. CBN is not common and CBNrelated melanoma cases are very rare, making it difficult for pathologists and clinicians to elucidate the biological nature and malignancy potential of these cases².

Certain blue nevus cases with CBN characteristics and some additional atypia findings that have not been identified as melanoma have been named atypical cellular blue nevus (ACBN)^3,8,9,17. Other authors have named these lesions CBN-like melanocytic tumor with local aggressive features or unclear malignant potential^6,18. ACBN is frequently seen in the gluteal and sacral region in young and middle-age adults^3,8,11.

ACBN diagnostic criteria are not yet clear. Atypia criteria can include asymmetry, hypercellular areas, focal cytological atypia and rare mitoses (<2/mm2). Many authors report that focal necrosis can be observed but no atypical mitosis is seen^{3,8,9,11,17,18}. Some authors feel that atypical mitotic activity and necrosis are releated to malignant blue nevi⁹. A large size (5-10 cm), vascular invasion, marked nuclear pleomorphism and more than 3 mitoses per mm2 have been identified as atypia criteria for malignant blue nevi^1,19,20,21. However, these criteria can be present both in CBN and melanoma cases and cannot be used as auxiliary criteria for the differential diagnosis¹.

Murali et al.¹¹ reported that they identified lesions with isolated mitosis or necrosis as atypical CBN when other atypia features such as intensive cellularity, nuclear atypia, hyperchromasia, and expansive growth were absent. However, they also reported that the biological behavior could not be predicted due to insufficient morphological signs but the risk of aggressive behavior risk was low.

There is therefore no clear consensus regarding diagnostic criteria for ACBN. This leads to poor consistency in the classification of these lesions among dermatopathologists¹. Barnhill et al² showed that there were inconsistencies regarding the biological nature definition and identification of CBN cases by histopathologists especially when atypical characteristics were present (ACBN) in their study of 26 melanocytic cases.

When we evaluated our cases using the atypia criteria identified above, five cases (one case with infiltrative development of six cm diameter, two cases with two mitoses and a MIB-1 index 3% and 2%, one case with one mitosis and confluent development and one case with one mitosis in addition to focal necrosis areas) were consistent with atypical CBN.

There are reports that ACBN does not recur or metastasize⁹ while others state that it can relapse and has a more aggressive course, especially following incomplete excision¹⁸. Some authors have diagnosed CBN cases with tumors deposits in lymph nodes as ACBN²².

Lymph node excision had not been performed in our cases. We did not observe any recurrence and/or metastasis during the follow-up of the five cases with atypical features or in the other cases.

Cases with atypical features should be excised totally with intact surgical borders and followed-up closely for nodal-distant spread as well as local recurrence due to the inconsistencies in the ACBN criteria and thus the malignancy potential definition in the literature as defined above.

More studies supported with molecular researches and long-term follow-up are required to clearly determine the morphological criteria affecting biological behavior in cellular blue nevi.

In conclusion, cellular atypia and proliferative activity is usually low in CBNs although they may have a prominent morphological appearance with intensive pigment with a quick look, and do not create a differential diagnosis problem for experienced dermatopathologists. Cases with atypical features indicating melanoma can create difficulties at the differential diagnosis but there are no definite criteria. The use of the term “Atypical cellular blue nevus” is not commonly accepted if there are only minor morphological deviations. We did not see any recurrence during followup in our “ACBN” cases with such minor deviations. This finding indicates that these cases are biologically closer to cellular blue nevus.

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