Multimodality imaging of penile cancer: what

ª Springer Science+Business Media New York 2014

Abdominal Imaging

Abdom Imaging (2014) DOI: 10.1007/s00261-014-0218-6

Multimodality imaging of penile cancer: what radiologists need to know Chong Hyun Suh,1 Akshay D. Baheti,2,3 Sree Harsha Tirumani,2,3 Michael H. Rosenthal,2,3 Kyung Won Kim,1 Nikhil H. Ramaiya,2,3 Atul B. Shinagare2,3 1

Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea 2 Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA 3 Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA

Abstract The purpose of this article is to provide a comprehensive update on the role of imaging in the diagnosis and management of penile cancer. Imaging plays a major role in the initial assessment, treatment planning, and followup of patients with penile carcinoma. MRI helps in assessing the T staging of the primary and in detecting local recurrence. PET/CT and CT are useful for detecting regional nodal and distant metastases. Key words: Penile cancer—2010 AJCC TNM staging—Role of imaging—Management

the primary tumor on the glans, followed by 13% on the prepuce, 5.3% in the penile shaft, with 4.5% overlapping and 42.5% unspecified. Clinically, penile cancer presents as a palpable, visible lesion that is characterized as nodular, ulcerative, or fungating lesion on the penis. Approximately, 30% to 60% of patients with penile cancer have palpable inguinal lymph nodes at presentation. In about one-half of these patients, the palpable inguinal lymph nodes represent metastatic lymphadenopathy [11]. Squamous cell carcinoma is the most common type of penile cancer, which accounts for more than 95% of all primary penile cancers [6]. The WHO classification for subtypes of penile squamous cell carcinomas includes basaloid carcinoma, warty (condylomatous) carcinoma, verrucous carcinoma, papillary carcinoma (not otherwise specified), sarcomatous carcinoma, adenosquamous carcinoma, and mixed carcinomas [12]. These subtypes vary in aggressiveness, with verrucous carcinoma being a well-differentiated type which has an expansile border and is essentially non-metastatic, while basaloid carcinoma is a poorly differentiated type which is infiltrative and frequently metastasizes to the inguinal lymph nodes [13]. The differential diagnosis of penile squamous cell carcinoma includes basal cell carcinoma, Kaposi sarcoma, malignant melanoma, extramammary Paget’s disease, urethral carcinoma, and metastasis [6, 9, 12]. In this review, we provide a comprehensive description of the staging, diagnostic workup, management, and surveillance of penile squamous cell carcinoma with an emphasis on imaging for multidisciplinary team approach-based patient care.

Penile cancer is a rare disease in developed countries. In the United States, it is estimated that approximately 1,600 new cases of penile and other male genital cancer were diagnosed in 2012, with a mortality rate of 310 persons/year [1]. Higher incidence rates are seen in the developing countries of Asia, Africa, and South America [2, 3]. Worldwide, an estimated 26,000 patients are newly diagnosed annually [4]. Penile cancer occurs most commonly in the sixth to eighth decades of life [5]. The presence of phimosis has a strong association with penile cancer and is seen in 25% of penile cancer patients [6]. Sexually transmitted diseases, especially HIV and HPV, chronic inflammatory conditions including balanitis and lichen sclerosis, trauma, cigarette smoking, and poor hygiene are other risk factors for penile cancer [5]. 45% to 80% of penile cancer correlated with 16 and 18 types of HPV [5, 7–9]. The most common site of penile cancer is the glans penis. In a study of 4,967 patients with penile cancer, Hernandez et al. [10] reported that 34.5% of patients had

Staging and workup

Correspondence to: Chong Hyun Suh; email: [email protected]

Accurate staging of disease at diagnosis provides important predictors of survival in penile cancer and is

C. H. Suh et al.: Multimodality imaging of penile cancer

an important factor in treatment selection. Early diagnosis is of extreme importance, with an overall 5-year survival rate of >85% for patients with negative lymph nodes that fall to 29% to 40% for patients with positive nodes and less than 10% for patients with pelvic lymph node involvement [11, 14, 15].

2010 AJCC TNM staging Penile carcinoma is staged according to the American Joint Committee on Cancer Tumor, Nodes, and Metastasis (TNM) system, the most recent update of which was published in 2010, with multiple changes from the prior edition (Table 1) [16]. T1 stage has been subdivided into T1a and T1b stages based on the presence or absence of lymphovascular invasion or poorly differentiated cancer. T2 stage continues to be defined as invasion of the corpus spongiosum or cavernosum. T3 stage is now defined as invasion of the urethra, and invasion of prostate gland is now considered T4 stage. The distinction between superficial and deep inguinal lymph nodes has been removed in the revised classification [16]. It is important to note that penile cancers progress in a predictable fashion, with

involvement of the locoregional (inguinal) nodes followed by the pelvic nodes, which precedes distant metastases.

Role of imaging Although the role of imaging in the staging of penile cancer has been sparsely defined due to its low prevalence, imaging has become an integral part of the initial evaluation of penile cancer at many institutions. The initial workup of penile cancer starts with physical examination of the penile lesion by visual inspection and palpation as well as assessment of regional lymph nodes. If the depth or extent of tumor infiltration cannot be determined by physical examination, MRI may help identify invasion into the corpora cavernosa or corpus spongiosum, urethra and prostrate [17]. For patients presenting with palpable lymphadenopathy, large body mass index, or previous inguinal procedures, radiologic imaging evaluation by MRI is suggested because of the limited usefulness of the physical examination in these settings for evaluating the extent of disease. CT is usually not indicated for newly diagnosed penile cancer patients without palpable inguinal lymph nodes [18].

Table 1. American Joint Committee on Cancer TNM staging of penile cancer (2010) Category and stage Primary tumor (T) Tx T0 Ta Tis T1a T1b T2 T3 T4 Regional lymph nodes (N) Nx N0 N1 N2 N3 Distant metastasis (M) M0 M1 Stage I II IIIa IIIb IV Histologic grade Gx G1 G2 G3 G4

Characteristic Primary tumor cannot be assessed No evidence of primary tumor Noninvasive verrucous carcinoma* Carcinoma in situ Tumor invades subepithelial connective tissue without lymph vascular invasion and is not poorly differentiated (i.e., grade 3–4) Tumor invades subepithelial connective tissue with lymph vascular invasion and is poorly differentiated Tumor invades corpus spongiosum or cavernosum Tumor invades urethra Tumor invades other adjacent structures Regional lymph nodes cannot be assessed No inguinal lymph nodes by clinical examination (cN0) or pathologic examination (pN0) Metastasis in a single inguinal node Metastasis in multiple or bilateral inguinal lymph nodes Extranodal extension of lymph node metastasis or pelvic lymph node(s) unilateral or bilateral No distant metastasis Distant metastasis§ T1aN0M0 T1b-3N0M0 T1-3N1M0 T1-3N2M0 T4 any N M0 or any T N3M0 or any T any N M1 Grade cannot be assessed Well differentiated Moderately differentiated Poorly differentiated Undifferentiated

Note—Reprinted with permission from AJCC [16] * Broad pushing penetration (invasion) is permitted; destructive invasion is against this diagnosis § Lymph node metastasis outside of the true pelvis in addition to visceral or bone sites


Fig. 1. Anatomy of penis. A and B Illustrations (A, axial view; B, sagittal view) show the normal penile anatomy.

Primary lesion The penis is composed of three tubular structures of cavernous tissue bound together by fibrous tissue. The paired corpora cavernosa are located in the dorsal aspect of the penis, and the corpus spongiosum is located in ventral midline of the penis (Fig. 1). The corpus spongiosum contains the greater part of urethra. The corpora cavernosa and the corpus spongiosum show intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Both the tunica albuginea and the Buck fascia, connective tissue layers covering the corpora of the penis, are hypointense relative to the erectile tissue as a single thick rim [15]. MRI cannot reliably help distinguish the tunica albuginea from the adjacent Buck fascia. Gadolinium-enhanced T1-weighted image shows that the enhancement of the corpus

spongiosum occurs almost immediately; however, the corpora cavernosa enhance gradually in a centrifugal fashion. This pattern of enhancement is due to the central location of the cavernosal artery [16]. MRI is superior to CT in the evaluation of primary penile cancer because MRI has superior soft-tissue contrast resolution, excellent spatial resolution, and multiplanar capability in the assessment of superficial structures [19]. Table 2 shows MR technique for penile cancer in our institution. Whenever possible we tape the penis to abdominal wall. T2-weighted and gadoliniumenhanced T1-weighted images are the most useful in determining the local extent of the penile cancer. The depth of tumor invasion, involvement of the tunica albuginea, the corpora cavernosa, the corpus spongiosum, and the urethra can also be determined.


Table 2. MR technique for penile cancer Sequence

TR (ms)

TE (ms)

3 Plane localizer Axial T2 Coronal T2 Sagittal T2 Axial opposed phase Axial in phase DWI 0-500-1000 Axial 3D T1 fat suppressed Coronal 3D T1 fat suppressed Sagittal 3D T1 fat suppressed Axial 3D T1 fat suppressed post-contrast Coronal 3D T1 fat suppressed post-contrast Sagittal 3D T1 fat suppressed post-contrast

7.8 3900 4900 3800 5.6 4.1 7000 3.9 5.0 5 3.9 5 5

3.7 87 100 86 1.3 2.5 60 1.5 2.5 2.5 1.5 2.5 2.5

Slice thickness (mm) 6 4 3 3 3 3 5 4 3 3 4 3 3

Matrix

FOV (cm)

512 320 320 320 320 320 240 260 320 320 260 320 320

40 24 22 22 29 29 29 22 22 22 22 22 22

9 9 9 9 9 9 9 9 9 9 9 9 9

512 320 320 320 320 320 320 320 260 320 320 260 320

9 9 9 9 9 9 9 9 9 9 9 9 9

40 24 22 22 36 36 36 22 22 22 22 22 22

Subtracted images obtained for the post-contrast sequences Parameters vary on a case to case basis. This is a representative protocol

for T1 stage and 75%, 89% for T2 stage, and 88% and 98% for T3 stage, respectively. They also reported that MR is highly accurate at delineating corpora cavernosa invasion from cases without corpora cavernosa involvement. In a study of 33 patients with penile cancer, Lont et al. [21] concluded that MRI should be used to examine primary tumors in which infiltration of the corpora cavernosa and proximal extension cannot be determined properly by physical examination only. MRI may improve surgical planning and allows conservative surgical treatments over more radical procedures [20]. Prostate gland involvement has been upstaged to T4 in the revised 2010 TNM staging of penile cancer because patients with direct extension into the prostate gland from the penile shaft have extensive tumors with poor prognosis [22]. Prostatic invasion can be assessed on MRI as a part of a comprehensive penile staging exam. The T staging of penile cancer is illustrated in Figure 2. MR images of the T stages are shown in Figures 3, 4.

Regional lymph nodes Fig. 2. Illustration of local staging of penile cancer: Ta, noninvasive verrucous carcinoma; T1a, tumor invades subepithelial connective tissue; T2, tumor invades corpus spongiosum or cavernosum; T3, tumor invades urethra; T4, tumor invades other adjacent structures.

Gadolinium-enhanced T1-weighted images are especially helpful for early recurrence, and small lesions or when findings on unenhanced MR are equivocal. Primary penile cancer is most often solitary, ill-defined infiltrating mass which shows low signal intensity relative to the corpora on both T1-weighted and T2-weighted images and relatively hypointense on contrast-enhanced MR images. In a study that included 55 patients with penile cancer, Kayes et al. [20] found that penile MRI is highly accurate in the local staging of penile cancer. Stagespecific sensitivities and specificities were 85% and 83%

The presence of lymph node involvement is the single most important prognostic factor for patients with penile cancer. In a study of 201 patients with penile cancer, Ravi [23] found that the 5-year survival rate declined from 95% for patients without nodal disease to 81% for patients with one to three positive inguinal lymph nodes and to 50% for patients with four or more positive lymph nodes. However, clinical staging studies of regional lymph nodes have shown disappointing results, with sensitivity of 40% to 60% and false-negative rate of around 10% to 20% [24, 25]. Resection of clinically occult sites of nodal disease has been shown to improve survival, which suggests the importance of thorough nodal staging [26]. The staging of inguinal lymph nodes may be done by US-guided fine needle aspiration, dynamic sentinel node biopsy detailed below, or superficial inguinal lymph node dissection. For patients with a clinically negative inguinal


Fig. 3. A 55-year-old man with stage T2 penile squamous cell carcinoma. A and B Axial T2-weighted (A, left) and contrast-enhanced T1-weighted (A, right) and sagittal T2-weighted (B) images show T2-hypointense and hypoenhancing mass (arrows) in left glans penis and invading corpus cavernosum without invasion of urethra. Another subcentimeter enhancing foreskin nodule (arrowhead) is also likely part of the neoplastic process. C Axial contrast-enhancing T1weighted image shows an enlarged right inguinal lymph node

(arrow), likely representing nodal metastasis. There is a small left inguinal lymph node visualized as well (arrowhead) with preserved fatty hilum. Surgical resection revealed only right lymph node metastases from squamous cell carcinoma. D, Axial enhanced CT image after superficial inguinal lymph node dissection shows bilateral inguinal fluid collection (arrows) with soft-tissue stranding, consistent with postoperative status.


Fig. 4. A 48-year-old man with stage T3 penile squamous cell carcinoma. A and B Coronal T2-weighted (A, left) and contrast-enhanced T1-weighted (A, right) and axial contrastenhanced T1- weighted (B) images show hypoenhancing penile mass (arrows) invading urethra. C Fused axial PET/CT

images demonstrate intensely FDG-avid lesions in the glans (arrow) with FDG-avid metastatic right inguinal lymphadenopathy (arrowhead). Patient was managed with partial penectomy and right inguinal lymph node excision.

exam, staging of the regional lymph nodes is based on risk estimates for occult nodal metastases. According to the European Association of Urology system [27], risk of nodal metastases is based on tumor size and grade. For low-risk group with pTis, Ta, or T1 grade 1 tumors,

surveillance rather than nodal assessment is recommended. For intermediate-risk group with pT1 grade 2 tumors, dynamic sentinel node biopsy is recommended. For high-risk group with ‡pT2 or grade 3 tumors, either dynamic sentinel node biopsy or superficial inguinal


node dissection is recommended. In contrast, for patients with a clinically suspicious inguinal exam, fine needle aspiration is recommended for pathologic assessment rather than observation or an initial course of antibiotic therapy. Various imaging methods, such as CT, MRI, or FDG PET/CT, can be used the for evaluation of inguinal lymph nodes. Imaging for palpable disease by CT or MRI (Fig. 3C) may be used to assess the size, extent, location, and structures that are in close proximity to the inguinal lymph node, as well as the presence of pelvic and retroperitoneal lymph nodes and distant metastases (Fig. 5A). The role of FDG PET/CT for penile cancer is promising in evaluation of regional lymph nodes and distant metastasis (Figs. 4C, 6C). In a prospective study of 35 patients with invasive penile cancer, Schlenker et al. [28] found that FDG PET/CT showed a sensitivity of 88.2%, a specificity of 98.1%, a positive predictive value of 93.8%, and a negative predictive value of 96.3%. In a study of 18 patients with inguinal lymph node-positive penile cancer, Graafland et al. [29] found that FDG PET/ CT showed a sensitivity of 91%, a specificity of 100%, and a diagnostic accuracy of 96% in detecting pelvic lymph node involvement. In a recent meta-analysis, Sadeghi et al. [30] found that patients with clinically palpable lymph nodes may benefit from FDG PET/CT (96.4%; 95% CI 81.7%–99.9%). The role of lymphotropic nanoparticle-enhanced MRI with ferumoxtran-10 is under investigation in regional lymph node staging of penile cancer [31].

Distant metastasis Hematogeneous spread is rare in penile cancer until late in the disease course, and distant metastases are seen at presentation in only 2.3% to 4% of cases [32, 33]. Therefore, routine diagnostic imaging to assess for distant metastases is not recommended. Screening for metastases is reserved for selected high-risk patients, including those with bulky regional nodal metastases due to higher likelihood of the presence of pelvic or retroperitoneal adenopathy, and those with signs and symptoms of metastatic disease such as cachexia, pain, and hepatomegaly. The most common sites of metastases are lung (Fig. 6D), liver, bone (Fig. 5B), and retroperitoneum. Pelvic lymph node metastasis is a poor prognostic factor, with a median 5-year survival of approximately 10% [11, 34–38]. In patients with metastatic inguinal lymph nodes, 20% to 30% will have pelvic lymph node metastases [11].

Management of penile cancer A multidisciplinary team approach with surgeons, oncologists, radiation oncologists, and radiologists is essential for management of penile cancer.

Role of surgery The NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines) recommend that the standard of care of patients with superficial tumors including stages Tis, Ta, and T1a should utilize conservative organ-preserving strategies including topical therapy, local excision, circumcision, laser therapy, or glansectomy [18]. The T1a/b stage subdivision has been adopted based on the impact of lymphovascular invasion and its associated increased risk of lymph node metastasis that should prompt more aggressive care. More aggressive surgical procedures are required for bulky disease, namely partial and total penile amputation (penectomy). Partial penectomy involves removal of the glans with or without part of the underlying corpora cavernosa leaving behind sufficient length for the patient to stand and void, whereas a total penectomy involves removal of the glans with the underlying corpora cavernosa without leaving behind enough penile length to enable micturition while standing. Partial penectomy is preferably performed for T2 stage tumors, provided negative margins are obtained (Fig. 4). As previously described, US-guided fine needle aspiration, dynamic sentinel node biopsy, and superficial lymph node dissection are important surgical tools in the staging of the inguinal lymph nodes. US-guided fine needle aspiration is the preferred minimally invasive method of evaluating palpable inguinal lymph nodes [39]. Dynamic sentinel node biopsy is a technique widely used in evaluation of breast cancer, cutaneous melanoma, and vulvar cancer. The sentinel lymph node is the first lymph node draining the anatomic region or primary tumor. Therefore, the sentinel lymph node is considered representative of the whole lymphatic area and has the highest chance to harbor metastatic cells. Dynamic sentinel node biopsy is performed with intradermal injection of technetium-99 m nanocolloid around the primary tumor followed by preoperative lymphoscintigraphy, and intraoperative identification of the sentinel lymph node with the aid of intradermally administered patent blue dye and a gamma ray detection probe [40]. In a recent meta-analysis, Sadeghi et al. [41] found that dynamic sentinel node biopsy showed pooled sensitivity of 88% (95% CI 82%–93%). The NCCN Guidelines list dynamic sentinel node biopsy as an option for the assessment of non-palpable inguinal lymph nodes [18]. Superficial inguinal lymph node dissection provides more information than biopsy for evaluating palpable inguinal lymph nodes. In a study of 31 patients with penile cancer, Spiess et al. [42] found that superficial inguinal lymph node dissection can identify microscopic metastases in patients with a clinically negative inguinal examination. At the time of inguinal lymph node dissection, pelvic lymph node dissection should be considered in patient with two or more inguinal lymph nodes


Fig. 5. A 57-year-old man presenting with penile squamous cell carcinoma with distant metastases. A Axial enhanced CT images show conglomerate left inguinal (arrow), bilateral pelvic side wall (arrowheads), and retroperitoneal adenopathy (thin arrows). B Coronal CT images shows a L3 vertebral metastasis with a pathologic compression fracture (arrows) in L3. C Axial enhanced CT images after cisplatin-based chemotherapy show markedly improvement in the left inguinal (arrow), bilateral pelvic sidewall (arrowhead), and retroperi-

toneal (thin arrow) lymphadenopathy. D The patient subsequently developed resistance to the chemotherapy with heterogeneously enhancing enlarged left inguinal node noted after 1 year (arrow). The patient was subsequently given local radiotherapy. Axial enhanced CT image (right) obtained 5 months after the radiotherapy shows decreased size of the lymph node (arrowhead) with diffuse subcutaneous edema in the left thigh, consistent with post-radiation changes (thin arrow).

on the ipsilateral inguinal lymph node dissection site or as a delayed procedure in patients with extranodal extension [11, 43]. However, superficial inguinal lymph node dissection was associated with a high overall complication rate (12% to 35%) (Fig. 3D). Post-operative complications including hematoma, fluid collections, lymphocele formation, and superimposed infection may be seen in the surgical beds on the initial surveillance scans.

medical treatment, i.e., neoadjuvant chemotherapy [18]. The purpose of neoadjuvant therapy is to induce a treatment response that will allow for subsequent surgery. The recommended first-line regimen is a combination of paclitaxel, ifosfamide, and cisplatin. In a phase II study of 30 patients with stage N2 or N3 penile cancer receiving neoadjuvant chemotherapy, Pagliaro et al. [44] found that half of patients were noted to have a clinically meaningful response and 73.3% of patients subsequently underwent surgery. They also found that there was a significantly improved time to progression and overall survival associated with chemotherapy responsiveness, the absence of bilateral residual tumor, and the absence of extranodal extension or skin involvement. Although there are no sufficient data to deduce conclusions about the use of adjuvant chemotherapy, the

Role of chemotherapy The NCCN Guidelines recommend that patients who present with an unresectable primary tumor, bulky inguinal lymphadenopathy (node size ‡4 cm), or bilateral inguinal lymphadenopathy should proceed with


Fig. 6. A 67-year-old man with history of penile squamous cell carcinoma managed with distal penectomy. He presented with a palpable mass in the left inguinal region 6 months after distal penectomy. A Axial T2-weighted images shows a T2-hypointense mass (arrow) and another small focus (arrowhead) in the left corpus cavernosum suggestive of local recurrence. B

Sagittal T2-weighted image shows T2-hypointense local recurrence (arrowhead) at the distal penectomy site. C Axial PET image of 18F-FDG PET shows recurrent FDG-avid lesions (arrows) in the penile stump and FDG-avid metastatic inguinal adenopathy (arrowheads). D Axial chest CT shows bilateral spiculated metastatic lung nodules (arrows).

NCCN Guidelines recommend that adjuvant chemotherapy is a reasonable option for patient with the following high-risk features: pelvic lymph node metastases,

extranodal extension, bilateral inguinal lymph node involvement, and greater than three positive lymph nodes [18].


Fig. 7. A 33-year-old man with T1 stage penile squamous cell carcinoma treated with circumcision. He developed right inguinal swelling after 6 months, evaluated with an MRI. Axial T2-weighted image (left) shows a 5.3 cm predominantly T2 hyperintense necrotic right inguinal node (arrows) with a T2 hypointense peripheral solid portion. There are two small left

inguinal lymph nodes (arrowheads). Axial contrast-enhanced fat-saturated T1-weighted image (right) confirms the necrotic nature with peripheral enhancement (arrows) with peripheral enhancing portion (arrowheads). Surgical resection revealed bilateral necrotic lymph node metastases from squamous cell carcinoma.

Systemic chemotherapy is a potential first-line treatment for patient with metastatic penile cancer, with an overall response rate of up to 30% (Fig. 5) [44–46]. In a review article for stage IV penile cancer, Pettaway et al. [47] concluded that cisplatin-based regimens are the most active first-line systemic chemotherapy regimens. They also concluded that surgery to achieve disease-free status or palliation should be considered in patients with an objective response to systemic chemotherapy.

recurrence. For patients with unresectable inguinal or bone metastases, radiotherapy may provide a palliative benefit after chemotherapy (Fig. 5D). Pettaway et al. [47] concluded that palliative radiotherapy to inguinal or skeletal metastases might be of benefit.

Role of radiotherapy Radiotherapy may have a role in the management of penile cancer. Radiotherapy is an alternative organ-preserving approach with good results in selected patients with T1 and T2 stage lesions