5 - Mesenchymal Tumors of the Skin and Soft Tissues

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Mesenchymal Tumors of the Skin and Soft Tissues Mattie J. Hendrick Marshfield Labs, Pennsylvania, USA

Mesenchymal tumors include those tumors arising from the supporting mesenchymal tissues of the dermis and subcutis (fibrous connective tissue, blood vessels, lymphatics, nerves, adipose tissue, and smooth muscle) and those round cell tumors of mesenchymal origin that present as cutaneous masses. The tumors described below comprise a wide range of entities, some of which are of uncertain classification. Various spindle cell and round cell neoplasms are included, but the term tumor is used broadly, and includes non‐neoplastic lesions of clinical importance or interest. These tumors have been classified using the revised International Histological Classification of Skin Tumors and Tumor‐like Lesions of Domestic Animals.1,2 This classification system is similar to that found in several old and new texts that deal with skin tumors.3–6 These references will not be further cited in the text, but they provide extensive information on the clinical aspects and histopathology of skin tumors. Spindle cell tumors of the skin and subcutis comprise a large diverse group but tend to have some features that encompass the group. They are locally expansile or infiltrative, but have low metastatic potential. Many have peripheral compression of their cells, creating a pseudocapsule that can lead to misinterpretation of margins and incomplete excisions. Although various treatment modalities have been employed, wide surgical excision remains the treatment of choice. Recurrence is usually dependent on adequacy of excision, mitotic count, and grade. Spindle cell tumors with excision margins that are free of tumor cells recur in less than 5% of cases. Even when tumor cells are present at the excision margin recurrence is expected in only 25% of the cases (see Appendix). Many grading systems have been used over the years in an attempt to predict the behavior and outcome of skin and soft tissue spindle cell tumors in dogs. Most are flawed, in the opinion of this author, due to low numbers, lack of controls, lack of consistency in Tumors in Domestic Animals, Fifth Edition. Edited by Donald J. Meuten. © 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

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treatment modalities given to the canine patients, and lack of documentation of metastasis. Even in those grading systems that have good quality control, successful prognostication is often hampered by interpathologist discordance and subjectivity. These problems are also seen in grading schemes in human pathology. In an elegant discussion on this subject in the American Journal of Clinical Pathologists,7 the authors state: The main purpose of an effective grading system is to segregate tumors into those with a favorable prognosis and those with a poor prognosis, leaving as few cases as possible in the uninformative intermediate grade 2 category. Ideally, the good prognosis group should encompass all tumors that, while having a propensity for local recurrence, have very low metastatic potential and are amenable to surgical treatment alone. The tumors in the poor prognosis group should include sarcomas likely to metastasize and for which adjuvant therapy might prove beneficial. Apart from this main function, histologic grading also constitutes a vital aspect of the comparison of patient outcomes in clinical trials. … Pathologists must take responsibility for informing and educating clinicians about the problems and present subjectivity of grading. Otherwise, the increasing obsession with selecting treatment based on histologic grade (type often being regarded clinically as irrelevant) can lead only to less sophisticated and less scientific treatment of patients with a soft tissue sarcoma.

Because of the inherent problems and frustration with grading, some veterinary pathologists and training programs are starting to diagnose spindle cell tumors as “Spindle cell tumor, Grade __.” A better approach, exemplified by some recent publications,8 is to try to improve the grading systems. In the Appendix are algorithms and/ or grading schemes modified from these references for your review that are used at North Carolina State University. The future should aim at consistency between pathologists using the same grading system. This author believes that although a good grading system can be valuable, the best predictor of outcome of these tumors is the

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histologic examination and accurate diagnosis of the specific tumor type by an experienced, knowledgeable pathologist. Therein lies the purpose of this chapter.

References

1. Goldschmidt, M.H., Dunstan, R.W., Stannard, A.A., et  al. (1998) World Health Organization International Histologic Classification of Tumors of Domestic Animals. Histological Classification of Tumors of the Skin of Domestic Animals, 2nd series, vol. III. Armed Forces Institute of Pathology, Washington, D.C. 2. Hendrick, M.J., Mahaffey, E.A., Moore, F.M., et al. (1998) World Health Organization International Histologic Classification of Tumors of Domestic Animals. Histological Classification of the Mesenchymal Tumors of Skin and Soft Tissues of Domestic Animals, 2nd series, vol. II. Armed Forces Institute of Pathology, Washington, D.C. 3. Goldschmidt, M.H. and Shofer, F.S. (1998) Skin Tumors of the Dog and Cat. Butterworth Heinemann, Oxford, pp. 1–301. 4. Gross, T.L., Ihrke, P.J., Walder, E.J., and Affolter, V.K. (2005) Veterinary Skin Diseases of the Dog and Cat, 2nd edn. Blackwell Publishing, Ames, pp. 562–893. 5. Scott D.W., Miller W.H., and Griffin, C.E. (2001): Neoplastic and nonneoplastic tumors. 1279–1369. In Small Animal Dermatology, 6th edn. (eds. D.W. Scott, W.H. Miller, and C.E. Griffin): W.B. Saunders, Philadelphia, PA, 1528 pp. 6. Yager, J.A. and Wilcock, B.P. (1994) Color Atlas and Text of Surgical Pathology of the Dog and Cat. Mosby Yearbook, London, pp. 243–303. 7. Brown, F.M. and Fletcher, D.M. (2000) Problems in grading soft tissue sarcomas. Am J Clin Pathol 114(suppl 1):82–89. 8. Dennis, M.M., McSporran, K.D., Bacon, N.J., et  al. (2011) Prognostic factors for cutaneous and subcutaneous soft tissue sarcomas in dogs. Vet Pathol 48: 73–84.

Figure  5.1  Fibroma, skin, canine. Note the dense pattern of repetitive

collagen.

Fibroma

Fibromas are benign neoplasms of fibrocytes with abundant collagenous stroma.

Growth, metastasis, and treatment

Incidence, age, breed, and sex

Keloidal fibroma/fibrosarcoma

Fibromas are uncommon, and are most often seen in the dog.  They  have been reported in cats, but some investigators believe that feline tumors with the histological appearance of fibromas are actually well‐differentiated fibrosarcomas. Canine breeds that are predisposed to the formation of these tumors include Rhodesian ridgebacks, doberman pinschers, and boxers. Fibromas in the skin and subcutis are rare in horses and food ­production animals.1

Site and gross morphology

Fibromas occur most commonly on the limbs and heads of dogs. The majority of tumors are small, round to oval intradermal or subcutaneous masses. They are firm, rubbery, and gray/white on cut surface.

Histological features

Fibroma is a benign, well‐circumscribed but unencapsulated neoplasm. It is composed of mature fibrocytes producing abundant collagen (Figure 5.1). The collagenous fibers are repetitive and are usually arranged in interwoven fascicles, more rarely in whorls. The neoplastic fibrocytes are uniform and low in number compared to the abundant dense collagen. They have oval normochromatic nuclei and an indistinct cytoplasm that blends into the extracellular collagenous stroma. Mitotic figures are rarely observed in fibromas.

Additional diagnostic criteria

Collagenous hamartomas (see below) can be distinguished from fibromas by the haphazard arrangement of the collagen fibers in hamartomas, which is similar to normal collagen, and by their superficial dermal location, which often raises the epidermis.

Fibromas are slow‐growing, and complete excision is curative.

This rare variant of fibroma is unique in that much of the collagen is brightly eosinophilic and hyaline, resembling keloids in humans.

Incidence, age, breed, and sex

These rare tumors are mostly seen in the dog, and can be seen in any breed and at any age. There is a male predominance. Keloidal change in a feline vaccine‐site sarcoma has been reported.2

Site and gross morphology

Most tumors arise on the flank, thorax, or shoulder. Occasionally, multiple tumors arise simultaneously or sequentially. This author has seen multiple sequential tumors in vaccination sites in one dog, suggesting local trauma/wound healing as part of the pathogenesis. Grossly, they can be found in the dermis and/or subcutis, and resemble other fibromas.

Histological features

Keloidal fibromas are well circumscribed but unencapsulated. They are composed of mature fibrocytes producing abundant collagen. However, some of the collagen fibers are wide, bright pink, and shiny (Figure  5.2A,B). There are variable numbers of thin, more normal‐appearing collagen fibers intermingled with the hyalinized ones. Nuclei are more prevalent than in fibromas. Mitotic figures are rarely observed. Malignant variants have been reported,3 based on local infiltration, increased cellular density, nuclear pleomorphism, and mitotic activity, however, metastasis has not been reported.

Growth, metastasis, and treatment

Complete excision for keloidal fibromas and keloid fibrosarcomas is typically curative.

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A

B

Figure 5.2  (A) Keloidal fibroma, skin, canine. (B) Higher magnification of (A) showing smudgy pink “keloid”‐like collagen.

Fibrosarcoma

This malignant neoplasm has variable presentations depending on species, age, site, and etiopathogenesis. Many other neoplasms (e.g., myopericytoma, malignant melanoma, and leiomyosarcoma) can have regions that are consistent with fibrosarcoma, but careful examination of several sections will usually identify areas characteristic of these other tumors.

Incidence, age, breed, sex, and site

Although fibrosarcomas occur in all domestic species, they are most commonly seen in adult and aged cats and dogs (mean age of 9 years). Fibrosarcoma is the most common tumor of the cat and has increased in incidence over the last two decades, most likely because of its association with vaccination (see below). No breed or sex predisposition has been reported in the cat, but in canines golden retrievers and doberman pinschers are at increased risk. Most tumors are focal and can develop anywhere on the body, although head and limbs are most often involved. One exception is the fibrosarcoma of cats that is induced by feline sarcomavirus (FeSV). FeSV is a defective mutant of feline leukemia virus (FeLV); in the presence of FeLV, it can replicate, resulting in oncogenesis. FeSV‐associated tumors can occur in individuals as young as a few months of age, with a mean age of 3 years. They are often multicentric and can metastasize.4 FeSV‐ associated neoplasms are rarely encountered (or the viral etiology documented) outside of the laboratory. Only 2% of fibrosarcomas in cats are virally induced. The rapid and unique clinical course is pathognomonic.

Gross morphology

Fibrosarcomas can be circumscribed or infiltrative, small or extremely large and disfiguring. Capsules are usually not seen. The cut surface is gray/white and glistening, often with an obvious interwoven fascicular pattern.

Figure 5.3  Fibrosarcoma, subcutis, canine. High nuclear density and paucity of collagen differentiate this from fibroma.

Histological features

Tumors can be well differentiated, with spindle‐shaped tumor cells arranged in interwoven or herringbone patterns (Figure  5.3). Cytoplasm in well‐differentiated tumors is scant, and nuclei are fairly uniform, elongated to oval with inconspicuous nucleoli. Mitotic figures are infrequent. More anaplastic tumors have marked cellular and nuclear pleomorphism. Ovoid, polygonal, and multinucleated giant cells are seen, often with large round to oval nuclei and prominent nucleoli. Multinucleation is a more prominent

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feature of fibrosarcomas in cats than dogs. The number of mitotic figures varies and increased numbers are associated with more aggressive tumors. Peripheral aggregates of lymphocytes are occasionally seen; some may contain eosinophils and a hypereosinophilic syndrome is seen rarely.

Additional diagnostic criteria

The diagnosis of fibrosarcoma is usually not difficult; however, in rare instances differentiation from peripheral nerve sheath tumors (PNSTs) and leiomyosarcomas can be problematic. PNSTs usually have finer, more delicate cells arranged in shorter interwoven fascicles, palisades, or whorls. The collagenous stroma can be more pronounced in fibrosarcomas than in PNSTs or leiomyosarcomas, and a Masson’s trichrome stain will distinguish between collagen and smooth muscle. There has been much ado about the more rounded shape of nuclei in leiomyosarcomas as opposed to fibrosarcomas, but this feature is not reliable. The cytoplasm of leiomyosarcoma cells tends to be more eosinophilic and abundant and can have a bubbly or vacuolar appearance. Immunohistochemistry is not particularly useful as all these tumors are vimentin positive, and S100 positivity is notoriously nonspecific; however, if needed, smooth muscle actin will stain the cytoplasm of smooth muscle tumors. Fibrosarcoma is one variant of injection‐site sarcoma (see below). The unique clinical, gross, and histologic changes are discussed in that section.

Growth, metastasis, and treatment

Tumors are infiltrative and recurrent, but metastasis is uncommon. Surgical excision remains the treatment of choice. Radiation can be a successful adjunct therapy, especially when complete excision is difficult. Surgery with follow‐up radiotherapy can result in increased tumor‐free intervals and overall improved long‐term control.5 Grading schemes for spindle cell tumors of dogs can be found in the Appendix of this book.

Injection‐site sarcomas

General considerations Pathologists have recognized foreign body and wound‐associated sarcomas in animals and humans since an initial report by Virchow in 1863.6 Rodents are especially predisposed to the development of these types of tumors.7 Most of our domestic species are not, and have an extremely low incidence, so low as to be clinically insignificant. The few reports of sarcomas arising in sites other than vaccination sites in cats and dogs (those associated with long‐acting antibiotics, steroids, the benzoylurea pesticide lufenuron, nonabsorbable suture material, and microchip implants)8,9 are consistent with this extremely low incidence. It was only after the development of new killed adjuvanted vaccines in the mid to late 1980s that the incidence of injection‐site sarcomas in cats rose to noticeable and alarming levels. Vaccine‐ associated sarcomas in cats continue to be a significant disease and will be the focus of this discussion. Feline vaccine‐associated fibrosarcoma

General considerations

This entity was first described in 1991.10 Since then it has been shown to be an especially aggressive, recurrent variant of fibrosarcoma with high mortality.11,12 Vaccine‐associated sarcomas occur in the cat (malignant fibrous histiocytomas, osteosarcomas,

chondrosarcomas, and rhabdomyosarcomas), but these are seen at decreased incidence.11,12 The histological features of these other sarcomas are described below and in other chapters, but the information listed here concerning signalment, incidence, site, gross morphology, growth, metastasis, and treatment pertain to all vaccine‐associated sarcomas.

Incidence, age, breed, and sex

The tumor is seen in cats as young as 3 years of age, but the mean age is 8.1 years, which is slightly younger than that seen in cats with fibrosarcomas that are not vaccine associated (mean 9.2 years).13 There is no sex predilection. True incidence is difficult to determine, but estimates range from 1:1000 to 1:10,000 tumors per vaccinated cat.13–15

Site and gross morphology

Vaccine‐associated sarcomas arise at vaccination sites on the neck, thorax, lumbar region, flank, and limbs. Since protocols proposed in 1996 recommending the right distal limb for feline rabies vaccination, there has been a decrease in interscapular tumors (Figure 5.4A) and a significant increase in tumors on the right limbs.16 The most typical presentation is a well‐circumscribed, firm white mass in the subcutis or skeletal muscle, with a cystic center containing thin watery or mucinous fluid. Size of the tumor varies widely and is probably dependent on how long owners wait before seeing veterinary care. The tumors tend to be very infiltrative and imaging studies may reveal foci or extension of the tumors into deep fascial planes.

Histological features

At low magnification, the tumor is circular. When in the subcutis, it is usually associated with and extends downward from the panniculus carnosus muscle. There is often a partial fibrous capsule. Despite the circumscribed gross appearance of the tumor, histological “tongues” of tumor are often seen extending away from the mass along fascial planes. Vaccine‐associated fibrosarcomas may be well differentiated, with plump spindle cells arranged in interwoven bundles; however, they tend to be more anaplastic, with cells of variable size and shape, pleomorphic nuclei, and increased numbers of multinucleated cells (Figure  5.4B). Multinucleation is marked in some tumors, with more than 20 nuclei seen in histologic and cytologic preparations (Figure  5.4B inset). Peripheral inflammation, consisting predominantly of lymphocytes and macrophages, is common.

Additional diagnostic criteria

The presence of peripheral aggregates of macrophages containing globular gray/brown intracytoplasmic material (shown to be aluminum, a common vaccine adjuvant) supports the diagnosis of vaccine‐associated sarcoma (Figure 5.4C).11 However, this material is found in a minority of cases. The cytological distinction between vaccine‐associated fibrosarcoma and postvaccinal inflammation is extremely difficult because fibroblasts arising in granulation tissue are often pleomorphic and anaplastic, mimicking neoplastic cells. Excisional biopsy is more reliable and is the method of choice for a definitive diagnosis; however, since there appears to be a continuum from inflammation and fibroplasia to neoplasia, even some ­histological preparations can be problematic. Large lesions that have fully transformed into a sarcoma are more easily

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A

B

C

Figure 5.4  (A) Vaccine‐associated fibrosarcoma in the interscapular region, feline. (B) Vaccine‐associated sarcoma with giant cells. Note band of macrophages at top. Inset: Cytological preparation with a few macrophages and a giant cell with numerous nuclei. (C) Vaccine product in macrophages. This material is not birefringent.

diagnosed – by cytology or biopsy, especially for lesions located in vaccine sites.

survival.17 Metastasis has been reported to occur in regional lymph nodes, mediastinum, and lungs.13,18,19

Growth and metastasis

Treatment

These tumors are highly recurrent, requiring surgical excision one, two, or three times within a 1‐ or 2‐year period.10 The majority of cats end up being euthanized after repeated surgeries, with or without adjuvant therapy. The metastatic potential of these neoplasms is low initially, but appears to increase with prolonged

Wide surgical margins in all directions should be obtained, which in some cases may include either partial scapulectomy or excision of epaxial muscles and dorsal cervical vertebral processes. Amputation of an involved limb should also be considered. Tail vaccinations are increasing in some parts of the country and have been shown to have

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no untoward effect. Aggressive surgical excision with wide margins appears to contribute to extended tumor‐free interval and survival times in cats.20,21 Various combinations of immunostimulatory agents and radiotherapy have been used to treat vaccine‐associated sarcomas in cats.17,22,23 Reports suggest that they can extend tumor‐ free interval and survival times. Targeted therapy using the tyrosine kinase inhibitor imatinib mesylate (Gleevac) – aimed at breaking the autocrine stimulation of platelet‐derived growth factor and its receptor – has resulted in stabilization of tumors for 2 months,17,24 but these were preliminary studies with low numbers of cats.

Canine maxillary well‐differentiated fibrosarcoma General considerations, age, sex, incidence, and site

This is an uncommon but distinctive variant of fibrosarcoma seen in the muzzle region of adult golden retrievers and other large breed dogs.25

Gross morphology

This tumor usually manifests itself as a lumpy enlargement of the maxillary or, less commonly, the mandibular region (Figure 5.5A,B)

A

B

C

Figure 5.5  (A,B) Well‐differentiated fibrosarcoma, maxilla, canine. (C) Note the bland fibrocytes of the neoplasm. Other examples will be more cellular.

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On cut surface, there is a poorly defined firm gray/white mass involving the dermal and subcutaneous tissues.

Histological features

The neoplasm is composed of well‐differentiated fibrocytes and fibroblasts in an extensive connective tissue stroma (Figure 5.5C). Nuclear pleomorphism and mitotic figures are rare. The collagen bundles are often haphazard as in the surrounding normal connective tissue, but often there is a repetitive fascicular pattern that sets the tumor apart. Rarely, there is an obvious border with compression, but more often the edge infiltrates the surrounding tissue, making complete excision difficult. There can be a superimposed inflammatory infiltrate, further obscuring the true nature of the neoplastic proliferation.

Additional diagnostic criteria

Because of the bland histological appearance of this neoplasm, it could be misdiagnosed as a fibroma or not recognized as abnormal tissue. However, the constellation of breed, site, and histology should lead one to the correct diagnosis.

Growth, metastasis, and treatment

Despite the bland appearance of the cells, the neoplasm is progressively infiltrative, with eventual disfigurement and loss of function. As mentioned above, complete surgical excision is difficult, necessitating partial mandidulectomy or removal of large portions of the maxilla. There are anecdotal reports that radiation with localized hyperthermia can result in longer survival times.

16. Shaw, S.C., Kent, M.S., Gordon, I.K., et al. (2009) Temporal changes in characteristics of injection‐site sarcomas in cats: 392 cases (1990–2006). J Am Vet Med Assoc 234:376–380. 17. Martano, M., Morello, E., and Buracco, P. (2011) Feline injection‐site sarcomas: Past, present and future perspectives. Vet J 2:136–141. 18. Rudmann, D.G., Van Alstine, W.G., Doddy, F., et  al. (1996) Pulmonary and mediastinal metastases of a vaccination‐site sarcoma in a cat. Vet Pathol 33:466–469. 19. Esplin, D.G. and Jaffe, M.H. (1996) McGill, L.D. Metastasizing liposarcoma associated with a vaccination site in a cat. Feline Pract 24:20–23. 20. Davidson, E.B., Gregory, C.R., and Kass, P.H. (1997) Surgical excision of soft tissue fibrosarcomas in cats. Vet Surg 26:265–269. 21. Hershey, A.E., Sorenmo, K.U., Hendrick, M.J., et al. (2000) Prognosis for presumed feline vaccine‐associated sarcoma after excision: 61 cases (1986–1996). J Am Vet Med Assoc 216:58–61. 22. King, G.K., Yates, K.M., Greenlee, P.G., et  al. (1995) The effect of acemannan immunostimulant in combination with surgery and radiation therapy on spontaneous canine and feline fibrosarcomas. J Am Anim Hosp Assoc 31:439–447. 23. Rassnick, K.M., Rodriquez Jr, C.O., Khanna, C., et al. (2006) Results of a phase II clinical trial on the use of ifosfamide for treatment of cats with vaccine‐associated sarcomas. Am J Vet Res 67:517–523. 24. Lachowicz, J.L., Post, G.S., and Brodsky, E. (2005) A phase I clinical trial evaluating imatinib mesylate (Gleevec) in tumor‐bearing cats. J Vet Intern Med 19:860–864. 25. Ciekot, P.A., Powers, B.E., Withrow, S.J., et al. (1994) Histologically low grade, yet biologically high‐grade, fibrosarcomas of the mandible and maxilla in dogs: 25 cases (1982–1991). J Am Vet Med Assoc 204:610–615.

Equine sarcoid

This unique equine lesion is the result of a nonproductive infection with bovine papillomavirus types 1 and 2.1,2 It is worldwide in distribution and is not related to human sarcoidosis.

Incidence, age, breed, and sex

References

1. Scott, D.W. and Miller, W.H. (2010) Equine Dermatology. Elsevier Saunders, St. Louis, MO, pp. 488–489. 2. Gumbar, S. and Wakamatsu, N. (2011) Vaccine‐associated fibrosarcoma with keloidal differentiation in a cat. J Vet Diagn Invest 23:1061–1064. 3. Mikelian, I. and Gross, T.L. (2002) Keloidal fibromas and fibrosarcomas in the dog. Vet Pathol 39:149–153. 4. Snyder, S.P. and Thielen, G.H. (1969) Transmissible feline fibrosarcoma. Nature 221:1074–1075. 5. McKnight, J.A., Mauldin, G.N., McEntee, M.C., et al. (2000) Radiation treatment for incompletely resected soft‐tissue sarcomas in dogs. J Am Vet Med Assoc 217:205–210. 6. Virchow, R. (1863) Die krankhaften Geschwulste. Dreissig Vorlesungen gehalten wahrend Wintersemesters 1862–1863, vols. 1–3, Heft 1. A Hirschwald, Berlin. 7. Brand, K.G., Johnson, K.H., and Buoen, L.C. (1976) Foreign body tumorigenesis. CRC Crit Rev Toxicol 4:353–394. 8. Kass, P.H., Spangler, W.L., Hendrick, M.J., et al. (2003) Multicenter case‐control study of risk factors associated with development of vaccine‐associated sarcomas in cats. J Am Vet Med Assoc 223:1283–1292. 9. Esplin, D.G. and Mcgill, L.D. (1999) Fibrosarcoma at the site of lufenuron injection in a cat. Vet Cancer Soc Newsl 23:8–9. 10. Hendrick, M.J. and Goldschmidt, M.H. (1991) Do injection site reactions induce fibrosarcomas in cats (lett)? J Am Vet Med Assoc 199:968. 11. Hendrick, M.J. and Brooks, J.J. (1994) Postvaccinal sarcomas in the cat: Histology and immunohistochemistry. Vet Pathol 31:126–129. 12. Dubielzig, R.R., Hawkins, K.L., and Miller, P.E. (1993) Myofibroblastic sarcoma originating at the site of rabies vaccination in a cat. J Vet Diagn Invest 5:637–638. 13. Hendrick, M.J., Shofer, F.S., Goldschmidt, M.H., et al. (1994) Comparison of fibrosarcomas that developed at vaccination sites and at nonvaccination sites in cats: 239 cases (1991–1992). J Am Vet Med Assoc 205:1425–1429. 14. Doddy, F.D., Glickman, L.T., Glickman, N.W., and Janovitz, E.B. (1996) Feline fibrosarcomas at vaccination sites and non‐vaccination sites. J Comp Pathol 114:165–174. 15. Kass, P.H., Barnes, W.G., Jr., Spangler, W.L., et al. (1993) Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats. J Am Vet Med Assoc 203:396–405.

This most common equine skin tumor can be seen in any age horse, but the majority of cases are seen in individuals younger than 4 years of age.

Site and gross morphology

Sarcoids can occur anywhere on the body, but especially the head, lips, legs, and ventral trunk (Figure 5.6A,B). About 40% of affected horses have multiple sarcoids.3 There are six gross morphological types: verrucous, fibroblastic, nodular, mixed, malevolent/malignant, and flat, the latter are also called “occult.”

Histological features

Most lesions are composed of a thickened epidermis with prominent epithelial pegs that extend into a dermal proliferation of spindle cells that are arranged in whorls, tangles, or herringbone patterns with a small amount of collagenous stroma (Figure 5.6C). Nuclear pleomorphism and mitoses vary, but can be pronounced in rapidly growing or recurrent tumors. There can be difficulty differentiating some sarcoids from fibrosarcomas or nerve sheath tumors, especially if the distinctive epidermal component has been lost by ulceration or is not present in the submitted section. In addition, a recent paper described an unusual variant of sarcoid without the epidermal component. These tumors were originally diagnosed as schwannomas, but were later found to have bovine papillomavirus (BPV) via polymerase chain reaction (PCR).4

Additional diagnostic criteria

Identification of bovine papillomavirus DNA in the nuclei of proliferating fibroblasts by in situ hybridization or PCR is diagnostic of equine sarcoid, but is seldom performed or considered necessary

Mesenchymal Tumors of the Skin    149

A

B

C

Figure 5.6  Equine sarcoid. (A) Nodular sarcoid on the eyelid/canthus. (B) Verrucous sarcoid on ear. (Image courtesy of Perry Habecker.) (C) Proliferation

of interwoven fibroblasts.

when the characteristic epidermal and fibroblastic proliferations are present. However, as just described these tools may have value on other spindle cell tumors of horses that lack concurrent epidermal proliferation. This distinction has clinical implications because sarcoids may require chemotherapy or immunotherapy (see below).

Incidence, age, breed, sex, and site

Growth, metastasis, and treatment

Gross morphology

Rare tumors spontaneously regress, but complete excision – often via cryosurgery  –  can be curative.5 Recurrence of inadequately excised masses is common. Other modalities, including radiation therapy, topical creams, and intralesional injections of BCG and ­cisplatin have been tried with variable success. Sarcoids do not metastasize.

Feline sarcoid (feline fibropapilloma)

This disease of cats resembles equine sarcoid in many ways. Papillomavirus DNA with high analogy to BPV type 1 can be found in the feline tumors6,7 and the histologic changes in the epidermis and dermis are similar in the two diseases.

This neoplasm occurs mostly in rural or barn cats that have exposure to cattle, hence the incidence is likely underreported. It is most common in young cats, and usually affects the nose or muzzle region. Tumors on the limbs, ventrum, and digits are less common. Tumors can be focal or multifocal, firm, and slightly raised – growing up to 2 cm in diameter. They can be ulcerated and are usually mildly infiltrative.

Histological features

As in equine sarcoids, these tumors are covered by a thickened epidermis with prominent epithelial pegs that extend into a dermal proliferation of spindle and stellate cells (Figure 5.7). The proliferation is unencapsulated and cells are arranged in haphazard streams and bundles, with occasional whorls. There is a variable amount of collageneous stroma often containing numerous mast cells. Spindle cell nuclei are mildly pleomorphic and the mitotic count is typically low – less than 3 per 10 HPFs.

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Figure 5.7  Feline sarcoid. Distinctive epidermal hyperplasia merging with a proliferating fibroblasts component is characteristic of feline and equine sarcoids. Both are associated with bovine papillomavirus DNA.

Additional diagnostic criteria

PCR testing of affected tissues will reveal papillomavirus DNA in most cases. However, this is rarely necessary, as the clinical and ­histologic features of this disease are quite distinctive.

Growth, metastasis, and treatment

Tumors are slow‐growing and self‐limiting. Like equine sarcoids they can be cured by complete excision, but recurrence is common. Metastasis has not been reported.

References

1. Otten, N., VonTscharner, C., Lazary, S., et al. (1993) DNA of bovine papillomavirus type 1 and 2 in equine sarcoids: PCR detection and direct sequencing. Arch Virol 132:121–131. 2. Angelos, J.A., Marti, E., Lazary, S., and Carmichael, L.E. (1991) Characterization of BPV‐like DNA in equine sarcoids. Arch Virol 119:95–109. 3. Scott, D.W. and Miller, W.H. (2010) Equine Dermatology. Elsevier Saunders, St. Louis, MO, pp. 479–488. 4. Bogaert, L.I., Heerden, M.V., Cock, H.E., et al. (2011) Molecular and immunohistochemical distinction of equine sarcoid from schwannoma. Vet Pathol 48:737–741. 5. Knottenbelt, D.C. (2008) Proceedings of the 10th International Congress of World Equine Veterinary Association Moscow, Russia. 6. Schulman, F.Y., Krafft, A.E., and Janczewski, T. (2001) Feline cutaneous fibropapillomas: clinicopathologic findings and association with papillomavirus infection. Vet Pathol 38:291–296. 7. Teifke, J.P., Kidney, B.A., Lohr, C.V., and Yager, J.A. (2003) Detection of papillomavirus‐ DNA in mesenchymal tumour cells and not in the hyperplastic epithelium of feline sarcoids. Vet Dermatol 14:47–56.

Pleomorphic sarcoma (anaplastic sarcoma with giant cells, malignant fibrous histiocytoma)

Previously called malignant fibrous histiocytoma, this entity is still controversial in human and veterinary medicine. Initially thought to be one neoplasm with different variants, it has been

shown to be a histologically and immunohistochemically diverse group of neoplasms, leading many to prefer the more generic diagnosis of “undifferentiated pleomorphic sarcoma” or “anaplastic sarcoma with giant cells.”1,2 This author believes there is within this group a tumor of primitive myofibroblast origin in dogs and cats that is analogous to the classical human entity called malignant fibrous histiocytoma (MFH). That tumor is briefly described below. However, the morphology of cells in this tumor merge easily into anaplastic versions of many other mesenchymal and histiocytic tumors in animals and humans, confounding definitive diagnosis and making prognostication difficult. Examination of large samples and further immunohistochemical testing can sometimes more specifically identify the histogenesis of the tumors. Without those aids, one can choose to “lump” these tumors into the grab bag diagnosis of “anaplastic sarcoma with giant cells,” or undifferentiated pleomorphic sarcoma, recognizing that one may be compromising one’s ability to prognosticate. Classic human MFH has been divided into subtypes based on the pattern and predominance of the cell types: storiform‐pleomorphic, giant cell, inflammatory, and myxoid.3 Only the first two types been  found with any consistency in the skin/subcutis of domestic ­animals.4–7 These are described below.

Gross morphology

Classical MFH occurs in most domestic animal species, but is most frequently seen in the dog. It arises in the skin as a single, expansive tumor, or it may appear as part of a multi‐organ disease that often involves lungs, lymph nodes, spleen, liver, bones, and kidneys.5 Golden retrievers and rottweilers are overrepresented for MFH.5 The relative incidence of focal versus multi‐ organ MFH in dogs is difficult to determine because most diagnoses are made on biopsy specimens with incomplete follow‐ up. However, autopsy files at the University of Pennsylvania contain at least 40 cases of multi‐organ MFH in dogs. Two of these animals had skin masses. In the cat, MFH is one of the histological variants of vaccine‐associated sarcomas,8 and can also occasionally be seen in the dermis or subcutis in nonvaccine sites. There is no sex predilection. Middle‐aged or older individuals are usually affected. The tumor is usually gray/white but can also have red mottling, depending on the amount of hemorrhage and necrosis. Margins are often distinct, but without encapsulation.

Histology Storiform‐pleomorphic This is the most common variant in the skin and organs of dogs. In this variant, fibroblast‐like cells are arranged in cartwheel (storiform) patterns, mixed with histiocytoid cells and an infiltrate of lymphocytes, plasma cells, neutrophils, and occasional eosinophils (Figure  5.8A). Histiocytoid cells are frequently karyomegalic or multinucleated, often with marked nuclear atypia. Some tumors have patchy zones of sclerotic collagenous stroma. Giant cell These tumors have numerous multinucleated giant cells mixed with spindle cells and mononuclear histiocytoid cells (Figure 5.8B). Although occasionally present, inflammatory cells are not a consistent feature of this variant. This is the most common subtype in cats.

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A

B

Figure 5.8  Malignant fibrous histiocytoma (pleomorphic sarcoma). (A) Storiform‐pleomorphic variant, subcutis, canine. (B) Giant cell variant, skin, canine.

Additional diagnostic criteria

Cytology of MFH will show variable numbers of poorly cohesive spindle cells and rounder mononuclear or multinucleated histiocytoid cells along with some inflammatory cells. Immunohistochemical analysis is compatible with a fibroblastic/ myofibroblastic phenotype, with consistent positivity for vimentin, and variable positivity for actin and desmin.8–10 The giant cells in MFH should have the same positivity as the fibroblastic cells. As histiocytic sarcoma is a primary differential for the giant cell variant of MFH, CD18 immunostaining should be performed to rule out that diagnosis. Complicating the diagnosis is the fact that reactive CD18‐positive multinucleated giant cells can be found in this neoplasm and other undifferentiated pleomorphic sarcomas. Diffuse CD18 positivity throughout the majority of fibroblastic and giant cells would support a diagnosis of histiocytic sarcoma. Ultrastructural studies reveal the tumor cells in MFH to be characteristic of fibroblasts with or without cytoplasmic filaments consistent with actin.3,11

Growth, metastasis, and treatment

Dermal or subcutaneous MFH tends to be locally expansile. Reports vary as to the metastatic potential of this neoplasm – again due to the lack of distinction between this and other pleomorphic sarcomas. Any individual with MFH should be given a guarded prognosis. Complete excision can be curative for solitary dermal or subcutaneous masses. There is no recognized successful treatment for multicentric MFH.

References

1. Fletcher, C.D.M., Unni, K.K., and Mertens, F. (2002) So‐called fibrohistiocytic tumours. In Pathology and Genetics of Tumours of Soft Tissue and Bone. World Health Organization Classification of Tumours. IARC Press, Lyon, pp. 109–125. 2. Al‐Agha, O.M. and Igbokwe, A.A. (2008) Malignant fibrous histiocytoma: between the past and the present. Arch Pathol Lab Med 132:1030–1035.

3. Weiss, S.E., Goldblum, J.R., and Folpe, L.R. (2007) Enzinger and Weiss’s Soft Tissue Tumors, 5th edn. Mosby Elsevier, Philadelphia, PA, pp. 406–425. 4. Waters, C.B., Morrison, W.B., DeNicola, D.B., et  al. (1994) Giant cell variant of malignant fibrous histiocytoma in dogs: 10 cases (1986–1993). J Am Vet Med Assoc 205:1420–1424. 5. Kerlin, R.L. and Hendrick, M.J. (1996) Malignant fibrous histiocytoma and malignant histiocytosis in the dog – convergent or divergent phenotypic differentiation? Vet Pathol 33:713–716. 6. Gibson, K.L., Blass, C.E., Simpson, M., and Gaunt, S.D. (1989) Malignant fibrous histiocytoma in a cat. J Am Vet Med Assoc 194:1443–1445. 7. Sartin, E.A., Hudson, J.A., Herrera, G.A., et al. (1996) Invasive malignant fibrous histiocytoma in a cow. J Am Vet Med Assoc 208:1709–1710. 8. Hendrick, M.J. and Brooks, J.J. (1994) Postvaccinal sarcomas in the cat: Histology and immunohistochemistry. Vet Pathol 31:126–129. 9. Pace, L.W., Kreeger, J.M., Miller, M.A., et al. (1994) Immunohistochemical staining of feline malignant fibrous histiocytomas. Vet Pathol 31:168–172. 10. Morris, J.S., McInnes, E.F., Bostock, D.E., et al. (2002) Immunohistochemical and histopathological features of 14 malignant fibrous histiocytomas from flat‐coated retrievers. Vet Pathol 39:473–479. 11. Confer, A.W., Enright, F.M., and Beard, G.B. (1981) Ultrastructure of a feline extraskeletal giant cell tumor (malignant fibrous histiocytoma). Vet Pathol 18:738–744.

Myxoma and myxosarcoma

These are tumors of fibroblast origin distinguished by their abundant myxoid matrix rich in mucopolysaccharides. Myxomas/myxosarcomas are rare, occurring in middle‐aged or older dogs and cats.

Gross morphology

The majority arise in the subcutis of the trunk or limbs. The gross appearance varies little between myxomas and myxosarcomas. They are soft, gray/white, poorly defined masses that exude a stringy clear mucoid fluid.

Histological features

Both tumors are composed of an unencapsulated proliferation of  stellate to spindle‐shaped fibroblasts loosely arranged in an abundant myxoid matrix (Figure  5.9). This matrix, rich in acid

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Figure  5.9  Myxosarcoma, subcutis, canine. Nuclear density warrants the

diagnosis of sarcoma, but the histologic distinction between myxoma and myxosarcoma can be subtle, and not clinically relevant as the behavior is the same for both.

mucopolysaccharides, stains light blue with routine hematoxylin and eosin (H&E) stains. Cellularity is low, mitoses are rare, and there is little or no cytological atypia in myxomas. Nuclei tend to be small and hyperchromatic. Increases in cellular density, nuclear pleomorphism, and mitoses warrant the diagnosis of myxosarcoma, but the distinction is often subtle. Histologic features of myxosarcoma are similar to those seen in myxoid variants of PNSTs and myxoid liposarcomas (see below in  this chapter), and when present as the primary pattern in the neoplasm, definitive diagnosis can be difficult. In those cases, this author prefers the term “myxoid sarcoma.”

Growth, metastasis, and treatment

Surgical excision is the treatment of choice. Myxomas and myxosarcomas are infiltrative, with poorly defined margins. Recurrence is likely in either case; metastasis is rare, however.

Additional diagnostic criteria

Cytological smears of these tumors are often difficult to prepare because of the slimy consistency of the tumor and the paucity of cells that adhere to slides. Differentiation from myxoid liposarcoma and PNST can sometimes be made based on special staining (Oil red O and S100, respectively) but the behavior and prognoses of these three entities are virtually identical, and the distinction is not clinically important.

Tumor‐like lesions

Collagenous hamartoma This common non‐neoplastic lesion of dogs is a nodular, poorly circumscribed focus of redundant collagen in the superficial dermis. Although this lesion is also called collagenous nevus, the

Figure  5.10  Collagenous hamartoma, skin, canine. Note the haphazard arrangement of collagen that is similar to the adjacent normal collagen.

term hamartoma, which precludes confusion of this lesion with pigmented (melanocytic) tumors or tumors present at birth, is  preferred. The pathogenesis of collagenous hamartomas is unknown. It is one of the many common dermal proliferations in aged dogs, and there is no recognized breed or sex predilection.

Site and gross morphology

Hamartomas can occur anywhere, but there appears to be a predilection for the head and limbs. These masses are usually small nodular elevations of the epidermis. There can be mild alopecia but no evidence of erosion, ulceration, or other signs of self‐trauma.

Histological features

These lesions have abundant collagen devoid of adnexa, but in contrast to fibromas, the collagen fiber pattern is not repetitive and is similar to that seen in adjacent normal collagen (Figure 5.10). The proliferation is limited to the superficial dermis and usually results in slight elevation of the epidermis and loss, separation, or distortion of adjacent adnexal structures.

Additional diagnostic criteria

The differentiation between skin tags and collagenous hamartomas is subtle in some instances and not clinically important. Unlike collagenous hamartomas, which usually show some loss or distortion of adnexa, skin tags are usually pedunculated pieces of excess skin that contain all of the skin’s normal constituents. Because of their nipple‐like growth, skin tags are subject to external trauma with secondary ulceration and inflammation.

Growth and treatment

These masses are slow‐growing and usually are excised to rule out other more clinically significant lesions. Excision is curative.

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Nodular dermatofibrosis This is a rare syndrome of multiple fibrous nodules in the dermis and subcutis. Female German shepherds are preferentially affected, but the disease can occasionally occur in other breeds. The skin lesions may precede or coincide with unilateral or bilateral renal cysts, adenomas, or carcinomas.1–5 Uterine muscle tumors have also been described, but due to the high percentage of spayed female dogs, this lesion is rare.

Site and gross morphology

The nodules, which can number in the hundreds, are generally found on the limbs, ears, and back. They range from a few millimeters to 4 cm in diameter. They are well circumscribed, but when large they can result in alopecia and ulceration of the overlying skin.

Histological features

There is a focal proliferation of collagen covered by a mildly hyperplastic epidermis. Collagen bundles can be normal or slightly thickened, but are arranged in the haphazard pattern seen in normal dermis. Adnexal structures are normal or hyperplastic. The collagenous proliferation is poorly demarcated from adjacent normal collagen bundles in the dermis, but the subcutaneous portion is well circumscribed and can push or separate normal structures in this location. Inflammation is usually minimal.

Additional diagnostic criteria

In contrast to collagenous hamartomas, these lesions are not limited to the superficial dermis, and adnexal structures are normal or hyperplastic. However, these differences can be subtle. It is the multiplicity of these lesions that is unique. When these lesions are found in female German shepherds, clinicians should run additional tests to evaluate the kidneys.

Growth and treatment

Because of the multicentricity of these lesions, there is no effective treatment. The nodules are benign, but some will be surgically removed for cosmetic reasons or if they interfere with function. Nodular fasciitis The term nodular fasciitis has been borrowed from the human literature6 and refers to a non‐neoplastic, enigmatic inflammatory lesion with many clinical and histological features suggestive of a locally invasive fibrosarcoma. There is considerable clinical and histologic overlap between this entity and nodular episcleritis, reactive fibrohistiocytic nodule, and palisading granuloma. Each of these lesions appears to be an overzealous inflammatory/immune response characterized by the proliferation of fibroblasts and ­myofibroblasts, with varying numbers of histiocytes and other inflammatory cells. They are typically focal lesions – often associated with previous trauma. Indeed, they may all represent different stages of wound healing, the predominant cell type depending on the degree of collagenolysis or the amount of TGFβ produced. This discussion will focus on the variant that is predominantly fibrous, with features similar to that seen in the human lesion called nodular fasciitis. Descriptions of nodular episcleritis can be found in Chapter  20. Reactive fibrohistiocytic nodules and palisading granulomas are described elsewhere.6,7

Incidence, age, breed, sex, and site

This lesion has been reported almost exclusively in the dog as a deep dermal or subcutaneous mass most often seen on the trunk

Figure 5.11  Nodular fasciitis, subcutis, canine. Center of lesion has streams of immature fibroblasts and mitotic figures, mimicking fibrosarcoma.

and limbs of dogs and periscleral, more often in collie breeds. All ages are affected, with no breed or sex predilection.

Gross and histological features

The lesion tends to be firm, nodular, and poorly demarcated. The cut surface is usually gray/white with varying degrees of red mottling. Nodular fasciitis is a mixture of myofibroblasts, fibroblasts and fibrocytes arranged in short bundles or whorls and mixed with variable amounts of lymphocytes, plasma cells, and macrophages. Fibroblasts, particularly in the center of the lesion, are immature in appearance, with numerous mitotic figures, sometimes leading to a misdiagnosis of fibrosarcoma (Figure 5.11). The edges of the lesion often merge with surrounding connective tissue and muscle, resulting in spiky or feathery margins.

Additional diagnostic criteria

There are no stains or immunohistochemical markers that can distinguish nodular fasciitis from fibrosarcoma or myofibroblastic sarcoma. If it is difficult to decide if the lesion is granulation tissue or a mesenchymal neoplasm, then nodular fasciitis is a good differential. The overall clinicopathological picture will most often distinguish this lesion from the more aggressive sarcomas. Factors that favor a diagnosis of nodular fasciitis are: canine, prior history of trauma, haphazard arrangement of spindle cells, and size of the lesion – smaller size favors nodular fasciitis and large (>6 cm) favors fibrosarcoma. Fibrosarcomas may have multiple foci of inflammation scattered through the tumor. If inflammation is present it is usually lymphocytic, rarely with eosinophils, but the majority of the mass is proliferating fibroblasts with variable amounts of collagen.

Growth and treatment

Lesions are benign and grow to a certain size and remain static. They are usually cured by complete excision.

References

1. Perry. W. (1995) Generalised nodular dermatofibrosis and renal cystadenoma in a series of 10 closely related German shepherd dogs. Aust Vet Pract 25:90–93. 2. Marks, S.L., Farman, C.A., and Peaston, A. (1993) Nodular dermatofibrosis and renal cystadenomas in a golden retriever. Vet Dermatol 4:133–137.

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3. Atlee, B.A., DeBoer, D.J., Ihrke, P.J., et al. (1991) Nodular dermatofibrosis in German shepherd dogs as a marker for renal cystadenocarcinoma. J Am Anim Hosp Assoc 27:481–487. 4. Lium, B. and Moe, L. (1985) Hereditary multifocal renal adenocarcinomas and nodular dermatofibrosis in the German shepherd dog: Macroscopic and histopathologic changes. Vet Pathol 22:447–455. 5. Suter, M., Lott‐Stolz, G., and Wild, P. (1983) Generalized nodular dermatofibrosis in six Alsatians. Vet Pathol 20:632–634. 6. Weiss, S.E., Goldblum, J.R., and Folpe, L.R. (2007) Enzinger and Weiss’s Soft Tissue Tumors, 5th edn. Mosby Elsevier, Philadelphia, pp. 177–368. 7. Gross, T.L., Ihrke, P.J., Walder, E.J., and Affolter, V.K. (2005) Veterinary Skin Diseases of the Dog and Cat, 2nd edn. Blackwell, Ames, pp. 337–340.

Canine hemangiopericytoma (myopericytoma, perivascular wall tumor)

The name hemangiopericytoma, given to this very common mesenchymal neoplasm, was bestowed because of some minor histological similarities to the tumor in humans, but the actual gross and histological characteristics of the human tumor are quite different from those of the canine tumor.1 Still, the original nomenclature has been retained in veterinary pathology. More recently, studies of the cytologic and immunohistochemical features of this neoplasm have revealed that it is not one tumor, but represents a spectrum of tumors arising from various cells of the perivascular wall and adventitia.2 These tumors include hemangiopericytomas, myopericytomas, angioleiomyomas, angiomyofibroblastomas, and angiofibromas, reflecting a continuum of contractile protein expression inherent in the normal vascular wall cell types. The latter three named neoplasms are rare in veterinary medicine and only one is discussed in this chapter: angioleiomyoma (see below in the section on Leiomyoma). Based on the study on ­perivascular wall tumors

A

(PWTs) the entity most resembling typical canine hemangiopericytoma in histological morphology and biological behavior is myopericytoma.2 This author prefers this nomenclature to the incorrect “hemangiopericytoma” and the all‐encompassing “perivascular wall tumor.” However, there appears to be too much blurring and overlap in histology of the numerous tumors previously called canine hemangiopericytoma to assign one name to them. The term PWT is becoming more widely accepted and used in the literature and will therefore be used in the description below to describe the tumor(s) previously called canine hemangiopericytoma.

Incidence, age, breed, and sex

PWTs are common in middle‐aged or older dogs. Large breed dogs appear overrepresented, but there is no sex predilection. Tumors with a similar morphology occur rarely in cats and are most likely of PNST origin.

Site and gross morphology

Tumors are usually solitary, arise most commonly around joints of limbs, and are often multilobulated. They are one of the most common tumors on the limbs of dogs and are also found on the trunk but rarely in the head region. They can be circumscribed or infiltrative. They have variable gross appearances: white/gray to red, soft to firm, rubbery to “fatty.” In fact, many lesions are thought by submitting veterinarians to be lipomas. When cut, these latter tumors may exude a slimy mucoid material.

Histological features, growth, and metastasis

Histologically, the hallmark of this neoplasm is the presence of perivascular whorls of fusiform cells (Figure  5.12A). Although this

B

Figure 5.12  Canine myopericytoma, subcutis, canine. (A) Classic perivascular whorling. The cells arise from components of the vascular wall and adventitia.

(B) Cytology specimen contains typical high cellular exfoliation and cohesion of the spindle cells. Note bi‐ and multinucleated cells, streams of cytoplasm, and considerable cellular and nuclear variability. PWT is a name for a group of spindle cell tumors. See the appendix on soft tissue mesenchymal tumor, page 957.

Mesenchymal Tumors of the Skin    155

feature may be present in other sarcomas, it is usually dominant in myopericytomas – the most common variant of PWTs.2–4 In other PWTs cells may also be arranged in staghorn vessels (thin‐walled branching vessels) and placentoid (multiple lobules with a central capillary) patterns.2–4 The neoplastic cells can range, sometimes within the same tumor, from thick to thin, spindle‐shaped to almost pyriform, and they are separated by variable amounts of collagenous stroma. In some tumors there is patchy, though abundant, mucinous matrix, which can lead to a misdiagnosis of myxosarcoma. The neoplasm may be well demarcated from the surrounding tissue, but it often invades along fascial planes, leading to frequent recurrences. Cellular pleomorphism and mitotic activity are usually low in primary tumors, but cellular atypia, number of mitoses, and multinucleated forms increase with each recurrence. Reports prior to the reclassification of canine hemangiopericytoma suggested that mitotic count and grade were key prognostic features, and that the usually low metastatic potential increased with higher grades.5–7 However, more recent studies have shown that grade is not prognostically significant in tumors identified as PWTs. Size and depth of the tumor are more significant to outcome and frequency of recurrence. Metastasis is rare.3,4,7

Additional diagnostic criteria

Cytology can be diagnostic of myopericytomas, as the high cellular density, cohesion of the spindle cells, the presence of small capillaries, and occasional multinucleated cells are features thought to be indicative of this neoplasm and other PWTs (Figure 5.12B). Of all the spindle cell tumors this one exfoliates the greatest number of neoplastic cells. It continues to be difficult to distinguish PWTs from PNSTs. Most diagnoses of these neoplasms are based on tradition rather than auxiliary tests such as electron microscopy or immunohistochemistry. PWTs can be differentiated by their varying immunopositivity to various contractile protein antigens. Myopericytomas are immunopositive for calponin, pan‐actin, α‐smooth muscle actin, and sometimes desmin. They are myosin negative. PNSTs can be S100‐positive or ‐negative, but in one study most were positive for nerve growth factor receptor (NGFR) and all were negative for α‐smooth muscle actin.8 Another recent study of cat PNSTs showed similar immunonegativity for muscle‐specific actin.9 These studies suggest that the use of actin immunomarkers can be helpful in distinguishing myopericytoma and other PWTs (positive) from PNSTs (negative).

Treatment

Aggressive initial surgery is considered the best treatment for PWTs. Complete excision is often curative.3,4 Studies indicate that even marginal excision can be curative for grade 1 tumors.6,7 Radiation therapy can result in some tumor control and longer survival times.10 Chemotherapy has proven unsuccessful.

Peripheral nerve sheath tumor (nerve sheath tumor)

Some pathologists would prefer to restrict the term peripheral nerve sheath tumor to those neoplasms that arise and spread within nerves. Others contend that there is a subset of PNSTs that arise in the skin and subcutis, presumably from small nerves. Most would agree that there are differences in the histology and biological behavior of these two entities.

The diagnosis of soft tissue PNSTs is well established in veterinary medicine and pathology, although as an editorial in Veterinary Pathology pointed out,11 there are central and peripheral nervous systems, but all nerves are peripheral and do not need that designation. Hence the tumors described below should simply be called nerve sheath tumors. Classically, the term schwannoma is used when the tumor cells are solely of Schwann cell origin. Neurofibroma/sarcoma is used when the tumor is composed of Schwann cells and perineural cells. In human tumors, this distinction can sometimes be made by immunostaining with S100, glial fibrillary acidic protein (GFAP), other specific neural markers, including Leu7 (myelin‐associated glycoprotein), and laminin. However, most veterinary pathologists combine these entities under the title “peripheral nerve sheath tumors” because most diagnoses are made without these ancillary tests and because the markers that are available for our veterinary species are often nonspecific or overlap in specificity. Therefore this chapter will continue to use the term nerve sheath tumor and it will encompass the entities called schwannoma and neurofibroma. In the previous edition of this chapter, benign and malignant forms of nerve sheath tumors were described as separate entities. Presently, they are grouped under one heading, as most are diagnosed as simply “peripheral nerve sheath tumors” and given a grade – higher grades signifying tumors more likely to exhibit malignant behavior (i.e shorter survival times, recurrence and/or metastasis).

Incidence, age, breed, sex, and site

In cats, nerve sheath tumors (NSTs) are uncommon and are found predominantly on the head.9 They are common in dogs, especially since hemangiopericytomas (PWT) are often diagnosed as NSTs. Most reports describe the site distribution, gross appearance, and biological behavior of this neoplasm in dogs as similar to that of hemangiopericytoma/PWT, which is not surprising. In cattle, multiple tumors may be seen in the subcutis, heart, and brachial plexus, resembling von Recklinghausen’s disease in humans. However, only rare bovine NSTs are in the skin.12 Horse NSTs are uncommon, mostly seen on the eyelids.13,14 Middle‐aged or older animals of all species are preferentially affected, but NSTs can occur in calves and in horses as young as 3 years of age.13

Gross morphology

Tumors are firm to soft, unencapsulated, circumscribed or infiltrative masses in the dermis (most common in the cat) or subcutis. They are usually white to gray and sometimes bulge slightly on cut surface.

Histological features

NST can be graded like other spindle cell tumors7 (see Appendix). Grade 1 NSTs are composed of wavy ovoid to spindle cells arranged in bundles, palisades, and whorls. They have low cellularity, with neoplastic cells loosely distributed in a fibrillar or mucinous matrix. Nuclei are small and normochromatic. The classic Antoni A configuration with Verocay bodies has been considered the hallmark of benign NSTs (schwannomas) in humans.1 These histologic patterns are seen in some feline NSTs (Figure 5.13A) but are rare in other domestic animals. Also more frequently seen in cats is a plexiform growth pattern, affecting multiple nerve fascicles, giving a multinodular pattern (Figure 5.13B). The histological features of higher grade NSTs are similar to those described for grade 1 tumors, but the classic palisading is usually absent and the cells are more densely grouped. Nuclei are oval

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A

B

C

Figure 5.13  (A) Nerve sheath tumor, skin, feline. (B) Note the plexiform pattern involving several small nerves. (C) NST, grade 2, skin, canine.

or oblong, with moderate pleomorphism (Figure  5.13C). The mitotic count varies, but it is usually low to moderate. Scattered lymphocytes and mast cells are commonly seen. Neoplastic cells are often compressed at the periphery, forming a pseudocapsule. The gross appearance of this pseudocapsule often leads to inaccurate identification of margins and incomplete excisions.

Additional diagnostic criteria

Markers that might be used in to identify cells of nerve sheath origin in veterinary species include S100, GFAP, NGFR, neuron‐ specific enolase (NSE), laminin, and CNPase.8,12 Schwannomas

should have diffuse staining with S100, laminin, and CNPase. Neurofibroma/sarcoma should have a scattered or patchy positivity with these markers. GFAP, NGFR, and NSE will usually stain all tumors of nerve sheath origin but are often patchy and not discriminatory. The myopericytoma variant of PWTs is the principal differential in the dog. One study found NGFR and actin immunomarkers to be most specific and best able to distinguish nerve sheath tumors from myopericytomas, respectively.8 However, this distinction is usually not clinically important, as the two tumors have similar behaviors and prognoses.

Mesenchymal Tumors of the Skin    157

Growth, metastasis, and treatment

Complete and even marginal excisions are usually curative for grade 1 tumors in dogs.7 Incompletely or marginally excised grade 2 and 3 tumors will likely recur. Recurrence is especially common in horses, often requiring multiple surgeries.14 However, NSTs and schwannomas do not metastasize in horses.

Leiomyoma (piloleiomyoma and angioleiomyoma)

Leiomyomas are rare in the skin and soft tissue. Below is a discussion of piloleiomyoma and angioleiomyoma – two variants with unique features. A more thorough description of leiomyomas can be found in Chapter 11.

Incidence, age, breed, sex, and site

These tumors are rare and have been reported in dogs and cat.15,16 The more common variant is of arrector pili muscle origin (piloleiomyoma), and therefore most tumors are on the dorsum, with fewer on the limbs and muzzle. Tumors arising from small dermal veins (angioleiomyomas) are less common, and can arise anywhere. There is no age, breed, or sex predilection.

There is often close association with the resident arrector pili ­ uscles and hair follicles. m Angioleiomyomas have a similar histological appearance but close examination can usually find the associated blood vessel wall apposed to the periphery, or vascular clefts within the tumor. Tumors with nuclear pleomorphism, mitoses, and local infiltration have been described and have been called piloleiomyosarcomas and angioleiomyosarcomas (Figure  5.14B) because of their more aggressive histologic features but there is no other evidence that they are malignant.

Growth, metastasis, and treatment

Typical tumors are circumscribed and cured by complete excision. Some of the tumors with features consistent with sarcomas have recurred locally, but metastasis has not been reported.

References

Most tumors present as solitary firm nodules in the dermis. Rarely, multiple tumors occur.15,16 Histologically, piloleiomyomas are usually circumscribed proliferations of monomorphic spindle cells with a classic smooth muscle appearance: abundant bright eosinophilic cytoplasm with an oblong to bullet‐shaped nucleus. Many cells have a slightly foamy perinuclear zone  –  a manifestation of glycogen accumulation. Mitoses are not seen. The cells have little to no stroma, and are arranged in long interwoven fascicles (Figure 5.14A).

1. Enzinger, F.M. and Weiss, S.E. (1995) Soft Tissue Tumors, 3rd edn. Mosby, St. Louis, MO. 2. Avallone, G., Helmbold, P., Caniatti, M., et  al. (2007) The spectrum of canine cutaneous perivascular wall tumors: morphologic, phenotypic and clinical characterization. Vet Pathol 44:607–620. 3. Stefanello, D., Avallone, G., Ferrari, R., et al. (2011) Canine cutaneous perivascular wall tumors at first presentation: clinical behavior and prognostic factors in 55 cases. J Vet Intern Med 25:1398–1405. 4. Avallone, G., Boracchi, P., Stefanello, D., et  al. (2014) Canine perivascular wall tumors: high prognostic impact of site, depth, and completeness of margins. Vet Pathol 51:713–721. 5. Bostock, D.E. and Dye, M.T. (1980) Prognosis after surgical excision of canine fibrous connective tissue sarcomas. Vet Pathol 17:581–588. 6. Postorino, N.C., Berg, R.J., Powers, B.E., et al. (1988) Prognostic variables for canine hemangiopericytoma: 50 cases (1979–1984). J Am Anim Hosp Assoc 24:501–509. 7. Dennis, M.M., McSporran, K.D., Bacon, N.J., et  al. (2011) Prognostic factors for cutaneous and subcutaneous soft tissue sarcomas in dogs. Vet Pathol 48: 73–84. 8. Chijiwa, K., Uchida, K., and Tteyama, S. (2004) Immunohistochemical evaluation of canine peripheral nerve sheath tumor and other soft tissue sarcomas. Vet Pathol 41:307–318.

A

B

Gross and histologic features

Figure 5.14  (A) Piloleiomyoma, skin, canine. Tumors are usually in the superficial dermis adjacent to hair follicles and their arrector pili muscles.

(B) Angioleiomyosarcoma, skin, canine. This tumor was intimately associated with dermal blood vessels, seen at the left side of the tumor. Nuclear density and pleomorphism are consistent with a sarcoma. Positivity for smooth muscle actin confirms the diagnosis.

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9. Schulman, F.Y., Johnson, T.O., Facemire, P.R., and Fanburg‐Smit, J.C. (2009) Feline peripheral nerve sheath tumors: histologic, immunohistochemical, and clinicopathologic correlation (59 tumors in 53 cats). Vet Pathol 46:1166–1211. 10 Evans, S.M. (1987) Canine hemangiopericytoma. A retrospective analysis of response to surgery and orthovoltage radiation. Vet Radiol 28:13–16. 11 De Lahunta, A. (2010) Feline nerve sheath tumors versus feline peripheral nerve sheath tumors. Vet Pathol 47:758. 12 Nielsen, A.B., Jensen, H.E., and Leifsson, P.S. (2011) Immunohistochemistry for 2′,3′‐cyclic nucleotide‐3′‐phosphohydrolase in 63 bovine peripheral nerve sheath tumors. Vet Pathol 48:798–802. 13 Scott, D.W. (1988) Large Animal Dermatology. W.B. Saunders Co., Philadelphia, PA, pp. 432–446.

14 Schoniger, S., Valentine, B.A., Fernandez, C.J., and Summers, B.A. (2011) Cutaneous schwannomas in 22 horses. Vet Pathol 48:433–442. 15 Liu, S.M. and Mikaelian, I. (2003) Cutaneous smooth muscle tumors in the dog and cat. Vet Pathol 40:685–692. 16 Jung, J., Kang, S.C., Park, D.S., et al. (2009) Cutaneous smooth muscle tumors in 3 dogs. Korean J Vet Res 49: 63–66.

Lipoma

This is a very common benign tumor of well‐differentiated adipocytes (Figure 5.15A) seen in most domestic animals. Rare tumors will contain collagen (fibrolipomas) or clusters of small blood ­vessels (angiolipomas) (Figure 5.15B).

A

B

C

Figure 5.15  Lipoma, subcutis, canine. (A) Lipoma. (B) Angiolipoma. (C) Infiltrative lipoma. Adipocytes infiltrate the skeletal muscle (red areas).

Mesenchymal Tumors of the Skin    159

Incidence, age, breed, and sex

Lipomas are most common in the dog and uncommon in other species. Mesenteric lipomas of horses are described in Chapter 13. Female dogs and castrated male Siamese cats appear predisposed to the formation of these tumors, and some animals will have multiple tumors at presentation.

Site and gross morphology

Predominantly subcutaneous, lipomas occur most commonly in the trunk, gluteal region, and proximal limbs. The tumors are well circumscribed, unencapsulated, soft white to yellow masses, indistinguishable from normal fat. Most are freely moveable over the underlying deeper tissues and can be easily shelled out. They have a distinctive greasy feel and float in water or formalin. A small percentage of lipomas are infiltrative.1 These look and feel like their counterparts but invade adjacent connective tissue and skeletal muscle, giving the area a marbled appearance (Figure 5.15C).

Histological features

The cells of lipomas are identical to those in normal adipose tissue. Large clear vacuoles replace the cytoplasm, with peripheralization and compression of nuclei. Some tumors have regions of necrosis, inflammation, and/or fibrosis. The predominant infiltrating cells are foamy macrophages, which occasionally are epithelioid and so numerous that they mimic the pleomorphic lipoblasts seen in liposarcoma. However, the overall pattern and general bland appearance of the macrophages precludes this diagnosis.

Growth and treatment

The majority of lipomas are slow‐growing expansile masses that are cured by excision. Infiltrative lipomas, although benign, are more difficult to completely excise and may require multiple excisions.

Liposarcoma

This malignant counterpart to the lipoma is rare in domestic animals but can be divided into subtypes based on cellular morphology. There is not an accepted classification for these subtypes, and most authors have simply applied nomenclature from the human literature.2 In this author’s experience, liposarcomas in animals can be divided into well‐ differentiated, anaplastic (pleomorphic), and myxoid variants. Myxoid liposarcoma is the most distinctive of the subvariants.3 A recent report describes the histology, proliferative rates, and immunohistochemistry (MDM2 CDK4) of three subtypes of liposarcoma in 53 dogs.6

Incidence, age, breed, and sex

Liposarcomas are the most common soft tissue sarcomas in humans; they occur in all domestic species but are rare. They are probably most common in the canine. Shetland sheepdogs are preferentially affected. There is no sex predisposition, but the incidence increases with age.

Site and gross morphology

The gross appearance of these tumors varies depending on the amount of lipid they produce. Some mimic lipomas, but others are firm, gray/white subcutaneous masses infiltrating adjacent soft tissues and muscle.

Histological features

Most tumors are composed of round to polygonal cells arranged in sheets, with little or no collagenous stroma. In the well‐ differentiated­variant (Figure  5.16A), the majority of cells resemble normal adipocytes, with a single clear fat vacuole and

a peripheral nucleus. Other cells have variably sized round to oval nuclei and abundant cytoplasm that contains variably sized lipid droplets. The diagnosis in these cases is clear. Compared to lipoma the nuclei in liposarcomas are generally larger and have varying degrees of pleomorphism. The anaplastic or pleomorphic variant (Figure 5.16B) has cells of highly variable morphology mixed with large, bizarre multinucleated cells. Diagnostic intracytoplasmic fat vacuoles are usually present, but only in a small percentage of cells. This rare tumor mimics the pleomorphic variants of histiocytic sarcoma (see Chapter  8) and anaplastic sarcoma with giant cells (malignant fibrous histiocytoma). The myxoid variant (Figure 5.16C) is identified by the presence of scattered spindle cells, lipocytes, and lipoblasts loosely arranged in a “bubbly” mucoid stroma that is alcian blue positive. Resembling myxosarcoma, this tumor can sometimes be differentiated by the presence of lipid‐filled vacuoles within the cytoplasm of some of the neoplastic cells. Demonstration of lipid may require histochemistry or ultrastructural study but is clinically unimportant and rarely warranted.

Growth and metastasis

Despite histological distinctions, there appears to be no difference in the biologic behavior of these variants of liposarcoma. Recurrence is uncommon, though more likely in pleomorphic variants. Reports of metastasis, usually to lung, liver, or bone, are rare.4,5

Treatment

Complete surgical excision is the best approach.5

References

1. Bergman, P.J., Withrow, S.J., Straw, R.C., and Powers, B.E. (1994) Infiltrative lipoma in dogs: 16 cases (1981–1992). J Am Vet Med Assoc 205:322–324. 2. Weiss, S.E. and Goldblum, J.R. (2001) Enzinger and Weiss’s Soft Tissue Tumors, 4th edn. Mosby, St. Louis, MO, pp. 648–690. 3. Messick, J.B. and Radin, M.J. (1989) Cytologic, histological and ultrastructural characteristics of a canine myxoid liposarcoma. Vet Pathol 26:520–522. 4. Theilen, G.H. and Madewell, B.R., eds. (1987) Veterinary Cancer Medicine, 2nd edn. Lea and Febiger, Philadelphia, p. 292. 5. Baez, J.L., Hendrick, M.J., Shofer, F.S., et al. (2004) Liposarcomas in dogs: 56 cases (1989–2000). J Am Vet Med Assoc 224:887–891. 6. Avallone, G., Roccabianca, P., Crippa, L., et al. (2016) Histological classification and immunohistochemical evaluation of MDM2 and CDK4 expression in canine liposarcoma. Vet Pathol 53:773–780.

Hemangioma Incidence, age, breed, sex, and site

Common in dogs, but rare in other domestic animals, hemangiomas are benign tumors of vascular endothelium. They are dermal or subcutaneous tumors occurring anywhere on the body. There is evidence that in some light‐skinned, short‐haired dog breeds, hemangiomas may be caused by prolonged exposure to sunlight.1 Individuals with solar‐induced vascular neoplasms can have multiple tumors – hemangiomas, hemangiosarcomas, or intermediate forms – simultaneously or sequentially. Hemangiomas can occur in very young horses, usually on the distal limbs. Hemangiomas in swine are rare, and when present they are usually seen in the scrotum of Yorkshire and Berkshire boars.2 In cattle, horses and pigs, hemangiomas can be congenital.2,3 There is considerable overlap (and subsequent confusion) between congenital hemangiomas in cattle and bovine juvenile angiomatosis (see below under Angiomatosis).

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A

B

C

Figure 5.16  Liposarcoma, subcutis, canine. (A) Well differentiated. Most cells have large fat vacuoles but there is nuclear enlargement and mild pleomor-

phism. (B) Pleomorphic. Nuclei are highly pleomorphic and multinucleated cells are seen. Few cells retain fat vacuoles. (C) Myxoid. Rare lipid‐containing cells distinguish this tumor from a myxosarcoma.

Gross morphology

Canine hemangiomas are well‐demarcated masses that range from bright red to dark brown. The darker‐colored specimens are often mistaken for melanomas. In larger specimens, the cut surface reveals a honeycomb pattern of fibrous trabeculae separating blood‐filled cavities. In the horse and pig, there is a verrucous variant of hemangioma that is less well demarcated, multinodular, and associated with epidermal hyperkeratosis.2

Histological features

Most tumors are well circumscribed and are composed of variably sized vascular spaces filled with erythrocytes and lined by a single layer of uniform endothelial cells with inconspicuous nuclei (Figure  5.17A,B). Organized thrombi are often found in tumors, with foci of hemosiderosis. Variants of these tumors have been called cavernous or capillary, based on the size of the vascular channels. In the cavernous type, the large channels are separated by a

Mesenchymal Tumors of the Skin    161

A

B

C Figure 5.17  (A) Hemangioma. (B) Higher magnification showing vascular channels containing red blood cells and lined by inconspicuous endothelial cells.

(C) Gross appearance of solar‐induced hemangiomas, ventral abdomen, canine. (Images courtesy of Michael Goldschmidt.)

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fibrous connective tissue stroma, which can contain lymphocytes and other inflammatory cells. Capillary variants have little stroma, a more cellular appearance, and larger, sometimes pleomorphic nuclei. Mitotic figures are rare. Solar‐induced hemangiomas tend to be located more superficially in the dermis, and are usually less circumscribed (Figure  5.17C). There are often regions of early malignant transformation, characterized by spotty nuclear enlargement and hyperchromasia.

retrospective study found, 4 out of 5 tumors were on the white‐ haired portions of the skin.5

Growth, metastasis, and treatment

Histological features

Hemangiomas are generally slow‐growing and are cured by complete excision. Cryosurgery may be necessary in some of the verrucous variants in large animals.2 One recent report described spontaneous regression of multiple congenital hemangiomas in a calf.3 Complete excision of solar‐induced hemangiomas is typically curative, but new tumors can arise if exposure to sunlight continues.

Hemangiosarcoma Incidence, age, breed, sex, and site

Hemangiosarcoma most commonly presents as a multicentric disease involving the spleen, liver, lungs, and right auricle of dogs, especially the German shepherd and golden retriever breeds. The tumor is less frequently seen in the cat, and rarely in large domestic animals.2 The incidence in cats appears to be on the rise, and it is seen on the head (eyelids, especially), distal limbs, and paws.4 Unusual solitary sites of hemangiosarcoma in the dog include the urinary bladder serosa and the capsule of the kidney. Cutaneous involvement can be solitary or, rarely, part of the multicentric syndrome. Some canine, feline, and equine dermal hemangiosarcomas appear to be the result of chronic solar irradiation.1,4 Short‐haired, light‐skinned dog breeds such as greyhounds, whippets, and American pit bulls are at increased risk.1 White‐haired male cats have an increased incidence of these tumors on the head and pinnae.4 Solar irradiation has been incriminated as the cause of some hemangiosarcomas on the conjunctiva of the eyelids of white horses. Vascular tumors are rare in goats, but in the only

A

Gross morphology

Dermal or subcutaneous hemangiosarcoma is usually a single well‐ defined mass that is red/brown to black, soft to firm, and exudes blood when cut. More aggressive tumors will be poorly delineated and infiltrate adjacent tissues. Histologically, the neoplastic cells are highly variable, ranging from spindle‐shaped to polygonal to ovoid, and usually form recognizable vascular clefts or channels somewhere in the tumor (Figure  5.18A). The cells lining the clefts often have prominent, bulging nuclei that are pleomorphic and hyperchromatic. Mitotic figures are frequent. In some areas, the stroma between the clefts is acellular, hyaline, and brightly eosinophilic. There can be large solid areas, indistinguishable from fibrosarcoma or other poorly differentiated sarcomas. Conversely, there can be large areas of hemorrhage with few cells that mimic hematomas. One report describes an uncommon epithelioid variant of hemangiosarcoma in dogs, horses, and cows.6 Vasoformative slits (which are often small or inconspicuous) can be present in none, some, or all of the neoplasm. When present, they are lined by polyhedral, columnar, or “hobnail” cells, giving the tumor a glandular appearance (Figure 5.18B).

Additional diagnostic criteria

Cytological diagnosis of hemangiosarcoma can be difficult because of the large amount of hemorrhage in the sample and the relatively low numbers of tumor cells compared with amount of blood. Pleomorphic spindle cells may be seen, but numbers can be small, and the cells nonspecific. Traditionally, factor VIII immunopositivity has been considered diagnostic of hemangiosarcoma. Unfortunately, experience has shown that some hemangiosarcomas will not stain with this antibody and that some tumors with the histological appearance of lymphangiomas or lymphangiosarcomas will stain for factor VIII. The use of

B

Figure 5.18  Hemangiosarcoma canine, skin. (A) Hemangiosarcoma, irregularly shaped and sized vessels with plump endothelial cells lining and filling trabeculae between lumens. (B) Epithelioid variant showing large polygonal cells and a glandular pattern.

Mesenchymal Tumors of the Skin    163

CD31 (PECAM) alone or in concert with factor VIII has been shown to be more specific, and may be necessary in cases of epithelioid hemangiosarcoma.6 CD34 has also classically been used as a marker for hemangiosarcoma, and produced the most intense staining in a study on 61 feline hemangiosarcoma.7,8 However, it also stained a high percentage of other nonvascular tumors. This lack of specificity limits the use of CD34 to confirm vascular tumors. A report on the use of factor VIII, CD31 and CD34 in feline vascular and nonvascular tumors details the utility of these different markers.8 Lymphatic endothelial cell immunomarkers are presented in the next section.

Growth and metastasis

Cutaneous hemangiosarcomas are less aggressive than their visceral counterparts, with lower metastatic potential and longer survival times.1 Grading systems have not proven prognostically beneficial. Studies suggest that the depth and degree of infiltration of the neoplasm is more predictive of outcome.8

Treatment

Surgical excision is the preferred choice for dermal or subcutaneous hemangiosarcomas. Various chemotherapeutic regimes have been attempted on dogs with multicentric visceral disease with little success.9,10

Lymphangioma and lymphangiosarcoma General considerations and classification

These are tumors of lymphatic endothelium. As with myxomas and myxosarcomas, the distinction between benign and malignant tumors can be minimal.

Incidence, age, breed, and sex

Most of the neoplastic cells in lymphangiomas are bland, and mitoses are not evident. The malignant tumor differs little from its benign counterpart except for its increased cellular and nuclear pleomorphism. Cells lining the clefts and channels have more rounded nuclei with hyperchromatism and a few mitotic figures (Figure 5.19C).

Additional diagnostic criteria

The distinction between hemangioma/hemangiosarcoma and lymphangioma/lymphangiosarcoma using light microscopy is based on the apparent close apposition of the cells on the collagen bundles and the relative lack, or total absence of blood cells in the channels in the latter. Ultrastructurally, lymphangiosarcomas are reported to lack a basal lamina and have discontinuous endothelial cells as opposed to hemangiosarcomas, which have a basal lamina and continuous endothelial cells.13 Factor VIII immunostaining is positive in most hemangiosarcomas, as is CD31 but also label in some lymphangiosarcomas. Specific lymphatic endothelial cell immunomarkers (lymphatic vessel endothelial receptor 1 (LYVE‐1) and Prospero‐related homeobox gene‐1 (PROX‐1) for example) are required for a definitive diagnosis.11,12

Growth, metastasis, and treatment

The infiltrative growth of these tumors makes borders difficult to assess. Recurrence is common. In the few reported cases of lymphangiosarcoma, metastasis occurred to regional lymph nodes, lungs, and abdominal viscera.14 Early surgical excision can be curative. One reported case of lymphangioma was cured by radiation therapy,15 but lymphangiosarcomas were not responsive to any other modalities.14

These are rare tumors in all species, but are most commonly reported in dogs, cats, and horses. Many are congenital or occur within the first few months of life, leading some to interpret these lesions as nevi rather than neoplasms. A somewhat unique manifestation of this tumor, seen in the caudoventral abdominal wall of cats, was previously called “feline ventral abdominal angiosarcoma.” It has now been identified as a lymphangiosarcoma by immunohistochemical analysis.11,12

Angiomatosis

Site and gross morphology

Incidence, age, breed, sex, and site

Lymphangiomas and lymphangiosarcomas tend to be found in the subcutis along the ventral midline and limbs as poorly demarcated dermal masses that are soft and spongy to the touch. They are often wet on cut surface and exude a clear serous fluid. In the feline ventral abdominal syndrome, there is more blood exudation throughout the neoplasm, leading to a purplish “bruised” appearance of the affected area (Figure 5.19A). A distinct mass is usually not discernible, but the area can vary in texture from soft and gelatinous to firm.

Histological features

Histologically, the neoplastic cells resemble normal endothelial cells; however, the cells grow directly on bundles of dermal collagen, dissecting them and forming numerous clefts and channels (Figure 5.19B). The majority of clefts are devoid of cells, but occasional erythrocytes may be seen, presumably due to trauma or extravasation from nearby blood vessels. As mentioned above, there is more extensive extravasation of blood into and around the clefts in feline ventral abdominal tumors.

This term refers to a group of proliferative vascular lesions with various clinical and histological manifestations. Though rare, specific syndromes occur in domestic animals. These, described below, include bovine cutaneous angiomatosis, progressive ­angiomatosis in cats and dogs, and scrotal vascular hamartoma in dogs. Bovine cutaneous angiomatosis Reports of this rare syndrome are few and have described the vasoproliferative lesions as hamartomas, angiomatosis, or hemangiomas.3,16 It is unclear whether there is a spectrum of vasoproliferative lesions in this syndrome or whether these reports represent different diagnoses of the same lesion. The signalment in the reports is similar. Lesions occur in young adult cattle in Great Britain, France, and the United States.16 The mean age is 5.5 years but some animals are less than a year old. Most masses are on the back, but they can be seen anywhere on the skin.

Gross morphology

Lesions occur as single or multiple, poorly circumscribed, soft, fleshy, sessile to pedunculated masses. They range from pink to gray to red. Some lesions can bleed profusely and uncontrollably.

Histological features

Most reports of bovine angiomatosis describe a nonencapsulated mixture of arteries, veins, and capillaries that is associated with an often intense inflammatory infiltrate. The proliferating vessels are of

164    Tumors in Domestic Animals

A

B

C

Figure  5.19  (A) Ventral abdominal lymphangiosarcoma, feline. Note bruising due to extravasation of blood in the neoplasm. (B) Lymphangioma, skin,

canine. Note thin, flat endothelium that lines collagen filled trabeculae, and lumens devoid of red blood cells. (C) Histology of ventral abdominal lymphangiosarcoma, feline.

various calibers, and in some areas the lumina are indistinct. Separating the vessels are scattered fibroblasts and variable amounts of collagen. Authors liken the lesion to exuberant granulation tissue, but the classic perpendicular orientation of vessels to collagen seen in granulation tissue is lacking. Bovine angiomatosis has many histologic similarities to lobular capillary hemangioma, a variant in humans also called granulation tissue‐type hemangioma. These entities can be very difficult to differentiate, leading to the confusion regarding the true nature of bovine cutaneous angiomatosis.

Growth and treatment

These are benign lesions that can be cured by complete excision. Rare tumors can be associated with extensive hemorrhage and blood loss. Progressive angiomatosis

Incidence, age, breed, sex, and site

Progressive angiomatosis can occur anywhere on the body of cats and dogs but is most commonly seen in the digital area.17,18 There is

Mesenchymal Tumors of the Skin    165

no breed, age, or sex predilection. Although the exact cause is uncertain, in most cases the lesion is believed to be a reactive vasoproliferative response, perhaps to previous or repeated trauma. Rare cases have occurred in very young animals, suggesting a congenital hamartomatous etiology.

Gross morphology and histological features

The lesions can be unapparent grossly, other than some localized swelling or thickening, but many animals have irregular red/blue

macules or patches that can feel spongy, and blanch when compressed. Traumatized lesions sometimes ooze blood. The affected area in the dermis and subcutis has a disorganized array of variably sized blood‐filled vascular structures. The stroma between can be normal or myxomatous. The vascular structures are a mixture of capillaries, small arterioles, veins, and larger cavernous spaces lined by mature or slightly enlarged endothelial cells (Figure 5.20A). In some areas the structures are interconnected by anastomosing vascular clefts or channels. Thrombi are sometimes

A

B

C

Figure 5.20  Various histologic manifestations of angiomatosis lesions in dogs and cats. Note the haphazard arrangement of blood vessels, with muscle

walls admixed with vascular clefts. (A) Progressive angiomatosis, skin, feline. (B) Vascular hamartoma, scrotum, canine (low magnification). (C) Vascular ­hamartoma, scrotum, canine (high magnification). Note the disorganized vascular stuctures of various calibers, some with smooth muscle walls.

166    Tumors in Domestic Animals

present in the vessels, and hemosiderin deposits and a few mixed inflammatory cells can be seen in the stroma. Mitoses are not seen. Lysis of digital bone is sometimes a consequence of this compressive and progressive proliferation.17

Additional diagnostic criteria

Some lesions can mimic low‐grade hemangiosarcoma, especially in small biopsy samples. However, the presence of recognizable capillaries and blood vessels with muscle walls precludes that diagnosis.

Growth, metastasis, and treatment

As the name implies, this type of angiomatosis is slowly infiltrative and progressive. Digital lesions are the most aggressive, and can extend long distances up the limb. Complete excision is often difficult, and amputation may be necessary for a cure. Treatment using other modalities has been unsuccessful. Scrotal vascular hamartoma

Incidence, age, breed, sex, and site

This uncommon lesion is seen only in dogs, and breeds with pigmented scrotal skin are predisposed. It first appears in middle‐aged individuals and progresses and enlarges with time.

Gross morphology and histological features

Initially, the lesion is a region of brown/black discoloration on the scrotal skin. It develops into a firm plaque in the superficial dermis. Histologically, there is a poorly circumscribed proliferation of vessels in the dermis (Figure 5.20B,C). The redundant vessels range from large hyperplastic arteries with thick muscular walls to capillary buds and are lined by endothelial cells with rounded nuclei. Most typically, the larger vessels are central and the smaller ones, peripheral. Atypia and mitoses are rare, but the proliferative capillary areas can resemble hemangioma or hemangiosarcoma.

Additional diagnostic criteria

The recognition of variably sized, disorganized, but relatively normal vessels with the characteristics of veins, arterioles, and capillaries distinguishes this lesion from hemangioma or hemangiosarcoma.

Treatment

Complete surgical excision is curative.

References

1. Hargis, A.M., Ihrke, P.J., Spangler, W.L., and Stannard, A.A. (1992) A retrospective clinicopathologic study of 212 dogs with cutaneous hemangiomas and hemangiosarcomas. Vet Pathol 29:316–328. 2. Scott, D.W. (1988) Large Animal Dermatology. W.B. Saunders Co., Philadelphia, pp. 432–446. 3. Priestnall, S.L., DeBellis, F., Bond, R., et al. (2010) Spontaneous regression of congenital hemangiomas in a calf. Vet Pathol 47:343–345. 4. Miller, M.A., Ramos, J.A., and Kreeger, J.M. (1992) Cutaneous vascular neoplasia in 15 cats: Clinical, morphologic, and immunohistochemical studies. Vet Pathol 29:329–336. 5. Bildfell, R.J., Valentine, B.A., and Whitney, K.M. (2002) Cutaneous vasoproliferative lesions in goats. Vet Pathol 39:273–277. 6. Warren, A.L. and Summers, B.A. (2007) Epithelioid variant of hemangioma and hemangiosarcoma in the dog, horse, and cow. Vet Pathol 44:15–24. 7. Jennings, R.N., Miller, M.A., and Ramos‐Vara, J.A. (2012) Comparison of CD34, CD31, and Factor VIII–related antigen immunohistochemical expression in feline vascular neoplasms and CD34 expression in feline nonvascular neoplasms. Vet Pathol 49:532–537. 8. Ward, H., Fox, L.E., Calderwood‐Mays, M.B., et al. (1994) Cutaneous hemangiosarcoma in 25 dogs: a retrospective study. J Vet Intern Med 8:345–348.

9. Hammer, A.S., Couto, C.G., Filppi, J., et al. (1991) Efficacy and toxicity of VAC chemotherapy (vincristine, doxorubicin, and cyclophosphamide) in dogs with hemangiosarcoma. J Vet Intern Med 5:160–166. 10. 10.Withrow, S.J. and MacEwen, E.G. (1996) Small Animal Clinial Oncology. W.B. Saunders, Philadelphia, pp. 524–526. 11. Galeotti, F., Barzagli, F., Vercelli, A., et  al. (2004) Feline lymphangiosarcoma – definitive identification using a lymphatic vascular marker. Vet Dermatol 15:13–18. 12. Sugiyama, A., Takeuchi, T., Morita, T., et al. (2007) Lymphangiosarcoma in a cat. J Comp Pathol 137:174–178. 13. Swayne, D.E., Mahaffey, E.A., and Haynes, S.G. (1989) Lymphangiosarcoma and haemangiosarcoma in a cat. J Comp Pathol 100:91–96. 14. Williams, J.H. (2005) Lymphangiosarcoma of dogs: a review. J South African Vet Assoc 76:127–131. 15. Turrel, J.M., Lowenstine, L.J., and Cowgill, L.D. (1988) Response to radiation therapy of recurrent lymphangioma in a dog. J Am Vet Med Assoc 193:1432–1434. 16. Watson, T.D. and Thompson, H. (1990) Juvenile bovine angiomatosis: a syndrome of young cattle. Vet Rec 127:279–282. 17. Bulman‐Fleming, J.C., Gibson, T.W., and Kruth, S.A. (2009) Invasive cutaneous angiomatosis and thrombocytopenia in a cat. J Am Vet Med Assoc 234:381–384. 18. Kim, Y., Reinecke, S., and Malarkey, D.E. (2005) Cutaneous angiomatosis in a young dog. Vet Pathol 42:378–381.

Canine cutaneous histiocytoma

Immunohistochemical and ultrastructural studies of canine cutaneous histiocytoma indicate that this round cell tumor is composed of epidermal dendritic cells and is a localized form of self‐limiting Langerhans cell histiocytosis.1–3

Incidence, age, breed, and sex

This benign tumor is extremely common and is unique to dogs. The majority occurs in dogs less than 4 years of age, but dogs of any age can be affected. Purebred dogs are predisposed toward development of histiocytomas, including Scottish terriers, bull terriers, boxers, English cocker spaniels, flat‐coated retrievers, doberman pinschers, and Shetland sheepdogs.

Site and gross morphology

This is the classic button tumor, a smooth, pink, raised mass usually covered by alopecic skin. Ulceration is common, leading to central umbilication. Head and pinnae are preferential sites. A small percentage of dogs will have multiple cutaneous histiocytomas either synchronously or sequentially.4 This is presumably due to an alteration in host immunity but does not reflect any change in the benign behavior of the tumor(s). A separate rare syndrome where there are multiple, sometimes coalescing, masses that are histologically identical to histiocytomas occurs in dogs. It has been called Langerhans cell histocytosis, and has a more aggressive behavior with spread to viscera. This entity and other histiocytoses are discussed in Chapter 8.

Histological features

The histological appearance of cutaneous histiocytoma varies greatly, depending on the age of the lesion and the degree of necrosis and secondary inflammation. Typically, there is a dermal infiltrate of densely packed, mildly pleomorphic, round cells arranged in cords and sheets. There is little or no stroma, and adnexal structures are obliterated. The cells extend from the dermoepidermal junction where the parallel, cord arrangement is most prominent, to the deep dermis and panniculus (Figures 5.21, 8.3, and 8.4). Deeper portions of the neoplasm tend to be narrower than those near the epidermis, giving the tumor a wedge‐shaped appearance at low magnification. The neoplastic cells look histiocytic, with bean‐shaped to ovoid nuclei

Mesenchymal Tumors of the Skin    167

A

B

Figure 5.21  Cutaneous histiocytoma. (A) Neoplastic cells immediately subjacent to the epidermis or infiltrating the epidermis are features of canine histiocytoma. (B) Cytology of neoplastic cells: fairly abundant light blue cytoplasm, round to oval‐shaped cells and nuclei. These tumors may have a high mitotic count and or lymphocytic inflammation associated with regression.

and moderate, lightly eosinophilic cytoplasm in histologic preparations vs lightly basophilic in cytologic preparations (Figure  5.21B). Mitotic figures are numerous, but nuclear atypia and multinucleated forms are rare. In some tumors, clusters of neoplastic cells infiltrate the epidermis, mimicking the so‐called Pautrier abscesses of cutaneous lymphoma. Dense aggregates of mature lymphocyes are commonly seen at the base of the tumor and are presumed to be part of the host’s immune response and to be partially responsible for tumor regression. In some cases these inflammatory cells predominate, obscuring the residual histiocytic tumor cells. However, the overall wedge‐shaped appearance of the lesion at low magnification, coupled with the typical clinical presentation (e.g., button tumor on the head of a young dog), should aid the diagnosis. Older tumors are often ulcerated, and areas of necrosis, which can be extensive, are present in some regressing tumors, usually at the deep and lateral margins.

Additional diagnostic criteria

Studies have shown the tumor cells in canine histiocytoma to have an immunophenotype of epidermal dendritic cells known as Langerhans cells.1–3 Canine histiocytoma cells express CD18, CD1 molecules (CD1a, ‐b, and ‐c), CD11c, and major histocompatibility complex class II. They express E‐cadherin, but do not express Thy‐1 or CD4, which are positive in other non‐Langerhans cell dendritic cells in humans. Ultrastructurally, the cells have coated vesicles, regularly laminated bodies, paracrystalline structures, and deep invaginations of the plasma membrane, all of which are structures seen in a human Langerhans cell tumor.1 Birbeck’s granules, characteristic rod‐shaped granules found in the cytoplasm of human Langerhans cells by electron microscopy, are not present in canine Langerhans cells. In approximately 35% of tumors, the majority of cells stain strongly

positive for lysozyme; in another 25%, there is regional positivity.5 Lysozyme is nonspecific and stains a variety of cell types.

Growth and treatment

Histiocytomas have been referred to, humorously, as “surgical emergencies.” One must remove them quickly before they regress. Complete excision is curative. Occasional tumors will recur, but it is unclear whether these are true recurrences or de novo tumors.

Reactive histiocytosis

The syndrome of reactive histiocytosis comprises cutaneous histiocytosis and systemic histiocytosis. Both proliferations can affect the skin, but in the cutaneous form infiltrates are limited to the skin and draining lymph nodes while systemic histiocytosis extends into internal organs. It is not known if they are a continuum or separate diseases. They are not neoplastic but unfortunately many cases of systemic histiocytosis progress and result in euthanasia. They are uncommon, and are characterized by multifocal nodular cutaneous proliferation of histiocytes, shown to be of dermal interstitial dendritic cell immunophenotype.6,7 These lesions are not thought to be neoplastic, but are similar to the ­proliferative histiocytoses of humans (Letterer–Siwe syndrome, Hand–Schüller–Christian disease). (See Chapter 8.)

Incidence, age, breed, and sex

Cutaneous histiocytosis has only been described in the dog, most often in collies, border collies, Shetland sheepdogs, briards, Bernese mountain dogs, and golden retrievers. There is no age or sex predilection.

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Systemic histiocytosis occurs primarily in Bernese mountain dogs, usually in young to middle‐age males.7

Site and gross morphology

Lesions can occur anywhere on the skin, but especially on the face, planum nasale, and scrotum. Single or multiple and coalescing nodules are seen, covered by epidermis that is sometimes alopecic or ulcerated. There can be bulbous enlargement of the planum nasale with swelling of the underlying nasal mucosa. This leads to difficulty in breathing and characteristic “bubble blowing.”8

Histological features

The epidermotropism seen in histiocytomas is absent. Sheets of large histiocytic cells with pale eosinophilic, often vacuolated cytoplasm are present in the dermis and/or subcutis, accompanied by diffusely scattered mature lymphocytes, neutrophils, and eosinophils (Figures 5.22 and 8.15). There is no organization to this mixed cellular proliferation, other than a tendency to aggregate around and infiltrate blood vessels (see Figure 8.16). Infarction can be a prominent feature because of the blood vessel involvement. The histiocytes are mildly pleomorphic, and mitotic figures are sometimes present, but nuclear atypia, giant cells with bizarre nuclei and abnormal mitoses are not seen. The lesion in reactive histiocytoses as a whole resembles disorganized, undirected inflammation. Special stains and cultures are invariably negative for microorganisms.

Additional diagnostic criteria

There is considerable clinical and histological overlap between cutaneous histiocytosis and systemic histiocytosis. Some solitary lesions wax and wane, but what distinguishes systemic histiocytosis from cutaneous histiocytosis is that in the former there is progression to widespread involvement of lymph nodes and viscera. Histiocytes in systemic and cutaneous histiocytosis express similar dendritic and leukocytic cell markers to those seen in

histiocytomas (CD1a, CD1b, CD1c, CD18, MHC II, and CD11c). However, they also express Thy‐1 and CD4 – a feature that can be used to distinguish them from cutaneous histiocytoma. The most specific dendritic cell markers require frozen sections and are rarely used in a diagnostic setting. Cutaneous histiocytomas have clearly different histological features from the histiocytoses. Histiocytic sarcoma complex can be differentiated from systemic and cutaneous histiocytosis because the former typically has nuclear atypia, giant cells, bizarre nuclei, and abnormal mitoses.

Growth and treatment

Cutaneous masses in cutaneous and systemic histiocytosis can be slow or fast growing. There can be spontaneous regression of some lesions, and others are responsive, at least temporarily, to steroid therapy. Systemic histiocytosis is non‐neoplastic, but its behavior is progressive, and cannot be considered benign since most dogs with this disease are euthanized. The more aggressive nature of systemic histiocytosis may be a manifestation of the genetically determined inability of the Bernese mountain dog to control these cell proliferations.

Histiocytic sarcoma complex

This is the most aggressive syndrome in the spectrum of histiocytic diseases and the most obscure in origin. Recent investigations suggest that there are three entities in this complex: localized histiocytic sarcoma, disseminated histiocytic sarcoma, and hemophagocytic histiocytic sarcoma. Cells in the first two entities are of interstitial dendritic cell immunophenotype. Hemophagocytic histiocytic sarcoma is a distinctive clinicopathologic entity thought to arise from macrophages in the splenic red pulp, originally of bone marrow origin. (See Chapter 8.) Histiocytic sarcoma is a single neoplasm arising in one location. When the localized tumor metastasizes beyond the regional lymph node, the disease is called disseminated histiocytic sarcoma. Malignant histiocytosis is a name that has been and continues to be used to describe an aggressive multivisceral infiltration by neoplastic histiocytes. Researchers in the field propose that the better name for this syndrome is disseminated histiocytic sarcoma.

Incidence, age, breed, and sex

First described in the Bernese mountain dog, this uncommon but highly malignant neoplasm has since been reported in various dog and cat breeds, as well as other domestic species.9–15 In the dog, there is a predilection for Bernese mountain dogs, rottweilers, golden retrievers, and flat‐coated retrievers.14

Site and gross morphology

Figure 5.22  Reactive histiocytosis, skin, canine. Sheets of large bland histiocytes with a few plasma cells and lymphocytes in the background.

Most commonly, neoplasms in the skin and subcutis of dogs are localized histiocytic sarcomas. Rarely, they are part of multi‐organ malignant histiocytosis. Regardless of nomenclature, tumors are usually first recognized in the skin/subcutis, usually around the joints of the limbs. At first presentation, there may be involvement of lymph nodes or viscera. Tumors in the skin of cats are rarely reported, and are usually part of multi‐organ malignant histiocytosis. However, one recent report described a periarticular tumor with only lymph node involvement, similar to localized histiocytic sarcoma of dogs.15 Skin lesions can be single or multiple, solitary or clustered. They are usually yellow‐tan nodules or plaques, covered by alopecic, thickened epidermis.

Mesenchymal Tumors of the Skin    169

Histological features

In many tumors, the predominant cells are large round to spindyloid cells with ovoid to reniform nuclei and abundant eosinophilic cytoplasm, sometimes containing phagocytosed erythrocytes, hemosiderin, or cellular debris (Figure  5.23A). The discrete cells form loose sheets with little or no stroma. Some cells resemble normal macrophages, but others will show marked variation in size and shape, with a range of 15–60 μm in diameter. Nuclei also vary in size and shape, are hyperchromatic, and often contain multiple prominent nucleoli. There is marked atypia, and numerous mitoses

are seen, many of which are bizarre. Multinucleate forms are often present in large numbers and show the same marked atypia (see Figure 8.8). Cells often have one or more clear cytoplasmic vacuoles. Inflammatory cells (e.g., neutrophils, lymphocytes, and plasma cells) can be seen scattered among the neoplastic cells but do not usually constitute a significant percentage of the total population. A spindle cell predominant form occurs in which there are pleomorphic spindyloid cells that form sheets or haphazardly arranged streams and bundles (Figure  5.23B). This form mimics a host of other spindle cell tumors (myofibroblastic sarcoma, anaplastic

A

B

C

Figure 5.23  Histiocytic sarcoma, skin, canine. (A) Round cell variant with multinucleated cells. (B) Spindle cell variant. There is scattered nuclear pyknosis. (C) CD18 immunostaining is strongly positive.

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sarcoma with giant cells, pleomorphic liposarcoma). Examination of multiple fields usually reveals the more typical round, discrete cells described above, enabling the correct diagnosis.

Additional diagnostic criteria

Cytological diagnosis of cells in the histiocytic complex can be challenging. Cells in the round cell predominant form have features reminiscent of large cell lymphoma and anaplastic plasma cell tumors. As mentioned above, the mixed cell population in the spindle cell predominant form are fairly nonspecific. Immunohistochemical analysis should reveal negative staining with lymphoid markers and positive staining for CD18 (Figure 5.23C) and more specific dendritic markers (CD1, CD11c, and MHC II). Plasma cell tumors should have some cells with a Golgi apparatus, eccentric nuclei, and cytoplasmic inclusions of immunoglobulins and can be ruled out if immunohistochemistry for multiple myeloma 1 (MUM1) is negative. However, anaplastic plasma cell tumors may have cytology and histology with numerous binucleated and multinucleated cells as well as positive immunohistochemistry for leukocytic origin, making the distinction from disseminated histiocytic sarcoma (malignant histiocytosis) a challenge. The periarticular location of the tumor, especially in a breed predisposed to histiocytic neoplasia should aid in the diagnosis.

Growth, metastasis, and treatment

Localized histiocytic sarcoma of the skin can be cured by complete excision if found early. Once progression past the regional lymph node occurs, the disease is uniformly fatal. Attempts at chemotherapy have been unsuccessful. There is no known effective treatment.

Xanthoma

Figure 5.24  Xanthoma, skin, feline. Sheets of lipid‐filled macrophages, with scattered cholesterol clefts, and background lymphocytes, plasma cells, and neutrophils.

metachromatic stains for mast cells. This suggests that one variant within the histiocytic type of mast cell tumor in cats can mimic xanthoma. Features that may help to distinguish this variant of mast cell tumor from xanthoma are the infiltrating eosinophils and scattered lymphocytic aggregates present in the former.

Xanthomas are non‐neoplastic masses composed of large foamy macrophages. Seen frequently in birds, they also occur in domestic animals. The appearance of these lesions is usually associated with abnormal plasma levels of cholesterol or triglycerides, but solitary, idiopathic xanthomas have also been reported.16,17

Growth and treatment

Incidence, age, breed, and sex

References

Seen rarely in the cat and less so in the dog, xanthomas can be focal or multifocal in the skin. In the cat, the lesions have been seen secondary to spontaneous or megestrol acetate–induced diabetes mellitus.

Gross morphology and histological features

The lesion usually presents as smooth white to pale yellow raised nodules or plaques in the skin. Lipid‐filled macrophages (Figure  5.24) are seen diffusely throughout the dermis, forming granulomas, often associated with cholesterol clefts. Between the cells are lakes of finely granular to amorphous acellular material.

Additional diagnostic criteria

Xanthomas must be differentiated from granulomatous inflammation secondary to infectious agents, such as fungi or mycobacteria. These latter lesions do not have cholesterol clefts, and special stains will be positive for organisms. This author has seen a few lesions in Siamese cats that resembled xanthomas but were, in fact, mast cell tumors. The cells in these lesions were large, often multinucleated, with markedly foamy to vacuolated cytoplasm. Despite the lipoid appearance to the cytoplasm, the cells stained strongly with

Single lesions respond to surgical excision. Multiple lesions can also be surgically excised if necessary for cosmetic reasons, but if the predisposing abnormal lipid levels persist, new lesions could appear.

1. Marchal, T., Dezutter‐Dambuyant, C., Fournel, C., et al. (1995) Immunophenotypic and ultrastructural evidence of the Langerhans cell origin of the canine cutaneous histiocytoma. Acta Anatom 153:189–202. 2. Moore, P.F., Schrenzel, M.D., Affolter, V.K., et al. (1996) Canine cutaneous histiocytoma is an epidermotropic Langerhans cell histiocytosis that expresses CD1 and specific beta 2‐integrin molecules. Am J Pathol 148:1699–1708. 3. Moore, P.F. (2014) A review of histiocytic diseases of dogs and cats. Vet Pathol 51:167–184. 4. Bender, W.M. and Muller, G.H. (1989) Multiple, resolving, cutaneous histiocytoma in a dog. J Am Vet Med Assoc 194:535–537. 5.. Moore, P.F. (1986) Utilizaton of cytoplasmic lysozyme immunoreactivity as a histocytic marker in canine histocytic disorders. Vet Pathol 23:757–762. 6. Affolter, V.K. and Moore, P.F. (2000) Canine cutaneous and systemic histiocytosis: a reactive histiocytosis of dermal dendritic origin. Am J Dermatopathol 22:40–48. 7. Moore, P.F. (1984) Systemic histiocytosis of Bernese mountain dogs. Vet Pathol 21:554–563. 8. Palmeiro, B.S., Morris, D.O., Goldschmidt, M.H., and Mauldin, E.A. (2007) Cutaneous reactive histiocytosis in dogs: a retrospective evaluation of 32 cases. Vet Dermatol 18:332–340. 9. Moore, P.F. and Rosin, A. (1986) Malignant histiocytosis of Bernese mountain dogs. Vet Pathol 23:1–10. 10. Freeman, L., Stevens, J., Loughman, C., and Tompkins, M. (1995) Malignant histiocytosis in a cat. J Vet Intern Med 9:171–173. 11. Lester, G.D., Alleman, A.R., Raskin, R.E., and Calderwood‐Mays, M.B. (1993) Malignant histiocytosis in an Arabian filly. Equine Vet J 25:471–473.

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12. Kerlin, R.L. and Hendrick, M.J. (1996) Malignant fibrous histiocytoma and malignant histiocytosis in the dog: Convergent or divergent phenotypic differentiation? Vet Pathol 33:713–716. 13. Hayden, D.W., Waters, D.J., Burke, B.A., and Manivel, J.C. (1993) Disseminated malignant histiocytosis in a golden retriever: Clinicopathologic, ultrastructural, and immunohistochemical findings. Vet Pathol 30:256–264. 14. Schmidt, M.L., Rutteman, G.R., Wolvekamp, P.T.C., and Van Niel, M.H.F. (1993) Clinical and radiographic manifestations of canine malignant histiocytosis. Vet Q 15:117–120. 15. Pinard, J., Wagg, C.R., Girard, C., et al. (2006) Histiocytic sarcoma in the tarsus of a cat. Vet Pathol 43:1014–1017. 16. Fawcett, J.F., Demaray, S.Y., and Altman, N. (1977) Multiple xanthomatosis in a cat. Feline Pract 5:31–33. 17. Banajee, K.H., Orandle, M.S., Ratterree, W., et al. (2011) Idiopathic solitary cutaneous xanthoma in a dog. Vet Clin Pathol 40:95–98.

cavity and rectum. On cut surface, the tumor is well demarcated but unencapsulated, and the color varies from white to red.

Histological features

Most plasma cell tumors are single, small, slightly raised dermal nodules covered by alopecic, occasionally ulcerated, skin. Some animals will have multiple plasma cell tumors at presentation. The pinnae and digits are preferentially affected. Other sites are oral

Although the gross appearance and site predilection of plasmacytomas resemble those of histiocytomas, the histological differences are apparent at low magnification. Sheets of round cells with ­pleomorphic nuclei are seen in poorly defined cords and nests (Figure  5.25A and see Figure  7.4). Scattered throughout this population are distinctive cells with large hyperchromatic nuclei. These cells can be mononuclear, multilobulated, binucleated, or multinucleated, and at low magnification these cells serve as a useful diagnostic marker for this neoplasm. Despite this nuclear pleomorphism, the cells are generally round with scant to moderate eosinophilic to amphophilic cytoplasm. Most neoplastic cells do not have the typical plasma cell clockface nuclear chromatin pattern; however, toward the periphery of the tumor, where the cells are not as densely packed, the cells more closely resemble normal plasma cells, with some cells showing perinuclear clear zones (Golgi) or circular cytoplasmic packets (immunoglobulins). The mitotic count varies, but is usually low. Some reports divide the histologic features of plasma into subvariants: hyaline, mature, cleaved, asynchronous, and polymorphous. However, cellular morphologic differences do not apparently have any clinical or prognostic significance.3–5 Amyloid can be found in a small percentage of cutaneous or oral plasma cell tumors (Figure  5.25B). It is immunoglobulin‐derived (primary) amyloid composed of lambda light chains and can be found in large lakes or in small deposits scattered throughout the tumor between cells and, occasionally, in blood vessel walls. Although only present in approximately 10% of canine cases it is a helpful diagnostic feature.

A

B

Plasma cell tumor (plasmacytoma, extramedullary plasmacytoma)

Although some cases of multiple myeloma can have skin involvement, most cutaneous plasma cell tumors are de novo proliferations unassociated with primary bone marrow neoplasia.1,2

Incidence, age, breed, sex, and site

The majority of plasma cell tumors occur in older dogs; rare tumors occur in the cat. Dog breeds preferentially affected include terrier breeds (Yorkshire, Airedale, Kerry blue, and Scottish), cocker spaniels, and standard poodles.3 Reports in cats are few, but one describing the disease in nine cats showed no particular age, breed, or sex predilection.4

Gross morphology

Figure 5.25  Plasma cell tumor, skin, canine. (A) Sheets of round cells, often with hyperchromatic, eccentric nuclei and occasional perinuclear clear zones (Golgi). (B) Amyloid is present amidst the neoplastic cells in this tumor. When seen it is a helpful aid to the diagnosis but it is present in only about 10% of canine tumors.

172    Tumors in Domestic Animals

Additional diagnostic criteria

The histological features of typical plasma cell tumors are distinctive, and diagnosis is usually not difficult. However, markedly anaplastic tumors can be misdiagnosed as disseminated histiocytic sarcoma (Figure  5.23A). Some of the cells in plasma cell tumors will stain positively with methyl green pyronine because of their high concentration of RNA; however, this stain is not specific and can be positive in fibrosarcomas and osteosarcomas. Positive thioflavine T cytoplasmic fluorescence can distinguish plasma cell tumors from other round cell neoplasms.6 Immunohistochemical positivity for monoclonal lambda light chains will confirm the diagnosis in less differentiated tumors.3,4 However, MUM1 is a superior and fairly specific plasma cell marker for normal and neoplastic plasma cells; labeling is nuclear with a weak cytoplasmic component. MUM1 is in the family of interferon regulatory factors (IRFs). It is required for immunoglobulin light‐chain rearrangement and is expressed in B cells, plasma cells, activated T cells and a subset of macrophages and dendritic cells in humans. In one study, CD79a and CD20 (other B‐cell markers commonly used in veterinary species) were positive in 56% and 19%, respectively, of plasma cell tumors, whereas MUM1 was positive in 94% of the tumors.7

Growth, metastasis, and treatment

The majority of cutaneous plasma cell tumors in the dog are benign. Most are cured by complete excision, though a few will recur. In one study, tumors with amyloid appeared to have a higher recurrence rate, but a more recent retrospective study found the presence or absence of amyloid to have no prognostic significance.3,8 Metastasis to distant skin sites has been reported rarely and probably reflects cases of multiple myeloma with skin involvement. If monoclonal gammopathy or hypercalcemia are detected then the dog is much more likely to have multiple myeloma. Feline plasma cell tumors and myeloma‐related disease is included in Chapter 7.

Lymphoma General considerations and classification

Lymphoma is an important and one of the most common tumors in animals and humans. This brief discussion centers on the cutaneous form of lymphoma, which is much less common.

Incidence, age, breed, sex, and site

Lymphoma of the skin is rare in all species, but is more commonly seen in dogs and cats. The mean age in dogs and cats is 10 years. There is no breed predilection in cats, but English cocker spaniels, bulldogs, boxers, Scottish terriers, and golden retrievers are predisposed to cutaneous lymphoma. Most of the tumors are on the trunk, but lesions can appear anywhere on the body. The cutaneous form of bovine lymphoma is part of the bovine leukosis syndrome. It usually develops in cattle between 2 and 3 years of age, and is the most indolent form of lymphoma in this syndrome. Skin lymphoma in horses is also typically indolent and some cases are cured by surgical excision. It is one of the most common forms of lymphoma in horses and is a T‐cell‐rich large B‐ cell lymphoma (see Chapter  7). It usually presents as multiple tumors in the skin and subcutis in horses of all ages. Mares appear to be more commonly affected.

Gross morphology

There is marked variability to the gross appearance of cutaneous lymphoma, which appears to correlate with the cell type (T or B) that is involved. As in humans, the lesions may manifest as patches, plaques, or tumors. Patches are uncommon in animals, but these erythematous scaly macules can wax and wane over many years. Plaques can develop from patches or arise de novo. As the name implies, these are areas of thickened, plaque skin, often covered by scaly and partially alopecic skin. Pruritus is common and often leads to ulceration. The color ranges from pink to brown. Tumors are variably sized, intradermal masses that can show ulceration, crusting, and alopecia. All of these forms can be single or multifocal in the skin.

Histological features

Cutaneous lymphoma in humans has traditionally been divided into the epitheliotropic and non‐epitheliotropic forms. Cases in dogs and cats seem to fall quite well into these categories, and the  veterinary profession has adopted this nomenclature.9 Both forms have been recognized in horses, although most cases are non‐epitheliotropic, T‐cell‐rich, B‐cell lymphomas.10,11 The descriptions that follow are those of canine and feline skin lymphomas, unless otherwise noted. Epitheliotropic tumors In epitheliotropic tumors, the neoplastic cells are T cells and have an affinity for epidermis and adnexal epithelium. The descriptive, but misleading name mycosis fungoides, has been applied to this form of lymphoma because of its gross infiltrative appearance. Neoplastic lymphocytes, which can range from small and well differentiated to large and histiocytoid, invade the epidermis either diffusely or in small clusters (Pautrier microabscesses; see Figures 7.42 and 7.43). Similar infiltrates are seen in hair follicular and apocrine gland epithelial cells  –  an important feature used to distinguish lymphoma from inflammation or other round cell tumors. Sometimes the infiltrate is so even that at first low magnification inspection the only change is a slight basophilia and hyperplasia of the basal cell layers of the epidermis and adnexa. Closer examination will reveal the lymphocytic population. Neoplastic cells are also seen in the dermis, but it is the epitheliotropism that distinguishes this form. Mitotic activity in this form is usually low. The term “pagetoid reticulosis” is used when the neoplastic infiltrate is limited to the epidermis and adnexal structures, and by some is considered a subvariant of mycosis fungoides (Figure 7.45).9 When epitheliotropic lymphoma is accompanied by simultaneous involvement of the lymph nodes and peripheral blood, the disease is called Sézary syndrome (Figure 7.46). Non‐epitheliotropic tumors Non‐epitheliotropic tumors are of B‐ or T‐cell origin and are characterized by sheets and clusters of neoplastic lymphocytes predominantly in the dermis (Figure 8.17). There can be mild epidermal infiltrates, but adnexae are not affected. Again, cells can vary tremendously in morphology, even in tumors in the same animal. Neoplastic lymphocytes are often intermingled with normal lymphocytes, plasma cells, and histiocytes, and the true neoplastic nature of the lesion can be hidden. When the neoplastic cells are  small and well differentiated, diagnosis can be difficult. Lymphoblastic and immunoblastic forms, which are the most common phenotypes of non‐epitheliotropic lymphoma in dogs and cats, can usually be recognized by their characteristic nuclear and cytoplasmic features. Mitotic indices vary from moderate to high.

Mesenchymal Tumors of the Skin    173

In horses, T‐cell‐rich B‐cell lymphomas are the most common variant. The B cells are large and scattered histiocytes and small lymphocytes are present (see Figures 7.25 and 26).

Additional diagnostic criteria

Cytologic and histologic examination of cutaneous lymphoma can be a challenge when the neoplastic cells are small and well differentiated, or when they are confined to the epidermis. These cases may require identification of a single clone of cells via immunohistochemistry or  flow cytometry to determine if the infiltration is neoplastic (Figure 8.17). Large cell and immunoblastic forms are easier to diagnose, but some medium to large cell variants can be difficult to distinguish from histiocytoma cells on cytology and on H&E slides. Histiocytoma cells never enter follicular or adnexal epithelium.

Growth, metastasis, and treatment

Cutaneous lymphoma tends to be a progressive disease, beginning with the development of multicentric skin tumors and ultimately involving the regional lymph nodes and viscera. Non‐epitheliotropic lymphomas tend to be more aggressive and rapidly progressive. Treatment based on standard chemotherapy regimens used for other forms of lymphoproliferative diseases has consisted of various combinations of chemotherapeutic drugs, retinoids, and topical mechlorethamine.12 Although some treatments have extended survival times, most are aimed at ­palliation; however, some horses may survive for 10 years post excision when only a few tumors are present.

Canine transmissible venereal tumor

This tumor is unusual in many regards. It is of unknown cell origin and is transmitted by physical transplantation between dogs rather than infectious means, and the chromosome counts of the cells of the neoplasm vary from 57 to 64 (averaging 59) rather than the normal 78 found in other cells of the dog.13,14 As the name implies, it is primarily located on the genitalia or, less commonly, on the lips or other portions of the skin or mucosa that come in contact with the genitalia. Transmission is usually during coitus. The unusual PNST of Tasmanian devils is another tumor that can be transferred via transplantation. This is a nerve sheath neoplasm of Schwann cell origin.

Incidence, age, breed, and sex

Dogs of both sexes and all ages are affected, but the tumor is more commonly seen in young, sexually active individuals. The distribution of transmissible venereal tumor (TVT) throughout the world is patchy and unexplained. The disease is enzootic in some regions of the Caribbean (e.g., Puerto Rico, St. Kitts) and India. TVT is now rare in pet and house dogs but is seen frequently in homeless dogs, especially in the southeastern United States and infrequently in portions of the Midwest. It occurs in pockets in Europe, Africa, and Asia.

Gross morphology

TVTs vary in their gross appearance, but most are proliferative verrucous, papillary, or nodular masses protruding from the surface of the penis or vulva (Figure 5.26A). The tumors can be small single or multiple nodules or multilobulated masses as large as 15 cm in diameter. The surface is usually ulcerated and friable, with a smooth or granular appearance.

Histological features

The neoplasm is composed of loose sheets, rows, and cords of relatively uniform round to ovoid cells. Cell margins are generally indistinct on histopathology. Nuclei are large, round, with a single centrally placed nucleolus surrounded by marginated chromatin. There is a moderate amount of light amphophilic to clear cytoplasm that is sometimes vacuolated (Figure  5.26B). These vacuoles are much more obvious in touch impression films of the tumor cells. The mitotic count is high. Variable numbers of lymphocytes (sometimes in aggregates), plasma cells, eosinophils, and macrophages infiltrate the tumor. In regressing tumors, increased inflammation and zones of necrosis and fibrosis are often present.

Additional diagnostic criteria

The primary differentials for TVTs are other round cell tumors of the skin, such as histiocytoma, lymphoma, and mast cell tumor. The location of the tumor should play an important role in diagnosis; genital round cell lesions should be considered TVTs until proven otherwise by special stains, immunohistochemistry, or PCR analysis. Regarding the latter, a rearranged LINE‐c‐myc gene sequence has been found in TVTs that can be used with PCR to diagnose them. TVTs have immunoreactivity with lysozyme, alpha‐1‐antitrypsin, and vimentin.15 They are negative for keratins, S100 protein, lambda light‐chain immunoglobulins, IgG, IgM, and CD3 antigen. These studies suggest a histiocytic origin, but numerous other tests have failed to confirm this. Ultrastructurally, TVT cells are nondescript, but their unique karyotype is diagnostic. On routine H&E‐stained slides, the nuclear and cytoplasmic differences between TVTs, lymphoma, and histiocytomas can be subtle. The presence of low nuclear‐to‐cytoplasmic ratios and distinct small cytoplasmic vacuoles have been reported as distinguishing features of this neoplasm on cytology.16 Touch imprints from the surface of non‐ulcerated regions of these tumors are diagnostic. Numerous cells exfoliate and they appear as discrete round cells with distinct cell borders and basophilic to gray cytoplasm with several uniform clear vacuoles (Figure  5.26C). Histiocytomas look similar, but do not yield as many cells. The cytoplasm is not as basophilic, and vacuoles are not present. The location on the genitalia strongly suggests TVT.

Growth, metastasis, and treatment

Tumors grow rapidly at first and then remain static for a time. Spontaneous regression can occur and is the result of cellular and humoral immune responses that make the dog highly resistant to subsequent tumor implantation. There is infrequent metastasis to regional lymph nodes and to viscera, primarily in animals with compromised immunocompetency.13

References

1. Baer, K.E., Patnaik, A.K., Gilbertson, S.R., et al. (1989) Cutaneous plasmacytomas in dogs: A morphologic and immunohistochemical study. Vet Pathol 26:216–221. 2. Rakich, P.M., Latimer, K.S., Weiss, R., et al. (1989) Mucocutaneous plasmacytomas in dogs: 75 cases (1980–1987). J Am Vet Med Assoc 194:803–810. 3. Cangul, I.T., Wijnen, M., Van Garderen, E., et  al. (2002) Clinico‐pathological aspects of canine cutaneous and mucocutaneous plasmacytomas. J Vet Med A Physiol Pathol Clin Med 49:307–312. 4. Majzoub, M., Breuer,W., Platz, S.J., et al. (203) Histopathologic and immunophenotypic characterization of extramedullary plasmacytomas in nine cats. Vet Pathol 40:249–253. 5. Platz, S.J., Breuer, W., Pfleghaar, S., et al. (1999) Prognostic value of histopathological grading in canine extramedullary plasmacytomas. Vet Pathol 36: 23–27.

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B

C Figure 5.26  Canine transmissible venereal cell tumor. (A) Multiple nodules and plaques cover the penis of this dog. (B) High magnification (oil) of sheets of uniform round cells with several mitotic figures. The mitotic count is typically high; some tumors will have lymphocytic inflammation. (C) Cytology showing uniform round cells with abundant light blue cytoplasm and vacuolation typical of TVT cells. Mitotic figure in lower left, spindle‐shaped cell is a supporting stromal cell. Images courtesy of D.J. Meuten.

Mesenchymal Tumors of the Skin    175

6. Brunnert, S.R. and Altman, N,H. (1991) Identification of immunoglobulin light chains in canine extramedullary plasmacytomas by thioflavine T and immunohistochemistry. J Vet Diag Invest 3:245–251. 7. Ramos‐Vera, J.A., Miller, M.A., and Valli, V.E.O. (2007) Immunohistochemical detection of multiple myeloma 1/interferon regulatory factor 4 (MUM1/IRF‐4) in canine plasmacytoma: comparison with CD79a and CD20. Vet Pathol 44:875–884. 8. Rowland, P.H., Valentine, B.A., Stebbins, K.E., et al. (1991) Cutaneous plasmacytomas with amyloid in six dogs. Vet Pathol 28:125–130. 9. Fontaine, J., Bovens, C., Bettenay, S., and Mueller, S.R. (2009) Canine cutaneous epitheliotropic T‐cell lymphoma: A review. Vet Comp Oncol 7:1–14. 10. Durham, A.C., Pillitteri, C.A., San Myint, M., and Valli, V.E. (2013) Two hundred three cases of equine lymphoma classified according to the World Health Organization (WHO) classification criteria. Vet Pathol 50:86–93.

11. Kelley, L.C. and Mahaffey, E.A. (1998) Equine malignant lymphomas: Morphologic and immunohistochemical classification. Vet Pathol 35: 241–252. 12. Withrow, S.J. and Vail, D.M. (2007) Withrow and MacEwen’s Small Animal Clinical Oncology, 4th edn. Saunders Elsevier, St. Louis, MO, pp. 719, 799–803. 13. Park, M., Kim, Y., Kang, M., et  al. (2006) Disseminated transmissible venereal tumor in a dog. J Vet Diagn Invest 18:130–133. 14. Mukaratirwa, S. and Gruys, E. (2003) Canine transmissible venereal tumour: cytogenetic origin, immunophenotype, and immunobiology. A review. Vet Q 25:101–111. 15. Mozos, E., Mendez, A., Gomez‐Villamandos, J.C., et al. (1996) Immunohistochemical characterization of canine transmissible venereal tumor. Vet Pathol 33:257–263. 16. Henson, K.L. (2001) Reproductive system. In Atlas of Canine and Feline Cytology. W.B. Saunders Co, Philadelphia, PA, pp. 296–297.