Precursors To Melanoma And The Problematic Nevomelanocytic Proliferation
Section 5 -
Combined Nevus, Cellular Blue Nevus, Deep Penetrating Nevus, and Plexiform Spindle Cell Nevus
Neil Crowson, MD
Cynthia M. Magro, MD
Martin C. Mihm, Jr., MD
Case # 4. Combined Nevus
The term combined nevus is applied to lesions with mixed patterns of
nevomelanocytic proliferation that combine, in variable proportions, type A, B, and C nevomelanocytes
with cells identical to those of Spitz and/or blue nevi. Combined nevi represent 1% of nevi and in our
view reflect divergent terminal differentiation, reflecting genotypic or epigenetic phenomena. With
respect to the latter, we have found combined nevi rich in dendritic nevomelanocytes to be common in
conjunctivae and eyelid skin, a finding that may reflect peculiarities of anatomic site. The mean age is
30 years, with the face and back being the most common sites of involvement, each accounting for roughly
one-quarter of cases (Pulitzer et al., 1991). Lesions are gray, brown, or black papules that average 5mm
in diameter (Pulitzer et al., 1991) and are brought to the clinician's attention by virtue of a
pigmentary change, increase in size, and/or alteration in surface morphology.
Pulitzer and co-workers (Pulitzer et al., 1991) the following nevus cell combinations: 1) Type A and
type B nevus cells, singly or in nests either along the dermoepidermal junction, in both the epidermis
and dermis, or solely in the dermis; 2) Pigmented spindle cells arranged in well-defined fascicles; 3)
Pigmented, slender dendritic cells typical of a blue nevus; and 4)Relatively amelanotic, plump, spindled
cells arranged in fascicles characteristic of a Spitz nevus. Eighty-five percent of such cases were
found to be admixtures of ordinary nevus cells and either pigmented or nonpigmented spindle cells of
Spitz nevus subtype. When the fascicles of non-Spitzian pigmented spindle cells are examined in
cross-section, they appear as small nodules with polygonal nuclei.
Our experience differs somewhat in that the most common form in our hands comprises nests of type A
nevomelanocytes admixed with dendritic melanocytes. In Pulitzer's series, 15% of the lesions had
concomitant features of dysplasia (Pulitzer et al., 1991); a combined nevus of dysplastic nevus and
benign common acquired nevus subtypes has been reported by others (Marchesi et al., 1994) but iin our
view is exceptional (Crowson et al., 2001). Melanoma in situ has been described in a combined nevus
(Requena et al., 1991). The disparate components are either intimately admixed or form discrete
collections imparting a biphasic morphology. Less common forms of combined nevus include the speckled
lentiginous nevus in concert with a blue nevus, Spitz nevus, and the common acquired nevus (Ishibashi et
al., 1990; Misago et al., 1993).
Case # 5 . Cellular Blue Nevus
- Cooper PH. Deep penetrating (plexiform spindle cell) nevus. A frequent participant in combined
nevus. J Cutan Pathol 1992;19:172180.
- Crowson AN, Magro CM, Mihm MC, Jr. Combined nevus, deep-penetrating nevus, and plexiform spindle cell
nevus. In: Crowson AN, Magro CM, Mihm MC, Jr. The melanocytic proliferations : a comprehensive
textbook of pigmented lesions. New York : John Wiley and sons, 2001:183-294.
- Ishibashi A, Kimura K, Kukita A. Plaque-type blue nevus combined with lentigo (nevus spilus). J
Cutan Pathol 1990;17:241245.
- Marchesi L, Naldi L, Locati F, Tribbia G, Pezzica E, Parma A, Cainelli T. Combined Clark's nevus. Am
J Dermatopathol 1994;16: 364371.
- Misago N, Narisawa Y, Kohda H. A combination of speckled lentiginous nevus with patch-type blue
nevus. J Dermatol 1993;20: 643647.
- Pulitzer DR , Martin PC, Cohen AP, Reed RJ. Histologic classification of the combined nevus.
Analysis of the variable expression of melanocytic nevi. Am J Surg Pathol 1991;15:11111122.
- Requena L, Barat A, Hasson A, Arias D, Gutierrez MC, Martin L, de Castro A. Malignant combined nevus.
Am J Dermatopathol 1991;13:169173.
The cellular blue nevus (CBN) classically occurs in children and young adults (Rodriguez and
Ackerman, 1968; Temple-Camp et al, 1988) but can present up to the seventh decade; the mean age is 33
years and the female-to-male ratio is roughly 2:1. All races are affected. The CBN is a large
multinodular mass with a mean diameter of 1.762 cm. Ulceration may be seen. The CBN may show
progressive enlargement to a size of 10 cm or more. Characteristic locations are the dorsa of the feet
or the buttocks, but lesions may occur anywhere on the body including the scalp, the conjunctiva and
spinal canal (melanocytoma) (Lach et al, 1988). They are sometimes mistaken for melanoma when invasion
of subjacent brain occurs (Nakano et al, 1987; Micali et al, 1997). Some CBNs are associated with
palpable lymph nodes reflecting intranodal melanocytes.
The CBN often has a characteristic low-power "dumbbell-shaped" configuration oriented perpendicularly
to the epidermis with extension deep into the dermis and subcutis. There are alternating zones of
hypercellularity and collagenous acellular pigmented foci. The cellular component comprises nodules or
fascicles of cuboidal, oval or spindle-shaped cells, the former within the nodular foci and the latter in
the fascicular zones. We feel that both represent the same cell type, rounded when cut en face or
spindled when cut in long axis. The cells manifest vacuolated, clear cytoplasms with frequent coarse
granular melanization and nuclei with delicate chromatin and small nucleoli. Draped around these cell
balls are pigmented dendritic cells. The cellular component compresses the dermal stroma, imparting a
pseudoencapsulated boundary. The interposed pigmented zones resemble a blue nevus. Cystic degeneration
may occur but the residual cellular elements within such foci appear viable and are embedded within an
edematous and mucinous stroma. In the malignant blue nevus, in contrast, cystic change reflects tumor
necrosis. Senescent atypia may be observed in the CBN and should not be confused with the anaplasia.
Multinucleated giant cells may be seen and typical mitoses may be observed; they are few in number (less
than one per Χ40 high-power field). A variant of CBN designated the desmoplastic CBN has abundant
desmoplastic stroma (Michal et al, 1995). The nevus cells are the apparent source of collagen matrix
production based on immunoreactivity with antibodies to S100 protein and HMB-45 and the absence of
expression of desmin or smooth muscle actin. Balloon cell change is described in the CBN (Perez and
Suster, 1999). The deeper aspects of the lesion may manifest an alveolar arrangement of epithelioid
cells surrounded by bipolar dendritic pigment-laden cells. The appellation
atypical blue nevus has been applied to cases that manifest certain architectural and cytologic
features that include an infiltrative margin, asymmetry, hypercellularity, pleomorphism, hyperchromasia,
mitotic figures, and/or focal necrosis (Tran et al, 1998). A dominant background lesion of CBN comprises
a fascicular or nodular architecture and a biphasic population of dendritic and clear cells .
The main differential diagnostic considerations embrace those malignant melanocytic neoplasms with
prominent melanin pigment produlction, the first of which is the exceedingly rare "malignant blue nevus"
(Mehregan et al, 1992) that occurs most often on the
scalp of men in the 5th decade of life, often metastasizing to regional lymph nodes and eventuating in
death (English et al, 1996); an occurrence in the vulva with ovarian metastases 15 years after the
initial diagnosis has been described (Spatz et al, 1998). Unlike the relatively amelanotic, bland
cytomorphology of the cellular component of the CBN, the malignant blue nevus comprises atypical
pigmented spindled cells showing marked variability of nuclear size and shape with overt malignant
cytology including increased and irregularly distributed chromatin, numerous and atypical mitoses and
confluent necrosis. The architectural disposition of the biphasic elements comprising the CBN is absent
and there is effacement of the dermal architecture by a densely cellular proliferation (Connelly and
Smith, 1991; Mehregan et al, 1992). Neurotropism may be observed in both CBN and malignant blue nevus
and therefore is not a distinguishing criterion. While the CBN may exhibit "aggressive" local growth
with extension into underlying tendons, muscle, and even brain, the histology is nonetheless typical of a
CBN. Although CBN may be observed in regional lymph nodes, if the CBN has none of the features of the
malignant blue nevus, this is interpreted as having the same clinical significance as the "metastasizing"
Spitz tumor, in which nodal deposits are not associated with widespread dissemination or death from
metastatic disease (Gonzalez-Campora et al., 1996). The second category of malignant neoplasm entering
into the differential diagnosis of the CBN is the malignant melanoma with prominent pigment synthesis or
"animal type" melanoma (Crowson et al, 1999).
Malignant Blue Nevus (Melanoma arising in blue nevus)
- Aloi F, Pich A, Pippione M. Malignant cellular blue nevus: a clinicopathological study of 6 cases.
Dermatology 1996;192: 3640.
- Bisceglia M, Carosi I, Fania M, Di Ciommo A, Lomuto M. Nevus of Ota. Presentation of a case
associated with a cellular blue nevus with suspected malignant degeneration and review of the literature.
Pathologica 1997;89: 168174.
- Blicker JA, Rootman J, White VA. Cellular blue nevus of the conjunctiva. Ophthalmology 1992; 99: 17141717.
- Connelly J, Smith JL JR. Malignant blue nevus. Cancer 1991;67: 26532657.
- Crowson AN, Magro CM, Mihm MC jr. Malignant melanoma with prominent pigment synthesis: Animal type
melanoma. Hum Pathol 1999;30: 543-550.
- English JC 3rd, McCollough ML, Grabski WJ. A pigmented scalp nodule: malignant blue nevus. Cutis
- Gonzalez-Campora R, Diaz-Cano S, Vazquez-Ramirez F, Ruiz HG, Moreno JC, Camacho F. Cellular blue
nevus with massive regional lymph node metastases. Dermatol Surg 1996;22: 8387.
- Hoos A, Berho M, Blumencranz PW, Brady MS. Giant cellular blue nevus of the anterior chest wall
mimicking metastatic melanoma to the breast: a case report. J Surg Oncol 2000;74: 278-281.
- Lach B, Russell N, Benoit B , Atack D. Cellular blue nevus (melanocytoma) of the spinal meninges:
electron microscopic and immunohistochemical features. Neurosurgery 1988;22: 773780.
- Micali G, Innocenzi D, Nasca MR. Cellular blue nevus of the scalp infiltrating the underlying bone:
case report and review. Pediatr Dermatol 1997;14: 199203.
- Lambert WC, Brodkin RH. Nodal and subcutaneous cellular blue nevi. A pseudometastasizing
pseudomelanoma. Arch Dermatol 1984;120: 367370.
- Mehregan DA, Gibson LE, Mehregan AH. Malignant blue nevus: a report of eight cases. J Dermatol Sci
- Mishima Y. Cellular blue nevus. Melanogenic activity and malignant transformation. Arch Dermatol
- Michal M, Kerekes Z, Kinkor Z, Ondrias F, Pizinger K. Desmoplastic cellular blue nevi. Am J
Dermatopathol 1995;17: 230235.
- Michal M . Cellular blue naevi with microalveolar patterna type of naevus frequently confused with
melanoma. Pathol Res Pract 1998;194: 8386.
- Nakano S, Kinoshita K, Morita Y, Inoue S, Kawana N. Cellular blue nevus of the scalp associated with
intracranial involvement. Surg Neurol 1987;27: 553557.
- Perez MT , Suster S. Balloon cell change in cellular blue nevus. Am J Dermatopathol 1999;21:
- Rodriguez HA, Ackerman LV. Cellular blue nevus. Clinicopathologic study of forty-five cases.
- 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;20:408412.
- Temple-Camp CR. Saxe N. King H. Benign and malignant cellular blue nevus. A clinicopathological
study of 30 cases. Am J Dermatopathol 1988;10:289296.
- 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;25:252258.
This rare lesion occurs most often on the scalp but does occur elsewhere on the body including on the
extremities (Ozgur et al, 1997). The lesion usually arises in association with a cellular blue nevus
(Merkow et al, 1969; Mishima et al, 1970; Hernandez, 1973), but has been described in association with
the nevi of Ito and Ota (van Krieken et al, 1989). Malignant transformation in a preexisting lesion
usually occurs in an older age group (Connelly and Smith, 1991) and manifests as rapid enlargement,
ulceration, and change in color. The diagnosis of malignant cellular blue nevus should be considered
when a lesion that has arisen in a preexisting cellular blue nevus exhibits highly atypical epithelioid
melanocytes with bizarre tumor giant cells and numerous abnormal mitoses. Characteristically, there is a
preexisting lesion such as a cellular blue nevus (Hernandez, 1973; Aloi et al, 1996) adjacent to the
malignant component, identifiable as a markedly disorganzied and highly infiltrative lesion with
hyperchromasia and often a moderately dense inflammatory infiltrate at the base. The malignant component
shows pleomorphic spindle and epithelioid cells disposed in fascicles and nodules that efface the dermal
architecture and extend into the subcutis with areas of necrosis. Admixed with the pleomorphic cells
are bizarre tumor giant cells. Numerous abnormal mitotic figures are observed, averaging 8 to 9 per
mm2 (Aloi et al, 1997).
The Deep-penetrating Nevus
The deep-penetrating nevus first described in 1989, occurs characteristically in the second to fourth
decades of life on the proximal aspect of the upper or lower extremities, the face, or the trunk (Seab et
al., 1989; Cooper, 1992) as a variably colored dome-shaped papules invariably less than 1 cm and rarely
more than 6.0 mm in diameter (Seab et al., 1989; Cooper 1992). As they are never devoid of pigment a
hemangioma is never a serious clinical diagnostic consideration; rather, clinicians often raise
consideration of a blue nevus or a cellular blue nevus and sometimes to melanoma. Deep-penetrating nevi
are rarely congenital. In the original series by none of the lesions recurred or metastasized (Seab et
al., 1989). The gross pathology comprises wedge-shaped hyperpigmentation extending to the reticular
dermis or subcutis.
The deep-penetrating nevus is a wedge-shaped symmetrical lesion whose dominant composition is of
closely apposed, vertically oriented fascicles that assume an orderly pattern of infiltration within the
dermis, and closely follow neurovascular bundles and the adventitial dermis of the hair follicles and
eccrine coil. There is a minor diffuse interstitial component whereby pigmented cells form a scaffold by
virtue of their laminated admixture with the reticular dermal collagen and elastic fibers. The tumor
extends into the deep reticular dermis and may even permeate the subcutis (Cooper, 1992). The fascicles
tend to be confluent in the upper dermis and dissipate in size toward the base to fashion an inverted
triangle. The fascicles may appear either elongated or round, depending on whether they are examined
en face or in cross-section. Pushing, nodular borders at the tumor base are
not observed. Junctional nests are seen in 85% and, when present, are separated from the dermal
component by a grenz zone. The nests vary in size from large to small. Some authors would classify the
deep-penetrating nevus as a combined nevus of deep-penetrating and common acquired subtypes. Cooper
recognized that in two-thirds of deep-penetrating nevi an ordinary nevus coexisted, indicating that it is
a frequent participant in the combined nevus (Cooper, 1992). Patterned periretal fibroplasia as seen in
the dysplastic nevus and perifascicular stromal desmoplasia are unusual in the deep-penetrating nevus.
The fascicles comprise spindle-shaped cells that manifest variable melanization ranging from cells with
virtually no pigment (i.e., those with a clear cytoplasmic morphology) to those with prominent pigment
deposition. Numerous peripherally disposed melanophages delimit adjacent fascicles. The spindle cell
component shows mild to moderate nuclear size and shape variability. In addition, there is a random
disposition of pleomorphic hyperchromatic cells, significantly larger than the aforesaid dominant spindle
cell component. These cells are designated as tumor giant cells and may be uni- or multinucleated.
Their nuclei appear dark and smudged with loss of all nuclear detail. They may demonstrate nuclear
pseudoinclusions (cytoplasmic invaginations into the nucleus). In those tumor giant cells with a
preserved chromatin, prominent nucleoli may be observed. Mitoses, typical in morphology, are seen in 10%
of lesions. However, they are rare, and no more than one or two are seen in any section examined. Their
presence within the deeper aspects of the lesion should also warrant concern regarding a potentially
aggressive biological behavior. A mild lymphocytic infiltrate may be present in some lesions (Seab et
al., 1989; Cooper, 1992). Neoplastic cells manifest diffuse decoration with antibodies to HMB-45 and
Exclusion of a vertical growth phase melanoma, including neurotropic melanoma, is important.
Melanomas invade the dermis in an irregular fashion, while the epidermis shows a single-cell
proliferation of cells with upward growth consistent with melanoma in situ, with the invasive dermal
component exhibiting a confluent growth pattern accompanied by dermal effacement and/or a dermal
sclerosing reaction. Pushing nodular borders are characteristic. Mitoses are seen with regular
frequency and may have an atypical morphology. The majority of cells show malignant nuclear details, as
characterized by coarse and irregular chromatin, prominent nucleoli, and increased nuclear to cytoplasmic
ratios. Hence, the cytologic and histologic features of vertical growth phase melanoma are polar
opposites of those seen with deep-penetrating nevi.
The CD44 standard (CD44s) isoform exhibits uniform and strong expression in the deep-penetrating
nevus, in contrast to its reduced and heterogeneous staining pattern in melanoma. CD44 variant
[CD44v(6)] exhibits cytoplasmic expression in melanoma tumor cells and no significant decoration of the
cells in the deep-penetrating nevus and other benign melanocytic proliferations. Antibody to CD44
recognizes a membrane glycoprotein receptor for hyaluronan (Leigh et al., 1996) that is involved in
interactions between cells and extracellular matrix.
A cellular blue nevus is also worthy of diagnostic consideration. Its dermal architecture is
dumbbell shaped. Characteristic of the cellular blue nevus are nodules of amelanotic bland and
monomorphous spindle and/or epithelioid cells, separated by sclerotic collagen within which dendritic
pigmented cells are present, without predilection for neurovascular bundles or adnexae and without any
Other nevomelanocytic proliferations that follow the arrector pili and other adnexal structures
should be considered in the differential diagnosis of the combined nevus, namely, congenital nevi and the
Spitz nevus. Unlike the combined nevus, the congenital nevus has a different cellular composition
restricted to characteristic type A, B, or C nevomelanocytes. Among the distinguishing features of the
Spitz nevus are:
- Kamino bodies,
- pagetoid spread,
- the relative frequency with which giant pleomorphic cells are
- lack of pigment in the reticular dermal based nevic cells, and
- a general absence, in the dermal-based component, of a
fascicular/plexiform growth pattern.
Recurrence is rare, and metastases have not been reported with the deep-penetrating nevus. However,
it is our recommendation that a complete simple excision be performed. We have seen cases in which the
incisional biopsy was interpreted as a deep-penetrating nevus, and yet, on reexcision, the lesion was
best categorized as a neurotropic melanoma. We also recently have seen a rare case in which an
incisional biopsy showed architecture and cytomorphology consistent with a deep-penetrating nevus but
with more numerous mitoses than usually associated with a deep-penetrating nevus, in which mitoses are
rare or absent. A reexcision revealed an invasive melanoma, arising in a background of congenital nevus.
It would appear that heterogeneity in melanoma morphology warrants complete excision of uncommon
melanocytic proliferations that manifest prominent cellularity such as the deep-penetrating nevus,
especially if unusual features are encountered. Furthermore, the deep-penetrating nevus is a recently
described entity (Seab et al., 1989) and therefore long term follow-up is still not available for
patients in whom this diagnosis has been made. Time will establish whether this lesion has the potential
for aggressive biological behavior.
The Plexiform Spindle Cell Nevus
- Cooper PH. Deep penetrating (plexiform spindle cell) nevus. A frequent participant in combined
nevus. J Cutan Pathol 1992;19:172180.
- Leigh CJ, Palechek PL, Knutson JR, McCarthy JB, Cohen MB, Argenyi ZB. CD44 expression in benign and
malignant nevomelanocytic lesions. Hum Pathol 1996;27: 12881294.
- Seab JA Jr, Graham JH, Helwig EB. Deep penetrating nevus. Am J Surg Pathol 1989;13: 3944.
The plexiform spindle cell nevus shares with the deep-penetrating nevus similarity in the age of the
patient, anatomical location, and, at times, certain features of the clinical appearance and
histomorphology (Barnhill et al., 1991). Many authors feel that this diagnosis is interchangeable with
that of deep-penetrating nevus but there are in fact two variants of deep-penetrating nevus, one with an
epithelioid cell morphology ("inverted type A nevus") and the other with a spindle cell morphology
("inverted spindle cell nevus"). It is the latter that, because of its spindle cell morphology, has been
the source of confusion. In point of fact the plexiform spindle cell nevus has clinical and histological
features that are distinctive. To highlight the critical distinguishing points seen at light microscopy,
both forms of deep-penetrating nevus have a wedge-shaped appearance whereas the plexiform spindle cell
nevus tracks along the superficial neurovascular bundles to generate the clinical appearance of a plaque.
Barnhill and co-workers, who originally coined the term plexiform spindle cell nevus felt that it was a
more suitable term than "deep-penetrating nevus," because not all such lesions deeply penetrated the
dermis and, furthermore, it is an appellation that more succinctly addresses the two fundamental features
that define this group of lesions: the distinctive plexiform architecture and the predominantly spindled
cytology. We recognize the validity of each diagnosis and acknowledge the contributions made by each
group of authors in enhancing our understanding of this important group of lesions.
- Barnhill RL, Mihm MC Jr, Magro CM. Plexiform spindle cell naevus: a distinctive variant of
plexiform melanocytic naevus. Histopathology 1991;18:243-7, 1991.