Cutaneous lumps and bumps: The good, the bad and the ugly (Proceedings)

Tumors of the skin and subcutaneous tissue are the most common tumors affecting dogs, accounting for approximately one-third of all tumors encountered in the species. Many tumor types occur in this site and a listing of the ten most frequent non-lymphoid cutaneous tumors in the dog based on over 6000 cases in 4 continents and the 5 most frequent in the cat based over 1000 cases are presented in table 1 & 2 respectively.

Table 1 and 2

Etiology

Specific etiologies have been proven for only a few tumors in the dog and cat. While the etiology of cutaneous tumors are likely multifactoral and largely unknown, investigations are currently shedding some light on the subject. Several contributing factors in the development of skin tumors include physical factors (e.g., radiation and thermal injury), genetic and molecular influences, hormones, vaccines, viruses, and immunologic influences.

History and Clinical Signs

The history for an animal with a cutaneous tumor is variable. Commonly an owner will discover a growth while examining or grooming their pet. Benign tumors are more likely to have a history of slow growth from weeks to years. Most benign tumors are well circumscribed, nonpainful, freely moveable and incite a minimal inflammatory response. Malignant tumors are often rapidly growing, fixed to underlying structures, ulcerated and will often have ill-defined margins. Invasion into vessels and regional lymphatics may be observed.

Diagnostic Techniques and Workup

One of the most important techniques employed in the diagnosis and management of skin tumors is a thorough history and physical examination. The history should include queries as to the duration of the lesion, rapidity of growth, change in appearance over time, travel history, presence of pruritus, response to previous therapy, and related medical history. Every tumor should be examined with respect to size, location, consistency, presence or absence of fixation to underlying tissue and whether the overlying skin is ulcerated. The two most common diagnostic procedures for skin tumors are fine needle aspirate or non-aspirate cytology and tissue biopsy.

Depending on the tumor type in question and/or the clinicians index of suspicion, an expanded diagnostics work-up may be indicated to determine the presence of systemic spread as well as the patients readiness for therapeutic intervention.

Mast Cell Tumors: Surgical and Medical Management

Overview

Mast cell tumors (MCT) are the most common cutaneous tumor in the dog and the 2nd most common in the cat. Older names for MCT include mast cell sarcoma and histiocytic mastocytoma. Mast Cell tumors (MCT) are primarily a disease of older dogs and most occur in mixed breeds; however, Boxers, Boston Terriers, Labrador Retrievers, Beagles, and Schnauzers have all been reported to be at higher risk. While Boxers are at increased risk for MCT development, they more commonly develop the histologically well-differentiated form of the disease that carries a more favorable prognosis. Two distinct forms of cutaneous MCT in the cat have been reported: (1) The more typical mastocytic MCT, histologically similar to MCT in dogs and (2) The less common histiocytic MCT, with morphologic features characteristic of histiocytic mast cells. The etiology of MCT in the dog and cat is for the most part unknown. On rare occasions MCT have been associated with chronic inflammation or the application of skin irritants. Recently, mutations of the tumor suppressor gene p53 and the proto-oncogene c-kit have been found in approximately 50% of canine mast cell tumors and their frequency appears to correlate with histologic grade. No association with feline leukemia virus (FeLV), feline immunodeficiency virus (FIV) or feline infectious peritonitis (FIP) has been reported. A genetic predisposition has been proposed due to the high incidence of MCT in the Siamese breed.

History and Clinical Signs

The history and clinical signs of dogs and cats with MCT is complicated by signs attributable to release of histamine, heparin and other vasoactive amines from the MCT granules. These include coagulation disorders, gastrointestinal ulceration (with related signs of vomiting [possibly with blood] anorexia, melena, and abdominal pain), altered smooth muscle tone, hypotensive shock, and anaphylactoid reactions. Occasionally, mechanical manipulation during examination of the tumor results in degranulation and subsequent erythema and wheal formation in surrounding tissues. This phenomenon has been referred to as "Darier's sign". In dogs, MCT are most commonly found on the trunk; tumors on the limbs account for only one-quarter of all sites and lesions are least common on the head and neck. This is in contrast to cats where the head and neck is the most common site for MCT. A visceral form of MCT, often referred to as disseminated mastocytosis, can also occur.

Diagnostic Work-Up

Mast cell tumors are initially diagnosed on the basis of fine-needle aspiration (FNA) cytology. Mast cells appear as small to medium-sized round cells with abundant, small, uniform cytoplasmic granules that stain purplish red (metachromatic). A small percentage of MCT have granules that do not stain readily, giving them an epithelial, 'fried egg', or macrophage-like appearance. In these cases, histological assessment is necessary for diagnosis. The extent of ancillary diagnostic work-up following FNA cytological diagnosis is predicated on the presence or absence of the negative prognostic factors for MCT in dogs (e.g., histologic grade, mitotic index, clinical signs, location).

Therapeutic Approach by Species

In the Dog

Treatment decisions are predicated on the presence or absence of negative prognostic factors and on the clinical stage of disease.

Surgical removal is the treatment of choice for local MCT disease. Grade II and III lesions warrant aggressive local resection, obtaining 3 cm lateral margins and one additional tissue margin deep to what the tumor touches. In certain areas, this type of resection will require some type of reconstructive procedure, or possibly a regional resection to be complete. Normal tissue margins should always be identified after removal so that the pathologist can assess the completeness of resection. In cases of incomplete resection, re-resection should be considered first if feasible. For re-resections, new margins are obtained as described above surrounding the old scar. Regional resection may also be re-considered. Complete surgical resection for dogs with no evidence of metastasis will result in upwards of 90% 1-year remission. For incomplete resection that is not amendable to surgery, radiation therapy to the site can be successful. Fractionated doses of approximately 48 Gy or higher have resulted in 80-90% 1-year remissions. Alternatively, if radiation is not an option due to availability or cost, time to recurrence can be greatly extended with adjuvant chemotherapy (see below). For cases that are not amenable to surgical resection, several options exist. Neoadjuvant prednisone or chemotherapy may make an otherwise unresectable lesion resectable following chemotherapy. The second option is external beam radiotherapy alone; however, in the gross disease setting this results in one-year control rates of only 50%. Recently, course fraction radiation protocols (3 or 4 weekly 8 Gy fractions) have, anecdotally, resulted in local responses lasting months to even a year or longer. The third, and in the authors opinion, the ideal option for low or intermediate grade MCT in areas where wide surgical excision is not possible is a combination of surgery and radiotherapy. The complimentary use of surgery to achieve clinical stage 0 disease (i.e. microscopically incomplete margins) and external beam radiotherapy is associated with long term control (two-year control rates of 85 to 95%) of low or intermediate grade differentiation. Some authors advocate prophylactic irradiation of cytologically negative regional lymph nodes however; definitive evidence of a survival advantage associated with this practice is lacking. Unfortunately, dogs with undifferentiated tumors do not fare as well, with the majority developing distant metastasis within 4 – 6 months of therapy.

The management of biologically high grade MCT remains a frustrating undertaking for both the client and the practicing clinician. Systemic adjuvant therapy should be offered in such cases in an attempt to decrease the likelihood of systemic involvement, or at least potentially improve disease-free intervals. Corticosteroids such as prednisone have been reported for many years in primarily preclinical or anecdotal settings to be of some benefit. In the authors practice, patients with poorly differentiated MCT receive prednisone and vinblastine as a first line. In this protocol, vinblastine (2.3 mg/m2 , IV) is given weekly for 4 consecutive weeks and then every other week for 4 additional treatments (total of 8 treatments). Prednisone is given at 1 mg/kg, P.O., once daily for 2 weeks, then decreased to 0.5 mg/kg daily or 10 additional weeks before being tapered off. Responses can also be expected with protocols using CCNU (Lomustine, 60 - 70 mg/m2 Q 3 weeks); however, CCNUs toxicity profile (i.e., thrombocytopenia, hepatic toxicity) temper its use in our hands to those cases having failed vinblastine or if oral chemotherapy is preferred. Recently, Tyrosine Kinase inhibition, in particular C-kit inhibitors have been investigated for the treatment of dogs with MCT. Early results are very promising and several TK-inhibitors are under field trial investigation at this time for use in veterinary practice.

Ancillary therapy for the systemic effects of MCT related to degranulation is sometimes, but not always recommended. Blocking all or some of the effects of histamine release can be accomplished by administering the H1 blocker diphenhydramine (2 - 4 mg/kg PO BID) and the H2 blockers cimetidine (4 mg/kg PO TID) or ranitidine (2 mg/kg BID).

In the Cat

Surgery is the treatment of choice for the mastocytic form of cutaneous MCT. As previously discussed, most are behaviorally benign and wide surgical margins may not be as critical as in the dog. This is fortunate, as most occur on the head where such margins would be difficult to achieve. Frequency of local recurrence and systemic spread vary widely in the literature. Local recurrence and frequency of systemic spread have been reported to occur in 5 – 10 % of cases. For histologically anaplastic (i.e. diffuse) mastocytic tumors, a more aggressive approach similar to that utilized for canine MCT may be prudent, as higher rates of recurrence and metastasis are associated with this type. Little is known about the effectiveness of adjunctive therapy for cutaneous MCT in the cat. Visceral MCT of cats occurs in two forms; the splenic (hemolymphatic) or gastrointestinal form. Cats with the splenic form present with massive splenomegaly, oft peritoneal effusion and gastrointestinal signs (i.e. vomiting). Peripheral mastocytosis with this form is common. Surprisingly, long-term survival appears to be the norm following splenectomy, even in the face of peripheral mastocytosis (median survivals =18 months). The gastrointestinal form of visceral MCT is quite different in behavior than the splenic form. None have been reported to have circulating mast cells. A grave prognosis is prudent based on the high rate of metastasis. No data is available on surgical resection or chemotherapeutic intervention.

Melanocytic Tumors (Melanocytic Nevus, Melanocytoma, Melanosarcoma, Malignant Melanoma)

Tumors of melanocytes and melanoblasts are relatively common skin tumors in the dog but are a rare tumor in the cat. Cutaneous melanomas in the dog can be behaviorally benign or malignant and can occur anywhere on the body. Benign forms are often referred to as melanocytic nevus, a term which in its purest sense implies any congenital, melanin-pigmented lesion. These tumors can usually be diagnosed by simple fine needle aspirate cytology. Behaviorally malignant melanomas tend to grow rapidly, can be greater than 2 cm, and are often ulcerated. Over 85% of melanomas in dogs arising from haired-skin are associated with benign behavior. The majority of oral and mucocutaneous junction melanomas (except eyelid), and approximately one-half of melanomas arising in the nail bed (See subungual tumors below) are behaviorally malignant. The histologic criteria of mitotic rate is highly predictive (approximately 90% accurate) of degree of malignancy. In the cat, melanogenic tumors can also be benign or malignant.

Squamous Cell Carcinoma

Squamous cell carcinoma (SCC) is a common tumor involving the skin and accounts for approximately 15% of cutaneous tumors in the cat and 5% of those in the dog. Squamous cell carcinomas are usually found in unpigmented or lightly pigmented skin. In many instances there is a recognized solar exposure relationship and these tumors are often referred to as 'actinic' SCC. The most common cutaneous locations for SCC in the dog are the nail bed, scrotum, nasal planum, limbs and anus. The most common cutaneous locations for SCC in the cat are the sparsely haired areas of the nasal planum, eyelids, and pinnae. Squamous cell carcinoma may present as either a proliferative or erosive lesion. Many therapeutic modalities have been applied to SCC involving the facial skin in cats. Surgery or cryosurgery are most commonly used and remain the mainstay for treating these lesions, although numerous reports now exist detailing the use of radiotherapy and photodynamic therapy. Outcomes are generally good for most modalities if tumors are treated early (i.e.Tis to T1) in their course. Chemotherapy for cutaneous SCC has shown little consistent efficacy in the veterinary literature. The nonsteroidal anti-inflammatory drug piroxicam, also known for its immunomodulating effects through inhibition of COX-2, has also been evaluated for efficacy in dogs with nonresectable SCC and in dogs with oral SCC. Response rates of 17 – 50% are reported with median durations of 3 – 6 months. Recently the immunomodulating topical compound imiquimod 5% cream (Aldara™) has shown some promise for treating early cutaneous SCC of cats.

Subungual Tumors

Subungual tumors are common in the dog and rare in the cat. Approximately one-third of subungual tumors in the dog are squamous cell carcinoma (SCC), followed in frequency by malignant melanoma, mast cell tumors and various soft tissue sarcomas (fibrosarcoma, neurofibrosarcoma). Radiographs of the affected digit should be a routine part of the work-up for nail-bed disease as many tumors result in local bone lysis. While benign or infectious processes (pododermatitis) of the digit can result in local bone lysis, it is much less likely to occur. Subungual tumors are often secondarily infected and initially misdiagnosed as chronic paronychia or osteomyelitis.