Version May 2024
INTRODUCTION — Carcinoma of the penis is rare in the United States, Europe, and other industrialized countries. However, the incidence of these malignancies is much higher in parts of South America, Africa, and Asia.
The clinical presentation, diagnosis, and staging of penile cancer are reviewed here. Related topics include:
●(See "Carcinoma of the penis: Epidemiology, risk factors, and pathology".)
●(See "Carcinoma of the penis: Surgical and medical treatment".)
ANATOMY OF THE PENIS AND REGIONAL NODES — The anatomic components of the penis include the following (figure 1):
●Penile shaft – The penile shaft consists of the skin, subepithelial connective tissue, the erectile bodies (ie, corpora cavernosum), and the urethra, which is surrounded by the corpora spongiosum.
●Penile glans – The penile glans (ie, head of the penis) consists of an epithelial covering and the underlying dermis but is largely made up of a "spongy" expansion of the corpora spongiosum. At the tip of the glans is the urethral meatus, which allows for urination and ejection of semen. The proximal rounded surface of the glans penis is called the corona and serves as the junction between the glans and the penile shaft.
●Foreskin – The foreskin is an extension of the shaft skin, which covers the glans penis at birth. Circumcision is a procedure that removes the foreskin at birth or later in life.
●Regional lymphatics – Penile lymphatics drain both the glans penis and shaft and form an interconnecting network of channels. Drainage proceeds from the superficial inguinal lymph nodes to the deep inguinal lymph nodes and then to the external iliac lymph nodes in the pelvis.
CLINICAL PRESENTATION — Penile carcinoma almost always presents with a skin abnormality or palpable lesion on the penis. The majority of cancers arise on the glans, in the coronal sulcus, or on the prepuce as either a mass or ulceration, and they may be associated with a secondary infection. In a series of 243 males with newly diagnosed penile cancer, the most common signs were a painless lump (25 percent) or ulcer (13 percent) [1]. Other signs included a rash (6 percent), bleeding (4 percent), or balanitis (4 percent).
Penile cancer is typically a disease of older males, and rates increase steadily with age [2,3]. The mean age at diagnosis is 60 years, although penile cancer can be seen in males less than 40 years old [4,5]. (See "Carcinoma of the penis: Epidemiology, risk factors, and pathology", section on 'Epidemiology'.)
Inguinal adenopathy is present in 30 to 60 percent of cases at diagnosis, although malignant infiltration of the lymph nodes is demonstrated in only approximately one-half of these cases. Lymphadenopathy in the remainder presumably represents an inflammatory reaction [6].
Distant metastases are uncommon until late in the disease course, with only 1 to 10 percent of cases having distant metastases at presentation [7-12]. (See 'TNM staging evaluation' below.)
INITIAL EVALUATION AND DIAGNOSIS — The diagnosis of penile carcinoma should be suspected in males who present with a penile mass or ulcer, particularly in those who have not been circumcised. The diagnosis requires biopsy for tissue confirmation. (See "Carcinoma of the penis: Epidemiology, risk factors, and pathology", section on 'Pathology'.)
The initial evaluation of a penile mass or ulcer depends upon whether the clinical presentation suggests that infection or malignancy is more likely:
●Suspected infection – If an infection appears to be more likely (eg, erythema, swelling, discharge), a four- to six-week course of antifungals or antibiotics may be indicated, depending on the clinical exam. The use of steroids is reserved for patients with a biopsy-confirmed diagnosis of an inflammatory lesion (ie, lichen sclerosus). Lesions that do not resolve after six weeks or that progress at any time during antibiotic or antifungal therapy should be biopsied. (See "Balanitis in adults".)
●Suspected malignancy – For males presenting with a penile lesion suspicious for malignancy or with a penile lesion and associated lymphadenopathy, our approach is to proceed with an immediate biopsy of the penile lesion. If this is positive, evaluation of the regional lymph nodes is indicated. (See 'Regional lymph node assessment' below.)
●Other signs or symptoms – The presence of other physical signs (eg, firm subcutaneous skin nodules at distant sites) or symptoms (eg, cachexia, confusion, cough, or bone pain) may indicate the presence of distant metastatic disease or associated metabolic abnormalities, such as hypercalcemia. Such patients require a full laboratory and imaging evaluation in addition to biopsy. (See 'Assessment for distant metastatic disease' below.)
Biopsy can be performed using punch, incisional, or excisional techniques [13]. Excisional biopsy is appropriate when the complete lesion can be removed and closed with little or no alteration to penile form and function. Otherwise, incisional or deep punch biopsies are performed.
All patients require close follow-up to prevent an unnecessary delay in diagnosis and treatment.
DIFFERENTIAL DIAGNOSIS — The definitive diagnosis of penile malignancy is based upon the biopsy of the penile lesion. An incisional or deep punch biopsy is preferred because it provides the most information to guide subsequent staging and treatment.
Malignant lesions — Approximately 95 percent of malignant lesions of the penis are squamous cell carcinoma. A number of other rare malignancies can also arise in the penis. (See "Carcinoma of the penis: Epidemiology, risk factors, and pathology", section on 'Other malignancies'.)
Squamous cell carcinoma must be distinguished from other malignancies that may present with penile lesions, as well as from premalignant and nonmalignant lesions. (See "Carcinoma of the penis: Epidemiology, risk factors, and pathology", section on 'Pathology'.)
Inflammatory conditions
●Genital psoriasis – Psoriasis involves the genital area in 40 percent of affected individuals [14]. The plaques are erythematous, with sharply defined margins that are raised above the surrounding normal skin. Typical psoriatic scales may not be present due to the moisture in the genital area. These lesions are usually asymptomatic, although some patients complain of pruritus. Psoriasis is rarely limited to the penis, and the presence of psoriatic scales elsewhere helps distinguish psoriasis from penile cancer. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)
●Angiokeratomas – Angiokeratomas are uncommon, benign, violaceous papules with overlying scale (picture 1). Penile angiokeratomas often occur on the glans penis but can be found on the scrotum, thigh, and elsewhere. Typically, they are multiple and measure less than 1 cm in diameter [15]. The small size and multiplicity are useful in distinguishing angiokeratomas from penile cancer, which is more commonly a single, larger lesion. In most patients, the lesions are asymptomatic and do not require treatment; however, intermittent bleeding, pruritus, and pain can occur.
●Lichen planus – Lichen planus involving the penis is characterized by violaceous papules on the glans (picture 2A-B). Unlike penile cancer, lichen planus lesions are rarely asymptomatic. Most patients experience pruritus, which can be severe and become intensely painful if the lesions ulcerate or erode. The disease usually heals with significant postinflammatory hyperpigmentation. (See "Lichen planus", section on 'Genital lichen planus'.)
Infectious conditions
●Genital herpes – Genital herpes is caused by infection with herpes simplex virus 1 (HSV1) or 2 (HSV2). The initial presentation can be severe, with painful genital ulcers in association with other manifestations, including systemic symptoms (eg, fever, headache, malaise) and tender local inguinal lymphadenopathy. In contrast, cancerous lesions are usually painless and not associated with systemic symptoms. A clinical diagnosis of genital herpes should be confirmed with laboratory testing. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection".)
●Primary syphilis – Syphilis is a chronic infection caused by the bacterium Treponema pallidum. Primary syphilis can present with a painless papule on the penis. With time, the papule ulcerates to produce the classic chancre of primary syphilis, a 1 to 2 cm ulcer with a raised, indurated margin. The ulcer generally has a nonexudative base and is associated with mild to moderate regional lymphadenopathy, which is often bilateral. Multiple chancres can occur, particularly in the setting of human immunodeficiency virus (HIV) infection. Unlike penile cancer, chancres heal spontaneously within three to six weeks, even in the absence of treatment. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Clinical manifestations'.)
Premalignant lesions — Several penile lesions are recognized as premalignant and have the capacity to evolve into frankly invasive squamous cell carcinoma. These premalignant lesions are generally differentiated from squamous cell carcinoma by biopsy.
The extent to which premalignant lesions precede invasive carcinoma is unknown. The available evidence suggests that the majority of cases of penile squamous cell carcinoma arise de novo [16]. As an example, in one series, only 39 of 511 males with penile cancer (8 percent) had a history of a previous or concomitant lesion [17].
●Condyloma acuminata – Condyloma acuminata, also known as genital or venereal warts, are soft papillomatous growths that are associated with human papillomavirus (HPV) infection in the anogenital area. Although condylomata generally follow a benign course and are most often associated with low-risk HPV types 6 and 11, malignant transformation has been noted, particularly in association with high-risk HPV subtypes 16, 18, 31, 33, 35, and 39 [18,19].
The increased incidence of penile carcinoma in males with condyloma acuminata was illustrated in a population-based case-control study of 110 males with penile cancer and 355 control subjects, in which there was a sixfold increased risk of penile carcinoma in males reporting a history of genital warts compared with those without such a history [20]. (See "Carcinoma of the penis: Epidemiology, risk factors, and pathology", section on 'HPV' and "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis".)
●Clinical premalignant penile lesions pathologically defined as PeIN – The following clinically defined entities are pathologically designated as Penile Intraepithelial Neoplasia (PeIN). PeIN is further stratified by the presence or absence of HPV infection (HPV associated or HPV independent) [21]. These entities were previously pathologically classified as "carcinoma in situ".
•Erythroplasia of Queyrat – Erythroplasia of Queyrat is a clinical entity used to describe PeIN arising within the penile mucocutaneous epithelium, namely the glans and prepuce (picture 3). It has a typical velvety red, well-marginated appearance. The lesions are usually solitary and occasionally erode or ulcerate, but pain is uncommon. In this regard, they may appear quite similar to penile carcinoma.
PeIN in this location usually affects older, uncircumcised males. The reported incidence of progression to invasive carcinoma ranges from 10 to 33 percent [22-25]. The development of ulceration and/or a papillary appearance is associated with disease progression [23]. In such lesions, a coinfection with HPV types 8 and 16 has been described, and such lesions would be pathologically classified as HPV-associated PeIN [24].
•Bowen disease – Bowen disease is a PeIN occurring within follicle-bearing epithelium, such as on the penile shaft (picture 4). It usually appears as a solitary, dull-red plaque with areas of crusting and oozing [22]. In one series, HPV-16 was present in four of five biopsy specimens of genital PeIN occurring in this location, which are pathologically classified as HPV-associated PeIN [26]. If left untreated, invasive squamous cell carcinoma develops in approximately 5 percent of cases [27].
•Bowenoid papulosis – Bowenoid papulosis is another lesion that histologically resembles PeIN. This form of PeIN is most often seen in younger males. It usually behaves in a benign fashion and rarely becomes invasive [25]. It is characterized by multiple slightly elevated papules that are red to violet in color, which distinguish this entity from penile carcinoma (picture 5). Lesions usually form on the penile shaft, although the glans and prepuce may also be affected [27,28]. HPV-16 has been implicated in the pathogenesis of this form of PeIN, so such lesions would be pathologically classified as HPV-associated PeIN [29-32].
While the clinical course of typical Bowenoid papulosis occurring in young males is usually benign [33], the disease has been shown to progress to invasive squamous cell carcinoma in some reports [30,31]. Advanced age and immunosuppression may enhance the risk of malignant progression [34].
●Lichen sclerosus (also known as balanitis xerotica obliterans) – Lichen sclerosus is characterized by white atrophic plaques on the glans and prepuce (picture 6). These plaques eventually enlarge and coalesce into a sclerotic mass with resultant adhesions, phimosis, and meatal stenosis. Although many of the cases appear in males who have not undergone neonatal circumcision [35,36], this is not always the case [37,38]. (See "Balanitis in adults".)
Although generally considered benign, there is a relationship between lichen sclerosus and squamous cell carcinoma in that the two may coexist or lichen sclerosus may precede the later development of penile cancer:
•In a series of 130 males with genital lichen sclerosus, 11 had malignant or premalignant features (8.5 percent), including squamous cell carcinoma in seven, verrucous carcinoma in two, squamous cell carcinoma associated with verrucous carcinoma in one, and erythroplasia of Queyrat in one [37].
•In another report of 86 males with genital lichen sclerosus, premalignant or malignant histologic features developed in five cases, four of whom were HPV positive. The average lag time from onset of lichen sclerosus to the development of penile cancer was 17 years (range 10 to 23 years) [39].
●Leukoplakia – Chronic irritation and/or inflammation are thought to be important in the pathogenesis of leukoplakia, a rare condition that typically presents as solitary or multiple, white, scaly plaques often involving the meatus. Although the exact relationship to penile carcinoma is unknown, leukoplakia is often found adjacent or contiguous to areas of squamous cell carcinoma. The premalignant nature of leukoplakia is suggested by the presence of dysplasia in 10 to 20 percent of cases [22,28].
●Cutaneous horn – The penile cutaneous horn is a rare lesion. It usually develops over a preexisting skin lesion (wart, nevus, traumatic abrasion, or malignant neoplasm) and is characterized by overgrowth and cornification of the epithelium, which forms a solid protuberance (picture 7) [40]. In one review, cutaneous horn was also associated with HPV-16, and 37 percent of such lesions were noted to have an underlying carcinoma [41]. Malignant degeneration has been noted in cases of recurrent disease [42]. Penile cutaneous horns may form as a result of or evolve into invasive carcinoma [43,44].
●Pseudoepitheliomatous keratotic and micaceous balanitis (PKMB) – PKMB is an uncommon lesion that is named for its clinical appearance as a hyperkeratotic, laminated, solitary plaque on the glans [45]. PKMB often occurs in older males who are circumcised later in life. While the exact cause of PKMB remains unknown, malignant transformation into verrucous carcinoma has been reported [46-48]. The hallmark of transformation is the development of a nodular exophytic lesion within the preexisting plaque. A biopsy is required to make this diagnosis and to rule out malignant transformation.
TNM STAGING EVALUATION — The eighth edition of the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) staging system is used for staging carcinoma of the penis (table 1). The TNM information is used to define prognostic stage groups and to establish the appropriate treatment plan. (See "Carcinoma of the penis: Surgical and medical treatment".)
The TNM staging system is supported by both the AJCC and the Union for International Cancer Control (UICC) [49]. The eighth edition changes included the following [49]:
●The International Society of Urologic Pathology (ISUP) Grading System [50] was adopted. Any proportion of anaplastic cells is sufficient to categorize a tumor as grade 3.
●Ta definition was broadened to include noninvasive localized-squamous carcinoma.
●The presence or absence of perineural invasion was added as another factor to separate T1a from T1b category tumors.
●The anatomic layers of the penis are now described for the three penile locations, including the glans, foreskin, and shaft.
●T2 definition now includes corpus spongiosum invasion.
●T3 definition now includes corpora cavernosum invasion.
●pN1 is now defined as ≤2 unilateral inguinal metastases, no extranodal extension.
●pN2 is now defined as ≥3 unilateral inguinal metastases or bilateral metastases.
The improved prognostic value of the eighth edition TNM penile cancer staging system compared with the prior seventh edition was shown using a multi-institutional data set including patients from both China and the United States [51].
Tumor assessment — Clinical examination by visual inspection and palpation is required to evaluate the primary lesion. When the depth or extent of tumor infiltration cannot be determined by clinical exam, magnetic resonance imaging (MRI) may help identify invasion into the corpora cavernosum or spongiosum [52]. The extent of the primary tumor is combined with the pathologic factors present in the tumor, such as histologic grade, the status of lymphovascular invasion, and perineural invasion, for staging and treatment planning. Thus, an adequate deep tumor biopsy is important to capture this information.
Regional lymph node assessment — Penile cancer initially spreads through the lymphatics, with the initial site of involvement being the inguinal nodes, followed sequentially by the pelvic and retroperitoneal nodes. Accurate assessment of regional lymph nodes is essential for proper management since resection of small-volume, pathologically involved regional lymph nodes can be curative [53].
For clinical staging, factors determining nodal stage include the location, size, and number of any palpable lymph nodes and whether or not such lymph nodes are fixed or mobile. Pathologic staging factors include the number of involved nodes and whether or not extranodal extension or pelvic lymph node metastases are present.
The presence or absence of lymph node involvement also provides important prognostic information. The single most important prognostic factors influencing survival in patients with penile cancer are the presence and extent of nodal metastases. In a review of the literature, the five-year cancer-specific survival stratified by the extent of nodal involvement was [54]:
●No inguinal node metastases – 85 to 100 percent
●Single inguinal lymph node metastasis – 79 to 89 percent
●Bilateral or multiple inguinal node metastases – 17 to 60 percent
●Pelvic node metastases – 0 to 17 percent
Staging techniques
Imaging studies — For males with a high body mass index (BMI), those who have had prior inguinal procedures, and those presenting with clinical adenopathy, we perform cross-sectional staging imaging studies along with physical examination to assess for regional lymphadenopathy and distant metastases.
•Options for chest imaging include chest radiograph (CXR) or contrast-enhanced computed tomography (CT) of the chest.
•Options for abdominal imaging include contrast-enhanced CT abdomen and pelvis or gadolinium-enhanced MRI of the abdomen and pelvis.
•For patients with clinically positive inguinal nodes, fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT may be helpful to evaluate for pelvic and distant metastases [55].
The rationale for the use of staging imaging studies is because clinical assessment of inguinal lymph nodes is not entirely reliable, and physical examination alone has limited accuracy in these settings [56]. A false-negative clinical evaluation of the inguinal region based upon palpation alone has been reported in 9 to 60 percent of patients, depending on pathologic features of the primary tumor [57,58]. False-positive assessments are also frequent.
Pathologic staging of inguinal lymph nodes — Pathologic staging of inguinal lymph nodes is required for patients with palpable lymphadenopathy and for those with no palpable adenopathy at high risk for metastases based upon pathologic features noted in the primary tumor. (See 'Staging approach' below.)
Fine needle aspiration — Fine needle aspiration (FNA) is a minimally invasive method to evaluate for malignancy in males with penile cancer who present with palpable adenopathy. It is performed without local anesthesia using a 23- to 27-gauge needle. Both the sensitivity and specificity of FNA among males with clinically palpable nodes are over 90 percent [59]. (See 'Clinically suspicious inguinal examination' below.)
FNA alone is not used for routine staging of males without clinically palpable adenopathy, as its sensitivity is much lower in this population. However, it may be performed prior to planned dynamic sentinel node biopsy (DSNB) to increase the sensitivity of detecting tumors [60,61]. As an example, in one such study, the sensitivity of ultrasound-guided FNA was 39 percent (9 of 23 groins containing metastases), with a specificity of 100 percent [60]. (See 'Clinically negative inguinal examination' below.)
Dynamic sentinel node biopsy (DSNB) — Lymphatic mapping and sentinel node biopsy are based upon the concept that penile cancers have specific patterns of lymphatic spread and that one or more lymph nodes (ie, sentinel nodes) are the first to be involved with metastatic disease within a given lymph node basin.
Dynamic sentinel node biopsy (DSNB) utilizes the injection of the penile tumor with vital blue dye and radioactive tracer, followed by examination of the draining inguinal lymph nodes. If the sentinel lymph nodes are not involved, the entire basin should be free of tumor.
A 2012 meta-analysis of 17 studies reported on the detection rate and sensitivity of sentinel node biopsy in penile cancer [62]:
●The pooled sensitivity was 88 percent (95% CI 83-92).
•When studies that included patients with palpable nodes were excluded, the pooled sensitivity increased to 90 percent (95% CI 85-94).
•Incorporation of inguinal ultrasound increased the pooled sensitivity of sentinel node biopsy to 93 percent.
Sentinel lymph node biopsy should be performed at centers staffed by experienced surgeons and nuclear medicine specialists to decrease the risk of a false-negative result. This recommendation is consistent with the National Comprehensive Cancer Network (NCCN) guidelines for penile cancer [63]. The importance of experience was demonstrated in a 2010 study that included 342 patients assessed with a modified DSNB protocol from two high-volume centers [64]. In this experience, the false-negative rate was 2 percent (six patients with groin metastases after a negative DSNB). However, in another center, the false-negative rate approached 15 percent while the technique was evolving [65].
Superficial inguinal lymph node dissection (ILND) — A superficial inguinal lymph node dissection (ILND) provides more information than biopsy of a single node or group of nodes. This dissection can be readily performed by a surgeon experienced in inguinal surgery, without the need for specialized equipment. For ILND, both laparoscopic and robotic approaches are also safe to stage the inguinal region if performed by an experienced surgeon, as both approaches have low recurrence and complication rates. ILND also requires intraoperative frozen sections of lymph nodes to aid in treatment planning.
Superficial ILND can identify microscopic metastases in patients with a clinically normal inguinal examination without the need for a pelvic dissection. This was demonstrated in a retrospective study of 31 males, most of whom had nonpalpable inguinal nodes at presentation [66]. There were no recurrences among males who underwent a superficial ILND [66]. However, superficial ILND was associated with a higher overall complication rate compared with DSNB (12 to 35 versus 5 to 14 percent, respectively) [67,68].
One study has shown that superficial ILND can be performed using a minimally invasive robotic-assisted approach, with similar lymph node yields compared with open surgical approaches [69]. Similarly, laparoscopic surgical resection techniques have been described that appear to be feasible as staging procedures. If performed by an experienced surgeon, these procedures can be used to stage patients with clinically negative nodes, as they have both low recurrence and complication rates [69-72]. Based on clinical guidelines from the American Society of Clinical Oncology and the European Association of Urology (ASCO-EAU), both laparoscopic and robotic approaches are acceptable techniques to stage the inguinal region among patients with no clinically palpable or visibly enlarged inguinal lymph nodes (cN0) who are being treated at centers with management expertise in penile cancer [68].
Staging approach — The optimal approach to staging the inguinal lymph nodes is based on the probability of lymph node involvement based upon tumor stage and other histologic features. This enables the selection of patients at high risk for nodal involvement who are most likely to benefit from surgical staging.
Clinically negative inguinal examination — For males with a clinically negative inguinal examination, the extent of staging is based upon the risk of occult nodal metastases.
Our approach is consistent with guidelines from the ASCO-EAU and the NCCN guidelines for staging of males with newly diagnosed penile cancer (algorithm 1) [63]:
●Low-risk disease – For males with low-risk disease (pTis [PeIN], Ta, or T1a (table 1)), we offer surveillance. However, patients must agree to be compliant with follow-up.
●High-risk disease – For males with high-risk disease (≥pT1b), DSNB is the preferred technique in experienced centers based on lower complication rates. When DSNB is not available or feasible, ILND via either an open, laparoscopic, or robotic approach is an appropriate alternative, depending upon local expertise patient preference. CT/MRI or inguinal ultrasound may be useful in planning surgical staging. Surveillance is not recommended for this patient cohort.
Clinically suspicious inguinal examination — For males with evidence of palpable adenopathy on clinical examination, we offer FNA for pathologic assessment. The FNA is sensitive and reliable enough for diagnostic purposes in this population and, thus, can aid in further treatment planning (algorithm 2 and algorithm 3).
●For males with low-risk disease (pTis [PeIN], pTa, pT1a (table 1)) with clinically suspicious adenopathy but a negative FNA, we perform an excisional biopsy for definitive evaluation.
●For males with high-risk disease (≥T1b) with clinically suspicious adenopathy but a negative FNA, we perform a superficial ILND with frozen section evaluation of the nodes.
●For males with a positive FNA, we proceed with definitive surgical treatment. (See "Carcinoma of the penis: Surgical and medical treatment".)
For patients with proven metastases by FNA or node biopsy, additional imaging studies, such as CT and PET-CT, may be of value in predicting adverse nodal features, such as ≥3 positive nodes, extranodal extension, or pelvic metastases [55,73].
Bulky inguinal nodes, pelvic nodes, or unresectable lymphadenopathy — Males with penile cancer who present with bulky, fixed inguinal nodes (size ≥4 cm), pelvic lymph nodes, or unresectable lymphadenopathy have relatively low survival rates when treated with surgery alone. Such patients are candidates for multimodality therapy, such as neoadjuvant chemotherapy or chemoradiation [74-76]. Biopsy confirmation with assessment for metastatic disease is recommended prior to treatment. (See "Carcinoma of the penis: Surgical and medical treatment", section on 'Neoadjuvant chemotherapy for locally advanced or unresectable disease'.)
Assessment for distant metastatic disease — Distant disease dissemination is rare until late in the disease course, and penile cancer rarely presents with distant metastases. Therefore, we do not perform routine diagnostic imaging to assess for distant metastatic disease unless the patient exhibits regional nodal metastases. As an example, in one series of 681 patients, only 24 (4 percent) developed distant metastatic disease and, in all cases, it was late in the course following locoregional treatment [77].
For patients with bulky regional nodal metastases and those presenting with signs and symptoms of metastatic disease (eg, cachexia, pain, cough, skin lesions away from the primary site), CT of the chest, abdomen, and pelvis should be performed. PET/CT is also a sensitive imaging option that should be considered [55,73]. In addition, routine laboratory studies should include serum calcium to evaluate for tumor-induced hypercalcemia because prompt treatment can rapidly reverse altered mental status [78]. Brain metastasis from penile carcinoma is exceedingly rare, and MRI of the brain for asymptomatic patients is not indicated.
SUMMARY AND RECOMMENDATIONS
●Diagnosis – The definitive diagnosis of penile cancer requires histopathologic examination of a biopsy specimen. (See 'Initial evaluation and diagnosis' above and "Carcinoma of the penis: Epidemiology, risk factors, and pathology", section on 'Pathology'.)
●Differential diagnosis – The differential diagnosis of a patient presenting with a penile lesion includes infectious, inflammatory, premalignant, and malignant etiologies. (See 'Differential diagnosis' above.)
•Suspected infection – For males with penile lesions that are more likely to be infectious (eg, erythema, swelling, discharge) and are not associated with inguinal lymphadenopathy, a course of antifungals or antibiotics may be indicated. Lesions that do not resolve after six weeks or that progress at any time should be biopsied. (See 'Initial evaluation and diagnosis' above.)
•Suspected malignancy – For males presenting with a penile lesion suspicious for malignancy or with a penile lesion and associated lymphadenopathy, our approach is to proceed with an immediate biopsy of the penile lesion. (See 'Initial evaluation and diagnosis' above.)
●Anatomy of the penis and regional nodes – Penile cancer initially spreads through the lymphatics, with the initial site of involvement being the inguinal nodes, followed sequentially by the pelvic and retroperitoneal nodes. Accurate assessment of regional lymph nodes is essential for proper management. (See 'Regional lymph node assessment' above and 'Anatomy of the penis and regional nodes' above.)
●Staging imaging studies – For males with a high body mass index (BMI), those with prior inguinal procedures, and those presenting with clinical adenopathy, we perform cross-sectional staging imaging studies of the chest, abdomen, and pelvis along with physical examination. (See 'Imaging studies' above.)
•Options for chest imaging include chest radiograph (CXR) or contrast-enhanced computed tomography (CT) of the chest.
•Options for abdominal imaging include contrast-enhanced CT abdomen and pelvis or gadolinium-enhanced magnetic resonance imaging (MRI) of the abdomen and pelvis.
•For patients with clinically positive inguinal nodes, fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT may be helpful to evaluate for pelvic and distant metastases.
●Pathologic staging of regional lymph nodes – The optimal approach to pathologic staging of the inguinal lymph nodes is based on the presence or absence of clinically palpable inguinal lymph nodes and the probability of lymph node involvement based upon tumor stage and other histologic features. (See 'Staging approach' above.)
•No clinically palpable inguinal lymph nodes (cN0) – For males with no palpable inguinal adenopathy on clinical examination (cN0) (algorithm 1) (see 'Clinically negative inguinal examination' above):
-Low-risk disease – For males with low-risk disease (pTis [PeIN], Ta, or T1a (table 1)), we offer surveillance. However, patients must agree to be compliant with follow-up. (See "Carcinoma of the penis: Surgical and medical treatment", section on 'Treatment of low-risk disease'.)
-High-risk disease – For males with high-risk disease (≥pT1b), we offer dynamic sentinel node biopsy (DSNB) in experienced centers based on lower complication rates. When DSNB is not available or feasible, superficial inguinal lymph node dissection (ILND) via an open, laparoscopic, or robotic approach is an appropriate alternative, depending upon local expertise and patient preferences. CT/MRI or inguinal ultrasound may be useful in planning surgical staging. Surveillance is not recommended for this patient cohort.
•Clinically palpable inguinal lymph nodes – For males with palpable inguinal adenopathy on clinical exam, we offer fine needle aspiration (FNA) for pathologic assessment. (algorithm 2 and algorithm 3) (See 'Clinically suspicious inguinal examination' above.)
-For males with low-risk disease with clinically suspicious adenopathy but a negative FNA, we perform an excisional biopsy for definitive diagnosis.
-For males with high-risk disease with clinically suspicious adenopathy but a negative FNA, we perform a superficial ILND with frozen section evaluation of lymph nodes.
-For males with a positive FNA, we proceed with definitive surgical treatment. (See "Carcinoma of the penis: Surgical and medical treatment".)
•Bulky inguinal nodes, pelvic nodes, or unresectable lymphadenopathy – For males who present with bulky (node ≥4 cm) or fixed inguinal nodes, pelvic lymph nodes, or unresectable lymphadenopathy, further staging workup to define the extent of disease is indicated prior to therapy. (See 'Bulky inguinal nodes, pelvic nodes, or unresectable lymphadenopathy' above and "Carcinoma of the penis: Surgical and medical treatment", section on 'Neoadjuvant chemotherapy for locally advanced or unresectable disease'.)
●Assessment for distant metastases – Distant metastases are rare until late in the disease course, and penile cancer rarely presents with disseminated disease. Laboratory and imaging workup should be guided by physical signs or symptoms. (See 'Assessment for distant metastatic disease' above.)
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