Penile and preputial squamous cell carcinoma in the horse and proposal of a classification system

Authors


email: j.g.b.vandentop@uu.nl

Summary

Squamous cell carcinoma (SCC) is the most common tumour of the penis and prepuce of the horse and is found mainly in older animals. Reports on breed predilection for penile tumour formation are equivocal but castration, coat colour, poor genital hygiene and various infectious agents have been suggested to predispose to the development of SCC. Careful assessment of the primary tumour is an important first step in the design of an optimal treatment protocol. Tumour size, invasiveness, differentiation grade and presence of metastases are relevant to the decision to pursue additional diagnostic procedures or specific treatment options. Complete elimination of the neoplasm and, therefore, risk of recurrence is highly dependent on the type of therapy chosen. However, the size and histopathological features of the primary tumour are also important factors with respect to prognosis. This review describes the clinical and pathological features of penile and preputial SCC in the horse and proposes a standard staging system.

Introduction

Penile and preputial tumours are among the most common tumours in the horse (Theilen and Madewell 1987). The prepuce and penis are covered with skin and can thus be affected by tumours of epithelial or mesenchymal origin. Squamous cell carcinomas in this region frequently cause discomfort but can also lead to more severe sequelae and even result in death. Recently, a standard protocol has been proposed to aid selection of treatment of horses with penile and preputial tumours, with treatments ranging from minimally invasive interventions (e.g. topical use of 5-fluorouracil) to radical surgery (e.g. en bloc penile and preputial resection with penile retroversion; Van den Top et al. 2010).

In this review, the most important characteristics of SCC are outlined and a staging system to optimally define the extensiveness of the SCC is proposed.

Epidemiology and aetiological factors

In the horse, 6–10% of all neoplasms affect the external genitalia (Theilen and Madewell 1987; Brinsko 1998), of which SCC is the most common neoplasm with an incidence of 49–82.5% (Klein et al. 1991; Brinsko 1998; Van den Top et al. 2008a). Penile and preputial SCC mainly affects adult horses (Strafuss 1976; Howarth et al. 1991; Brinsko 1998; Mair et al. 2000; Van den Top et al. 2008a). Markel et al. (1988) reported that the average age of affected horses was 12.4 years, but most other studies suggest a higher average age (17.4–19.5 years) (Strafuss 1976; Howarth et al. 1991; Mair et al. 2000; Van den Top et al. 2008a).

Reports of possible breed predisposition for genital tumours are equivocal and difficult to interpret because of strong breed biases in many of the study populations. For example, Strafuss (1976) and Akerejola et al. (1978) evaluated genital SCC and reported among the affected horses a high incidence of American Quarter Horses (19%) and Arabian horses (100%), respectively. However, these breeds may have been overrepresented due to their relative abundance in the equine population in the areas where these studies were conducted. Ponies seem to be overrepresented among sufferers of male genital tumours but this may be related to their higher average life expectancy (Van den Top et al. 2008a). Of 45 horses treated surgically for SCC in one study, 17 were ponies (Mair et al. 2000), but other breeds were not specified. In a survey of geldings subjected to penile amputation and urethrostomy, 36 of the 43 patients were ponies, leading the authors to suggest that ponies are more susceptible to genital SCC than the horses (Howarth et al. 1991). Breeds with nonpigmented genitalia such as Appaloosas and American Paint horses, are thought to have a predilection for the development of SCCs (Schumacher 2006).

In man, infection with papilloma viruses (HPV) has been reported to be a risk factor for the development of SCC, but secondary factors must also be present (Jarrett et al. 1978; Smith and Campo 1985; Rubin et al. 2001; Postey et al. 2007). In the horse, a similar cause seems to be involved because histopathological investigations of equine penile tumours regularly report papillomas undergoing transition to SCC (J.G.B. van den Top, unpublished observations). In horses, infection of the basal cell layer of the cutaneous epithelium with a host-specific papilloma virus is thought to be responsible for, of contribute to, the development of papillomas (Joyce 1976; Postey et al. 2007) and it has been suggested that papillomas of the penis and prepuce are caused by an equine papilloma virus different from the one causing papillomas in skin of other regions of the body (O'Banion et al. 1986). Scase (2007) reported the presence of a novel papilloma virus in penile papillomas and SCCs of horses. Equus caballus Papilloma Virus 2 (EcPV-2) was detected in fresh tissue of 8/8 equine penile papillomas, 11/11 penile intraepithelial neoplasia (PIN) and 17/17 equine SCCs (Martens et al. 2009). Recently, the full genome of EcPV-2 was characterised from genital SCC tissue. Viral DNA or RNA was identified in genital tumour samples, but not in adjacent normal tissue or in scrotal tissue and smegma from tumour-free horses (Scase et al. 2010). Smegma has repeatedly been proposed to be an important aetiological factor in the formation of genital SCC based on a study in which equine smegma produced a papilloma, SCC or a fibrosarcoma at the site of injection in mice (Plaut and Kohn-Spayer 1947). However, assertions that smegma is carcinogenic per se cannot be justified from that study. Nevertheless, there is support for the theory that smegma predisposes to genital cancer in man (Van Howe and Hodges 2006). Klein et al. (1991) described horses with a combination of penile SCCs and papillomas and suggested that, although the papilloma virus may be the initiator of SCC development, smegma may act as a promoter. In a similar way, poor hygiene, followed by chronic irritation and balanoposthitis, has been proposed to induce formation of genital carcinomas of horses (Brinsko 1998).

Symptoms and diagnosis

The clinical signs of preputial or penile SCC can result from the primary tumour or from secondary inflammatory processes. Signs commonly include depigmented plaques (Figs 1 and 3), irregularities of the penile or preputial surface, nonhealing erosions with or without accompanied granulation tissue (Fig 2). In more advanced stages, the tumour can become a solid mass with or without a cauliflower-like appearance (Figs 3 and 4), and may contain large necrotic areas (Fig 5). Clinical signs of SCC previously reported are sanguineous or purulent discharge, pungent odour due to infection that may be secondary to necrosis, oedema of the prepuce and disturbed micturition. Large SCCs can interfere with coitus or normal protrusion and retraction of the penis. Other signs may include excoriation of the penile or preputial integument, frequent protrusion of the penis, a gait abnormality and a wide-based stance (Howarth et al. 1991; Fortier and MacHarg 1994; Archer and Edwards 2004; Van den Top et al. 2008a). The glans penis is involved in 53–84% of cases of equine penile and preputial SCC (Howarth et al. 1991; Mair et al. 2000; Van den Top et al. 2008b).

Figure 1.

Depigmented skin lesion present at the internal lamina of the inner fold of the preputium. The lesion is a penile intraepithelial neoplasm (PIN).

Figure 3.

Squamous cell carcinoma infiltrating the corpus spongiosum (T2); invasion of corporeal tissue could be palpated (blue arrow). PIN lesions (yellow arrow). Papilloma-like lesion (red arrow).

Figure 2.

Ulcerative process (yellow arrow) and granulation-like tissue (blue arrow) at the internal lamina of the outer fold of the prepuce. Histopathological examination revelaed a well differentiated SCC (grade 1) mixed with granulation tissue.

Figure 4.

Noninvasive verrucous SCC (Ta). Histopathological examination revealed a well differentiated type (G1). Corpus spongious body (2); Corpus cavernosum penis (3); Tunica albuginea of the corpus cavernosum penis (4); urethra (5); urethral fossa (6).

Figure 5.

Large, ulcerative SCC at the distal end of the penis invading corpus spongiosum, corpus cavernosum and urethra (T3).

The examination of a horse's external genitalia for evidence of neoplasms should begin with visual inspection and palpation of the skin of the prepuce and scrotum. Assessment of an apparent primary tumour should include size, location, mobility, degree of invasion and involvement of the urethra, corpus cavernosum penis or corpus spongiosum. Examination of the penis itself and internal fold of the prepuce may be difficult in the nonsedated horse because the horse tends to keep these structures retracted within the preputial cavity. Partial penile protrusion usually occurs during urination and can be provoked by placing the horse in a bedded stall or by administering a diuretic (Brinsko 1998). Adequate inspection and palpation of the penis can be accomplished after i.v. injection of acepromazine (0.04–0.1 mg/kg bwt), or detomidine (0.01 mg/kg bwt), or xylazine (0.5–1 mg/kg bwt). For horses that resist penile protrusion and examination, administration of a combination of 0.02–0.05 mg/kg bwt acepromazine and 0.2–0.3 mg/kg bwt xylazine has been reported to be effective (Brinsko 1998), with penile relaxation being more profound and longer lasting than from administration of xylazine alone. Acepromazine induces more profound relaxation of the retractor penis muscle and, although detomidine may be slightly less effective than acepromazine in promoting penile protrusion, it induces placidity of the horse more quickly. It should be emphasised that phenothiazine tranquilisers have been reported to cause paraphimosis, priapism or penile paralysis. None of these side effects have been associated with use of detomidine (Brinsko 1998; Van der Harst et al. 2002).

In man, ultrasonography is a common adjunct to clinical examination of genital SCC (Horenblas et al. 1994; Agrawal et al. 2000), which is usually visible as a hypoechoic lesion (Horenblas et al. 1994). In one study, ultrasonographical examination of the glans penis could not differentiate between invasion of subepithelial tissue and invasion of the corpus spongiosum (Horenblas et al. 1994); absence or presence of invasion of the neoplasm into the tunica albuginea of the corpus cavernosum could, however, be determined unequivocally. The authors concluded that ultrasonographical examination was a useful additional tool for the examination of larger tumours because it helped to determine the anatomical relationships of the tumour to structures, such as the tunica albuginea and urethra. Ultrasonography was not accurate enough for staging small penile cancers located at the glans penis (Horenblas et al. 1994). In horses, ultrasonographical examination of the penis and prepuce may be useful for determining gross extent of the tumour and the degree of involvement of various structures. Ultrasonographical examination is easily performed and the soft tissue structures are well suited for evaluation by this diagnostic technique (Figs 6 and 7)

Figure 6.

Ultrasonographical examination of the tumour seen in Figure 4. No infiltration in the subepithelial tissue and spongious body is visible.

Figure 7.

Ultrasongraphical image of preputial SCC shown in Figure 2. Note the poorly defined margins of the tumour and some oedema between the probe and tumour.

Preoperative pathological evaluation of the primary tumour is required to classify the tumour and design a treatment plan. This can be performed by fine needle aspiration biopsy (FNAB) or by punch or excisional biopsy (Klein et al. 1991; Brinsko 1998; Bosch and Klein 2005). Fine needle aspiration biopsy can be used to identify cells with malignant features, but it is not a very reliable means of assessing SCCs, because early neoplastic, hyperplastic or dysplastic keratinocytes can appear similar cytologically. Tumour architecture and depth of invasion can only be assessed by evaluating a full thickness biopsy; therefore a full thickness biopsy of the lesion is more reliable than FNAB. Independent of the type of tumour, the lesion can be so severe that complete excision is necessary in any case. In such cases, surgical removal or debulking can be combined with harvesting material for histopathological examination.

Metastasis is a major concern when evaluating horses with SCCs of the external genitalia. Van den Top et al. (2008a) reported that in 13 of 77 (16.9%) male horses with genital SCC, the neoplasm had metastasised to the inguinal lymph nodes, which is similar to the 12.5% incidence of metastasis found by Howarth et al. (1991) and the 13% incidence of metastasis reported by Mair et al. (2000). Lymph node enlargement may be an indicator of metastasis and can sometimes be detected by palpation of the regional lymph nodes, but false positive results can occur because penile neoplasms can become secondarily infected leading to lymphadenopathy. Van den Top et al. (2008a) described enlargement of the inguinal lymph nodes in a relatively high proportion (34.1%) of horses with various penile and preputial tumour types in which lymph node size was recorded, whereas metastases were confirmed in only 32.1% of horses with enlarged inguinal lymph nodes. Palpation of the inguinal lymph nodes can be difficult in horses due to extensive fat deposition in the inguinal region.

When a penile tumour metastasises, the first lymph nodes affected are usually the superficial (palpable dorsolateral to the penis) and deep (just outside the pelvis adjacent to the internal inguinal ring) inguinal lymph nodes (Van den Top et al. 2008a; Dyce et al. 2010). The next lymph nodes to be affected are the medial iliac lymph nodes (Dyce et al. 2010), which can be evaluated per rectum by palpation and ultrasonographically (Fig 8). If enlarged lymph nodes are detected, samples collected by ultrasonograpically guided FNAB should be examined cytologically (Fig 9). Although identification of neoplastic cells is a reliable indicator of metastasis, failure to identify metastatic cells is less conclusive. An incidence of false negative results of up to 29% has been reported in man (Kroon et al. 2005a). Absence of lymph node enlargement does not rule out metastasis. In 36% of cases where lymph node enlargement could not be discerned, so-called ‘occult’ metastasis was found after en bloc penile and preputial resection with penile retroversion or at post mortem histopathological examination of the lymph nodes (Van den Top et al. 2008a).

Figure 8.

Ultrasonographic image. Despite G1 SCC, metastasis to the internal iliac lymph node (N3) was detected in the horse illustrated in Figure 4.

Figure 9.

Aspirate of internal iliac lymph node shown in Figure 8. A group of rather undifferentiated carcinoma cells with clear anisokaryosis, multiple prominent nucleoli and some squamous metaplasia is seen against a background of reactive lymphoid cells (May-Grünwald Giemsa stain, 500×).

Distant metastases can sometimes be detected by radiology of the lungs, although distant metastases are relatively rare. In a study by Van den Top et al. 2008a, the thorax of 27 horses with a preputial or penile tumour was radiographed, but only one horse had radiographic suspicion of metastases to the lungs, and metastases to the lungs of that horse were not confirmed because gross or histological post mortem inspection of the lungs was not performed. Regional lymph node enlargement is generally considered an indication for thoracic radiolography in men, but pulmonary macrometastases can be present, although rarely, without palpable enlargement of the inguinal lymph nodes (Kroon et al. 2005a).

Histopathological features

Histologically, invasive SCCs consist of small aggregates, irregular islands, nests or cords of neoplastic keratinocytes that proliferate downward from the surface (epidermis) and invade the subepithelial stroma of the dermis. Frequent findings include keratin formation, horn pearls, mitoses and cellular atypia (Scott and Miller Jr 2003). A high nucleus : cytoplasma ratio, thick nuclear membranes and clumped chromatin are often found. Depending on the differentiation grade, the overall architecture of the tissue can be still visible in well differentiated tumours (Fig 10), whereas it is often absent in poorly differentiated SCCs (Fig 11). The term penile intraepithelial neoplasia (PIN), synonymous with carcinoma in situ, is used to describe a cluster of malignant cells that has not yet invaded the deeper subepithelial tissues and is limited in its extent to the epithelium.

Figure 10.

Well differentiated SCC (H&E). Island and cords are infiltrating subepithelial stromal tissue. Differentiation of basal cells to keratinocytes is still present. A concentric aggregation of cornified squamous epithelial cells (horn pearl; arrow) is visible.

Figure 11.

Poorly differentiated SCC (H&E). No normal architecture is visible and differentiation to normal keratinocytes is absent.

Tumour classification

Ideally, grading and staging of a tumour should permit accurate prediction of tumour behaviour. A difficulty with retrospective studies is the diversity and sometimes inconsistency in the registration of clinical and pathological features of diseases examined and treated. A standard staging system that aims at aiding clinicians with planning of treatment, prognostication, evaluation of results of treatment and exchange of information between treatment centres would be most helpful for the continued study of equine penile and preputial cancer and to support cancer control activities in horses.

Histopathological grading

Histopathological tumour grading involves assessment of anaplasia in cells obtained by biopsy or excision (Broders 1928; Van den Top et al. 2008b; Chaux et al. 2009). In contrast to the horse, several variations of grading of SCCs have been described in man (Broders 1928; Chaux et al. 2009). However, no clear consensus as to what is the best system of grading has so far been reached. The basis of grading is classification of the extent to which cancer cells are similar in appearance and function to healthy cells of the same tissue type (Chaux et al. 2009). Table 1 describes the characteristics of the grading system reported by Chaux et al. (2009) used in man. In short, a well differentiated SCC (Grade 1) has minimal basal or parabasal atypia, whereas poorly differentiated (Grade 3) tumours have minimal or no architectural and cellular similarity with normal tissue. Grade 2: all tumours not fitting into criteria described for G1 or G3. Squamous cell carcinoma can be heterogeneous, i.e. areas of various degrees of differentiation can be present in the same tumour. Van den Top et al. (2008b) assessed histopathological reports to grade SCC in horses retrospectively. Eighty-one SCC were evaluated histopathologically and grouped by differentiation grade. Metastasis was confirmed in 44% of tumours graded as G3, as compared to only 3% for tumours graded as G1 and 25% tumours graded as G2 (Van den Top et al. 2008a).

Table 1. Grading criteria in man (Chaux et al. 2009)
Well differentiated (G1)Moderately differentiated (G2)Poorly differentiated (G3)
• Minimal basal/parabasal atypia• More disorganised• Any proportion of anaplastic cells
 • Less keratinisation• Solid sheets
 • Higher nuclear: cytoplasmic ratios• Irregular small aggregates
 • Thicker nuclear membranes• Cords
 • Moderate nuclear pleomorphism• Nests
 • Evident nucleoli• Absence of keratinisation
 • More obvious mitoses• High nucleus/cytoplasma ratio
 • Occasionally clumped chromatin• Thick nuclear membrane
  • Nuclear pleomorphism
  • Clumped chromatin
  • Prominent nucleoli
  • Numerous mitotic figures

Of the treated horses with G3 SCCs, 6 of 9 treatments were unsuccessful. Of the 3 succesfully treated horses, 2 treatments consisted of en bloc penile and prepuce resection with penile retroversion. These 2 horses had metastatic involvement of the regional lymph nodes. By correlating histological classifications of SCC lesions with outcome, more horses with moderately or poorly differentiated SCC were treated unsuccessfully (42.9% for G2 and 66.7% for G3 tumours) than were horses with well differentiated tumours (30.8%) for G1 tumour. The outcome was even less favourable than the results of treatment suggested because some horses were subjected to euthanasia or received no treatment at all and 50% of horses with G1 tumours, 75% with G2 tumours and 80% with G3 tumours had an unsuccessful outcome (i.e. recurrence of tumour, no treatment or euthanasia; Van den Top et al. 2008b).

The relationship between tumour grade and prognosis indicates that standardisation for histopathological grading of penile and prepuce SCC in horses should be developed.

Tumour staging and proposal for TNM classification system in the horse

In human medicine the most commonly used staging system for malignant tumours is the TNM classification system (Sobin et al. 2010), which was developed between 1943 and 1952 (Denoix 1944). In this system, the ‘T’ describes the size of the tumour and whether it has invaded adjoining tissue, the ‘N’ describes the extent of regional lymph node involvement and the ‘M’ refers to the presence of distant metastases. The practice of dividing cancers into groups according to so-called stages arose from the observation that the incidence of survival rates was higher for people whose disease was localised than for those in which the tumour extended beyond organ of origin (Sobin et al. 2010). Staging is based on information about tumour spread obtained by physical examination and various imaging techniques (e.g. radiography, ultrasonography and urethral endoscopy). Pathological examination provides additional information via macroscopic and microscopic examination of the tumour margins and lymph nodes. Thus far, no comparable system has been described in the horse.

Table 2 describes a staging system for penile and preputial SCC in the horse analogous to the system used for man. The size (i.e. depth of invasion and extension; T) and grade (G) of a primary SCC in man are considered to be the most important indicators of lymphatic spread. Invasiveness of the tumour is an important factor in the tumour's tendency to metastasise and, consequently, is an important factor in the risk of incomplete removal. Deeply (T>1) infiltrating tumours have a high propensity for nodal spread and several reports have shown a relationship between poorly differentiated tumours and presence of nodal metastases. Well differentiated (G1) or intermediately differentiated (G2) and superficial tumours (Tis [i.e. carcinoma in situ] and T1) have a low tendency to metastasise (McDougal 1995; Kroon et al. 2005b). The most important indices of metastasis to lymph nodes are likely similar for horses. In a case series described by Mair et al. (2000), 4 of 6 horses with local recurrence of a penile tumour had metastases in the abdomen. Three of these 4 horses had penile lesions characterised by a palpable, firm thickening of the penis, associated with extension of the neoplasm into the urethra and involvement of the corpus cavernosum and with lymphovascular invasion. Howarth et al. (1991) reported that only 28.6% in of 22 horses treated for SCC that had urethral involvement had a successful outcome, whereas 66% of the 22 horses that had SCC present at the glans penis but had not involvement of the urethra had a successful outcome. Both studies suggest that horses with a SCC involving the corporeal bodies and urethra are at higher risk of metastasis of the SCC. Squamous cell carcinoma that involve the corpus cavernosum penis, corpus spongiosum and urethra are classified as T2 and T3 in Table 2. Less invasive tumours, such as carcinoma in situ (Tis), verrucous carcinomas (Ta) and tumours without lymphovascular invasion (T1a) are less likely to metastasise. Extensive involvement of the penis and prepuce is qualified as T1c in Table 2. The pTNM categories are based on information gained after surgical excision and histological examination.

Table 2. Proposal for TNM classification system for penile SCCs in the horse
 TNM clinical classification
TPrimary tumour (physical examination, imaging, biopsy)
 TXPrimary tumour cannot be assessed
 T0No evidence of primary tumour
 TisCarcinoma in situ (PIN)
 TaNoninvasive verrucous carcinoma
 T1T1a: Tumour invades subepithelial connective tissue of the penis or prepuce without lymphovascular invasion
T1b: Tumour invades subepithelial connective tissue of the penis or prepuce with lymphovascular invasion
T1c: Tumour invades subepithelial connective tissue of the penis and prepuce with or without lymphovascular invasion
 T2Tumour invades corpus spongiosum or corpus cavernosum penis
 T3Tumour invades urethra
 T4Tumour invades other adjacent structures
NRegional lymph nodes (physical examination, imaging, biopsy)
 NXRegional lymph nodes cannot be assessed
 N0No regional lymph node metastasis
 N1Metastasis bilateral or unilateral inguinal lymph node(s)
 N2Metastasis in inguinal lymph node(s) fixed to surrounding tissue
 N3Metastasis in pelvic lymph node(s)
MDistant metastasis (physical examination and imaging)
 M0No distant metastasis
 M1Distant metastasis
 pTNM pathological classification
 The p categories correspond to the T and N categories assessed histologically. The pN categories are based on surgical excision followed by assessment histologically. pM1 is distant metastasis microscopically confirmed.
 Stage grouping
Stage 0TisN0M0
TaN0M0
Stage IT1aN0M0
T1bN0M0
Stage IIT1cN0M0
T2N0M0
T3N0M0
Stage IIIAT1, T2, T3N1M0
Stage IIIBT1, T2, T3N2M0
Stage IVT4Any NM0
 Any TN3M0
 Any T,Any NM1

Involvement of the regional lymph nodes (N1 and N2) has been shown to increase the risk of recurrence. Van den Top et al. (2008b) described 25% recurrence in horses with metastasis to the regional lymph nodes, irrespective of treatment chosen. In the horse, no successful treatment has yet been described when pelvic lymph nodes (N3) are involved or when distant metastasis (M1) is present.

Treatment

Several therapies have been described, ranging from topical treatment to en bloc penile and preputial resection with penile retroversion, with the choice of surgical therapy depending primarily on the size and site of the lesion and presence of inguinal metastases (Scott 1976; Markel et al. 1988; Schumacher and Vaughan 1988; Klein et al. 1991; Mair et al. 2000; Doles et al. 2001; Archer and Edwards 2004; Gardiner et al. 2008; Van den Top et al. 2008b). The ideal treatment would eliminate the tumour while preserving the function of the external genitalia (i.e. micturition, erection and ejaculation); however, both elimination of the tumour and preservation of function are not always achievable.

Some surgical techniques (e.g. partial phallectomy with sheath ablation and en bloc penile and prepuce resection with penile retroversion) can cause post operative discomfort and this should be considered prior to surgery (Markel et al. 1988; Doles et al. 2001; Archer and Edwards 2004). In some cases, an owner may refuse for the horse to have invasive surgery and instead opt for less radical surgery, despite a higher risk of incomplete tumour removal.

Nonsurgical interventions

Hyperthermia (i.e. heating the tumour to a temperature of >50°C by radiofrequency) has been used successfully to treat horses for sarcoids and ocular neoplasms. High temperatures damage and kill cancer cells by altering cell membrane structure and function, impairing intracellular protein synthesis and transport or RNA/DNA synthesis, inhibiting repair enzymes and altering DNA conformation (Hildebrandt et al. 2007). Besides its cytotoxic effect, hyperthermia has been shown to decrease tumour blood flow, thereby impairing oxygen and nutrient supply to the tumour and inducing acidosis (Hildebrandt et al. 2007). Although it has been suggested that radiofrequency-induced hyperthermia could be useful in treating horses with penile and preputial tumours (Schumacher and Vaughan 1988; Schumacher 2006), its use to treat horses with genital neoplasms has not been reported.

Cryotherapy appears to be an effective treatment for horses with penile or preputial tumours that are small or in an early stage. Tissue sloughing usually begins 7–10 days after the intervention and the wound is left to heal by second intention. Cryotherapy is minimally invasive, does not require a sterile field and is therefore a good treatment for horses with early malignant neoplasms (Bosch and Klein 2005; Stick 2006). The major limiting factor for cryotherapy is the size of the tumour; debulking the tumour is often necessary to reduce the size prior to freezing. In several murine tumour systems, cryosurgery induces specific immunity against the tumour (Neel 1980). In horses, such an affect has not yet been confirmed.

Radiotherapy has been previously described for the treatment of men with penile or preputial carcinomas (Theilen and Madewell 1987). Reported treatments include external beam therapy and radioactive implants (β-radiation). In general, the use of radiotherapy in horses is limited because of the special equipment needed and special housing requirements for horses during treatment.

Topical use of 5-fluorouracil has been described as an effective treatment for horses with nonmetastasised SCCs of the external genitalia (Fortier and MacHarg 1994). However, only a small number of horses (11) were treated in this study and the results may have been influenced by the stage and grade of the tumours. The drug interferes with cellular DNA synthesis, leading to preferential death of neoplastic cells and enhanced recognition and destruction of these cells by the immune system. Topical application of 5-fluorouracil is an effective method of treating horses with small penile or preputial tumours, but larger lesions require surgical debulking prior to treatment.

Cisplatin has been used for intratumour injection, but is only effective for small tumours or when used in combination with surgery (Theon et al. 1993, 1999). In general, debulking of large tumours before chemotherapeutic treatment is important to reduce the recurrence rate. Topical or intra-tumoural chemotherapy is not particularly useful for horses with metastasised SCCs. Piroxicam administration has been described for the treatment of a single horse with a SCC of the lower lip complicated by metastasis to regional lymph nodes. Treatment was highly successful; within 3 months the primary SCC had disappeared completely and a neoplastic regional lymph node had returned to its normal size (Moore et al. 2003). To date, the authors can find no other reports that describe the use of systematically administered chemotherapy for the treatment of horses with metastasised genital SCCs.

Surgical intervention

Surgical intervention at the primary site aims to remove the malignant lesion(s) with adequate margins to minimise the risk of recurrence. Surgical modalities include simple excision, segmental posthioplasty, partial phallectomy, partial phallectomy combined with sheath ablation and en bloc penile and preputial resection with penile retroversion.

For smaller penile tumours or lesions not involving the tunica albuginea, penile amputation can be avoided by local excision. However, this therapy carries a high risk of recurrence because of incomplete removal (Van den Top et al. 2008b). Because of the abundance of loose tissue, tumour excision from the prepuce is easier to perform than tumour excision from the penis.

Segmental posthioplasty is indicated for removal of preputial neoplasms that are too extensive to permit excision (Schumacher and Vaughan 1988). The objective of segmental posthioplasty, also known as circumcision or ‘reefing’, is to remove large circumferential penile or preputial lesions that do not extend beyond the dermis, while preserving the ‘telescopic function’ of the prepuce (Brinsko 1998; Schumacher 2006).

Suturing the wound created by removing a tumour and a tumour-free margin from the prepuce-free portion of the penis is often difficult. In man, excision of grades 1 and 2 SCCs should include a tumour-free margin of 10 mm; for grade 3 lesions a tumour free margin of 15 mm is necessary. In the horse, the margins might need to be larger than those mentioned above because, in many cases, tumours are discovered relatively late when invasion might be extensive.

When the tumour invades the tunica albuginea or is too extensive for treatment by noninvasive techniques or by relatively minimally invasive surgery, or if neoplasia is complicated by permanent penile paralysis or irreparable trauma, partial phallectomy (i.e. partial penile amputation) is indicated. When the tumour is located on the glans penis, the free part of the penis, or on the internal fold of the prepuce, Scott's, Williams' or Vinsot's techniques can be performed (Fig 12; Scott 1976; Schumacher 2006).

Figure 12.

Stoma of partial phallectomy (Williams' technique). In this case, resection was just proximal to the glans penis.

Unsuccessful outcome (i.e. recurrence or incomplete removal) of a SCC treated by partial phallectomy, such as the Williams' technique, is not uncommon (43.5%), possibly as a result of the limitation to the amount of tissue that can be removed combined with the frequent presence on the more proximal part of the penis or the prepuce of premalignant tumours, such as papillomas that may subsequently transform to SCCs (Van den Top et al. 2008b). In addition, in some cases, by using the Williams' technique the primary tumour may be too close to the amputation site to allow excision with an adequate margin.

Another possible explanation for the high incidence of recurrence is that a SCC of the glans penis has a higher risk than does a SCC proximal to the glans of invading the underlying tissue because the tunica albuginea of the corpus spongiosum glandis is very thin and merges distally with the integument (Schumacher 2006). In man, it has been found that once the tumour has entered the corpus spongiosum it can easily spread proximally in the cavernous tissue (McDougal 1995), where detection of small neoplastic processes is more difficult.

In conclusion, partial phallectomy, such as the Williams' technique, is indicated only if the distal portion of the penis is involved and there is no spread proximally and no involvement of the prepuce and regional lymph nodes. Involvement of prepuce, urethra and cavernous tissue are indications for performing more radical surgery.

More invasive techniques include en bloc penile and preputial resection with penile retroversion, and partial phallectomy with sheath ablation. In the en bloc penile and preputial resection with the penile retroversion technique, a large part of the penis, the entire prepuce and the inguinal lymph nodes are resected. The resection is followed by retroversion of the penis and creation of a stoma ventrally to the anus (Fig 13). Complications include partial dehiscence of the urethrostomy, dehiscence of the ventral skin incision, urine scalding, severe haemorrhage, cystitis and diarrhoea (Markel et al. 1988; Archer and Edwards 2004). During partial phallectomy with sheath ablation the penile shaft is resected proximal to the diseased tissue and the fornix of the prepuce and a new stoma is created on the ventral aspect of the abdomen (Fig 14; Doles et al. 2001). Although it is not routine, the technique can also be adapted to include lymphadenectomy (i.e. en bloc partial phallectomy with sheath ablation). The incidence of significant complications for this technique is less than for retroversion, but post operative problems can include haemorrhage, dehiscence at the mucocutaneous junction and post operative pain (Doles et al. 2001).

Figure 13.

Post operative view of stoma created by en bloc penile and preputial resection and penile retroversion.

Figure 14.

Creation of a stoma ventral to abdomen using partial phallectomy with sheath ablation technique.

Standardised approach for treating horses with penile and preputial SCC

Recently, a standardised approach to treating horses with penile and preputial tumours was proposed (Van den Top et al. 2010) and a flow chart describing the assessment and treatment for all types of penile and preputial tumours made. An adapted version of this, with the TNM classification system incorporated, for the specific approach to treating horses with SCC is presented at the end of this overview (Fig 15).

Figure 15.

Penile SCC assessment and treatment protocol (lnn = lymph nodes: US = ultrasonography: FNAB = fine needle aspiration biopsy).

According to these guidelines, the primary tumour should first be assessed macroscopically, and then examined ultrasonographically to determine the gross extent of the neoplasia and by histopathological examination to assess tumour type and differentiation grade. Examination of the regional lymph nodes is important to distinguish between lymph node metastasis and inflammatory response and can be performed by FNAB and ultrasonography. However, failure to identify neoplastic cells does not necessarily guarantee a metastasis-free lymph node. Rectal palpation, with special attention to the inguinal area and iliac lymph nodes, will allow detection of swellings in the abdomen that could include metastases and should thus be part of the standard protocol. Large tumours in the lungs can be detected by radiography. However, because lung metastases are rare (Van den Top et al. 2008a), it can be justified to use this modality only when regional lymph nodes are involved.

Local excision, cryotherapy and posthioplasty can be considered if the tumour is well or moderately differentiated (i.e. G1 or G2) and does not appear to invade the underlying structures (e.g. tunica albuginea, corpora and urethra; i.e. stage 0 or stage I). Poorly differentiated (i.e. G3) tumours require more radical techniques (partial phallectomy with sheath ablation or en bloc penile and preputial resection with penile retroversion). Partial phallectomy (i.e. Williams' technique) is indicated when the tumour is relatively circumscribed but infiltration of subepithelial tissue is suspected and/or reconstruction of normal anatomical structures is unlikely to be possible after excision (stage I). If the tumour is more extensive or poorly differentiated (stage II, G3), partial phallectomy with sheath ablation should be considered. The dotted line in the diagram indicates treatment of small stage 0/I G3 lesions. Local excision with reefing can be indicated when the tumour is a small G3 lesions and, therefore, can be easily excised with a wide margin. Although not shown in Figure 15, partial phallectomy (i.e. Williams' technique) to remove stage II lesions without lymph node involvement can be indicated when the owner rejects more radical surgery. However, it needs to be emphasised that the risk of recurrence or incomplete removal may be high.

En bloc partial phallectomy with sheath ablation or en bloc penile and preputial resection with penile retroversion should be the treatment of choice when metastasis to the regional lymph nodes is detected without evidence of metastases to the abdomen, thorax or other distant sites (stage IIIA, IIIB). A stage IV tumour (i.e. invasion to structures adjacent to the penile and preputial integument, metastasis of the iliac lymph nodes and distant metastases) is usually untreatable and warrants euthanasia, possibly preceded by palliative treatment.

Post operative histopathological evaluation is essential to determine if a tumour has been completely removed. Incomplete removal of a primary, genital SCC is an indication for a more radical surgical follow-up, a palliative treatment or euthanasia. If the tumour has been removed completely or when there is no information about the completeness of removal, long-term follow-up is required to monitor for tumour recurrence.

Prognosis

Recurrence of a SCC is the main factor affecting prognosis and the majority of tumours that recur do so within 1 year (range 14 days–7 years) with an overall recurrence incidence of 11–30% (Markel et al. 1988; Howarth et al. 1991; Mair et al. 2000; Doles et al. 2001; Van den Top et al. 2008b).

Reports of the incidence of recurrence after specific treatments are generally based on low numbers of patients and hence should be considered with caution. Topical treatment with 5-fluorouracil resulted in complete remission in all (8) horses followed-up for 7–52 months (Fortier and MacHarg 1994). The incidence of recurrence after simple excision or excision combined with cryosurgery is 50% (Van den Top et al. 2008b). In line with this figure, the success of treating horses with a penile or preputial SCC by partial phallectomy (i.e. Williams' technique), in the presence or absence of papillomas, is only 54–67% (Howarth et al. 1991; Mair et al. 2000; Van den Top et al. 2008b). The reason for the high incidence of recurrence following penile preservation techniques (techniques which do not exclude future breeding such as 5-fluorouracil, simple excision, cryosurgery, partial phallectomy [i.e. Williams' technique]) is most likely related to the removal of an insufficient margin. Post operative histopathology showed incomplete removal in 18% of horses treated exclusively by partial phallectomy (Van den Top et al. 2008b).

En bloc penile and preputial resection with penile retroversion has a higher incidence of success. Even when local metastases are present, 80–86% post operative survival has been reported (Van den Top et al. 2008b). Markel et al. (1988) reported no recurrence in 8 of 9 horses (88%). Similarly, Doles et al. (2001) reported no evidence of disease recurrence and/or complications after partial phallectomy with sheath ablation in a small group of 8 horses for which long-term follow-up was available.

Conclusion

Penile and preputial tumours are commonly encountered in elderly male horses and SCC is by far the most common type. Equine genital tumours pose significant diagnostic, prognostic and treatment challenges. Treatments modalities, such as local excision and partial phallectomy (i.e. Williams' technique), have a relatively high incidence of recurrence. More invasive therapies have a lower incidence of recurrence but post operative complications are common and more serious.

Because little is known about the behaviour of SCC on the external genitalia of the male horse, deciding on the most appropriate treatment is difficult. Poorly differentiated SCCs on the external genitalia of the male horse seem to metastasise relatively frequently, but prospective research on the relationship between tumour grade, treatment performed and incidence of recurrence is needed to confirm this clinical impression. Because invasion of penile tumours into the corpus spongiosum, corpus cavernosum penis and urethra carry a higher risk of metastasis (Howarth et al. 1991; Mair et al. 2000), standard use of ultrasonography to assess tumour extent (already a standard procedure in man), should be considered. The introduction of a TNM classification system for equine SCCs may aid the clinician in therapeutic decision-making and in the evaluation of the results of treatment. Such a classification system may further facilitate exchange of information between treatment centres, contribute to the development of therapeutic guidelines and help in prognostication. The system proposed in this study, admittedly not based on large case series and entirely open to any modification or improvement, is offered as a first step in this direction.

Acknowledgements

The authors thank E. Teske DVM PhD for providing illustrations of cytology and S. Veraa DVM and A.J. van den Belt DVM PhD for providing ultrasonographic images.

Authors' declaration of interests

No conflicts of interest have been declared.

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