Mammary Tumors in Small Mammals

Key Points

  • Mammary gland tumors are relatively common in rats and mice. Most rat mammary tumors are fibroadenomas. Mice more commonly have mammary adenocarcinomas.
  • Mammary tissue can occur anywhere along the shoulder, neck, ventrum, flank or tail base in rats and mice.
  • Mammary gland tumors are typically seen in middle-aged to older animals.
  • Mammary tumors are more common in male guinea pigs than in females, which is unique among mammals.
  • Neoplasia is relatively common in African pygmy hedgehogs, and mammary gland adenocarcinoma is one of the most common tumors reported in this species.
  • Always screen affected hedgehogs for concurrent disease since retrospective work has documented multiple tumors in approximately 10% of affected animals.

Introduction

Among small mammals, mammary tumors are reported most commonly in rats (Rattus norvegicus), mice (Mus musculus), and African pygmy hedgehogs (Atelerix albiventris). Mammary gland tumors have also been reported in guinea pigs (Cavia porcellus) and hamsters. Disease is typically seen in middle-aged to geriatric animals.

 

Rat

Mammary gland tissue is extensive in rats, extending from the cervical to the inguinal region ventrally and as high as the shoulders and flanks laterally. Mammary tissue can be found anywhere along the shoulder, neck, ventrum, flank or tail base.

Mammary tumors are common in rats. The incidence of tumor varies dramatically with the strain as well as age, sex, diet, caloric intake, and environment. The reported incidence of mammary gland tumors may range from 30% to 90% in aged female rats, and approximately 16% of male rats may be affected. Most mammary tumors in rats are fibroadenomas; about 10% are adenocarcinomas. These egg or disc-shaped tumors are well demarcated and usually associated with one large vessel. Masses can reach a relatively large size fairly quickly (up to 10 cm in diameter) but they are not attached to deeper structures (Fig 1). Even large masses are usually well tolerated by the rat, until they become large enough to interfere with movement. The mass may then become ulcerated, hemorrhagic, and even necrotic leading to secondary bacterial infection and sepsis. Rat mammary gland tumors are known to be sensitive to hormonal stimuli including exogenous estrogens.

Masses can reach a relatively large size fairly quickly (up to 10 cm in diameter) but they are not attached to deeper structures

Figure 1. Large mammary gland tumor in a rat (Rattus norvegicus). Image provided by Christal Pollock. Click on image to enlarge.

Pituitary adenoma or prolactinoma is the second most common tumor of rats, and high prolactin levels secreted from the tumor may be the underlying cause of mammary tumor development. To complicate matters, estrogen may contribute to the development of pituitary tumors. Recent work has also found that prolactin is synthesized by mammary epithelial cells in humans and rats. Regardless of its source, prolactin is known to stimulate proliferation in breast cancer cells.

 

Mouse

As in rats, mammary tissue in mice can occur anywhere along the shoulder, neck (even the dorsal surface of the neck), ventrum, flank, tail base, as well as the inguinal and axillary regions.

According to some sources, mammary tumors are the most common spontaneous tumor in mice, with an incidence of 30% to 70% in aged females. In wild and outbred mice, the incidence of fibrosarcoma ranges from 1% to 6%. Unlike rats, mice are more commonly affected by mammary adenocarcinoma. These tumors are usually soft, fleshy, infiltrative, highly vascular, and they often metastasize to the lungs. Mammary tumors in mice are also usually associated with a retrovirus called the mammary tumor virus or the Bittner agent. When present in a susceptible strain of mouse, the virus predisposes the animal to mammary adenocarcinoma formation. Mouse mammary tumor virus is passed transplacentally and through milk. The prognosis for this tumor is poor.

 

Guinea pig

Guinea pigs possess a single pair of mammary glands in the inguinal region (Fig 2). These two glands do not share a common blood or lymphatic supply.

Both male and female guinea pigs possess a single pair of mammary glands

Figure 2. Both male and female guinea pigs possess a single pair of mammary glands (arrows) in the inguinal region. Image provided by Dr. Dorcas O’Rourke. Click image to enlarge.

Laboratory animal literature historically reports that cancer is rare in guinea pigs, however mammary gland tumors were among the most common mass lesions according to a survey of tissues submitted to Northwest Zoo Path between 2001 and 2008. Reported tumors include mammary gland adenocarcinoma, malignant mixed tumor, liposarcoma, papillary cystadenoma, and carcinosarcoma. Fibroadenomas have been reported in male and female guinea pigs, but are rarely seen in practice. Malignant tumors can metastasize to regional lymph nodes, abdominal viscera, or lungs.

 

Hedgehog

Both male and female hedgehogs have up to 10 nipples. When fully developed, mammary glands create two continuous strips of tissue.

A variety of tumors are relatively common in African pygmy hedgehogs with retrospective studies reporting an incidence of neoplasia ranging from 30% to 53%. About 10% of affected hedgehogs have multiple tumors, with mammary gland adenocarcinoma among the most common neoplasms encountered. Papillary adenoma of the mammary gland has also been described. Mammary tumors in hedgehogs present as subcutaneous swellings in the ventral thorax or abdomen (Fig 3). These tumors are typically unrelated to gender and affected hedgehogs are often middle-aged with a mean age of 3.5 years reported (range 2 to 5.5 years).

African pygmy hedgehog with mammary mass.

Figure 3. Mammary mass in an African pygmy hedgehog (Atelerix albiventris) with secondary bacterial infection. Image provided by Dr. M. Scott Echols. Click on image to enlarge.

Rabbit

Unlike other mammals, male rabbits or bucks do not have nipples. Female rabbits or does may have four or five pairs of mammary glands.

Noninfectious cystic mastitis may be seen in breeding and non-breeding does. Affected glands exhibit non-painful, firm swelling with clear to serosanguinous discharge. Cystic mammary glands may progress and coalesce until malignant changes eventually occur leading to invasive mammary adenocarcinoma, which is not uncommon in middle-aged to older multiparous does. Metastasis to the regional lymph nodes, lungs, or other organs can occur.

 

Rare reports

Mammary tissue is confined to the ventral thorax and abdomen in hamsters. Mammary tumors have been described in this rodent, particularly the Russian or Djungarian hamster (Phodopus sungorus) but were not considered common. However in a survey of cases seen at the University of Tennessee Veterinary Medical Teaching Hospital over 35 years, mammary gland tumors were the most commonly encountered tumor seen in six hamsters.

Chinchillas (Chinchilla lanigera) have two pairs of mammary glands, and there is one description of mammary tumor in the chinchilla. Mammary gland tumors are also rare in ferrets (Mustela putorius furo). In a review by Williams and Weiss, six benign tumors were described.

The incidence of spontaneous tumors in gerbils ranges from 8.4% to 26.5%. This high rate was true even in the older literature when gerbils were wild caught or first-generation or second-generation laboratory-raised, however mammary tumors have rarely been reported.

 

Diagnosis

Important differential diagnoses for mammary tumor include mastitis and mammary gland hyperplasia, as well as abscess and granuloma. Mammary gland disorders are often accompanied by ovarian and/or uterine abnormalities in the rabbit. There is also a report of gynecomastia in a male rabbit associated with testicular interstitial cell neoplasia. Mammary dysplasia, associated with pituitary adenomas, has been described in older female rabbits.

To confirm a presumptive diagnosis of mammary gland neoplasia, submit excisional biopsy samples for histopathology, or less ideally, submit needle aspirates for cytological examination. Pre-surgical evaluation is particularly important in guinea pigs and hedgehogs because of the risk of malignancy and the difference in surgical margins needed for benign versus malignant tumors. It is highly recommended to perform whole body radiographs in hedgehogs before beginning a treatment regimen because multiple tumors are common in this species. It is also reasonable to look for evidence of metastasis in guinea pigs. Ideally, this would include three radiographic views (dorsoventral, left lateral, and right lateral) and inguinal lymph node biopsy.

 

Therapy

Mass removal

Treatment of mammary tumors in small mammals currently relies on surgical excision of the tumor and the associated mammary gland. Mammary tumors in rodents, both benign and malignant, typically grow by expansion until they reach a size that causes the overlying skin to become traumatized and infected.

The well-encapsulated tumors seen in rats are easily removed surgically, except for some inguinal masses that are associated with the urethra. In rats, additional mammary tumors often occur, and several surgeries may be necessary in intact females. Ovariectomy or ovariohysterectomy in conjunction with mass removal may help prevent the formation of new tumors, but this has not been proven in rats older than 90 days of age.

Whenever possible, remove 5 to 10-mm margins and local lymph nodes in guinea pigs and hedgehogs, unless the tumor has been diagnosed as benign via excisional biopsy. Plan carefully beforehand to allow for adequate closure because tissue is not abundant in this area. Although bilateral disease is rare, plan unilateral mastectomy 2 to 4 weeks apart, allowing one side to heal.

Surgery is generally not recommended in the mouse because there is a high rate of metatasis and masses are difficult to remove without significant tissue damage and hemorrhage. Also, the underlying cause of neoplasia in mice is often the mammary tumor retrovirus.

Medical management

Surgery is usually the treatment of choice, however owners may have questions about medications mentioned on the Internet such as leuprolide acetate, cabergoline, melatonin, and tamoxifen.

Tamoxifen (Nolvadex, AstraZeneca) is a SERM or selective estrogen receptor modulator. This antiestrogen is used in the treatment of human breast cancer. In women, the number of estrogen receptors in breast cancer cells can be high, intermediate or absent. Seventy percent of tumors with estrogen receptors regress after hormonal manipulation. Tamoxifen (1mg/kg PO daily) is frequently used in experimental studies in rats, but this medication is unlikely to have any beneficial effects clinically, because most rat mammary tumors are fibroadenomas, and in fact, the drug has been shown to induce hepatic cancer in rats.

Leuprolide acetate, a gonadotropin releasing hormone agonist, has been used experimentally in 55 day old, female Sprague-Dawley rats with mammary carcinoma induced by 7,12-dimethylbenz[a]anthracene or DMBA injection. The number of rats with tumors was significantly reduced (30%) with ultra-high doses of leuprolide (40 ug/kg/day) when compared to controls (77.8%).

Some empirical treatments are based on the relationship between pituitary prolactin-secreting tumors and mammary tumors, although at this time there is no empirical evidence that these drugs are clinically effective. Studies have shown that melatonin reduces the growth of rat pituitary prolactin-secreting tumor by inhibiting proliferation and inducing apoptosis of prolactinoma cells. The potent prolactin inhibitor, cabergoline (Dostinex, Pharmacia) (0.6 mg/kg PO every 3 day) has also been tried empirically in rats with mammary tumors (personal communication, Tom Donnelly, June 2010). Studies in rats have shown significant concentrations of cabergoline within the mammary glands. An alternative medication is bromocriptine (Parlodel, Novartis) (3.0 mg/kg PO daily), used to treat symptoms of hyperprolactinemia.

Ancillary therapies

Systemic cancer chemotherapy, immunotherapy, or radiation therapy may help guinea pigs or hedgehogs with local tumor recurrence or metastasis, but these treatments have not been studied.

 

Prevention

Weight control may reduce the risk of mammary gland tumor development. Obesity in women is associated with an increased risk for postmenopausal breast cancer. Intact obese Zucker rats also have increased susceptibility to DMBA-induced mammary tumors. Adipose tissue-derived estrogen in obese animals may be sufficient to promote DMBA-induced tumors in this model.

The correlation between mammary and uterine disorders in rabbits suggests that ovariohysterectomy may reduce the risk of mammary tumors at a later age. As for rats, studies have found that ovariectomy in rats before 5-7 months of age can inhibit development of spontaneous mammary tumors by up to 95%. Work by Hotchkiss et al showed that rats ovariectomized at 3 months of age had a signicantly lower incidence of mammary tumors than intact female rats, 2/47 (4%) versus 24/49 (47%) respectively. The frequency of pituitary adenomas is also much lower in ovariectomized rats when compared to sexually intact rats (2/46 versus 27/41). Taken together, the available research supports routine, elective ovariectomy in young rats. Recent work suggests that ovariectomy in middle aged rats may also prevent spontaneous mammary tumor development.

 

Summary

Mammary gland tumors are relatively common in middle-aged to older rats, mice, and African pygmy hedgehogs. Most rat mammary tumors are fibroadenomas, while mice and hedgehogs are more commonly affected by mammary adenocarcinoma. A presumptive diagnosis of mammary gland neoplasia may be confirmed by histopathology or cytology. Species such as guinea pigs and hedgehogs are prone to malignant tumors and should be screened for metastasis, and remember multiple tumors are common in hedgehogs. Treatment of mammary tumors in most small mammals currently relies on surgical excision of the tumor and the associated mammary gland. Surgery is not recommended in mice because there is a high rate of metastasis and masses are difficult to remove without significant complications. Most of the well-encapsulated tumors seen in rats are easily removed, however masses often recur in distant mammary tissue.

References