Two for one! (VII)
Usually, a section of tissue that comes into a dermatopathology laboratory is “signed out” with just one diagnosis. Sometimes, however, more than one disease may be present in a specimen, and those conditions may either exist next to each other or they may overlap each other in a manner that makes it difficult to come to a specific diagnosis.
The biopsy shown in Figures 1-18 comes from the arm of a 37-year-old woman. It had clinically been a redbrown papule. What is your diagnosis of this lesion? Or, is there more than one disease to be diagnosed in this specimen?
What is your diagnosis?
Answer and explanation
Spitz nevus and lichen planus.
In the photomicrographs shown here, a relatively well- circumscribed pigmented lesion is seen. The epidermis is unevenly acanthotic and there is hypergranulosis and compact hyperkeratosis. Nests of epithelioid melanocytes are placed at the base of rete ridges and in the superficial dermis. Melanocytes have large nuclei sometimes with prominent nucleoli. Nests are relatively even in size but in foci, they become confluent. In other foci, single melanocytes predominate along the dermo-epidermal junction. A few melanocytes are present in suprabasal layers. Eosinophilic globules, so-called Kamino bodies, are present in the epidermis. An inflammatory infiltrate together with melanophages is accompanying. These changes are diagnostic of a Spitz nevus.
While acanthosis, hypergranulosis, and hyperkeratosis and an infiltrate of lymphocytes are typical of a Spitz nevus, some features in this specimen are unusual: There is a jagged appearance of the rete ridges. Vacuolar alteration and numerous necrotic keratinocytes are present at the dermo-epidermal junction. The infiltrate of lymphocytes is band-like and obscures the dermo-epidermal junction. These findings are diagnostic of lichen planus.
Spitz nevus, described in 1948 by Sophie Spitz in her famous article “Melanomas of childhood” is a relatively uncommon melanocytic lesion. It is usually described as a solitary, asymptomatic, red, pink, or flesh colored, dome shaped, hairless nodule observed in children or young adults. There is considerable variation in clinical morphology; pigmented variants (among young adults)  angiomatous, eruptive (agminated),[6,7] pendulating and verrucous  forms have been described. In a recent large study of 349 Spitz nevi, 40% of the patients were 15 years old and younger with a male to female ratio of 1:1. Among patients older than 15 years, there was striking female predominance with a male to female ratio of 1:3. In fact, the incidence of Spitz nevi in the general population is unknown. Epidemiological data exist only on excised lesions and depends on the source.[2,3]
Spitz nevi are usually located on the face, especially cheeks, head, neck, lower and upper extremities, less commonly they are found on the back and other sites. However, they can appear anywhere, i.e., some rare localizations like genital  and oral mucosa  have been described.
Typically, Spitz nevus presents as a junctional, compound, or intradermal lesion which is sharply circumscribed and measuring less than 1 cm in diameter. Histopathologically, it is symmetrical and consists of large epithelioid and /or spindle melanocytes in different proportions. At the dermo-epidermal junction, the cells are arranged in nests or fascicles with vertical orientation at the base of elongated rete ridges.[13,14] In the dermis, melanocytes may be present in nests and fascicles and, towards the base of the lesion, single cells are present between the collagen bundles. The overlying epidermis frequently shows pseudoepitheliomatous hyperplasia, the stroma might be edematous (especially in the upper part of the dermis), and there are eosinophilic amorphous globules (Kamino bodies) in the epidermis. Kamino bodies are similar morphologically to necrotic keratinocytes (Civatte bodies) of lichen planus but they show positive reaction with type IV collagen and / or laminin because they consist of basement membrane material. Necrotic keratinocytes of the interface dermatitis of lichen planus, however, stain positive with cytokeratine antibodies. 
In the large study of Spitz nevi mentioned above, the authors found that “the constitution by epithelioid and/or spindled cells was the only histopathological finding present in 100% of cases.” Other findings studied were, from more to less frequent: maturation (72%), inflammatory infiltrate (70%), epidermal hyperplasia (66%), melanin (50%), telangiectasias (40%), Kamino bodies (34%), desmoplastic stroma (26%), mitosis (23%), pagetoid extension (13%), and hyalinization of the stroma (8%), which was was the only histopathological parameter that was statistically more frequent in adults than in children.
Lichen planus (LP) is an immunologcally mediated disease. However, genetic factors may also play a role as an association with certain HLA-types and presence of the disease in identical twins have been documented.[18,19,20] An epidemiologic association of LP with hepatitis C infection among the population of Italy, Japan, Spain, France, and Pakistan has beed decribed although such association has not ben report in populations of Northern Europe, USA, or Nepal. The higher incidence of certain HLA antigens (HLA-DR6) among mediteranian populations migh be a possible explanation for the association. Genetic reseach has shown that cutaneous and purely mucosal LP migh have a different pathogenesis. Up to 97% of patients with purely oral LP benefit from removal of mercuray dental amalgam, however only 28-39% of patients had postitive patch tests on amalgam or anogranic mercury. The incidence of LP varies from 0.38% to 1.2% worldwide, without racial predisposition.
Clinical lesions of LP are polygonal, flat-topped, shiny, dark red to violaceus papules, measuring a few mm in diameter and retaining the skin lines. Papules of LP are usually very itchy and the Koebner phenomenon is positive. White lines known as Wickham’s striae are seen especially well on mucous membranes. Sites of predilection are the lower back, ankles, flexural sites of wrists, oral mucosa, dorsum of penile shaft, and labia majora. The association of erosive LP of vulva and vagina with desquamative gingivitis has been termed as vulvaginal-gingival syndrome. There are not many diseases in dermatology with such variety in clinical appearances as typical of LP, i.e., annular, linear, atrophic, pigmented, hypertrophic, guttate, follicular, bullous, ulcerated, and purely mucosal forms. Involvement of the nails can lead to their complete destruction and lichen planopilaris might end with permanent alopecia.
Histopathologically, typical lesions of LP show irregular acanthosis of the epidermis with focal “V”-shaped hypergranulosis topped by hyperkeratosis which corresponds with the striae of Wickham seen clinically. At the dermo-epidermal junction, vacuolar alteration and necrotic keratinocytes are seen and rete ridges may show saw tooth appearance. Confluence of vacuolar alteration and necrosis may lead to formation of a subepidermal separation, the Max-Joseph space. A dense, band like, infiltrate consisting of lymphocytes and histiocytes obscures the dermo-epidermal junction. Epidermal melanocytes are absent or considerably reduced in number while many melanophages in the dermis are a characteristic finding.
The diagnosis of LP in this patient was confirmed by a second biopsy taken from a typical papule of LP. The patient had presented herself with itchy papules on the wrists and the lumbosacral region.
Differential diagnoses to be considered in this particular specimen are melanoma, halo nevus, and Meyerson nevus. At scanning magnification, the melanocytic lesion seen here seems to be asymmetric, but on closer view and with the assist of Melan A staining, a nest-like structure on the right side of the specimen is caused by the interface dermatitis of LP and the melanocytic lesion itself is symmetric (Figs. 19A-C). Pagetoid spread and pleomorphism of melanocytes are present in both, melanoma and Spitz nevus, and cannot be used for differentiation between the two. In a halo nevus, an infiltrate may obscure the melanocytic lesion almost entirely but marked interface changes are not a typical feature. The infiltrate in halo nevi may have granulomatous features which are not seen in LP. In a Meyerson nevus, epidermal changes consist of spongiosis and not of interface changes and the dermal infiltrate often houses eosinophils.
Staining with Melan A.
Graft versus host disease (GVHD) might be difficult to differentiate from LP. The changes at the dermo-epidermal junction closely resemble LP. However, the infiltrate in GVHD is not so dense and may contain eosinophils. The epidermis may shows acanthosis, hypergranulosis and hyperkeratosis. The dermal collagen often appears thickened and numerous melanophages are housed in the papillary dermis. GVHD is often associated with decreased numbers of melanocytic nevi.
A rare but well documented phenomenon is the appearance of eruptive melanocytic nevi (MN), sometimes hundreds of them often in grouped distribution  among patients with severe bullous diseases. Histopathologically, the lesions are mostly compound nevi, but some of them show architectural irregularity and/or cytologic pleomorphism.[27,28] Eruption of melanocytic nevi was described in association with erythema multiforme  and Stevens-Johnson syndome,[27,30] epidermolysis bullosa,[31,36] and Lyell syndrome.[32,33] Spitz nevi, however, have not been described with such association. The pathogenesis of the phenomenon is not fully understood. Some authors suggested that during epidermal regeneration specific cytokines and growth factors are secreted, leading to epithelial regeneration and melanocytic proliferation.[30,34,35] Several growth factors and individual melanocytes were found in blister fluid overlying an eruptive nevus which arise on epidermolysis bullosa lesion. Eruptive MN have also been described in association with chronic immunosuppression and they probably have different pathogenesis.[37,38] It seems that immunodeficiency itself and not the type of immunosuppression plays a role in development of eruptive MN.
This specimen illustrates that the coincidence of two diseases, one neoplastic, and one inflammatory, can sometimes pose difficulties in interpretation. In this specific setting, the morphologic similarities between Kamino bodies and necrotic keratinocytes make it difficult to be sure, that eosinophilic globules in the spinous zone really are Kamino bodies. Staining with basement membrane material antibodies may help to clarify. Moreover, the interface dermatitis of lichen planus forms nest-like structures consisting of necrotic keratinocytes and lymphocytes which simulate an asymmetric silhouette of the melanocytic proliferation at scanning magnification. Staining with Melan A highlights the symmetry of the Spitz nevus while the cells in the nest-like structures of an interface dermatitis are negative with Melan A.
While some inflammatory diseases of the skin such as bullous diseases, erythema multiforme, and Lyell syndrome have been reported to cause eruptive onset of melanocytic nevi, the presence together of Spitz nevus and lichen planus in this case is mere coincidence.
Usually, a section of tissue that comes into a dermatopathology laboratory is “signed out” with just one diagnosis. Sometimes, however, more than one disease may be present in a specimen, and those conditions may either exist next to each other or they may overlap each other in a manner that makes it difficult to come to a specific diagnosis. Here, an excisional specimen of a Spitz nevus is presented in which features of lichen planus are present, too.
Lichen planus and Spitz nevi have in common hypergranulosis and compact orthokeratosis as well as a dermal infiltrate. Interface changes, however, are not seen in Spitz nevi. The interface changes of lichen planus in this patient make it more difficult to interpret eosinophilic globules in the epidermis and symmetry and circumscription of the melanocytic lesion. Diagnoses and differential diagnoses are discussed. While some inflammatory diseases of the skin such as bullous diseases, erythema multiforme, and Lyell syndrome have been reported to cause eruptive onset of melanocytic nevi, the presence together of Spitz nevus and lichen planus in this case is mere coincidence.
Aida Kapetanovic, M.D., is from the Department of Dermatology, Clinical Center of the University in Sarajevo, Bosnia and Herzegovina. This article was reviewed by Almut Böer-Auer, M.D. Contact author via email: email@example.com .
1. Spitz S. Melanomas of childhood. Am J Pathol.1948;24:591-609.
2. Weedon D, Little J. Spindle and epitheloid cell nevi in children and adults: A review of 211 cases of Spitz nevus. Cancer. 1977;40:217-225.
3. Wolff K, Johnson RA (eds). Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 6 edition. New York City: The McGraw-Hill Companies, 2009, pp 188.
4. Echevarria R, Ackerman IV. Spindle and epitheloid nevi in the adult: Clinicopathologic report of 26 cases. Cancer. 1967; 20:1756-189.
5. Tetzlaff MT, Xu X, Elder DE, Elenitsas R. Angiomatoid Spitz nevus: a clinicopathological study of six cases and a review of the literature. J Cutan Pathol. 2009;36(4):471-6.
6. Aida K, Monia K, Ahlem S, Dominique HT, Becima F, Sylvie F, Ridha KM. Agminated Spitz nevi arising on a nevus spilus after chemotherapy. Pediatr Dermatol. 2010 ;27(4):411-3.
7. Levy RM, Ming ME, Shapiro M, Tucker M, Guerry D 4th, Cirillo-Hyland VA, Elenitsas R. Eruptive disseminated Spitz nevi. J Am Acad Dermatol. 2007;57(3):519-23.
8. Kopf A, Andrade R. Benign juvenile melanoma. In: Kopf A, Andrade R (eds). Yearbook of Dermatology 1965-1966. Chicago: Year Book Medical Publishers, 1966, pp 7-52.
9. Requena C, Requena L, Kutzner H, Sánchez Yus E. Spitz nevus: a clinicopathological study of 349 cases. Am J Dermatopathol. 2009;31(2):107-16.
10. Peters M, Goellner J: Spitz nevi and malignant melanomas of children and adolescence. Histopathology. 1986;10:1289-1302.
11. Polat M, Topcuoglu MA, Tahtaci Y, Hapa A, Yilmaz F. Spitz nevus of the genital mucosa. Indian J Dermatol Venereol Leprol. 2009;75(2):167-9.
12. Zätterström U, Thor A, Nordgren H. Cervical metastasis from Spitz nevus of the buccal mucosa. Melanoma Res. 2008;18(1):36-9.
13. Piepkorn M. On the nature of histologic observations: the case of the Spitz nevus. Report of three cases. Arch Dermatol. 1979;115: 1416-1420.
14. Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle and /or epitheloid cells (Spitz nevus). Arch Dermatol.1978; 1811-1823.
15. Edwards SL, Blessing K. Problematic pigmented lesions: approach to diagnosis. J Clin Pathol. 2000;53:409-418.
16. Skelton HG, Miller ML, Lupton GP, Smith KJ. Eosinophilic globules in spindle cell and epithelioid cell nevi: composition and possible origin. Am J Dermatopathol. 1998; 20(6):547-50.
17. Shiohara T. The lichenoid tissue reactions. An immunological perspective. Am J Dermathopathol. 1988;10:252-6.
18. Gibstine CF, Esterly NB. Lichen planus in monozygotic twins. Arch Dermatol 1984;120: 580.
19. Graells J, Notario J, Badia F. Lichen planus in monozygotic twins. Clin Exp Dermatol. 1998;23:299.
20. Lowe NJ, Cudworth AG, Woodrow JC. HLA antigens in lichen planus. Br J Dermatol. 1976;95: 169 -71.
21. Breathnach SM, Black MM. Lichen planus et lichenoid disorders. In: Burns T, Breathnach S, Cox N, Griffiths C (eds). Rook’s Textbook of Dermatology, 7th edition. Oxford: Blackwell Science, 2004 pp 42.1-42.2.
22. Nasa GL, Cottoni F, Mulargia M et al. HLA antigen distribution in different clinical subgroups demonstrates genetic heterogenity in lichen planus. Br J Dermatol. 1955;132:897-900.
23. Rogers RS III, Eisen D. Erosive oral lichen planus with genital lesions: the vulvovaginal-gingival yndrome and the peno-gingival syndrome. Dermatol Clin. 2003; 21:91-8.
24. Gupta SN, Palceski D. Lichen planopilaris presenting as truncal alopecia: a case presentation and review of the literature. Cutis. 2003;72:63-6.
25. Andreani V, Richard MA, Blaise D, et al. Naevi in allogeneic bone marrow transplantation recipients: the effect of graft-versus-host disease on naevi. Br J Dermatol. 2002;147:433-41.
26. Shulman JM , Sale GE, Lerner KG, et al. Chronic cutaneous graft-versus-host disease in man. Am J Pathol. 1978;91: 545-70.
27. Gelfer A, Rivers JK. Long-term following-up of a patient with eruptive melanocityc nevi after Stevens-Johnson syndrome. Arch Dermatol. 2007;143:1555-1557.
28. Kopf AW, Grupper C, Baer RL, Mitchell JC. Eruptive nevocytic nevi after severe bullous disease. Arch Dermatol. 1977;113(8):1080-4.
29. Soltani K, Bernstein JE, Lorincz AL. Eruptive nevocytic nevi following erythema multiforme. J Am Acad Dermatol. 1979;1(6):503-5.
30. Shoji T, Cockerell CJ, Koff AB, Bhawan J. Eruptive melanocytic nevi after Stevens-Johnson syndrome. J Am Acad Dermatol. 1997;37(2 Pt 2):337-9.
31. Bauer JW, Schaeppi H, Kaserer C, Hantich B, Hintner H. Large melanocytic nevi in hereditary epidermolysis bullosa. J Am Acad Dermatol. 2001;44(4):577-584.
32. Jullien D, Prévot G, Wolkenstein P, Roujeau JC, Revuz J. Eruptive nevus in the course of Lyell syndrome. Ann Dermatol Venereol. 1995;122(8):540-2.
33. Goerz G, Tsambaos D. Eruptive nevocytic nevi after Lyell’s syndrome. Arch Dermatol. 1978;114(9):1400-1.
34. Firooz A, Komeili A, Dowlati Y. Eruptive melanocytic nevi and cherry angiomas secondary to exposure to sulfur mustard gas. J Am Acad Dermatol. 1999;40(4):646-647.
35. Richert S, Bloom E, Flynn K, Seraly M. Widespread eruptive dermal and atypicalmelanocytic nevi in association with chronic myelocytic leukemia: case report and review of the literature. J Am Acad Dermatol. 1996;35(2 pt 2):326-329.
36. Lanschuetzer CM, Emberger M, Hametner R, et al. Pathogenic mechanisms in epidermolysis bullosa naevi. Acta Derm Venereol. 2003;83(5):332-337.
37. Bovenschen HJ, Tijoe M, Vermaat H, et al. Induction of eruptive benign melanocytic naevi by immune suppressive agents, including biologicals. Br J Dermatol.2006;154(5):880-886.
38. Grob JJ, Bastuji-Garin S, Vaillant L, et al. Excess of nevi related to immunodeficiency:a study in HIV-infected patients and renal transplant recipients. J Invest Dermatol. 1996;107(5):694-697.