Demonstration of HPV 24 in long-standing Heck’s disease with malignant transformation

ARTICLE

Heck's disease, which is also known as "focal epithelial hyperplasia" and "hyperplasia multilocularis mucosae oris", was first described in 1965 by Archard et al. as an entity among younger Eskimos and Indians with reference to the first observation by Heck in 1963. The appearance of this disease among Europeans and elderly people is rare, family history and endemic occurrence are possible [1-4]. The viral genesis is exemplified by HPV-DNA evidence in oral lesions. HPV 13 and HPV 32 are associated with Heck's disease [5, 6].

We report on the rare and unusual case of Heck's disease in a 64-year-old European woman with an HPV-associated malignant transformation.

Case report

The 64-year-old patient presented for the first time at the clinic in 1997. The oral mucosa showed whitish, cauliflowerlike, papillomatous vegetations, which stretched to the corner of the mouth buccally on the right side. They were partly pediculate, partly resting in a wide basis with a fissured surface (Fig. 1). The cheek mucosa on the left side was free of any lesions.

In 1979 a whitish striation in the cheek mucosa on the right side had appeared for the first time, it was treated antimycotically. In 1993 an excision of papillomatous vegetations on the right side was performed. Histologically a benign, apparently virus-induced papillomato-squamous epithelium hyperplasia developed. After some months a relapse occurred. In 1994 another excision was performed. The histological finding was the same, with chronic inflammation and detection of candida-superinfection. After several weeks a second relapse occurred. At that time the patient refused any therapy.

Stomatological history: the patient had partial dentures since she was 36; periodental illness; no nicotine and alcohol abuse.

The paraclinical findings did not indicate any cellular or humoral immuno-deficiency, apart from an anergic recall-antigen-test. The PAS stain showed strong mycotic superinfection.

The histological verification suggested a viral acanthoma of the Heck type. In the exophytically growing part of the tumor, focal carcinomatous proliferations were found (Fig. 2). In the immunohistology, viral particles reacted with the PAN-HPV marker partly intracytoplasmatically, partly intranuclearly (Fig. 3). The electron microscopic analysis at 30.000-fold magnification showed aggregates of condensed viral particles within the nucleus. A cytological smear of the lesion showed a positive amplification for an HPV sequence. The DNA was extracted, consensus PCR with a universal primer MY09/MY011 or HPVL1 was used [7, 8]. Cellular DNA, extracted from a biopsy of the tumor, was amplified by PCR at the Deutsches Krebsforschungszentrum Heidelberg (Fig. 4) using primers within the L1 ORF [9] with modified amplification conditions [9]. The amplified product was cloned and 10 clones subsequently sequenced. Sequences were compared to the L1 DNA sequences of all known HPV types. The presence of HPV-24-DNA was demonstrated.

Based on these findings it was decided to perform radical surgery of the infected mucous area in the buccal planum on the right side. In the course of the same operation the defect was closed with a split-skin graft from the right thigh. Post-operatively a relapse prophylaxis was initiated with acitretin 20 mg/day p.o. and recombinative alpha-interferon 5 mio. IE/3 times a week s.c. The retinoid-dose was subsequently reduced to 10 mg/day because of side effects and we switched to peri- and intratumoral application of natural alpha-interferon 3 times 3 mio.IE/week, due to a circumscribed local relapse of the viral acanthoma at the posterior border of the transplant (Fig. 5). This resulted in a significant regression of the relapse within 12 weeks (Fig. 6).

The remnant tumor, which remained in spite of the INF-therapy, was excised in June 1998. Histologically, however, we found a viral acanthoma and a leukokeratosis without any indication of cellular atypia or infiltrative tumor growth. HPV 20 and HPV 52 were demonstrated in a biopsy from the fringe area.

Discussion

Heck's disease, as first observation by Heck in 1963, is an unusually bland, acquired leukoplakia. It is also referred to as oral focal epithelial hyperplasia and was reported as an entity among Eskimos for the first time by Archard et al. [10] in 1965. Mostly, Heck's disease was found in multiple locations, but it also appears in one region or as isolated lesions [10, 11]. Often HPV 13 and 32 are associated with this disease [5, 6], in rare cases HPV 1 and 18 were demonstrated, in some cases no viral DNA could be detected [12]. The present report is on a case of long-standing Heck's disease changing into a precancerous leukoplakia of the oral mucosa. The most recent histology revealed the transition of a viral acanthoma (Heck's disease) with additional focal transition into an invasive carcinoma. HPV 24 DNA was demonstrated in this lesion.

After surgical treatment, a combined antiviral and antiproliferative therapy with acitretin perorally and alpha-interferon subcutaneously was initiated as a relapse prophylaxis.

Then, in the fringe area of the transplant, a relapse of the viral acanthoma developed, which was largely brought to involution within the space of three months by intralesional injections of interferon-alpha. The tumor remnant was excised in June 1998. Histologically we observed a viral acanthoma without any sign of malignant transformation. HPV 20 and HPV 52 DNA could be amplified by PCR from the tissue of the fringe area.

This case is unusual not only because of a lesion of Heck's disease undergoing malignant transformation, but also because of the presence of HPV 24 DNA.

HPV 24 belongs to the group of HPV types associated with the disease epidermodysplasia verruciformis (EV) [6, 13] and has to date not been associated with malignant lesions, although it has been demonstrated in a dysplastic PUVA keratosis [14] and 3 putative new HPV types closely related to HPV 24, have been demonstrated in a basal cell carcinoma [15] and two intraepidermal carcinomas [7, 16].

HPV 20 and HPV 52 were both demonstrated in a single biopsy taken from the relapse of the viral acanthoma. HPV 20 also belongs to the EV-associated HPV types, whereas HPV 52 is considered as a "high-risk" mucosal HPV type [8]. HPV 20 has recently been demonstrated in a high percentage of non-melanoma skin cancers and has frequently been detected in combination with another HPV type within the same lesion [7].

In summary our case presents therefore the following characteristics: a) transition of a long-standing relapsing viral acanthoma of Heck's type into focal verrucous carcinoma, b) induction of the transformation by HPV 24, c) focal relapse of the viral acanthoma but not the malignant tissue, d) unilocular occurrence.

CONCLUSION

Acknowledgements

The authors are indebted to Dr. med. P. Buhtz, Department of Pathology and Forensic Medicine (Director: Pr. Dr. med. A. Roessner) and Dr. med. B. König, Department of Microbiology (Director: Pr. Dr. med. W. König) of the Otto-von-Guericke-University Magdeburg.

REFERENCES

1. Grußendorf-Conen EJ, Schwarz E. Viral warts in the skin and mucosa: germs, clinic, therapy. Oxford: Blackwell-Verlag, 1995.

2. Hornstein OP. Erkrankung des Mundes: Mouth diseases, an interdiscipinary manual and atlas. Kohlhammer-Verlag, 1996.

3. Syjänen S, Kellokoski J. Oral Manifestations of HPV infections. In: Genital Papillomavirus Infections. Gross G, Jablonska S, Pfister H, Stegner HE, eds. Heidelberg-Berlin: Springer Verlag, 1996: 209-23.

4. Weidner F. Focal epithelial hyperplasia (Heck) in a Turkish family. Dermatology 1996; 47: 927-9.

5. Gross GE, Barrasso R. Human Papilloma Virus Infection. A Clinical Atlas. Ullstein Mosby Verlag, 1997.

6. Majewski S, Jablonska S. Human papillomavirus-associated tumors of the skin and mucosa. J Am Acad Dermatol 1997; 36: 659-85.

7. De Villiers EM, Lavergne D, McLaren K, Benton EC. Prevailing papillomavirus types in non-melanoma carcinomas of the skin in renal allograft recipients. Int J Cancer 1997; 73: 356-61.

8. De Villiers EM. Papillomavirus and HPV typing. Clin Dermatol 1997; 15: 199-206.

9. Berkhout RJM, Tieben LM, Smits HL, Bouwes Bavinck JN, Vermeer BJ, ter Schegget J. Nested approach for detection and typing of epidermodysplasia verruciformis associated human papillomavirus types in cutaneous cancers from renal transplant recipients. J Clin Microbiol 1995; 33: 690-5.

10. Archard HO, Heck JW, Stanley HR. Focal epithelial hyperplasia: an unusual oral mucosal lesion found in Indian children. Am Acad Oral Pathol 1965; 20: 201-12.

11. Knoth W, Boepple D. Hyperplasia multilocularis mucosae oris Heck (Sog. "Focal epithelial hyperplasia"). Z Hautkr 1978; 53: 675-9.

12. Lang E, Zabel M, Ikenberg H. Fokale epitheliale Hyperplasie. Dt Med Wochenschr 1984; 109: 1763-6.

13. Majewski S, Jablonska S. Skin autografts in epidermodysplasia verruciformis human papilloma virus associated cutaneous changes need over 20 years for malignant conversion. Cancer Resarch 1997; 57: 4214-6.

14. Harwood CA, Spink PJ, Surentheran T, Leigh IM, Hawke JLM, Proby CM, Breuer J, Mcgregor JM. Detection of human papillomavirus DNA in PUVA-associated non-melanoma skin cancers. J Invest Dermatol 1998; 111: 123-7.

15. Shamanin V, zur Hausen H, Lavergne D, Proby CM, Leigh IM, Neumann C, Hamm H, Goos G, Haustein UF, Jung EG, Plewig G, Wolff H, de Villiers EM. Human papillomavirus infections in non melanoma skin cancer from renal transplantat recipients and non-immunosupressed patients. J Natl Cancer Inst 1996; 88: 802-11.

16. Astori G, Lavergne D, Benton C, Höckmayr B, Egawa K, Garbe C, de Villiers EM. Human papillomaviruses are commonly found in normal skin of immunocompetent hosts. J Invest Dermatol 1998; 110: 752-5.