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Deep Penetrating Nevus - Submitted on: Thursday November, 11, 2010
Contributed by:Andrea Boni, MD, N/A
Deep penetrating nevus (DPN) is a benign, dermal based, melanocytic proliferation.

Definition:
This histological entity was first described by Seab and colleagues in The American Journal of Surgical Pathology in 1989 (1). In a study that included 70 patients they describe the DPN as a lesion characterized by cellular pleomorphism, deep dermis infiltration and benign clinical course. The main diagnostic problem with this entity stems primarily from the difficulty to clearly distinguish it from malignant melanoma.

Clinical Features:
DPN usually occurs in the second or third decade of life, with even distribution between males and females. It presents as a well circumscribed, dome shaped, darkly pigmented papule or nodule usually ranging from 2 to 10 mm in diameter. Common locations are the face, upper trunk and proximal extremities (1, 2).

Histology:
Figures
(Click on an image for a larger view)
: Scanning magnification of a classic example of the deep penetrating nevus. One can appreciate the triangular, symmetric and sharply demarcated shape of the lesion with the base towards the epidermis and the apex diving down in the deep dermis. The supe
Figure 2: The superficial aspect of the lesion resembles an ordinary dermal nevus with small type B cells. The epidermal component is limited to some melanocytic hyperplasia and occasional nests of few cells.
Figure 3: The deep penetrating component of the lesion shows larger nests surrounded by heavily pigmented melanophages. It follows adnexal structures down in the deep dermis. At this magnification it is possible to appreciate the relationship between the
Figure 4: A closer look at the deep penetrating component of the lesion reveal the characteristic epitheliod and spindle cells with dusty cytoplasm. In this picture one can better appreciate the nests of cells surrounded by melanophages. Also note presenc
Histologically the lesion is symmetrical, sharply demarcated and triangular in shape, with the base towards the epidermis and the apex located in the deep dermis or subcutis. In some tumors several apices may be present.
The superficial aspect can resemble an ordinary nevus, leading many pathologists to diagnose these lesions as combined nevi. The epidermal component is usually inconspicuous, ranging from an increased number of uniform melanocytes with a lentiginous pattern to the occasional junctional nest. The deep component is what gives this entity its worrisome morphological features. It is composed of nests or vertically oriented fascicles of epithelioid or spindle cells, usually surrounded by melanophages. The tumor infiltrates deeply along neurovascular bundles and adnexal structures, many times involving the subcutaneus fat. At low power, the infiltrating component can look very atypical. At higher power the cells lack the classic malignant features such as nuclear hyperchromasia, cellular pleomorphism and mitotic figures (Fig. 1-4)
Malignant melanoma with deep penetrating features shows obvious cytological malignant features, such as pleomorphic and hyperchromatic nuclei with clumped chromatin, large red nucleoli and atypical dermal mitoses. The architectural characteristics that point in the direction of malignancy are fusion of nests, large expansile nests in the deepest parts of the tumor, the loss of the Grenz zone and the erosion of the epidermis and other adnexal structures. Lymphovascular and neural invasion should also prompt a closer evaluation.

When these malignant features are present, it is recommended that the lesion be treated as melanoma, with appropriate excision and sentinel lymph node biopsy when indicated. There have been anecdotal reports of “metastasizing” deep penetrating nevi, but larger and more systematic studies with prolonged follow up are needed to establish the true nature of these lesions.

Routine immuno-stains such as S100, Mart-1, Melan-A, HMB45, are usually not helpful in distinguishing DPN from malignant melanoma or other benign nevi with overlapping features (1, 3). Ki-67 may be helpful, but it has a low sensitivity and it cannot be interpreted outside the morphological context. A possibly useful antibody to help in distinguishing DPN from cellular blue nevi, Spitz nevi and congenital nevi is the anti-MAGE B57 antibody. MAGE is part of the cancer testis antigen family and is normally expressed only in the testis, the placenta and during skin wound repair. Melanomas are positive for this antigen in about 25 to 40% of the cases. Interestingly, DPN nevi and clonal nevi, which may represent a superficial variant of the DPN (4), are often focally positive while cellular blue nevi, Spitz nevi and congenital nevi are mostly negative (5). This phenomenon is more of academic interest than practical usefulness and further studies would be needed to validate this observation.
A number of special immunoenzymatic stains and other molecular biology techniques, such as in situ hybridization, have been proposed to help in correctly distinguish benign lesions such as DPN from MM. Loss of dipeptil peptidase IV expression by IHC was reported to be specific for malignant lesions by Roesch and colleagues (6). Up regulation of ATM protein was also shown to correlate with malignant transformation in a very small sample of DPN and malignant melanomas (7).
Analysis of chromosomal aberrations by FISH has been suggested as an ancillary tool for the distinction of benign and malignant melanocytic proliferation (8). The use of four FISH probes targeting frequently altered genetic loci in melanoma cells was reported to have 86.7% specificity and 95.4% specificity in correctly classifying the nature of the lesion in a test cohort of 169 unequivocal nevi and melanoma. An identical experimental approach was later used to help with the classification of mitotically active nevi versus melanoma (9). Again, the use of the four-probe FISH approach proved to be very effective. However, whether this technique could be use to reliably discriminate ambiguous lesions remains to be tested. The aforementioned studies validated the technique by using cases that were unequivocal based on morphology alone or, for a very small sample, based on poor clinical course.


Treatment:
The treatment of choice for these lesions is complete surgical removal. If the biopsy does not contain the entire lesion one may wish to conservatively re-excise to fully evaluate the lesion and prevent recurrence. Another option would be to follow up the site and only re-excise if the lesion should recur.

Bibliography:
  • Seab JA, Jr., Graham JH, Helwig EB. Deep penetrating nevus. The American journal of surgical pathology 1989;13(1):39-44.
  • Robson A, Morley-Quante M, Hempel H, McKee PH, Calonje E. Deep penetrating naevus: clinicopathological study of 31 cases with further delineation of histological features allowing distinction from other pigmented benign melanocytic lesions and melanoma. Histopathology 2003;43(6):529-37.
  • Skelton HG, 3rd, Smith KJ, Barrett TL, Lupton GP, Graham JH. HMB-45 staining in benign and malignant melanocytic lesions. A reflection of cellular activation. The American Journal of dermatopathology 1991;13(6):543-50
  • High WA, Alanen KW, Golitz LE. Is melanocytic nevus with focal atypical epithelioid components (clonal nevus) a superficial variant of deep penetrating nevus? Journal of the American Academy of Dermatology 2006;55(3):460-6.
  • Kazakov DV, Kutzner H, Rutten A, et al. The anti-MAGE antibody B57 as a diagnostic marker in melanocytic lesions. The American Journal of dermatopathology 2004;26(2):102-7.
  • Roesch A, Wittschier S, Becker B, Landthaler M, Vogt T. Loss of dipeptidyl peptidase IV immunostaining discriminates malignant melanomas from deep penetrating nevi. Mod Pathol 2006;19(10):1378-85.
  • Roesch A, Becker B, Bentink S, et al. Ataxia telangiectasia-mutated gene is a possible biomarker for discrimination of infiltrative deep penetrating nevi and metastatic vertical growth phase melanoma. Cancer Epidemiol Biomarkers Prev 2007;16(11):2486-90.
  • Gerami P, Jewell SS, Morrison LE, et al. Fluorescence in situ hybridization (FISH) as an ancillary diagnostic tool in the diagnosis of melanoma. The American journal of surgical pathology 2009;33(8):1146-56.
  • Gerami P, Wass A, Mafee M, Fang Y, Pulitzer MP, Busam KJ. Fluorescence in situ hybridization for distinguishing nevoid melanomas from mitotically active nevi. The American journal of surgical pathology 2009;33(12):1783-8.
     

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