Adenosquamous cell carcinoma of the penis: a case report and literature review
Highlight box
Key findings
• We report a case of primary adenosquamous carcinoma of the penis (ASC) in a 77-year-old man.
What is known and what is new?
• ASC is an extremely rare subtype of squamous cell carcinoma, with only 13 cases reported worldwide to date. We report the case of a 77-year-old male patient with adenosquamous carcinoma.
• We provide a comprehensive and updated overview of the etiology, epidemiology, clinical manifestations, histopathology, diagnosis, and treatment options for ASC.
What is the implication, and what should change now?
• We believe that there are currently no uniform prognostic criteria for ASC. However, it can be observed that survival and recurrence rates are higher with radical resection with or without adjuvant therapy compared to other treatments.
Introduction
Penile cancer is a relatively uncommon malignancy. It is most commonly a squamous cell carcinoma (SCC), but other non-squamous malignancies, including basal cell carcinoma, melanoma, sarcoma, metastatic carcinoma and adenosquamous cell carcinoma, have also been documented (1-5). Adenosquamous carcinoma of the penis (ASC) is an extremely rare subtype of SCC, with only 13 cases reported worldwide to date (Table 1).
Table 1
| Author, journal, year | Patient’s nationality | Age (years) | Patient’s condition | Lymph node transfer | Therapeutics | Outcomes |
|---|---|---|---|---|---|---|
| Jamieson et al., Br J Urol, 1986 (6) | The United Kingdom | 50 | Penile nodules with occlusive dry glans penis | No | Radiotherapy | Local recurrence after 2 years |
| Cubilla et al., Am J Surg Pathol, 1996 (7) | The United States | 37 | Penile warty nodules | Yes | Partial penectomy | No evidence of disease after 8.5 years |
| 72 | Penile warty nodules | Unreported | Radical penectomy | Unreported | ||
| 74 | White-grey granular exophytic masses | No | Radical penectomy | No evidence of disease after 1 years | ||
| Masera et al., J Urol, 1997 (8) | Slovenia | 30 | Penile nodules | Yes | Partial penectomy | Died of ASC 5 months after the operation |
| Lam et al., Arch Pathol Lab Med, 1999 (9) | China | 50 | Unreported | Unreported | Unreported | Unreported |
| Romero et al., Clinics (Sao Paulo), 2006 (10) | Japan | 70 | Penile ulcers, tumours that are partially necrotic and prone to bleeding | Yes | Radical resection, perineal urethrostomy | No evidence of disease after 5 years |
| Khazaei et al., Pathology, 2009 (11) | Iran | 62 | Painful erection and stiff penis shaft | Yes | Urethroplasty, radical penectomy, postoperative chemotherapy | There was no evidence of disease recurrence other than bilateral leg oedema at 1 year follow-up |
| Guimarães, et al., J Urol, 2009 (12) | Unreported | Unreported | Unreported | Yes | Unreported | Recurrence after 5 years |
| Unreported | Unreported | Yes | Unreported | Death from other causes after 5 years | ||
| Unreported | Unreported | Yes | Unreported | No evidence of disease after 5 years | ||
| Unreported | Unreported | Yes | Unreported | Lost to visit after 5 years | ||
| Rush et al., J Cutan Pathol, 2016 (13) | The United States | 43 | Tender erythematous nodules on the penis, with purulent drainage. A palpable left inguinal mass with erythema | Yes | Preoperative chemotherapy, partial resection, and postoperative radical radiotherapy | Pelvic discomfort, no evidence of recurrence after 8 months |
| Current case | China | 77 | Enlargement of penis with pain | Yes | Radical resection, urethroperineostomy | No evidence of disease after 5 years |
ASC, adenosquamous carcinoma of the penis.
The most common presentation of ASC is the presence of nodules, which may or may not be accompanied by pain. The role of diagnostic imaging in determining the depth of cavernous invasion by penile malignancy is crucial, with computed tomography (CT) and magnetic resonance imaging (MRI) playing a pivotal role in this regard. These imaging modalities can provide supportive evidence for the diagnosis of ASC. However, a definitive pathological diagnosis requires an organ biopsy. It is noteworthy that a considerable number of patients receive creams, ointments and antibiotics provided by community physicians prior to consulting a urologist, but the efficacy of these treatments is often unsatisfactory (1-5).
The rarity of ASC means that there are no established treatment guidelines. Of the 13 previously reported cases, all underwent surgical treatment with the exception of one case published by Jamieson et al. in 1986 in which only radiotherapy was used (6-13). The present case report details a patient who underwent surgical resection, with subsequent long-term follow-up data demonstrating a favourable prognosis. Consequently, the treatment plan and outcome of this case offer a valuable reference point for the selection and optimisation of treatment modalities for this disease. The submission of this article adheres to the CARE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-616/rc).
Case presentation
A 77-year-old man presented to The First Affiliated Hospital of Xiamen University with an enlarged penile head with persistent pain, urinary tract infection and thin urine stream, with a gradual worsening of the complaints over the past month. He reported a 77-year history of ‘priapism’, a 60-year history of smoking, and a 50-year history of alcohol consumption, with the remainder of his medical history unremarkable. His family history was unremarkable. The history is summarised in Table 2. Specialist examination showed normal penile development without malformation, but the foreskin was long and could not be turned up and was circumcised. The head of the penis had a localised nodular swelling and was hard. A discharge of pus was visible at the opening of the prepuce. Lymph node enlargement was palpable bilaterally in the groin, more so on the right side. The presence of infection was confirmed by elevated blood neutrophils and leukocytes. One day after surgery, blood leukocytes and neutrophils decreased to normal levels.
Table 2
| Date | Incident |
|---|---|
| 2019/4/2 | A 77-year-old male presented to The First Affiliated Hospital of Xiamen University with an enlarged penile head, persistent pain, urinary tract infection, and dilute urine |
| 2019/4/3 | Expert examination shows normal development, no deformities, long foreskin, local nodular swelling, and hardness of the glans penis. Purulent discharge can be seen at the opening of the foreskin |
| 2019/4/5 | Inguinal ultrasound shows multiple hypoechoic nodules in the left inguinal region, with lymph node visible (Figure 1). CT scan of the middle and lower abdomen shows a lesion occupying the glans penis, with increased swelling, uneven density, and uneven enhancement after enhancement. There are multiple enlarged lymph node shadows in the bilateral inguinal regions, with the largest size not mentioned |
| 2019/4/7 | Penile MRI: abnormal penile morphology, obvious swelling in the lower segment-glans region, irregular soft tissue abnormal signal shadow, T1 low signal, T2 high signal, border still clear, diameter about 4.6 cm, diameter about 4.4 cm (Figure 2) |
| 2019/4/10 | Pathological puncture biopsy: microscopic examination revealed irregular nests of tumor cells, infiltrative growth, polygonal cells, red-staining of the cytoplasm, enlarged and deeply stained nuclei, thickened chromatin, visible nucleoli, and pathological nuclear division. Mucus was observed in some cells, and necrosis was seen in certain areas. Immunohistochemistry also showed CK5/6 (+) and CEA (+). The pathological findings were more consistent with adenosquamous carcinoma |
| 2019/4/12 | There was evidence of lymph node metastasis, and a multimodal management treatment plan was considered, but the patient refused it. After obtaining the patient’s consent, we performed radical penile resection, urethral resection, and bilateral inguinal lymph node dissection |
| 2024/5/7 | After 5 years of follow-up, the patient reported only perineal and urinary discomfort without any evidence of disease |
CEA, carcinoembryonic antigen; CK5/6, cytokeratin 5/6; CT, computed tomography; MRI, magnetic resonance imaging.
Inguinal ultrasound showed multiple hypoechoic nodules in the right inguinal region, the largest was about 1.3 cm × 0.7 cm, with cortical thickening, homogeneous echogenicity and visible lymphatic gates, and no obvious enlarged lymph nodes were seen in the left inguinal region (Figure 1). CT of the middle and lower abdomen showed occupational lesion of the penile head, swelling and enlargement, uneven density, uneven enhancement after enhancement, the largest cross-section 5.1 cm × 4.3 cm. At the same time, the bilateral inguinal area showed multiple enlarged lymph nodes. MRI of the penis: abnormal penis morphology, obvious swelling in the lower part of the lower segment-glans area, irregular soft tissue, abnormal signal shadow, T1 low signal, T2 high signal, with a still clear border, the diameter is about 4.6 cm, and the enhancement is stronger after enhancement (Figure 2).
After the above examination, we strongly suspected a malignant tumour of the penis, and then we performed a pathological puncture biopsy, and the microscopic results showed irregular nested clusters of tumour cells, infiltrative growth, polygonal cells, red cytoplasmic staining, enlarged and deeply stained nuclei, coarsening of chromatin, nucleoli and pathological nuclear schizophrenia, mucus was seen in some of the cells, and necrosis was seen in some areas. Immunohistochemistry (IHC) also showed cytokeratin 5/6 (CK5/6) (+) and carcinoembryonic antigen (CEA) (+). The pathological findings were more consistent with adenosquamous carcinoma. Therefore, with the patient’s consent, we performed a radical penectomy, urethroperineostomy and bilateral inguinal lymph node dissection. The surgical specimen was sent to us for examination and the gross findings were as follows: penectomy specimen, size 12.5 cm × 6.5 cm × 5.5 cm, 7 cm from the severed end of the penis, and an infiltrative mass at the head of the penis, size 6 cm × 5 cm × 5 cm, greyish white on the cut surface, hard and poorly demarcated, which was involved in the cavernous body of the penis to the naked eye and was immediately adjacent to the urethra, with the structure of the coronal groove, prepuce and urethral orifice not clear (Figure 3). The microscopic and immunohistochemical findings were similar to those obtained at puncture, with the addition of glycogen-periodic acid-schiff stain (partial +). The final pathological diagnosis was invasive ASC, with carcinoma involvement of the corpus cavernosum, corpus cavernosum and interstitial nerve bundles, and no carcinoma involvement of the skin margins.
It is regrettable that the patient did not consent to multimodal management and only underwent surgery. However, he was advised to undergo regular review and follow-up. Following a 5-year period of follow-up, the patient reported only perineal and urinary discomfort, with no evidence of disease present.
All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of The First Affiliated Hospital of Xiamen University and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient and the patient’s carer for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.
Discussion
Primary ASC is a rare variant of SCC that appears to originate from bimodal cells (3,5). The exact aetiology of ASC is unknown but may be associated with a number of factors including phimosis, chronic inflammation of the foreskin, lack of neonatal circumcision, smoking, poor genital hygiene, and a history of sexually transmitted infections (STIs), particularly human papillomavirus (HPV). It is well established that chronic irritation may promote abnormal proliferative changes in the penile epithelium, thereby increasing the risk of developing invasive cancer. Furthermore, penile intraepithelial neoplasia is widely recognised as a risk factor for penile SCC (6-9). However, the World Health Organization considers adenosquamous carcinoma and mucoepidermoid carcinoma to be synonymous, whereas the Armed Forces Institute of Pathology does not (10-13).
The grading of ASC is primarily based on the 2016 edition of the World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs. Staging, on the other hand, is chiefly informed by the eighth edition of the tumour-node-metastasis staging classification for urological cancers (1,2) (Tables 3,4). The pathogenesis of ASC remains unclear, although a hypothesis suggests its origin in embryonic mucus-producing glandular cells that are subsequently discarded and deposited in the navicular fossa (1,2). Morphologically, ASC is characterised by squamous differentiation and glandular differentiation, and specific histochemical and immunological markers, such as CEA, high molecular weight cytokeratin and focal mucin carmine, have been identified (1,2).
Table 3
| ASC | Epidemiological and clinical features |
|---|---|
| Epidemiological | Mainly reported in the developing world, accounting for about 1–2% of all SCCs |
| Classification | Non-HPV-related SCC of the penis |
| Pathological and histological features | Coexisting squamous and glandular component, predominant squamous component, positive IHC for keratin and carcinoma membrane antigens |
| Treatment | Individualised treatment based on different stages, mainly surgical resection, promoting multimodal management |
| Prognosis | Highly aggressive, one of the worst prognostic subtypes of all SCCs |
ASC, adenosquamous carcinoma of the penis; HPV, human papillomavirus; IHC, immunohistochemistry; SCC, squamous cell carcinoma.
Table 4
| ASC | Details |
|---|---|
| TNM staging | |
| Ta | Non-invasive limited SCC |
| The tumour invades the subepithelial connective tissue and is classified according to the presence or absence of lymphovascular or peripheral nerve infiltration | |
| T1 | |
| T1a | No lymphovascular infiltration or peripheral nerve infiltration and no hypo-differentiation |
| T1b | Lymphovascular infiltration or peripheral nerve infiltration or hypo-differentiation |
| T2 | Tumour invasion of the corpus cavernosum (or ventral trunk) with or without urethral infiltration |
| T3 | Tumour invasion of the corpus cavernosum (including the tunica albuginea), with or without urethral infiltration |
| T4 | Tumour invasion into adjacent structures (scrotum, prostate, pubic bone) |
| N1 | One or two inguinal lymph node metastases (unilateral) |
| N2 | Increased unilateral or bilateral inguinal LN metastases to >2 without extranodal extension |
| N3 | Fixed pelvic LN or inguinal LN metastasis, or extranodal extension, unilateral or bilateral |
| M0 | No distant metastases |
| M1 | Distant metastases |
| Prognostic staging | |
| I | T1a, N0, M0 |
| IIa | T1b, N0, M0 |
| T2, N0, M0 | |
| IIb | T3, N0, M0 |
| IIIa | T1–3, N1, M0 |
| IIIb | T1–3, N2, M0 |
| IV | T4, any N, M0 |
| Any T, N3, M0 | |
| Any T, any N, M1 | |
| Grade | |
| 1 | Highly differentiated carcinoma: cytological features of normal squamous tissue, with tumour cells growing in an irregular nested pattern with little or no stroma in between |
| 2 | Moderately differentiated: those that do not qualify for grade 1 or grade 3 |
| 3 | Poorly differentiated carcinoma: irregular growth patterns comprising small nests of tumour cells, poor keratinisation, pleomorphic tumour cells with deeply stained nuclei, frequent mitotic divisions, and a marked stromal reaction |
ASC, adenosquamous carcinoma of the penis; HPV, human papillomavirus; IHC, immunohistochemistry; LN, lymphatic node; SCC, squamous cell carcinoma; TNM, tumour-node-metastasis.
Penile ASC is characterised by the presence of a palpable nodule on the glans, which may or may not be accompanied by discomfort. Diagnosis is primarily dependent on a physical examination and pathological analysis, with imaging techniques such as CT and MRI playing an adjunctive role, particularly in staging the disease. However, positron emission tomography (PET)-CT can be utilised to detect distant metastases (8-10). IHC is a valuable tool in the differentiation of ASC from other malignancies, as certain markers, such as 34βE12 and CEA staining, are positive in ASC and mucoepidermoid carcinoma, and negative in pure SCC or adenocarcinoma (11-13). Given the rarity of ASC, there are no established treatment standards. However, the 2023 European Association of Urology and American Society of Oncology Penile Cancer Collaboration guidelines provide some guidance. Surgical resection remains the primary treatment modality, with chemotherapy and radiotherapy serving as adjuvant therapies. Nevertheless, a multimodal approach is advocated for optimal treatment (1-3). Of the 13 cases documented, the majority of patients underwent partial resection (those of a younger and middle-aged demographic) or radical resection (middle-aged and elderly patients). A small number of patients received adjuvant therapy alone or in combination with surgery. It is noteworthy that the limited efficacy of radiotherapy alone may be attributable to the resistance of the glandular component to radiation (4). The 5-year survival rate of patients who underwent surgical intervention is significantly higher than that of patients who received radiotherapy alone.
Conclusions
In conclusion, primary adenosquamous carcinoma is a rare but distinct variant of SCC. It presents as a large, aggressive tumour, usually associated with lymph node metastasis and poor prognosis. Our case adds to the literature and reviews the treatment options for this rare disease and the poor prognosis associated with this malignancy.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-616/rc
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Funding: This work was supported in part by grants from
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-616/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of The First Affiliated Hospital of Xiamen University and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient and the patient’s carer for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.
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References
- Menon S, Moch H, Berney DM, et al. WHO 2022 classification of penile and scrotal cancers: updates and evolution. Histopathology 2023;82:508-20. [Crossref] [PubMed]
- Moch H, Cubilla AL, Humphrey PA, et al. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur Urol 2016;70:93-105. [Crossref] [PubMed]
- Paner GP, Stadler WM, Hansel DE, et al. Updates in the Eighth Edition of the Tumor-Node-Metastasis Staging Classification for Urologic Cancers. Eur Urol 2018;73:560-9.
- Montironi R, Cheng L, Scarpelli M, et al. Pathology and Genetics: Tumours of the Urinary System and Male Genital System: Clinical Implications of the 4th Edition of the WHO Classification and Beyond. Eur Urol 2016;70:120-3.
- Mohanty SK, Lobo A, Cheng L. The 2022 revision of the World Health Organization classification of tumors of the urinary system and male genital organs: advances and challenges. Hum Pathol 2023;136:123-43. [Crossref] [PubMed]
- Jamieson NV, Bullock KN, Barker TH. Adenosquamous carcinoma of the penis associated with balanitis xerotica obliterans. Br J Urol 1986;58:730-1. [Crossref] [PubMed]
- Cubilla AL, Ayala MT, Barreto JE, et al. Surface adenosquamous carcinoma of the penis. A report of three cases. Am J Surg Pathol 1996;20:156-60. [Crossref] [PubMed]
- Masera A, Ovcak Z, Volavsek M, et al. Adenosquamous carcinoma of the penis. J Urol 1997;157:2261. [Crossref] [PubMed]
- Lam KY, Chan KW. Molecular pathology and clinicopathologic features of penile tumors: with special reference to analyses of p21 and p53 expression and unusual histologic features. Arch Pathol Lab Med 1999;123:895-904. [Crossref] [PubMed]
- Romero FR, de Castro MG, Garcia CR, et al. Adenosquamous carcinoma of the penis. Clinics (Sao Paulo) 2006;61:363-4. [Crossref] [PubMed]
- Khazaei S, Izadi B, Kanani M, et al. Adenosquamous carcinoma of the penis. Pathology 2009;41:61.
- Guimarães GC, Cunha IW, Soares FA, et al. Penile squamous cell carcinoma clinicopathological features, nodal metastasis and outcome in 333 cases. J Urol 2009;182:528-34; discussion 534. [Crossref] [PubMed]
- Rush PS, Shiau JM, Hibler BP, et al. Primary cutaneous adenosquamous carcinoma of the penis: the first characterization of HPV status in this rare and diagnostically challenging entity with review of glandular carcinomas of the penis. J Cutan Pathol 2016;43:1226-30. [Crossref] [PubMed]
