Predominant formation of heavily pigmented dermal melanocytomas resembling 'animal-type' melanomas in hepatocyte growth factor (C57BL/6 x C3H)F1 mice following neonatal UV irradiation

Abstract

Background: Transgenic mice expressing hepatocyte growth factor (HGF) develop cutaneous melanocytic tumors following neonatal UV exposure. Here, we examined the histologic spectrum of UV-induced melanocytic tumors in HGF mice on a pigmented (C57BL/6 x C3H/HeN)F(1) background.

Methods: Neonatally irradiated (4000 J/m(2)) mice were monitored for 43 weeks, and 31/34 (91%) animals developed a total of 163 melanocytic tumors.

Results: Of 54 primary tumors analyzed, most (49/54, 91%) demonstrated exclusively dermal collections of epithelioid cells with voluminous densely pigmented cytoplasm. Seven of these also demonstrated a population of spindled cells with mitoses. Several (3/54, 6%) tumors exhibited a junctional component with melanocytes present in the epidermis. Staining with PEP8 confirmed the presence of interfollicular melanocytes at the dermal-epidermal junction in neonatal skin.

Conclusions: In contrast to HGF animals on an albino (FVB) background, HGF animals on the pigmented (C57BL/6 x C3H/HeN)F(1) background do not develop classic radial growth phase melanoma but rather predominantly develop dermal melanocytomas resembling the 'animal-type' melanoma occasionally seen in humans. These results demonstrate the influence of genetic background on histologic pattern of UV-induced melanomas in mice.

Figure 1

Dermal melanocytosis in skin and early UV-induced tumor from adult HGF (C57BL/6xC3H)F₁ mice. H&E-stained sections of skin from (A) untreated and (B) UV-irradiated (neonatally) HGF (C57BL/6xC3H)F₁ mouse, both showing dermal infiltration of pigmented cells. Original magnification, x200. (C) H&E-stained section of skin from UV-irradiated (neonatally) non-transgenic (C57BL/6xC3H)F₁ mouse, lacking dermal pigmented cells. Original magnification, x200. (D) H&E-stained sections of an early developing tumor in UV-irradiated (neonatally) HGF (C57BL/6xC3H)F₁ mouse, showing dermal aggregates of pigmented cells. Original magnification, x100.

Figure 2

Striking similarity of UV-induced tumors in HGF (C57BL/6xC3H)F₁ mice and EBN. Histology of a UV-induced dermal melanocytoma arising in a HGF (C57BL/6xC3H)F₁ mouse (left panel) and an EBN excised from a 8 year-old child (right panel). (A, B) H&E-stained sections, showing dermal infiltration of pigmented cells. Original magnification, x40. (C, D) H&E-stained sections, showing highly pigmented tumor cells. Original magnification, x400. (E, F) Melanin-bleached sections, revealing large bland histiocytic-like cells. Original magnification, x400.

Figure 3

Histology of UV-induced tumors in HGF (C57BL/6xC3H)F₁ mice. H&E-stained sections of tumors demonstrating (A) dermal melanocytosis, original magnification x400, with isolated epidermal melanocyte overlying tumor (arrow); (B) spindled tumor composed of epithelioid and pigmented cells, original magnification x400, with mitotic figures (arrow); (C) pigmented tumor with junctional involvement, original magnification x200. (D) amelanotic tumor consistent with sarcoma, original magnification x200.

Figure 4

Melanocyte distribution in neonatal HGF (C57BL/6xC3H)F₁ skin. Skin was harvested from 2-day-old HGF (C57BL/6xC3H)F₁ (left panel) and (C57BL/6xC3H)F₁ (right panel) mice and stained as indicated. (A, B) H&E-stained sections. Original magnification, x100. (C, D) Fontana-Masson. Original magnification, x100. (E, F) PEP8 staining of separate bleached sections. Original magnification, x100.