—  SHORT COURSE #31  —

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.

Histology
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).

References
  1. Cooper PH. Deep penetrating (plexiform spindle cell) nevus. A frequent participant in combined nevus. J Cutan Pathol 1992;19:172–180.

  2. 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.

  3. Ishibashi A, Kimura K, Kukita A. Plaque-type blue nevus combined with lentigo (nevus spilus). J Cutan Pathol 1990;17:241–245.

  4. Marchesi L, Naldi L, Locati F, Tribbia G, Pezzica E, Parma A, Cainelli T. Combined Clark's nevus. Am J Dermatopathol 1994;16: 364–371.

  5. Misago N, Narisawa Y, Kohda H. A combination of speckled lentiginous nevus with patch-type blue nevus. J Dermatol 1993;20: 643–647.

  6. 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;15:1111–1122.

  7. Requena L, Barat A, Hasson A, Arias D, Gutierrez MC, Martin L, de Castro A. Malignant combined nevus. Am J Dermatopathol 1991;13:169–173.

Case # 5 . Cellular Blue Nevus

Clinical Features
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 1.76–2 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.

Histology
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 .

Differential Diagnosis
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).

References
  1. Aloi F, Pich A, Pippione M. Malignant cellular blue nevus: a clinicopathological study of 6 cases. Dermatology 1996;192: 36–40.

  2. 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: 168–174.

  3. Blicker JA, Rootman J, White VA. Cellular blue nevus of the conjunctiva. Ophthalmology 1992; 99: 1714–1717.

  4. Connelly J, Smith JL JR. Malignant blue nevus. Cancer 1991;67: 2653–2657.

  5. Crowson AN, Magro CM, Mihm MC jr. Malignant melanoma with prominent pigment synthesis: Animal type melanoma. Hum Pathol 1999;30: 543-550.

  6. English JC 3rd, McCollough ML, Grabski WJ. A pigmented scalp nodule: malignant blue nevus. Cutis 1996;58: 40–42.

  7. 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: 83–87.

  8. 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.

  9. Lach B, Russell N, Benoit B , Atack D. Cellular blue nevus (melanocytoma) of the spinal meninges: electron microscopic and immunohistochemical features. Neurosurgery 1988;22: 773–780.

  10. Micali G, Innocenzi D, Nasca MR. Cellular blue nevus of the scalp infiltrating the underlying bone: case report and review. Pediatr Dermatol 1997;14: 199–203.

  11. Lambert WC, Brodkin RH. Nodal and subcutaneous cellular blue nevi. A pseudometastasizing pseudomelanoma. Arch Dermatol 1984;120: 367–370.

  12. Mehregan DA, Gibson LE, Mehregan AH. Malignant blue nevus: a report of eight cases. J Dermatol Sci 1992;4: 185–192.

  13. Mishima Y. Cellular blue nevus. Melanogenic activity and malignant transformation. Arch Dermatol 1970;101: 104–110.

  14. Michal M, Kerekes Z, Kinkor Z, Ondrias F, Pizinger K. Desmoplastic cellular blue nevi. Am J Dermatopathol 1995;17: 230–235.

  15. Michal M . Cellular blue naevi with microalveolar pattern—a type of naevus frequently confused with melanoma. Pathol Res Pract 1998;194: 83–86.

  16. Nakano S, Kinoshita K, Morita Y, Inoue S, Kawana N. Cellular blue nevus of the scalp associated with intracranial involvement. Surg Neurol 1987;27: 553–557.

  17. Perez MT , Suster S. Balloon cell change in cellular blue nevus. Am J Dermatopathol 1999;21: 181–184.

  18. Rodriguez HA, Ackerman LV. Cellular blue nevus. Clinicopathologic study of forty-five cases. Cancer 1968;21:393–405.

  19. 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;20:408–412.

  20. Temple-Camp CR. Saxe N. King H. Benign and malignant cellular blue nevus. A clinicopathological study of 30 cases. Am J Dermatopathol 1988;10:289–296.

  21. 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;25:252–258.

Malignant Blue Nevus (Melanoma arising in blue nevus)

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

Clinical Features
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.

Histopathology
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 S100 protein.

Differential Diagnosis
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 epidermal component.

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:
  1. Kamino bodies,

  2. pagetoid spread,

  3. the relative frequency with which giant pleomorphic cells are identified,

  4. lack of pigment in the reticular dermal based nevic cells, and

  5. a general absence, in the dermal-based component, of a fascicular/plexiform growth pattern.

Management
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.

References
  1. Cooper PH. Deep penetrating (plexiform spindle cell) nevus. A frequent participant in combined nevus. J Cutan Pathol 1992;19:172–180.

  2. Leigh CJ, Palechek PL, Knutson JR, McCarthy JB, Cohen MB, Argenyi ZB. CD44 expression in benign and malignant nevomelanocytic lesions. Hum Pathol 1996;27: 1288–1294.

  3. Seab JA Jr, Graham JH, Helwig EB. Deep penetrating nevus. Am J Surg Pathol 1989;13: 39–44.

The Plexiform Spindle Cell Nevus

Clinical Features
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.

Reference
  1. Barnhill RL, Mihm MC Jr, Magro CM. Plexiform spindle cell naevus: a distinctive variant of plexiform melanocytic naevus. Histopathology 1991;18:243-7, 1991.