Signalment:  

Unknown age and gender, guinea pig, (Cavia porcellus).The animal developed a skin tumor of 1 cm in diameter at the right flank. The mass was completely resected. Unfortunately, further clinical data were not available.


Gross Description:  

A 2 x 1 cm skin sample was submitted for histopathologic examination. Centrally there was a well-demarcated, 1 x 1 cm partially exophytic firm nodule. The cut surface was light brown.


Histopathologic Description:

Haired skin: Elevating an ulcerated epidermis and infiltrating into the underlying dermis (in some slides, tumor overlies an intact epidermis) is densely cellular, well-demarcated, exophytic, partly infiltrative and ulcerated, unencapsulated neoplasm composed of sheets of pleomorphic round cells within a scant fibrovascular stroma. Neoplastic cells are round to polygonal, up to 40 um in diameter with variable distinct cell borders and moderate amounts of eosinophilic cytoplasm. Nuclei are round to oval, centrally located with finely stippled chromatin and up to four prominent magenta nucleoli. Mitoses average 2-3 per high power field (some bizarre) and cells show moderate anisocytosis and anisokaryosis. Occasionally, vascular invasion of tumor cells can be observed (not in all slides). There are multifocal hemorrhages within and around the tumor and hemorrhagic and serocellular crusts at the ulcerated surface. The adjacent skin is hyperplastic with a moderate perivascular infiltration with lymphocytes, plasma cells, and few heterophils.


Morphologic Diagnosis:  

Haired skin: Amelanotic malignant melanoma, guinea pig, Cavia porcellus


Lab Results:  

Immuno-histochemically the neoplastic cells were positive for Melan-A and PNL2.


Condition:  

Amelanotic melanoma


Contributor Comment:  

Melanomas are described in a variety of animal species including domestic animals and wildlife species. However, they are most common in dogs, horses and some breed of swine10, only few reports of melanoma in birds, laboratory animals and more recently in reptiles exist.6,16 The histologic diagnosis of melanoma is complicated due to variable degree of pigmentation and the high variability of cell shapes. With the help of immunohistochemistry, most amelanotic melanoma can be routinely diagnosed.3,4,10

With our case, we present a well-known neoplasm in an unusual species. Case reports of spontaneous melanoma in the guinea pig are extremely rare, but the guinea pig is a well-defined model of experimental melanoma using the potent carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), a polycyclic aromatic hydrocarbon.7 This substance is proven to transform cells in different oncogenic pathways.2

Mutations that affect cell cycle control (p16/INK4a, CDK4), pro-growth pathways (growth factor receptors, RAS, BRAF), and telomerase were identified in the patho-genesis of malignant melanoma. Furthermore, melanomas can be inherited, and UV light-induced DNA damage plays a role as do other factors.8 The most common naturally occurring skin tumors in guinea pigs are trichofolliculomas. They are a subtype of trichoepithelioma and occur as expansible, often centrally cystic neoplasia in the skin often of the lumbosacral region.13,15,18 Other tumors, like fibrosarcoma, lipoma, sebaceous gland adenoma, and hemangioma were also reported in this species.

In this melanoma, there is abundant vascularity. As observed in other species5,12 the amount of blood vessels may be a prognostic factor for this neoplasia in guinea pigs, and particularly mast cells may play a significant role in angiogenesis as the major source of VEGF.1Unfortunately, further information regarding the clinical course of the presented case was not available.


JPC Diagnosis:  

Haired skin: Amelanotic melanoma, guinea pig, Cavia porcellus.


Conference Comment:  

Melanocytic neoplasms arise from melanocytes or melanoblasts which are derived from the neural crest ectoderm. As mentioned by the contributor, melanomas have been identified in most veterinary species and humans. The histologic diagnosis of melanomas is sometimes complicated due to the variability of pigmentation and arrangement of neoplastic cells into clear cells (balloon cell), spindle cell, epithelioid cell, and signet ring cell histomorphology.10 Additionally, there are often multiple different tumor cell morphologies within a single neoplasm. For this reason, melanomas are sometimes referred to as one of the “great imitators” due to their common embryologic connection with both neural and epithelial origin.10

This case nicely demonstrates this point, due to variation in round to polygonal cellular appearance across various regions of the neoplasm. Despite the rarity of melanocytic neoplasms in guinea pigs and the lack of melanin granularity in this case, most conference participants included amelanotic melanoma high within their differential diagnosis. Prior to the conference, the Joint Pathology Center ran the histochemical stain Fontana-Masson and immuno-histochemical stains melan-A and S100. The Fontana-Masson stain highlighted multifocal positive argentaffin granules and melanin within the cytoplasm of neoplastic cells. Additionally, neoplastic cells are immunopositive for S100 and melan-A red, confirming the diagnosis of an amelanotic melanoma, in this case.

As mentioned by the contributor, trichofolliculomas are the most common tumor in the skin of guinea pigs; although, spontaneous neoplasms in this species are rare in animals under three years old.13 These benign dome-shaped subcutaneous nodules, typically less than 2cm in diameter, most commonly occur along the dorsal lumbar region and may represent a hamartomatous rather than a neoplastic process.10,13 Trichofolliculoma development is thought to occur secondary to inhibition of bone morphogenic protein (BMP), an important tumor suppressor gene.13,14,18 Studies indicate that BMP plays a critical role in maintaining homeostasis of hair follicles and regulation of skin develop-ment.14 In addition, BMP is an important growth factor for a variety of tissues throughout the body and its con-centration is tightly regulated in health. Interestingly, recent research in humans have shown that absence of BMP signaling leads to the progression of colorectal carcinoma; conversely, overexpression of BMP signaling induces epithelial-mesenchymal transition, tumor invasion, and metastasis in a variety of malignant neoplasms.9,11,14


References:

1. Ch'ng S, Wallis RA, Yuan L, Davis PF, Tan ST. Mast cells and cutaneous malignancies. Mod Pathol. 2006; 19(1):149-159.
2. Currier N, Solomon SE, Demicco EG, Chang DL, Farago M, Ying H, Dominguez I, Sonenshein GE, Cardiff RD, Xiao ZX, Sherr DH, Seldin DC. Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors. Toxicol Pathol. 2005;33(6):726-37.
3. Goldschmidt MH, Dunstan RW, Stannard AA, Tscharner CV, et al. Histological classification of epithelial and melanocytic tumors of the skin of domestic animals. Vol III. 2nd series. Washington D.C.: Armed Forces Institute of Pathology. 1998.
4. Goldschmidt MH, Hendrick MJ. Tumors of the skin and soft tissue. In: Meuten DJ, ed. Tumors in Domestic Animals. 4th Ed. Ames, IA, USA: Blackwell Publishing; 2002:45-117.
5. Gregório H, Raposo TP, Queiroga FL, Prada J, Pires I. Investigating associations of cyclooxygenase-2 expression with angiogenesis, proliferation, macrophage and T-lymphocyte infiltration in canine melanocytic tumours. Melanoma Res. 2016; 26(4):338-347.
6. Heckers KO, Schmidt V, Krastel D, Hildebrandt G, Kiefer I, Pees M. Malignant melanophoroma in a Hermann's tortoise (Testudo hermanni). A case report. Tierarztl Prax (K) 2011; 39:45-50.
7. Ingram AJ. Review of chemical and UV light-induced melanomas in experimental animals in relation to human melanoma incidence. J Appl Toxicol. 1992; 12(1):39-43.
8. Lazar AJF, Murphy GF. The skin. In: Kumar Abbas Aster Robbins and Cotran. Pathologic basis of disease. 9th Edition. Philadelphia, PA, Elsevier Saunders. 2015. 1147-1150.
9. Kan L, Liu Y, et al. Inhibition of BMP signaling in P-cadherin positive hair progenitor cells leads to tricho-folliculoma-like hair follicle neoplasms. J Biomed Sci. 2011; 14:92.
10. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. 6th ed. Vol 1. Elsevier, St. Louis, Missouri; 2016:705,720-736.
11. Owens p, Pickup MW, et al. Inhibition of BMP signaling suppresses metastasis in mammary cancer. Oncogene. 2015; 34:2437-2449.
12. Pastushenko I, Vermeulen PB, Carapeto FJ, Van den Eynden G, Rutten A, Ara M, Dirix LY, Van Laere S. Blood microvessel density, lymphatic microvessel density and lymphatic invasion in predicting melanoma metastases: systematic review and meta-analysis. Br J Dermatol. 2014; 170(1):66-77.
13. Percy DH, Barthold SW. Pathology of Laboratory Rodents and Rabbits, 4th ed. Ames, IA: Blackwell Publishing; 2016:251.
14. Sharov AA, Mardaryev AN, Sharova TY, Grachtchouk M, Atoyan R, Byers HR, Seykora JT, Overbeek P,  Dlugosz A, Botchkare VA. Bone morphogenetic protein antagonist noggin promotes skin tumorigenesis via stimulation of the Wnt and Shh signaling pathways. Am J Path. 2009; 175(3):1303-1314.
15. Sommerey CC, Köhler K, Reinacher M. Erkrankungen des Meerschweinchens aus Sicht der Pathologie. Tierarztl Prax (K) 2004; 32:377-383.
16. Thompson KA, Campbell M, Levens G, Agnew D. Bilaterally symmetrical oral amelanotic melanoma in a Boa constrictor (Boa constrictor constrictor). J Zoo Wildl Med. 2015; 46(3):629-32.
17. Voorneveld PW, Kodach LL, et al. Loss of SMAD4 alters BMP signaling to promote colorectal cancer cell metastasis via activation of Rho and ROCK. Gastroenterology. 2014; 147:196-208.
18. Williams BH. Non-infectious disease. III Guinea pigs. In: Suckow MA, Stevens KA, Wilson RP. The laboratory rabbit, guinea pig, hamster and other rodents. First Edition. London, Waltham, MA, San Diego, CA. Elsevier, Academic press, 2012, 685-704.


Click the slide to view.



2-1. Haired skin, rabbit.


2-2. Haired skin, rabbit.



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