Surgery and radiation therapy for extramedullary plasmacytoma of the penile mucosa in a dog

Abstract

A 10-year-old neutered male Italian greyhound dog was presented because it had a penile plasmacytoma. Surgery followed by radiation therapy resulted in local control and survival for 1688 days. This is the first report of surgery and definitive radiation therapy for curative intent therapy of extramedullary penile plasmacytoma in a dog.

A 10-year-old neutered male blue and white Italian grey-hound dog was referred to the Medical Oncology Service at the University of Illinois Veterinary Teaching Hospital (UIVTH), for further evaluation of a penile plasma cell tumor. Six weeks earlier, a subcutaneous soft-tissue mass had been noted at the base of the penis. There was no clinical improvement following empirical treatment with amoxicillin-clavulanic acid (Clavamox; Pfizer Animal Health, New York, New York, USA), 13 mg/kg body weight (BW), PO, q12h for 14 d. Two weeks later surgical excision via a transcutaneous midline incision was attempted by the referring veterinarian. Upon surgical exploration of the penis, the mass was found to be arising from the penile urethra cranial to the bulbus. Only cytoreductive surgery was possible and visible macroscopic disease remained at the surgical site. A plasma cell tumor was diagnosed based on histopathologic and immunohistologic characteristics [positive co-labeling of tumor cells with CD79a (B-cell marker) and methyl green pyronine (MGP, DNA/RNA labeling)]. Surgical margins were incomplete and local recurrence was predicted. The dog had been previously diagnosed with chronic progressive retinal degeneration, hypothyroidism, and color dilution alopecia.

Case description

On presentation to the UIVTH, the dog was bright and alert with a body condition score of 5/9 and normal vital signs. The pigmented areas of skin were alopecic (color dilution alopecia), and the dog had minimal sight (retinal degeneration). The dog had a 5-mm subcutaneous lipoma on the left side of the neck, multiple missing teeth from recent dental extractions, and a healed callus from a previous bone fracture over the right metatarsal region. There was a healing midline incision in the prescrotal area with no palpable subcutaneous or penile mass. The superficial inguinal lymph nodes were not palpable. The results of the remainder of the physical examination were unremarkable.

A complete blood (cell) count (CBC), serum biochemistry profile, and urinalysis did not demonstrate any clinically significant abnormalities. The appearance of three-view digital thoracic radiographs was within normal limits. Abdominal ultrasonography revealed bilateral nephrocalcinosis, mineralization of a splenic vessel, and a 4.5-mm hypoechoic mesenteric lymph node; no evidence of metastasis or systemic involvement was identified. Ultrasonography of the penile urethra was unremarkable and the superficial inguinal lymph nodes were not identified sonographically. Protein electrophoresis performed on both serum and urine was within normal limits. Bone marrow cytologic evaluation was declined by the owners. Ophthalmologic examination revealed an incipient subcapsular cataract OS, nuclear sclerosis and vitreal degeneration OU, and diffuse tapetal hyper-reflectivity and retinal vascular attenuation OU consistent with retinal degeneration.

Because of the tumor location at the caudal aspect of the penis and the intimate association with the urethra, curative intent surgical intervention was limited to penile amputation and scrotal urethrostomy. Systemic chemotherapy (melphalan/prednisone) and definitive (fractionated) radiation therapy were presented as alternative curative-intent treatment options for the residual disease. The owners declined aggressive local surgery or systemic chemotherapy and elected to pursue definitive radiation therapy. The dog was placed in dorsal recumbency and the radiation plan consisted of right- and left-lateral opposed fields at 40° and 320° that prescribed 45 Gy in 18 fractions (2.5 Gy/fraction) via ⁶⁰Cobalt. Manual planning and dose calculation were based on caliper measurements of the scar with 2-cm margins, directed isocentrically with 100% of the dose prescribed to the geometric isocenter of the planning target volume (PTV). The entire shaft of the penis was included in the treatment field. The dog was sedated daily for treatment with an intramuscular (IM) sedative combining medetomidine (Domitor; Pfizer Animal Health), 0.01 mg/kg BW, butorphanol tartrate (Torbugesic; Fort Dodge Animal Health, Fort Dodge, Illinois, USA), 0.22 mg/kg BW, and glycopyrrolate (Baxter Healthcare Corporation, Deerfield, Illinois, USA), 0.01 mg/kg BW. Reversal with the alpha2-adrenergic antagonist atipamezole hydrochloride (Antisedan; Pfizer Animal Health), 0.05 mg/kg BW, IM, was administered after completion of the procedure.

Grade 1 acute side effects [VRTOG score (1)] to the skin were characterized by minimal erythema in the inguinal treatment area, noted 10 d after the beginning of radiation therapy. Topical wheat-based cream (Damor saturation cream; Damor America, Melrose Park, Illinois, USA) was applied locally twice daily. The erythema did not progress and resolved completely within 1 wk of completing treatment. The dog remained free of detectable local disease or clinical signs until he was euthanized due to chronic renal failure 1688 d after diagnosis. Although the owners declined repeat clinical staging post-therapy, no clinical signs suggestive of metastatic disease or development of multiple myeloma were reported.

Discussion

Solitary plasma cell tumors, or extramedullary plasmacytomas (EMPs), are infrequently reported in dogs and most commonly affect cutaneous sites, mucocutaneous sites, and the oral cavity (2). Solitary osseous plasmacytomas are similar histologically, but are more likely to eventually progress to multiple myeloma (3). The median age of dogs with mucocutaneous EMPs is 10.5 y, with Cocker spaniels being most commonly affected (2). Dogs with tumors of the mucous membranes are usually presented for a single, visible mass (red, ulcerated, raised, bleeding) (2–5). Surgical excision achieving complete margins is generally considered curative for cutaneous and oral EMPs. There is limited information on the use of systemic chemotherapy for EMPs; however, protocols similar to those used for multiple myeloma, generally combining melphalan and prednisone, have been used with debatable results (2,3,5,6). Nearly one-third of canine EMPs occur in mucous membrane sites in the oral cavity or rectum; EMPs are uncommonly reported in the esophagus, stomach, small intestine, kidney, brain, lung, liver, larynx/trachea, uterus, and third eyelid, with a single previous report involving the penis (2–15). Although oral EMPs appear to behave similarly to cutaneous EMPs, other non-cutaneous, non-oral sites are reported to have lymph node metastasis, local recurrence post-surgery, and/or progression to disseminated myeloma (2–5,16–20).

Before pursuing aggressive definitive local therapy for an atypical EMP, it is important to consider thorough clinical staging to rule out multiple myeloma and ensure there is no evidence of lymph node involvement or systemic illness. This is especially important with plasmacytomas associated with more aggressive disease, such as non-cutaneous, non-oral EMP, and solitary osseous plasmacytomas (SOP). Staging tests should include a minimum database (CBC, serum biochemistry profile, urinalysis), regional lymph node evaluation (palpation, aspiration or biopsy, and sonography), survey skeletal radiographs or bone scintigraphy, bone marrow aspiration and cytology, and serum and/or urine electrophoresis.

Plasma cell tumors affecting the canine penis are rare and the prognosis is unknown. A single report described a 5-year-old Cocker spaniel treated with curative intent surgery with follow-up limited to 4 mo (15). In humans, penile EMPs are reported to derive from the penile urethra, and in the 8 cases reported in the English literature, curative-intent treatment consisted of radiation therapy alone (n = 2) or in combination with surgery (n = 6) (21). Radiation therapy is effective for EMPs, with nearly 92% local control rate for solitary plasmacytomas in humans (22). Although radiation therapy is also reported to be effective for canine EMPs, experience is limited (5,23).

Tumors of the canine penis and prepuce are uncommon, and the most common ones are transmissible venereal tumors (TVTs), papillomas, and squamous cell carcinoma (SCC) (9,24). In humans, SCC is the most common penile tumor and although penectomy is considered curative, the associated impairment of sexual function and quality of life have led to incorporation of radiation therapy with external beam protocols administered at 60 to 74 Gy (25). Protocols for microscopic disease usually incorporate external beam radiation therapy to the entire shaft at 40 to 50 Gy in 1.8 to 2.0 Gy fractions, then a boost to the primary lesion (with 2-cm margins) to total 60 to 65 Gy (26,27). Major risk factors for radiation-induced complications include total dose, dose per fraction, and volume of normal tissue, although previous surgery and old age may have a minor role (28). Potential late side effects occur in up to 27% of human patients treated with external beam radiation, and include asymptomatic urethral stenosis (most common), telengectasia, urethral fistula, radiation necrosis, and radiation-induced secondary tumors (25,27–29). Intra-operative radiation therapy (IORT) administered to the canine upper urinary tract (ureters/bladder) often resulted in stenosis and fibrosis; however, this procedure involved intra-operative selective delivery of a large boost dose of radiation directly to the tumor, followed or preceded by fractionated external beam radiation therapy with the goal of reducing the volume of normal tissue in the treatment field (30). Radiation therapy has been reported for canine penile TVTs; however, these tumors are exquisitely radiosensitive and cured with total doses of 10 to 15 Gy; other reports demonstrate radiation of 22.5 Gy to the canine penis (31,32). As expected with this relatively low dose of radiation, early side effects included only temporary epilation in some dogs and late side effects were not reported (26,27).

In 1 report of canine mast cell tumors treated with radiation therapy, at least 1 dog was administered 52 Gy to the preputial region in an 18-fraction alternating-day protocol, but the number of dogs affected and extent of inclusion of the penis itself in the treatment field were not reported (33). Normal tissue considered to be at risk for late side effects in our patient include the urethra and, specific to the dog, the risk of osteoradionecrosis or secondary tumor of the baculum (os penis). In humans treated with conventional fractionation at 1.8 to 2.0 Gy, the normal tissue tolerance (TD 5/5, or total dose associated with 5% risk of late side effects at 5 y) for the at-risk organs were: urethra (65 Gy) and bone (> 60 Gy) (27,28). Given the reported sensitivity of this tumor (5,21–23), a total dose of 45 Gy would likely be curative and therefore treatment to normal tissue tolerance was unnecessary. Conventional fractionation in veterinary radiation therapy is often 3 Gy/fraction daily; however, we reduced the fraction size to 2.5 Gy based on potential risk of late side effects and conventional dosing of human penile tumors with external beam radiation therapy at 1.8 to 2.0 Gy/fraction (26–28). To the best of our knowledge, this is only the second reported case of penile EMP in a dog, and the first treated with long-term success using a combination of surgery and definitive radiation therapy.

In summary, in this dog, curative-intent radiation therapy was effective for long-term control of an incompletely resected extramedullary plasmacytoma of the penile mucosa with macroscopic residual disease. A total dose of 45 Gy was administered in small fractions to the tumor site and surrounding tissues with minimal side effects. Although additional systemic staging was not performed, there was no evidence of local recurrence or systemic illness when the dog was euthanized for an unrelated disease more than 4.6 y (1688 d) after diagnosis. To the authors’ knowledge, this is the first report of radiation therapy for an extramedullary plasma cell tumor of the canine penile urethra, first report of long-term follow-up for an EMP at this site, and first detailed report of definitive, high-dose external beam radiation therapy for macroscopic residual tumor of this anatomic site in the dog. CVJ