- Email: [email protected]
Imaging of Penile Neoplasm
Imaging of Penile Neoplasm Ajay K. Singh, MD,*,† Pedro Gonzalez-Torrez, MD,* Rathachai Kaewlai, MD,† Shahin Tabatabaei, MD,‡ and Mukesh G. Harisinghani, MD§ Penile malignancies are rare, accounting for less than 1% of all male malignancy in the United States. The diagnosis can be very devastating psychologically to patients and often presents a challenge for physicians to accurately diagnose and treat these neoplasms. Clinical examination is known to have certain limitations and cross-sectional imaging techniques are increasingly utilized. Knowledge in imaging characteristics of the normal anatomy of the penis, vascular supply, lymphatic drainage, and pathology of penile malignancy is essential for an accurate staging. In this article, normal anatomy of the penis is briefly discussed and is followed by a review of multiple imaging approaches for characterization of the primary tumor and nodal staging. Semin Ultrasound CT MRI 28:287-296 © 2007 Elsevier Inc. All rights reserved.
P
enile malignancy presents a challenge to the urologist in precise diagnosis, staging, as well as curative treatment. Clinical examination for lymph nodal staging suffers from inaccuracy associated false-positive assessment for metastases in the presence of reactive lymph node enlargement. Also, the presence of metastases in normal or borderline lymph nodes makes clinical assessment fraught with pitfalls. Imaging can not only help with the local extent of the penile neoplasm but can also help in accurately stage metastatic disease. Penile cancer is a rare uro-oncological disease in the industrialized countries, accounting for less than 1% of all male malignancies in the United States. Higher incidence rates are seen in Africa, Asia, and South America; however, there appears to be no racial predilections. It has a peak incidence between the sixth and seventh decades of life.1,2 Penile neoplasm can be categorized into two broad categories: primary or secondary. Metastatic lesions to the penis are much less common than primary malignancy.1 Although the etiology of penile cancer is somewhat controversial, several factors such as the presence of foreskin and exposure to human papilloma virus appear to play a role in the development of this disease. Multiple lesions *University of Massachusetts Memorial Medical Center, Worcester, MA. †Division of Emergency Radiology, Massachusetts General Hospital, Boston, MA. ‡Department of Urology, Massachusetts General Hospital, Boston, MA. §Division of Abdominal Imaging and Interventional Radiology, Massachusetts General Hospital, Boston, MA. Address reprint requests to Ajay K. Singh, MD, 10 Museum Way, #524, Boston, MA 02141. E-mail: [email protected].
0887-2171/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.sult.2007.05.005
are clearly premalignant, pincluding leukoplakia, balanitis xerotica obliterans, in situ carcinomas, and cutaneous horns. If left untreated, they can progress toward an invasive carcinoma.2,3
Squamous Cell Carcinoma Histologically, 95% of all primary penile neoplasms are squamous cell carcinoma. The remaining 5% are sarcoma, melanoma, basal cell carcinoma, and lymphoma.4 Clinically, penile cancer may appear as erythema, induration, bleeding, or enlarging ulcers. If left neglected, the lesion advances along the entire glans and shaft and invades the corpora cavernosa and urethra. Bleeding, urinary retention, urinary fistula, or total destruction of the phallus may result. Although penile cancer may occur at any anatomic location, glans (48%) is the most common location, followed by prepuce (21%), both glans and prepuce (9%), and shaft (⬍2%).1 Two different growth patterns of penile cancer have been described: papillary and flat. Papillary tumors usually originate as single or multiple coalescing, elevated, warty lesions that may subsequently ulcerate. The flat tumors usually present as small, superficial, round ulcers on a slightly elevated base. They extend on the surface and infiltrate deep tissues. Considerable involvement of deeper tissues with relatively minor surface changes is not unusual.1 The most significant predictor of survival in men with penile cancer is the presence and extent of nodal metastasis. 287
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Table 2 TNM Classification of Penile Carcinoma Stage Tumor (T) Tx T0 Tis T1
Description Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Invasion of subepithelial connective tissue Invasion of one or more corpora Invasion of urethra or prostate gland Invasion of other adjacent structures
T2 T3 T4 Lymph node (N) Nx Regional lymph node cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single superficial inguinal lymph node N2 Metastases in multiple or bilateral superficial inguinal lymph nodes N3 Unilateral or bilateral metastases in deep inguinal or pelvic lymph nodes Metastasis (M) Mx Distant metastasis cannot be assessed M0 No evidence of distant metastasis M1 Distant metastasis
Figure 1 Secondary metastases to the penis. Axial (A) and sagittal (B) postcontrast T1-weighted sequence shows multiple low signal intensity lesions (straight arrows) involving corpora cavernosa and corpora spongiosa. The dominant palpable lesion in the corpora cavernosa is marked with a vitamin E tablet (curved arrow) placed on the skin.
Table 1 Jackson Classification of Penile Carcinoma Stage
Involvement
1 2 3 4
Confined to the glans penis Invasion of the shaft or corpora Operable inguinal lymph node metastasis Invasion of adjacent structures, inoperable inguinal lymph node metastasis
Figure 2 Schematic representation of local staging of penile neoplasm. (Color version of figure is available online.)
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Figure 3 (A) Axial anatomy of the penis. The two corpora cavernosa (straight arrows) dorsal to one ventral corpora spongiosum (curved arrow) are seen on the T2-weighted image. The two testicles are also seen on this coronal image. (B) Contrast-enhanced sagittal T1-weighted image shows the relationship of corpora cavernosa (straight arrow) and corpus spongiosum (curved arrow). (C) Axial T1-weighted image shows the attachment of posterior aspect of the corpora cavernosa, known as crura (arrowhead), to the pubic arch.
Distant metastases to lung and liver—less often to bone, brain, and skin—are rare and usually late.1
are based on multiple variables, ie, type of tumor, grading, depth, extent, and propensity for distant metastasis.
Other Primary Penile Malignant Neoplasm
Metastasis to the Penis
Sarcoma, melanoma, basal cell carcinoma, lymphoma, and other rare malignancy account for 5% of all penile malignancy. While all of these tumors may have similar clinical presentation, the natural progression of the disease is different. Melanoma is known to metastasize at an earlier stage, while basal cell carcinoma is usually localized. Lymphoma usually extends from neighboring organs or progresses by hematologic or lymphatic route. Clinical and imaging evaluation patterns are different depending on histology and
Penile metastases typically manifest as multiple discrete masses in the corpora cavernosa and corpus spongiosum. The primary neoplasm is often located in the urogenital tract. These masses are seen as low signal intensity areas relative to normal corporal tissues in both T1- and T2-weighted images.5 Metastasis to the penis usually represents a terminal stage in patients with diffuse metastatic disease1 (Fig. 1). It should be suspected in patients with a known diagnosis of cancer who present with multiple palpable painless nodules or unexplained priapism.
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and may lead to long-term survival. However, the procedure is associated with a high incidence of significant morbidity, even with modern surgical techniques. Minor and major morbidity rates of 68 and 32% have been reported.7 For this reason, unnecessary groin dissection should be avoided and an effort to identify the patients with lymph node metastasis has been advocated. Approximately 58% (range 20-96%) of patients with penile cancer have palpable inguinal lymphadenopathy at diagnosis. Of these, metastatic lymph nodes are found in less than half. The remaining cases are inflammatory lymph nodes. In addition, about 10-20% of nonpalpable lymph nodes contain metastasis.1 To reduce the morbidity from unnecessary lymphadenectomy, the current practice includes a course of antibiotics before surgical resection, and noninvasive imaging technique for sentinel node mapping and targeted dissection.6
Anatomy of the Penis
Figure 4 A 88-year-old man with well-differentiated squamous cell carcinoma of the glans penis. Axial T2-weighted (A) and contrastenhanced T1-weighted (B) images show neoplastic (arrows) involvement of the glans with sparing of the corpora cavernosa.
Clinical Evaluation The optimal therapeutic approach can be planned based on the Jackson classification (Table 1) and tumor node metastasis (TNM) classification clinical staging (Table 2). A schematic drawing of local staging by TNM classification is presented in Figure 2. To establish the diagnosis, histologic grade, and depth of the tumor extension, an initial biopsy of the primary penile lesion is necessary.6 Besides clinical inspection and palpation to determine extent of the tumor, various cross-sectional imaging techniques may be useful for a more accurate staging when tumor infiltration cannot be determined properly based on clinical grounds. In men with penile cancer who have lymph node metastasis, lymph node dissection has been shown to be therapeutic
The penis consists of a root, shaft, and glans. The penile shaft is composed of two paired dorsolateral corpora cavernosa and a single ventral corpus spongiosum. The glans of the penis is an extension of corpus spongiosum. The corpora cavernosa are proximally attached to the symphysis pubis and linea alba by the suspensory ligament of the penis. The corpus spongiosum contains the urethra and proximally attaches to the urogenital diaphragm. Each corpora cavernosa contains a deep centrally located artery providing blood for these erectile tissues. The erectile tissues are covered by three layers of connective tissue. The innermost fibrous capsule is the tunica albuginea. It is covered by the deep fascia of the penis (Buck’s fascia) that is a continuation of the deep perineal fascia that forms a strong membranous covering for the erectile tissues. External to Buck’s fascia is a loose subcutaneous areolar connective tissue layer surrounded by the dartos fascia. The corporal bodies have intermediate signal intensity on T1-weighted images, and high signal intensity on T2weighted images relative to skeletal muscle (Fig. 3). The corpus spongiosum may have different signal intensity from that of the corpora cavernosa. The muscular wall of the urethra appears hypointense relative to the corpus spongiosum. Both the tunica albuginea and the Buck’s fascia are hypointense on T1- and T2-weighted images. The tissue contrast between the corpora and the tunica albuginea increases on T2-weighted images, making this sequence preferable for depicting focal pathology of the penis including the extension to the corpora by malignancy. The penis is supplied by branches of internal pudendal arteries, which give rise to paired dorsal arteries running between Buck’s fascia and corpora cavernosa. These arteries are accompanied by a single deep dorsal vein and two dorsal nerves. There are two cavernosal arteries and one artery of the bulb of the penis that supply the erectile tissue, corpus spongiosum, and bulbourethral gland. They give rise to numerous branches that open directly into the cavernous spaces. The venous drainage is via the plexus within the cavernous
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Figure 5 A 76-year-old male with squamous cell carcinoma of the penis. Coronal (A) and axial (B) postcontrast T1-weighted sequence shows heterogeneous signal intensity mass (arrowhead) with involvement of the corpora cavernosa. Sagittal T2-weighted (C) and postcontrast T1-weighted (D) sequence shows postpenectomy changes with urethrostomy (arrow) located posterior to the scrotum.
spaces joining the deep dorsal vein of the penis. The corpus spongiosum and corpora cavernosa enhance with the administration of contrast agent. The enhancement of corpus spongiosum occurs almost immediately, whereas the cavernosal bodies enhance gradually in the centrifugal fashion. Superficial inguinal nodes represent one of the primary lymphatic pathways by which penile cancer, located in the glans, prepuce, and shaft, may metastasize. The other two pathways of lymphatic drainage from the glans include the deep inguinal or femoral node chain, specifically medial femoral node (node of Cloquet), and the lateral retrofemoral node, which is part of the external iliac nodes. The lymphatics of the glans may access the deep inguinal nodes or even the iliac nodes, bypassing the superficial inguinal nodes.8
Imaging Cavernosography is the exam in which contrast medium is injected directly into the corpora cavernosa to determine tumor extension into corpora cavernosa. Corpus cavernosography was used to correctly assess the extent of tumor in 10 patients with carcinoma of the penis.9 The author advocated cavernosography as a safe, simple, and valuable procedure to obtain additional information for staging of penile tumors preoperatively and plan the level of resection during penectomy. However, due to the invasive nature of the procedure and modern cross-sectional imaging techniques, cavernosography does not find routine use in practice. Ultrasound has been shown to be a useful imaging technique for primary tumor staging.10,11 Invasion of the tunica albuginea, corpora cavernosa, and urethra can be demon-
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Figure 6 A 54-year-old male who refused surgery for verrucous cancer of the penis. T2-WI imaging in axial (A) and longitudinal (B) plane of the penis shows heterogeneous signal intensity mass (arrows) involving the corpora cavernosa. Axial noncontrast (C) CT shows bulky distal half of the penis with dissection of air (curved arrow) in it.
strated on ultrasound. On ultrasound, the penile carcinoma is hypoechoic, hyperechoic, or mixed echoic, in order of decreasing frequency.10 Due to poor differentiation of the tumor and surrounding corporal bodies, the role of computed tomography (CT) is currently limited to evaluation of nodal status, not the primary tumor. The investigation utilizing positron emission tomography (PET)/CT for penile cancer has shown that the majority of primary penile squamous cell carcinoma can be detected on PET/CT.12 The sensitivity and specificity to detect primary penile cancer has been shown to be 75%.
Magnetic resonance imaging (MRI) of the penis can offer a noninvasive means of staging of the primary tumor due to its high soft-tissue contrast and multiplanar capability. The ability to detect invasion of the tunica albuginea, corpora, and urethra has made MRI preferable to other cross-sectional imaging modalities for the staging of penile cancer. MRI has been shown to upstage the primary tumors when compared to clinical exam alone in many studies. de Kerviler and colleagues13 described two patients whose MRI upstaged the tumor from stage T1 to stage T2. In a series of 33 patients (3 T1 lesions, 23 T2 lesions, and 7 T3 lesions),14 MRI had been shown to have a comparable sensitivity and specificity as
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293 negative-predictive values. In our practice, we do not routinely use PGE1 injection prior to the MRI for penile cancer staging. MRI techniques for primary tumor include appropriate patient positioning with the patient supine and a folded towel underneath the patient’s leg inferior to the perineum to elevate the scrotum and penis. The penis is dorsiflexed against the lower abdomen in the midline and taped in position to reduce motion during the examination. A surface coil is placed on the penis to obtain optimal quality, high-resolution images with a relatively small field-of-view, high matrix, and thin slices. Axial spin-echo T1-weighted images without and with gadolinium enhancement, and axial, coronal, sagittal fast spin-echo T2-weighted images are used. On MRI, lesions typically have lower signal intensity than the adjacent corpora on T1- and T2-weighted images.13,15,18 MRI can demonstrate the depth of tumor invasion, involvement of the tunica albuginea, corpora, or urethra, which can
Figure 7 A 36-year-old male with lymph nodal metastases from penile carcinoma. Axial contrast-enhanced CT (A and B) shows metastatic enlarged lymph nodes involving retroperitoneal lymph nodes (arrowheads).
clinical exam for detection of invasion of corpus cavernosum. However, regarding detection of urethral involvement, MRI was superior to ultrasound and clinical exam. When used in conjunction with artificial erection by prostaglandin E1 (PGE1) intracorporal injection, MRI may provide increased diagnostic accuracy for detection of invasion of the tunica albuginea and corpora cavernosa. Imaging during penile tumescence may be desirable due to problems in image resolution and lesion detection of the variable size of penis in the flaccid stage.15 This technique has some undesirable side effects including local pain, prolonged erection, hematoma, rash, headache, and hypotension. Priapism requiring evacuation of the corpora cavernosa was seen in one patient from the report of Scardino and coworkers,16 who performed MRI in nine patients with penile cancer. In a large recent series,17 MRI with PGE1 injection was used to assess 55 men with penile cancer preoperatively and had a sensitivity of 89, 75, 88% (for T1, T2, and T3 lesions, respectively), and a specificity of 83, 89, 98% for T1, T2, and T3 lesions, respectively. MRI correctly predicted all 20 patients with corpus cavernosum invasion, representing 100% positive- and
Figure 8 Inguinal lymphadenopathy in an 82-year-old man with moderately differentiated squamous cell carcinoma of the penis. (A) Precontrast and (B) postcontrast T1-weighted image shows an oval right inguinal lymph node with peripheral nodular enhancement. Surgical right groin dissection showed metastatic lymph node in 1 of 10 lymph nodes resected.
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sis, especially in the pelvic region, which is not accessible to palpation. Of historical interest, pedal lymphangiography was performed by pedal or penile injection of contrast medium that opacifies the three major lymphatic systems of the external and common iliac chains. A change in flow dynamics of the lymphatics, increased nodal size, and alteration of internal characteristics are the criteria for diagnosis of nodal involvement of cancer. Although it has a reported accuracy of approximately 70 to 80%, the limitations of this technique are the inability to distinguish inflammatory from metastatic lymphadenopathy, false-negative study when the enlarged node is completely replaced by tumor, and the possibility of inadequate evaluation of all lymph node chains.19 The use of this technique has declined due to its limitations, invasiveness, and increased availability of CT and MRI. Although CT plays an important role for the detection of lymphadenopathy, it suffers from the inability to detect metastasis in normal-sized lymph (Fig. 7). In addition, CT is nonspecific because enlargement of the lymph nodes may be caused by inflammation. Distant metastasis is uncommon in patients who present with penile cancer. Only 5% of patients with penile cancer have distant metastasis at the time of diagnosis. Generally, distant metastases occur late in the course of the disease and are associated with dismal prognosis. Lung, liver, bone, brain, and skin are common locations for metastatic disease from penile cancer. Evaluation for distant metastasis is most commonly done with standard chest radiographs in posteroanterior and lateral projections, and a radionuclide bone scan. Further assessment with chest CT is performed if more resolution is needed. Brain, liver, and retroperitoneal lymph nodes are evaluated with CT or MRI. Figure 9 MR lymphangiography of groin lymph nodes in a 59-yearold man with grade 2 squamous cell carcinoma of the penis. (A) Pre-USPIO T2*-weighted MR sequence shows multiple external inguinal lymph nodes (arrows), less than 1 cm in short-axis diameter. (B) Post-USPIO T2*-weighted MR sequence shows USPIO uptake by the inguinal lymph nodes (arrows), indicating benign etiology. The hypointensity of these lymph nodes is due to the susceptibility effect created by uptake of USPIO.
be determined by MRI (Figs. 4-6). The limitations of MRI for the determination of the extent of primary lesion are probably related to technical problems including lack of erection, motion artifact, previous radiation therapy to the penis, and associated infection.
Lymph Nodal Staging The detection of positive lymph nodes before surgery is the key to avoiding unnecessary lymphadenectomy and related complications. It is well known that inflammation of the lymph nodes can commonly be present in a patient with penile cancer, resulting in high rates of false-positive nodes on pathologic examination. Imaging plays an increasingly important role in the determination of lymph nodal metasta-
Recent Developments A recent study using 18F-fluorodeoxyglucose (FDG) PET/ CT12 in 13 patients with penile cancer showed 15 of the 16 lymph nodal metastases, including 9 superficial inguinal, 5 deep inguinal, and 2 obturator lymph nodes. A single falsenegative lymph node, a 1.8-cm superficial inguinal node with rather discrete FDG uptake with a standardized uptake valve (SUVmax) of 1.1, was later found to be micrometastasis on pathologic examination. The sensitivity of PET/CT was 89% for detection of superficial inguinal lesions and 100% for the detection of deep inguinal and obturator lymph nodes. The specificity was 100%. Although MRI more clearly differentiates nodes from blood vessels, the detection of metastatic lymph nodes is again dependent on lymph nodal size criterion and, to a certain extent, enhancement characteristics (Fig. 8). This limitation is similar to the difficulties inherent on CT. Newer lymphotropic MR contrast agents make MRI for detection of metastatic lymph node a promising noninvasive investigation. MR lymphangiography performed at 24 hours after intravenous injection of feromoxtran-10, an ultrasmall superparamagnetic iron oxide, has shown improved accuracy in the staging of lymph nodes of patients with various
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Figure 10 Postpartial penectomy changes in a 40-year-old male with penile carcinoma. Axial contrast-enhanced CT (A, B, and C) shows partial penectomy changes with penile implant (arrows) in situ. The reservoir (arrowhead) for the penile prosthesis is seen in the pelvis.
primary tumors. A normal lymph node containing macrophages with phagocytic function takes up a substantial amount of ferumoxtran-10 and then shows marked reduction in signal intensity because of the T2 shortening effect of the nanoparticles. In tumor-infiltrated lymph nodes, the tumor replaces the macrophages; hence, the nodes retain their high signal intensity after contrast administration.20 A few studies evaluating the role of ferumoxtran-10 MR lymphangiography in primary pelvic malignancy have shown varying results with sensitivity ranging from 90.5 to 100% and specificity ranging from 80 to 95.7% for the detection of pelvic and retroperitoneal lymph node metastasis.21,22 One exception was in Keller and coworkers,23 where only nine patients with primary gynecologic tumors were studied. In this study, two micrometastases ⬍5 mm and one metastasis of 5 mm were not detected on MRI and the study was not optimized for detecting nodal susceptibility. With a more recent trial, sensitivity and specificity increased with optimized MR protocols.24,25 Moreover, significant numbers of non-enlarged lymph nodes were correctly characterized by
this technique. A growing knowledge has shown MR lymphangiography to be a promising imaging tool for noninvasive lymph nodal staging in patients with various primary malignancies (Fig. 9).
Treatment and Posttreatment Changes Treatment of penile cancer varies according to the clinical stage. Primary tumor characteristics including size, location, and depth of invasion are major determinants for selecting surgical management. Surgery consists of ablative techniques (Mohs micrographic surgery, laser therapy, or cryosurgery), penile conservation techniques, partial penectomy, and total penectomy. Management of regional lymph nodes is somewhat controversial due to high perioperative morbidity. Some surgeons advocate a conservative approach at the time of presentation; others advocate an immediate surgery toward regional node dissection at an early course of disease.26
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4. 5. 6. 7.
8. 9. 10. 11.
12. 13.
14.
15. 16.
17.
18. 19. 20.
Figure 11 Postpenectomy abscess in a 56-year-old male with penile cancer. Contrast-enhanced CT (A and B) shows abscess (arrows) in the penectomy bed, which was drained with a percutaneous catheter (arrowhead).
21.
22.
Early complications after partial or total penectomy include wound infection and hematoma, and stricture of the neomeatus. Cross-sectional imaging can be used to postoperatively assess a penile implant and can provide guidance in the drainage of postoperative abscess (Figs. 10 and 11).
References 1. Burgers JK, Badalament RA, Drago JR: Penile cancer, clinical presentation, diagnosis and staging. Urol Clin North Am 19:247-256, 1992 2. Lucia MS, Miller GJ: Histopathology of malignant lesions of the penis. Urol Clin North Am 19:227-245, 1992 3. Tabatabaei S, McDougal WS: Penile cancer: clinical signs and symptoms, in Vogelzang NJ, Scardino PT, Shipley WU, et al (eds): Compre-
23.
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26.
hensive Textbook of Genitourinary Oncology. Philadelphia, PA, Lippincott Williams & Wilkins, 2006, pp 805-808 Grossman HB: Premalignant and early carcinomas of the penis and scrotum. Urol Clin North Am 19:221-226, 1992 Demuren OA, Koriech O: Isolated penile metastasis from bladder carcinoma. Eur Radiol 9:1596-1598, 1999 Micali G, Nasca MR, Innocenzi D, et al: Invasive penile carcinoma: a review. Dermatol Surg 30:311-320, 2004 Bevan-Thomas R, Slaton J, Pettaway CA: Contemporary morbidity from lymphadenectomy for penile squamous cell carcinoma: the MD Anderson Cancer Center Experience. J Urol 167:1638-1642, 2002 Dewire D, Lepor H: Anatomic considerations of the penis and its lymphatic drainage. Urol Clin North Am 19:211-219, 1992 Raghavaiah NV: Corpus cavernosogram in the evaluation of carcinoma of the penis. J Urol 120:423-424, 1978 Agrawal A, Pai D, Ananthakrishnan N, et al: Clinical and sonographic findings in carcinoma of the penis. J Clin Ultrasound 28:399-406, 2000 Horenblas S, Kroger R, Gallee MP, et al: Ultrasound in squamous cell carcinoma of the penis; a useful addition to clinical staging? A comparison of ultrasound with histopathology. Urology 43:702-707, 1994 Scher B, Seitz M, Reiser M, et al: 18F-FDG PET/CT for staging of penile cancer. J Nucl Med 46:1460-1465, 2005 de Kerviler E, Ollier P, Desgrandchamps F, et al: Magnetic resonance imaging in patients with penile carcinoma. Br J Radiol 68:704-711, 1995 Lont AP, Besnard AP, Gallee MP, et al: A comparison of physical examination and imaging in determining the extent of primary penile carcinoma. BJU Int 91:493-495, 2003 Vossough A, Pretorius ES, Siegelman ES, et al: Magnetic resonance imaging of the penis. Abdom Imaging 27:640-659, 2002 Scardino E, Villa G, Bonomo G, et al: Magnetic resonance imaging combined with artificial erection for local staging of penile cancer. Urology 63:1158-1162, 2004 Kayes O, Minhas S, Allen C, et al: The role of magnetic resonance imaging in the local staging of penile cancer. Eur Urol doi:10.1016/ j.eururo.2006.11.014, 2006 (in press) Singh AK, Saokar A, Hahn PF, et al: Imaging of penile neoplasms. Radiographics 25:1629-1638, 2005 Castellino RA: Lymphography, in Pollack HM, McClennan BL (eds): Clinical Urography. Philadelphia, PA, WB Saunders, 2000, pp 602-619 Saksena MA, Saokar A, Harisinghani MG: Lymphotropic nanoparticle enhanced MR imaging (LNMRI) technique for lymph node imaging. Eur J Radiol 58:367-374, 2006 Bellin MF, Roy C, Kinkel K, et al: Lymph node metastases: safety and effectiveness of MR imaging with ultrasmall superparamagnetic iron oxide particles—initial clinical experience. Radiology 207:799-808, 1998 Harisinghani MG, Blezek DJ, Hahn PF: MR lymphangiography with USPIO: can quantitative T2* estimation differentiate benign from malignant lymph nodes Radiology 229:409, 2003 (suppl) Keller TM, Michel SC, Frohlich J, et al: USPIO-enhanced MRI for preoperative staging of gynecological pelvic tumors: preliminary results. Eur Radiol 14:937-944, 2004 Harisinghani MG, Dixon WT, Saksena MA, et al: MR lymphangiography: imaging strategies to optimize the imaging of lymph nodes with feromoxtran-10. Radiographics 24:867-878, 2004 Harisinghani MG, Barentsz J, Hahn PF, et al: Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 348:2491-2499, 2003 Erratum in N Engl J Med 349:1010, 2003 Russo P, Horenblas S: Surgical management of penile cancer: in Vogelzang NJ, Scardino PT, Shipley WU, et al (eds): Comprehensive Textbook of Genitourinary Oncology, Philadelphia, PA, Lippincott Williams & Wilkins, 2006, pp 809-818.
P
enile malignancy presents a challenge to the urologist in precise diagnosis, staging, as well as curative treatment. Clinical examination for lymph nodal staging suffers from inaccuracy associated false-positive assessment for metastases in the presence of reactive lymph node enlargement. Also, the presence of metastases in normal or borderline lymph nodes makes clinical assessment fraught with pitfalls. Imaging can not only help with the local extent of the penile neoplasm but can also help in accurately stage metastatic disease. Penile cancer is a rare uro-oncological disease in the industrialized countries, accounting for less than 1% of all male malignancies in the United States. Higher incidence rates are seen in Africa, Asia, and South America; however, there appears to be no racial predilections. It has a peak incidence between the sixth and seventh decades of life.1,2 Penile neoplasm can be categorized into two broad categories: primary or secondary. Metastatic lesions to the penis are much less common than primary malignancy.1 Although the etiology of penile cancer is somewhat controversial, several factors such as the presence of foreskin and exposure to human papilloma virus appear to play a role in the development of this disease. Multiple lesions *University of Massachusetts Memorial Medical Center, Worcester, MA. †Division of Emergency Radiology, Massachusetts General Hospital, Boston, MA. ‡Department of Urology, Massachusetts General Hospital, Boston, MA. §Division of Abdominal Imaging and Interventional Radiology, Massachusetts General Hospital, Boston, MA. Address reprint requests to Ajay K. Singh, MD, 10 Museum Way, #524, Boston, MA 02141. E-mail: [email protected].
0887-2171/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.sult.2007.05.005
are clearly premalignant, pincluding leukoplakia, balanitis xerotica obliterans, in situ carcinomas, and cutaneous horns. If left untreated, they can progress toward an invasive carcinoma.2,3
Squamous Cell Carcinoma Histologically, 95% of all primary penile neoplasms are squamous cell carcinoma. The remaining 5% are sarcoma, melanoma, basal cell carcinoma, and lymphoma.4 Clinically, penile cancer may appear as erythema, induration, bleeding, or enlarging ulcers. If left neglected, the lesion advances along the entire glans and shaft and invades the corpora cavernosa and urethra. Bleeding, urinary retention, urinary fistula, or total destruction of the phallus may result. Although penile cancer may occur at any anatomic location, glans (48%) is the most common location, followed by prepuce (21%), both glans and prepuce (9%), and shaft (⬍2%).1 Two different growth patterns of penile cancer have been described: papillary and flat. Papillary tumors usually originate as single or multiple coalescing, elevated, warty lesions that may subsequently ulcerate. The flat tumors usually present as small, superficial, round ulcers on a slightly elevated base. They extend on the surface and infiltrate deep tissues. Considerable involvement of deeper tissues with relatively minor surface changes is not unusual.1 The most significant predictor of survival in men with penile cancer is the presence and extent of nodal metastasis. 287
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Table 2 TNM Classification of Penile Carcinoma Stage Tumor (T) Tx T0 Tis T1
Description Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Invasion of subepithelial connective tissue Invasion of one or more corpora Invasion of urethra or prostate gland Invasion of other adjacent structures
T2 T3 T4 Lymph node (N) Nx Regional lymph node cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single superficial inguinal lymph node N2 Metastases in multiple or bilateral superficial inguinal lymph nodes N3 Unilateral or bilateral metastases in deep inguinal or pelvic lymph nodes Metastasis (M) Mx Distant metastasis cannot be assessed M0 No evidence of distant metastasis M1 Distant metastasis
Figure 1 Secondary metastases to the penis. Axial (A) and sagittal (B) postcontrast T1-weighted sequence shows multiple low signal intensity lesions (straight arrows) involving corpora cavernosa and corpora spongiosa. The dominant palpable lesion in the corpora cavernosa is marked with a vitamin E tablet (curved arrow) placed on the skin.
Table 1 Jackson Classification of Penile Carcinoma Stage
Involvement
1 2 3 4
Confined to the glans penis Invasion of the shaft or corpora Operable inguinal lymph node metastasis Invasion of adjacent structures, inoperable inguinal lymph node metastasis
Figure 2 Schematic representation of local staging of penile neoplasm. (Color version of figure is available online.)
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Figure 3 (A) Axial anatomy of the penis. The two corpora cavernosa (straight arrows) dorsal to one ventral corpora spongiosum (curved arrow) are seen on the T2-weighted image. The two testicles are also seen on this coronal image. (B) Contrast-enhanced sagittal T1-weighted image shows the relationship of corpora cavernosa (straight arrow) and corpus spongiosum (curved arrow). (C) Axial T1-weighted image shows the attachment of posterior aspect of the corpora cavernosa, known as crura (arrowhead), to the pubic arch.
Distant metastases to lung and liver—less often to bone, brain, and skin—are rare and usually late.1
are based on multiple variables, ie, type of tumor, grading, depth, extent, and propensity for distant metastasis.
Other Primary Penile Malignant Neoplasm
Metastasis to the Penis
Sarcoma, melanoma, basal cell carcinoma, lymphoma, and other rare malignancy account for 5% of all penile malignancy. While all of these tumors may have similar clinical presentation, the natural progression of the disease is different. Melanoma is known to metastasize at an earlier stage, while basal cell carcinoma is usually localized. Lymphoma usually extends from neighboring organs or progresses by hematologic or lymphatic route. Clinical and imaging evaluation patterns are different depending on histology and
Penile metastases typically manifest as multiple discrete masses in the corpora cavernosa and corpus spongiosum. The primary neoplasm is often located in the urogenital tract. These masses are seen as low signal intensity areas relative to normal corporal tissues in both T1- and T2-weighted images.5 Metastasis to the penis usually represents a terminal stage in patients with diffuse metastatic disease1 (Fig. 1). It should be suspected in patients with a known diagnosis of cancer who present with multiple palpable painless nodules or unexplained priapism.
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and may lead to long-term survival. However, the procedure is associated with a high incidence of significant morbidity, even with modern surgical techniques. Minor and major morbidity rates of 68 and 32% have been reported.7 For this reason, unnecessary groin dissection should be avoided and an effort to identify the patients with lymph node metastasis has been advocated. Approximately 58% (range 20-96%) of patients with penile cancer have palpable inguinal lymphadenopathy at diagnosis. Of these, metastatic lymph nodes are found in less than half. The remaining cases are inflammatory lymph nodes. In addition, about 10-20% of nonpalpable lymph nodes contain metastasis.1 To reduce the morbidity from unnecessary lymphadenectomy, the current practice includes a course of antibiotics before surgical resection, and noninvasive imaging technique for sentinel node mapping and targeted dissection.6
Anatomy of the Penis
Figure 4 A 88-year-old man with well-differentiated squamous cell carcinoma of the glans penis. Axial T2-weighted (A) and contrastenhanced T1-weighted (B) images show neoplastic (arrows) involvement of the glans with sparing of the corpora cavernosa.
Clinical Evaluation The optimal therapeutic approach can be planned based on the Jackson classification (Table 1) and tumor node metastasis (TNM) classification clinical staging (Table 2). A schematic drawing of local staging by TNM classification is presented in Figure 2. To establish the diagnosis, histologic grade, and depth of the tumor extension, an initial biopsy of the primary penile lesion is necessary.6 Besides clinical inspection and palpation to determine extent of the tumor, various cross-sectional imaging techniques may be useful for a more accurate staging when tumor infiltration cannot be determined properly based on clinical grounds. In men with penile cancer who have lymph node metastasis, lymph node dissection has been shown to be therapeutic
The penis consists of a root, shaft, and glans. The penile shaft is composed of two paired dorsolateral corpora cavernosa and a single ventral corpus spongiosum. The glans of the penis is an extension of corpus spongiosum. The corpora cavernosa are proximally attached to the symphysis pubis and linea alba by the suspensory ligament of the penis. The corpus spongiosum contains the urethra and proximally attaches to the urogenital diaphragm. Each corpora cavernosa contains a deep centrally located artery providing blood for these erectile tissues. The erectile tissues are covered by three layers of connective tissue. The innermost fibrous capsule is the tunica albuginea. It is covered by the deep fascia of the penis (Buck’s fascia) that is a continuation of the deep perineal fascia that forms a strong membranous covering for the erectile tissues. External to Buck’s fascia is a loose subcutaneous areolar connective tissue layer surrounded by the dartos fascia. The corporal bodies have intermediate signal intensity on T1-weighted images, and high signal intensity on T2weighted images relative to skeletal muscle (Fig. 3). The corpus spongiosum may have different signal intensity from that of the corpora cavernosa. The muscular wall of the urethra appears hypointense relative to the corpus spongiosum. Both the tunica albuginea and the Buck’s fascia are hypointense on T1- and T2-weighted images. The tissue contrast between the corpora and the tunica albuginea increases on T2-weighted images, making this sequence preferable for depicting focal pathology of the penis including the extension to the corpora by malignancy. The penis is supplied by branches of internal pudendal arteries, which give rise to paired dorsal arteries running between Buck’s fascia and corpora cavernosa. These arteries are accompanied by a single deep dorsal vein and two dorsal nerves. There are two cavernosal arteries and one artery of the bulb of the penis that supply the erectile tissue, corpus spongiosum, and bulbourethral gland. They give rise to numerous branches that open directly into the cavernous spaces. The venous drainage is via the plexus within the cavernous
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Figure 5 A 76-year-old male with squamous cell carcinoma of the penis. Coronal (A) and axial (B) postcontrast T1-weighted sequence shows heterogeneous signal intensity mass (arrowhead) with involvement of the corpora cavernosa. Sagittal T2-weighted (C) and postcontrast T1-weighted (D) sequence shows postpenectomy changes with urethrostomy (arrow) located posterior to the scrotum.
spaces joining the deep dorsal vein of the penis. The corpus spongiosum and corpora cavernosa enhance with the administration of contrast agent. The enhancement of corpus spongiosum occurs almost immediately, whereas the cavernosal bodies enhance gradually in the centrifugal fashion. Superficial inguinal nodes represent one of the primary lymphatic pathways by which penile cancer, located in the glans, prepuce, and shaft, may metastasize. The other two pathways of lymphatic drainage from the glans include the deep inguinal or femoral node chain, specifically medial femoral node (node of Cloquet), and the lateral retrofemoral node, which is part of the external iliac nodes. The lymphatics of the glans may access the deep inguinal nodes or even the iliac nodes, bypassing the superficial inguinal nodes.8
Imaging Cavernosography is the exam in which contrast medium is injected directly into the corpora cavernosa to determine tumor extension into corpora cavernosa. Corpus cavernosography was used to correctly assess the extent of tumor in 10 patients with carcinoma of the penis.9 The author advocated cavernosography as a safe, simple, and valuable procedure to obtain additional information for staging of penile tumors preoperatively and plan the level of resection during penectomy. However, due to the invasive nature of the procedure and modern cross-sectional imaging techniques, cavernosography does not find routine use in practice. Ultrasound has been shown to be a useful imaging technique for primary tumor staging.10,11 Invasion of the tunica albuginea, corpora cavernosa, and urethra can be demon-
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Figure 6 A 54-year-old male who refused surgery for verrucous cancer of the penis. T2-WI imaging in axial (A) and longitudinal (B) plane of the penis shows heterogeneous signal intensity mass (arrows) involving the corpora cavernosa. Axial noncontrast (C) CT shows bulky distal half of the penis with dissection of air (curved arrow) in it.
strated on ultrasound. On ultrasound, the penile carcinoma is hypoechoic, hyperechoic, or mixed echoic, in order of decreasing frequency.10 Due to poor differentiation of the tumor and surrounding corporal bodies, the role of computed tomography (CT) is currently limited to evaluation of nodal status, not the primary tumor. The investigation utilizing positron emission tomography (PET)/CT for penile cancer has shown that the majority of primary penile squamous cell carcinoma can be detected on PET/CT.12 The sensitivity and specificity to detect primary penile cancer has been shown to be 75%.
Magnetic resonance imaging (MRI) of the penis can offer a noninvasive means of staging of the primary tumor due to its high soft-tissue contrast and multiplanar capability. The ability to detect invasion of the tunica albuginea, corpora, and urethra has made MRI preferable to other cross-sectional imaging modalities for the staging of penile cancer. MRI has been shown to upstage the primary tumors when compared to clinical exam alone in many studies. de Kerviler and colleagues13 described two patients whose MRI upstaged the tumor from stage T1 to stage T2. In a series of 33 patients (3 T1 lesions, 23 T2 lesions, and 7 T3 lesions),14 MRI had been shown to have a comparable sensitivity and specificity as
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293 negative-predictive values. In our practice, we do not routinely use PGE1 injection prior to the MRI for penile cancer staging. MRI techniques for primary tumor include appropriate patient positioning with the patient supine and a folded towel underneath the patient’s leg inferior to the perineum to elevate the scrotum and penis. The penis is dorsiflexed against the lower abdomen in the midline and taped in position to reduce motion during the examination. A surface coil is placed on the penis to obtain optimal quality, high-resolution images with a relatively small field-of-view, high matrix, and thin slices. Axial spin-echo T1-weighted images without and with gadolinium enhancement, and axial, coronal, sagittal fast spin-echo T2-weighted images are used. On MRI, lesions typically have lower signal intensity than the adjacent corpora on T1- and T2-weighted images.13,15,18 MRI can demonstrate the depth of tumor invasion, involvement of the tunica albuginea, corpora, or urethra, which can
Figure 7 A 36-year-old male with lymph nodal metastases from penile carcinoma. Axial contrast-enhanced CT (A and B) shows metastatic enlarged lymph nodes involving retroperitoneal lymph nodes (arrowheads).
clinical exam for detection of invasion of corpus cavernosum. However, regarding detection of urethral involvement, MRI was superior to ultrasound and clinical exam. When used in conjunction with artificial erection by prostaglandin E1 (PGE1) intracorporal injection, MRI may provide increased diagnostic accuracy for detection of invasion of the tunica albuginea and corpora cavernosa. Imaging during penile tumescence may be desirable due to problems in image resolution and lesion detection of the variable size of penis in the flaccid stage.15 This technique has some undesirable side effects including local pain, prolonged erection, hematoma, rash, headache, and hypotension. Priapism requiring evacuation of the corpora cavernosa was seen in one patient from the report of Scardino and coworkers,16 who performed MRI in nine patients with penile cancer. In a large recent series,17 MRI with PGE1 injection was used to assess 55 men with penile cancer preoperatively and had a sensitivity of 89, 75, 88% (for T1, T2, and T3 lesions, respectively), and a specificity of 83, 89, 98% for T1, T2, and T3 lesions, respectively. MRI correctly predicted all 20 patients with corpus cavernosum invasion, representing 100% positive- and
Figure 8 Inguinal lymphadenopathy in an 82-year-old man with moderately differentiated squamous cell carcinoma of the penis. (A) Precontrast and (B) postcontrast T1-weighted image shows an oval right inguinal lymph node with peripheral nodular enhancement. Surgical right groin dissection showed metastatic lymph node in 1 of 10 lymph nodes resected.
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sis, especially in the pelvic region, which is not accessible to palpation. Of historical interest, pedal lymphangiography was performed by pedal or penile injection of contrast medium that opacifies the three major lymphatic systems of the external and common iliac chains. A change in flow dynamics of the lymphatics, increased nodal size, and alteration of internal characteristics are the criteria for diagnosis of nodal involvement of cancer. Although it has a reported accuracy of approximately 70 to 80%, the limitations of this technique are the inability to distinguish inflammatory from metastatic lymphadenopathy, false-negative study when the enlarged node is completely replaced by tumor, and the possibility of inadequate evaluation of all lymph node chains.19 The use of this technique has declined due to its limitations, invasiveness, and increased availability of CT and MRI. Although CT plays an important role for the detection of lymphadenopathy, it suffers from the inability to detect metastasis in normal-sized lymph (Fig. 7). In addition, CT is nonspecific because enlargement of the lymph nodes may be caused by inflammation. Distant metastasis is uncommon in patients who present with penile cancer. Only 5% of patients with penile cancer have distant metastasis at the time of diagnosis. Generally, distant metastases occur late in the course of the disease and are associated with dismal prognosis. Lung, liver, bone, brain, and skin are common locations for metastatic disease from penile cancer. Evaluation for distant metastasis is most commonly done with standard chest radiographs in posteroanterior and lateral projections, and a radionuclide bone scan. Further assessment with chest CT is performed if more resolution is needed. Brain, liver, and retroperitoneal lymph nodes are evaluated with CT or MRI. Figure 9 MR lymphangiography of groin lymph nodes in a 59-yearold man with grade 2 squamous cell carcinoma of the penis. (A) Pre-USPIO T2*-weighted MR sequence shows multiple external inguinal lymph nodes (arrows), less than 1 cm in short-axis diameter. (B) Post-USPIO T2*-weighted MR sequence shows USPIO uptake by the inguinal lymph nodes (arrows), indicating benign etiology. The hypointensity of these lymph nodes is due to the susceptibility effect created by uptake of USPIO.
be determined by MRI (Figs. 4-6). The limitations of MRI for the determination of the extent of primary lesion are probably related to technical problems including lack of erection, motion artifact, previous radiation therapy to the penis, and associated infection.
Lymph Nodal Staging The detection of positive lymph nodes before surgery is the key to avoiding unnecessary lymphadenectomy and related complications. It is well known that inflammation of the lymph nodes can commonly be present in a patient with penile cancer, resulting in high rates of false-positive nodes on pathologic examination. Imaging plays an increasingly important role in the determination of lymph nodal metasta-
Recent Developments A recent study using 18F-fluorodeoxyglucose (FDG) PET/ CT12 in 13 patients with penile cancer showed 15 of the 16 lymph nodal metastases, including 9 superficial inguinal, 5 deep inguinal, and 2 obturator lymph nodes. A single falsenegative lymph node, a 1.8-cm superficial inguinal node with rather discrete FDG uptake with a standardized uptake valve (SUVmax) of 1.1, was later found to be micrometastasis on pathologic examination. The sensitivity of PET/CT was 89% for detection of superficial inguinal lesions and 100% for the detection of deep inguinal and obturator lymph nodes. The specificity was 100%. Although MRI more clearly differentiates nodes from blood vessels, the detection of metastatic lymph nodes is again dependent on lymph nodal size criterion and, to a certain extent, enhancement characteristics (Fig. 8). This limitation is similar to the difficulties inherent on CT. Newer lymphotropic MR contrast agents make MRI for detection of metastatic lymph node a promising noninvasive investigation. MR lymphangiography performed at 24 hours after intravenous injection of feromoxtran-10, an ultrasmall superparamagnetic iron oxide, has shown improved accuracy in the staging of lymph nodes of patients with various
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Figure 10 Postpartial penectomy changes in a 40-year-old male with penile carcinoma. Axial contrast-enhanced CT (A, B, and C) shows partial penectomy changes with penile implant (arrows) in situ. The reservoir (arrowhead) for the penile prosthesis is seen in the pelvis.
primary tumors. A normal lymph node containing macrophages with phagocytic function takes up a substantial amount of ferumoxtran-10 and then shows marked reduction in signal intensity because of the T2 shortening effect of the nanoparticles. In tumor-infiltrated lymph nodes, the tumor replaces the macrophages; hence, the nodes retain their high signal intensity after contrast administration.20 A few studies evaluating the role of ferumoxtran-10 MR lymphangiography in primary pelvic malignancy have shown varying results with sensitivity ranging from 90.5 to 100% and specificity ranging from 80 to 95.7% for the detection of pelvic and retroperitoneal lymph node metastasis.21,22 One exception was in Keller and coworkers,23 where only nine patients with primary gynecologic tumors were studied. In this study, two micrometastases ⬍5 mm and one metastasis of 5 mm were not detected on MRI and the study was not optimized for detecting nodal susceptibility. With a more recent trial, sensitivity and specificity increased with optimized MR protocols.24,25 Moreover, significant numbers of non-enlarged lymph nodes were correctly characterized by
this technique. A growing knowledge has shown MR lymphangiography to be a promising imaging tool for noninvasive lymph nodal staging in patients with various primary malignancies (Fig. 9).
Treatment and Posttreatment Changes Treatment of penile cancer varies according to the clinical stage. Primary tumor characteristics including size, location, and depth of invasion are major determinants for selecting surgical management. Surgery consists of ablative techniques (Mohs micrographic surgery, laser therapy, or cryosurgery), penile conservation techniques, partial penectomy, and total penectomy. Management of regional lymph nodes is somewhat controversial due to high perioperative morbidity. Some surgeons advocate a conservative approach at the time of presentation; others advocate an immediate surgery toward regional node dissection at an early course of disease.26
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Figure 11 Postpenectomy abscess in a 56-year-old male with penile cancer. Contrast-enhanced CT (A and B) shows abscess (arrows) in the penectomy bed, which was drained with a percutaneous catheter (arrowhead).
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Early complications after partial or total penectomy include wound infection and hematoma, and stricture of the neomeatus. Cross-sectional imaging can be used to postoperatively assess a penile implant and can provide guidance in the drainage of postoperative abscess (Figs. 10 and 11).
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