2015, Volume 31, Number 2, Page(s) 089-094
Atypia and Differential Diagnosis in Cellular Blue Nevi: Clinicopathological Study of 21 Cases
Banu YAMAN, Gülşen KANDİLOĞLU, Banu SARSIK KUMBARACI, Taner AKALIN
Department of Pathology, Ege University Faculty of Medicine, İZMİR, TURKEY
Keywords: Cellular blue nevus, Differential diagnosis, MIB-1 protein
Cellular blue nevus differs from the classic blue nevus with
characteristics such as large size, cellularity, intense pigmentation,
and growing pattern with subcutaneous infiltration. It is a dermal
melanocytic tumor that can be confused with melanoma due to the
atypia it may contain.
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.
Blue nevi are dermal melanocytic proliferations containing
cells similar to dendritic melanocyte precursors of
embryonic neural crest origin1
. The nature and
developmental biology of these melanocytic lesions are not
clearly understood. It is therefore difficult to classify benign
and malignant blue nevi and to differentiate them from
other melanocytic lesions2-9
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 190610,11. Blue nevi
are commonly classified among dermal hamartomatous
dendritic melanocytic lesions such as nevus of Ota and Ito1,11. 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 melanoma1,11,13.
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
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
All blue nevus cases diagnosed between 2000 and 2014
at our pathology department were reviewed and 21 cases
with cellular characteristics, such as larger size, prominent
pigmentation, subcutaneous infiltration, and cellularity
were included in the study. Seven of the cases included
in the study were sent from various external centers for
consultation with a diagnosis of malignant melanoma.
Clinical data such as age of patient, localization and
diameter of lesion were obtained from archival records
of pathology department. Hematoxylin-eosin (H&E) and
MIB-1 stained slides belonging to all blocks of the cases
were re-evaluated. The following parameters were assessed:
ulceration, degree of pigmentation, confluence, growth pattern, and mitoses per millimeter. Most follow-up data
was gathered via a telephone call.
There were 13 (61.9%) females and 8 (38.1%) males with a
mean age of 25.4 (2-73) years. The most frequent localization
was the sacral and gluteal region (11 cases). Mean tumor
size was 14.4 (4-60) mm. Two cases had combined nevus
accompanied by a banal nevus component. One case had
CBN with a sinus pilonidalis lesion at the sacral region.
The demographic characteristics of the cases and
histopathological features of the lesions are presented in
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.
Click Here to Zoom
|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),
growth pattern into
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
Click Here to Zoom
|Figure 2: A) Nevus
cells of epithelioid
cellular blue nevus
B) Presence of focal
(H&E; x 200),
C) Two mitoses in
D) MIB-1 positivity
The mean follow-up period was 58.38±48.00 (9-179
months). No recurrence and/or metastasis were observed
Cellular blue nevus (CBN) is usually seen in adults under
the age of 40 but can be seen at all ages. The incidence is
higher in females7,11
. The most frequent location is the
gluteal and sacrococcygeal region but it can also be seen in
the scalp, facial region and extremities. Genital tract, breast,
subungual, intraocular and conjunctival CBN cases have
also been reported1,7,8,11,14,15
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-black1,7,11,14.
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 seen1,7,8,11. Mitosis is
usually not seen or less than one per square millimeter8,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 literatüre11,16. 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 potential6,18. ACBN is
frequently seen in the gluteal and sacral region in young
and middle-age adults3,8,11.
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 seen3,8,9,11,17,18. 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
nevi1,19,20,21. 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
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
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
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.
1) Zembowicz A, Phadke PA. Blue nevi and variants: An update.
Arch Pathol Lab Med. 2011;135:327-36.
2) Barnhill RL, Argenyi Z, Berwick M, Duray PH, Erickson L,
Guitart J, Horenstein MG, Lowe L, Messina J, Paine S, Piepkorn
MW, Prieto V, Rabkin MS, Schmidt B, Selim A, Shea CR, Trotter
MJ. Atypical cellular blue nevi (cellular blue nevi with atypical
features): Lack of consensus for diagnosis and distinction from
cellular blue nevi and malignant melanoma (“malignant blue
nevus”). Am J Surg Pathol. 2008;32:36-44.
3) Avidor I, Kessler E. ‘‘Atypical'' blue nevus—a benign variant of
cellular blue nevus. Dermatologica. 1977;154:39–44.
4) Elder DE, Murphy GF. Melanocytic tumors of the skin. Atlas of
tumor pathology, Washington: AFIP; 1990.
5) Goldenhersh MA, Savin RC, Barnhill RL, Stenn KS. Malignant
cellular blue nevus. Case report and literature review. J Am Acad
6) Leopold JG, Richards DB. Cellular blue nevi. J Path Bact.
7) R odriguez HA, Ackerman LV. Cellular blue nevus.
Clinicopathologic study of forty-five cases. Cancer. 1968;21:393–
8) Temple-Camp CRE, Saxe N, King H. Benign and malignant
cellular blue nevus. A clinicopathological study of 30 cases. Am J
9) Tran TA, Carlson JA, Basaca PC, Mihm MC. Cellular blue nevus
with atypia (atypical cellular blue nevus): A clinicopathologic
study of nine cases. J Cutan Pathol. 1998;25:252–8.
10) Tieche M. Uber benigne Melanome (‘‘Chromatophorome'') der
Haut- ‘‘blaue Naevi''. Virchows Arch Pathol Anat. 1906;186:212–29.
11) M urali R, McCarthy SW, Scolyer RA. Blue nevi and related
lesions: A review highlighting atypical and newly described
variants, distinguishing features and diagnostic pitfalls. Adv Anat
12) Allen AC. A reorientation on the histogenesis and clinical
significance of cutaneous nevi and melanomas. Cancer.
13) Lever WF. Histopathology of the Skin. Philadelphia: JB Lippincott
14) Causeret AS, Skowron F, Viallard AM, Balme B, Thomas L.
Subungual blue nevus. J Am Acad Dermatol. 2003;49:310–2.
15) Speakman JS, Phillips MJ. Cellular and malignant blue nevus
complicating oculodermal melanosis (nevus of Ota syndrome).
Can J Ophthalmol. 1973;8:539-47.
16) Aloi F, Pich A, Pippione M. Malignant cellular blue nevus: A
clinicopathological study of 6 cases. Dermatology. 1996;192:36–40.
17) M aize JC Jr, McCalmont TH, Carlson JA, Busam KJ, Kutzner H,
Bastian BC. Genomic analysis of blue nevi and related dermal
melanocytic proliferations. Am J Surg Pathol. 2005;29:1214–20.
18) Elder DE, Murphy GF. Malignant tumors (melanomas and
related lesions). In: Rosai J, editor. Atlas of tumor pathology:
Melanocytic tumors of the skin. Washington, DC: Armed Forces
Institute of Pathology; 1991:177–85.
19) Zembowicz A, Mihm MC. Dermal dendritic melanocytic
proliferations: An update. Histopathology. 2004;45:433–51.
20) Spatz A, Zimmermann U, Bachollet B, Pautier P, Michel G,
Duvillard P. Malignant blue nevus of the vulva with late ovarian
metastasis. Am J Dermatopathol. 1998;20:408-12.
21) M ehregan DA, Gibson LE, Mehregan AH. Malignant blue nevus:
A report of eight cases. J Dermatol Sci. 1992;4:185-92.
22) Sterchi JM, Muss HB, Weidner N. Cellular blue nevus simulating
metastatic melanoma: Report of an unusually large lesion
associated with nevus-cell aggregates in regional lymph nodes. J
Surg Oncol. 1987;36:71-5.