Abstract
Bladder cancer is one of the main causes of urogenital cancer (30-35% of the total urological cancers). Although metastases from urologic tumors are rare, it is associated with a high mortality rate. The location and pattern of metastasis are random and unpredictable. A literature search was done, and a total of 49 studies published from 1949 to 2021 were included. All published studies were case reports. A total number of 59 patients were included: 50 men and nine women. Multiple types of bladder cancer were described, 72.8% were urothelial/transitional cell carcinoma of different grades and stages (n=43). Other reported cancers were adenocarcinoma of the bladder (n=4), poorly differentiated carcinoma (n=5), bladder sarcoma (n=1), sarcomatoid carcinoma (n=1), renal cell carcinoma (n=1), myeloid sarcoma (n=1), and grade III papillary carcinoma (n=2). The most common site for cutaneous lesions was the abdomen, followed by the chest. Further randomized cohort studies assessing the sites and patterns of metastasis should be done to help physicians in their clinical work.
Keywords: bladder cancer, bladder metastasis, cutaneous metastasis, upper urinary tract cancer, uro oncology
Introduction and background
Metastasis is the most ominous and dreaded stage of cancer progression with a devastating prognosis and high mortality rate. It encompasses a spectrum of multistep biological processes leading to tumor transformation, a cornerstone in seed-soil implantation [1,2]. Fortunately, metastasis only occurs in a low percentage of cancers with the ability to overcome these inordinate biological boundaries. Cutaneous metastasis of bladder cancer is an uncommon phenomenon that induces a significant implication. The cancer can spread to distant sites through the bloodstream or lymphatics. Urogenital cancers have a vanishingly low propensity for cutaneous metastasis. Despite the dawning of new cancer treatment modalities in recent decades, a perversely counter-intuitive global figure of cutaneous metastasis originating from urological cancers has risen. However, the complex genomic landscape underlying tumor seeding is not fully elucidated yet [3].
This systematic review aims to provide a comprehensive overview of this rare manifestation. The review states various aspects of cutaneous metastasis of bladder cancer including incidence, clinical presentation, diagnostic methods, and treatment options. This systemic review will summarize the recently reported cases of urological cancer with skin metastasis, the proposed underlying pathophysiology, and the current knowledge of urogenetic metastasis.
Before conducting this systemic review, our hypothesis was that cutaneous metastasis of bladder cancer is uncommon and frequently denotes an advanced disease stage. We anticipated that the review would reveal a variety of clinical presentations, posing the diagnostic challenges and the underlying mechanisms that will give us an advantage in choosing the effective treatment for this rare manifestation.
Review
Materials and methods
The systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [4]. A literature search in February 2022 was conducted and focused on cutaneous metastasis from bladder cancer. The databases were searched using the following query: "cutaneous metastasis from bladder cancer", "skin and bladder cancer", "skin metastasis and bladder cancer", and "transitional cell cancer and cutaneous metastases". Articles were evaluated by the authors and the most relevant articles were selected according to their titles and abstract. All articles published before the search date and pertaining to the topic were included. Systematic reviews, literature reviews, in vitro studies, articles not assessing the efficacy of xenografts, articles not written in English, articles conducted on animals, letters to the editor, and commentaries were excluded. For each included article, a reference list was extracted, and additional articles were identified and included.
Results
A total of 334 articles from 49 studies (with 59 patients) published between 1949 and 2021 were included in the study [5-56]. All included studies were case reports. Twelve studies were done in the United States, seven in Japan, five in India, four in Italy, and four in the United Kingdom. The rest of the included articles were published from several countries with a total of less than three articles from each country. Most of the studies included one patient except for seven studies that recruited two patients each [5-11]. A study published by Bischoff and Fishkin included four patients [12].
Patient Characteristics, History, and Laboratory Findings
Patient characteristics and past medical history: A total of 84.7% of the included patients were men (n=50) and 15.2% were women (n=9). Patients’ ages ranged between 33 and 88 years. Patients’ past medical history was not mentioned in almost half of the reports. Four patients had malignancies not related to the genito-urinary tract: superficial esophageal cancer, Hodgkin lymphoma, and two laryngeal cancers [13-16]. The most common urinary symptom was hematuria (47.4%, n=28) (Table 1).
Table 1. Summary of the Extracted Data From the Included Studies.
CR: clinical research; PMH: past medical history; UTI: urinary tract infection; NR: not recorded; HTN: hypertension; M: male; F: female; BPH: benign prostatic hyperplasia.
Study (year) | Country | Study design (level of evidence) | Total number of patients | Gender | Age (years) | PMH not related to urinary tract | PMH related to the urinary tract | Laboratory tests (abnormal) | Urinary tests | Positive immunohistochemical markers |
Giunchi et al. (2017) [5] | Italy | CR | 1 | M | 69 | NR | Hematuria | NR | NR | GATA3, CK7, CK20, CK14 |
1 | M | 71 | NR | Hematuria | NR | NR | GATA3, CK7 | |||
Kumar et al. (2006) [6] | India | CR | 1 | M | 55 | NR | Hematuria | NR | NR | NR |
1 | M | 49 | NR | NR | NR | NR | NR | |||
Fujita et al.(1994) [7] | Japan | CR | 1 | M | 77 | NR | NR | NR | NR | NR |
1 | M | 72 | NR | Pollakiuria, pain on urination | NR | NR | NR | |||
Rebelakos et al. (1989) [8] | UK | CR | 2 | M | NR | NR | NR | NR | NR | NR |
Bachrach and Dahlen (1973) [9] | USA | CR | 1 | M | 77 | NR | Dysuria | NR | NR | NR |
1 | M | 47 | NR | NR | NR | NR | NR | |||
Higgins and Hausfeld (1948) [10] | USA | CR | 1 | M | 52 | Normal | Pain on urination, intermittent frequency and nocturia, hematuria | NR | Heavy trace of albumin, RBC | NR |
1 | M | 51 | Mastoidectomy, right inguinal hernia | Pain on urination, nocturia, hematuria, dysuria | NR | RBC, WBC | NR | |||
McCrea (1949) [11] | USA | CR | 1 | M | 71 | NR | Painless hematuria | NR | NR | NR |
1 | F | 54 | NR | Dysuria, hematuria | NR | NR | NR | |||
Bischoff and Fishkin (1956) [12] | USA | CR | 1 | M | 58 | NR | Gross hematuria | NR | RBC, WBC | NR |
1 | M | 58 | NR | Hematuria, frequency, burning dysuria | NR | RBC, WBC, albumin | NR | |||
1 | M | 55 | TB | Hematuria, dysuria, retention | NR | RBC, albumin, WBC | NR | |||
1 | M | 76 | NR | Hematuria, dysuria, urgency | NR | Albumin, RBC | NR | |||
Yajima et al. (2021) [13] | Japan | CR | 1 | M | 70 | Superficial esophageal cancer | Gross hematuria | NR | Urine cytology: HGUC | CK7, CK20, and GATA 3 |
Blalock et al. (2011) [14] | USA | CR | 1 | M | 80 | Hodgkin lymphoma | NR | NR | NR | CK7, CD20, CK19, CD138 |
Wormer et al. (1956) [15] | USA | CR | 1 | M | 88 | Laryngeal carcinoma | Gross hematuria, nocturia, urgency | Normal | Albumin, RBC | NR |
Cohen et al. (2017) [16] | USA | CR | 1 | M | 75 | Laryngeal cancer, depression, glaucoma, seizure, arthritis, thyroid disease, HTN, diabetes, GI hemorrhage | Gross hematuria with clots, frequency, nocturia, urgency, and dysuria | Hgb 5 g/dl | NR | Pan CK, CK7 |
Garg et al. (2018) [17] | India | CR | 1 | M | 62 | Decreased appetite | Oliguria | Hgb 7.2 g/dl, BUN 220 mg/dl, serum creatinine 6.5 mg/dl, K+ 6.5 meq/l, pH=7.2 | NR | NR |
Lees (2015) [18] | USA | CR | 1 | M | 81 | NR | NR | Hgb 10.3 g/dl, iron 3 umol/L, TSH 0.19 mU/L, creatinine 1.32 mg/dl | NR | CK5/6 and P63 |
Agarwal et al. (2014) [19] | India | CR | 1 | M | 49 | NR | Hematuria | Serum creatinine (2.2 mg/dl), BUN (23 mg/dl), K+(5.9 mg/dl), LDH (429 U/L) | RBC | CK7, CK20, keratin cocktail (AE1/A3), p63 |
Salemis et al. (2011) [20] | Greece | CR | 1 | M | 68 | NR | NR | Hgb (7.6 mg/dl), CRP (161 mg/dl), ALP (175 U/L), ESR (137 mm/h) | RBC | CEA, CA19-9 |
Gowardhan et al. (2004) [21] | UK | CR | 1 | M | 51 | NR | NR | NR | RBC | NR |
Endo et al. (2021) [22] | Japan | CR | 1 | F | 74 | NR | NR | NR | Urine cytology: tumor cells | CK7+, CK20+ |
Schmiedecke et al. (2014) [23] | USA | CR | 1 | F | 80 | Ulcerative colitis, total colectomy, and ileostomy | Hematuria | Normal | Normal | CK7, CK20, p63, uroplakin III |
Roos and Wigg (1993) [24] | Austria | CR | 1 | M | 75 | NR | Hematuria | Elevation ALP, LDH | Normal | NR |
Stolla et al. (1994) [25] | France | CR | 1 | M | 58 | NR | Macroscopic hematuria | NR | NR | NR |
Ghalleb et al. (2019) [26] | Tunisia | CR | 1 | M | 61 | NR | Hematuria | Hgb 10 g/dl | NR | CK7, P63 |
Miyamoto et al. (2000) [27] | Japan | CR | 1 | M | 75 | NR | NR | NR | NR | NR |
Saito (1998) [28] | Japan | CR | 1 | M | 79 | NR | Asymptomatic hematuria | NR | NR | NR |
Swick and Gordon (2010) [29] | USA | CR | 1 | M | 69 | NR | NR | NR | NR | Pan-keratin, CK7, CK20 |
Chin et al. (2011) [30] | Malaysia | CR | 1 | F | 70 | Diabetes, HTN, MDS | Frank hematuria | NR | NR | MPO |
Hamer and Nourse (1953) [31] | USA | CR | 1 | M | 71 | BPH | Frequency, urgency, painful urination, hematuria | NR | NR | NR |
Mathew et al. (2021) [32] | India | CR | 1 | M | 76 | Diabetes | Urinary symptoms without hematuria or dysuria | Normal | NR | Pan CK, CK7, CK20, and GATA 3 |
Hasan et al. (2020) [33] | USA | CR | 1 | F | 71 | NR | No | NR | NR | P63, P40, CK7, CK20, uroplakin |
Kerkeni et al. (2017) [34] | Tunisia | CR | 1 | M | 74 | NR | NR | NR | NR | CK p63 |
Elumalai et al. (2020) [35] | India | CR | 1 | M | 62 | NR | NR | NR | NR | NR |
Pomara et al. (2004) [36] | Italy | CR | 1 | M | 76 | NR | NR | NR | NR | NR |
Manzelli et al. (2011) [37] | Italy | CR | 1 | M | 68 | NR | Gross hematuria | NR | NR | CK7, Cerb-B2 |
Zwenzner et al. (2006) [38] | Germany | CR | 1 | M | 68 | NR | NR | NR | NR | NR |
Takematsu et al. (1984) [39] | Japan | CR | 1 | F | 60 | NR | NR | NR | NR | NR |
Yoshida et al. (2012) [40] | Japan | CR | 1 | F | 65 | NR | NR | NR | NR | NR |
Wyldes and Osborn (1988) [41] | UK | CR | 1 | M | 43 | NR | NR | NR | NR | NR |
Yang et al. (2015) [42] | China | CR | 1 | M | 53 | NR | NR | NR | NR | CAM5.2, CDX2, CA199 |
Atmaca et al. (2007) [46] | Turkey | CR | 1 | M | 66 | NR | NR | NR | NR | LMW CK, HMFG-1 |
Akman et al. (2003) [47] | Turkey | CR | 1 | M | 78 | Normal | Hematuria | Inconclusive | NR | NR |
Chang et al. (2013) [48] | China | CR | 1 | M | 72 | NR | Weak urine stream and dysuria | NR | NR | CK7, CK20 |
Chung et al. (2013) [49] | Korea | CR | 1 | M | 60 | NR | NR | Normal | NR | NR |
Filho et al. (2016) [50] | Brazil | CR | 1 | M | 63 | Intermittent abdominal pain | UTI, hematuria | NR | NR | CK AE1/AE3, antivimentin |
Somani et al. (2006) [52] | UK | CR | 1 | F | 83 | NR | Gross hematuria | NR | NR | CK7, CK20 |
Sgambato et al. (2009) [53] | Italy | CR | 1 | F | 72 | NR | NR | NR | NR | NR |
Kumar et al. (2000) [54] | Iran | CR | 1 | M | 58 | NR | Hematuria and dysuria | NR | NR | NR |
Feldmann et al. (2020) [55] | Austria | CR | 1 | M | 78 | NR | NR | NR | NR | CK7, CK20, and GATA 3 |
Salmanpoor et al. (2013) [56] | Iran | CR | 1 | M | 33 | NR | NR | NR | NR | CK (AE1/AE3), CK7, CK20, EMA, vimentin |
Laboratory findings: Laboratory findings were not reported for most patients (77.9%, n=46). The most reported laboratory finding was anemia (8.4%, n=5). Elevated creatinine was reported in three patients [17-19]. The most common finding in urinalysis was the presence of RBCs seen in 16.9% of patients (n=10) [19-21]. Albumin was found on urinalysis in five patients and WBCs in four patients [10-12]. Malignant cells were found on urine cytology in two cases [13,22], and normal urinalysis was seen in two cases [23,24]. However, for the remaining 76.2% of patients, no urinalysis results were mentioned in the original papers (n=45). Additionally, the most common immunohistochemical marker was CK7 positive in 28.8% of patients (n=17) followed by CK20 in 20.3% of patients (n=12). Then, GATA3 and P63 were positive in five and six patients, respectively. The immunohistochemical studies were either not done or missing in 34 papers.
Characteristics of Skin Cancer
Types of urinary tract cancer, lymph node invasion, and non-cutaneous metastasis: Multiple types of bladder cancer were described in the different cases exposed in this paper. The vast majority, 72.8%, were urothelial/transitional cell carcinoma of different grades and stages (n=43). Other reported cancers were adenocarcinoma of the bladder (n=4), poorly differentiated carcinoma (n=5), bladder sarcoma (n=1), sarcomatoid carcinoma (n=1), renal cell carcinoma (n=1), myeloid sarcoma (n=1), and grade III papillary carcinoma (n=2). The type of bladder cancer was not reported in only one patient [25].
Interestingly, 12% of patients (n=7) had no lymph node involvement [16,18,21,26-28], whereas 45.7% of patients had an extension to lymph nodes (n=27) suggested mostly by enlarged lymph nodes on physical examination or on imaging, with the most involved nodes being inguinal and iliac. For the rest of the patients, data concerning the lymph nodes were not reported. Metastases to organs other than the skin were reported in the original articles in half of the patients (n=29), and only four patients had no metastasis to non-cutaneous organs [16,21,29,30]. The most common sites of metastasis were the lungs (n=11) followed by the liver (n=9), bone (n=5), and adrenals (n=5). Other mentioned sites of metastasis included the prostate (n=2), ureter (n=3), peritoneal carcinomatosis (n=3), the brain (n=2), the GI tract (n=4), and pericardium (n=2) (Table 2).
Table 2. Clinical Data Extracted From Individual Studies.
NR: not recorded; TCC: transitional cell carcinoma.
Study (year) | Total number of patients | Type of bladder cancer | Lymph node invasion | Non-cutaneous tumor metastasis | Skin lesion location | Cutaneous symptoms | Biopsy location | Biopsy finding | Date of skin manifestation occurrence | Non-cutaneous associated symptoms |
Mathew et al (2021) [32] | 1 | Urothelial carcinoma | Enlarged lymph nodes along the bilateral iliac vessels | NR | The upper abdomen, back, and the scalp (above the right ear) | Firm, non-tender skin nodules | Abdominal wall nodule | Atypical pleomorphic cells with round nuclei, coarse chromatin, conspicuous nucleoli, and a moderate amount of cytoplasm with perineural invasion | At the time of diagnosis | Proptosis of the left eye |
Yajima et al. (2021) [13] | 1 | Invasive high-grade urothelial carcinoma | Multiple lymph node metastases in the pelvis, enlarged para-aortic lymph nodes | Prostate | Left chest skin | Reddish mass on the skin | Cutaneous mass | Small nests of tumor cells in the dermis | 2 months after detection of bladder cancer | NR |
Endo et al. (2021) [22] | 1 | Renal pelvic urothelial carcinoma UC | Right neck, mediastinum, and para-aortic | NR | Neck and chest | Purpuritic, indurated plaque | NR | Nests of round, atypical cells with frequent tumor cell invasion into blood vessels and vascular destruction | 1 month before detection of bladder cancer | Tracheal shifting and stenosis |
Elumalai et al. (2020) [35] | 1 | Metastatic bladder carcinoma | NR | Osteolytic skeletal lesions, right 11th rib posteriorly | Anterior pelvic wall, walls of the scrotum, and base of the penis | Nodular thickening of cutaneous and subcutaneous tissue and ulcerations | Ulcerative lesion from the base of the penis | Nuclear atypia and lymphovascular emboli | 8 years after diagnosis of primary urinary bladder carcinoma | NR |
Feldmann et al. (2020) [55] | 1 | Transitional cell carcinoma of the bladder | The left inguinal region, single lymph node | NR | Pitting edema of the lower extremities with cobblestone appearance, including the genital area and the lower abdomen. On the border of the edema, there were erythematous patches mimicking erysipelas. | Erythematous patches mimicking erysipelas on the borders of the lower limb edema | Erythematous skin area | Atypical cells with pleomorphic and hyperchromatic nuclei within dermal lymphatic vessels | 2 years after diagnosis | Pitting edema of lower extremities, including genital area and lower abdomen, with a cobblestone appearance |
Hasan et al. (2020) [33] | 1 | Uroepithelial carcinoma of the bladder | Significant right inguinal, iliac, and retroperitoneal lymphadenopathy | Adrenal mass, left ureter | Suprapubic extended to the umbilicus, perianal, medial gluteal clefts, and anterior lower pelvis | Large erythematous indurated plaque, interval size soft-tissue nodules, and nodular skin thickening | Left abdomen | NR | At the time of diagnosis | Left lower extremity edema, suprapubic and external genital edema |
Ghalleb et al. (2019) [26] | 1 | Urothelial carcinoma of the bladder and renal pelvis | No | Left ureter, lung | Left hypochondriac, cervical, and back regions | Cutaneous masses | Left hypochondriac lesion | NR | 1 year after diagnosis of bladder carcinoma | NR |
Garg et al. (2018) [17] | 1 | Adenocarcinoma of the bladder | NR | Multiple rounded cannon ball opacities in the lung | Neck, axilla, and scapula | Multiple rounded firm swellings with soft, cystic, non-tender erythematous swelling, with overlying superficial skin necrosis. | NR | NR | 3 months before diagnosis | NR |
Cohen et al. (2017) [16] | 1 | High-grade urothelial cell carcinoma with submucosal invasion | No | No | Right inguinal region and scrotum | Nodular, fibrotic, and hemorrhagic nodules | NR | Large anaplastic cells | 9 months after diagnosis | Altered mental status |
Kerkeni et al. (2017) [34] | 1 | Non-metastatic muscle-invasive transitional cell bladder carcinoma | 2 lymph nodes | Liver mets and peritoneal carcinosis | NR | Multiple disseminated pigmented and flat skin lesions with subcutaneous nodules | Chest lesion | Poorly differentiated metastatic carcinoma | 4 months after surgery | NR |
Filho et al. (2016) [50] | 1 | High-grade urothelial carcinoma with invasion of the muscle | NR | Multiple peritoneal nodules of irregular outline and heterogeneous enhancement | Infra-umbilical, midline, and suprapubic region | Infra-umbilical scar, erythematous-purpuric plaque, infiltrated, fistula with urine drainage at midline, infra-umbilical region and 2 erythematous, wine-colored nodules at midline, suprapubic region | Midline scar nodule | Atypical epithelioid and pleomorphic cells with numerous mitoses and areas of necrosis | 1 month after diagnosis | Abdominal distention and pain |
Lees (2015) [18] | 1 | High-grade transitional cell carcinoma of the bladder | No | Osteoblastic metastases in the bony pelvis | Left anterior thigh | Maculo-nodular rash | Thigh lesions | Poorly differentiated non-small-cell carcinoma | 8 years after diagnosis | NR |
Giunchi et al. (2017) [5] | 1 | Urothelial carcinoma of the bladder | No | NR | Penis foreskin and glans | Condyloma acuminata, several brownish warty fragments on normal foreskin | Penis | Superficially spreading lesion composed of papillae with fibro-vascular cores. Neoplastic cells with wide cytoplasms, round nuclei, and prominent nucleoli. Squamous-like, nuclear atypias and micro-infiltrative areas | 7 months after diagnosis | NR |
1 | High-grade urothelial carcinoma of the bladder, prostatic urethra, and membranous urethra | Abdominal lymph nodes | Multiple repetitive hepatic lesion 11 years after diagnosis | Penis glans | Reddish skin lesion | Penis | High-grade papillary urothelial carcinoma with infiltration of corpus spongiosum, large pale cells arranged in small nests above the basal layer with cleft-like separation between neoplastic cells and normal epidermal keratinocytes in the glans | 10 years after diagnosis | NR | |
Yang et al. (2015) [42] | 1 | Urachal adenocarcinoma of the bladder with enteric-type differentiation, mucinous adenocarcinoma, and ring cell carcinoma | NR | NR | Penis and scrotum | 2 cm diameter mass, 10 cm erysipeloid-like mass | Penis | Original and metastatic urachal tumor, well-differentiated mucinous adenocarcinoma, signet ring cells | 2 months after diagnosis | NR |
Schmiedecke et al. (2014) [23] | 1 | Transitional cell carcinoma of the bladder | Inguinal node | NR | Adjacent to RLQ ileostomy site | Nodular-appearing erythematous plaque | Ileostomy site | Cohesive nests of malignant cells in dermoplastic stroma | 10 years after diagnosis | NR |
Agarwal et al. (2014) [19] | 1 | Transitional cell carcinoma of the bladder | Peritoneal nodules, posterior abdominal wall, gluteal region, bilateral axillary, pelvic, and inguinal | Large liver mass, multiple right adrenal masses | Flank mass | Mass | Flank mass | Undifferentiated carcinoma with clear cell features | At the time of diagnosis | Fatigue, chronic renal insufficiency, balanitis |
Salmanpoor et al. (2013) [56] | 1 | Urothelial carcinoma | NR | NR | Back and posterior neck | Extensive rapidly growing, indurated, firm violaceous erythematous tumor with ill-defined borders and woody induration | Back skin | Oval- to spindle-shaped nuclei, conspicuous nucleoli, ill-defined cell borders with mitotic figures | At the time of diagnosis | Free fluid in the peritoneal cavity, thickening of the wall of the fundus and body of the stomach |
Chang et al. (2013) [48] | 1 | High-grade urothelial carcinoma | Para-aortic lymph node enlargement | Pulmonary mass and peribronchial lesions | Left flank area and suprapubic area, then on suprapubic area, chest, and abdomen | Palm-sized erythematous plaques, extensive painful erythematous plaques with an erysipelas-like appearance | Left chest and suprapubic area | Tumor nests in lymphatics with outgrowth into the surrounding dermis, with pleomorphic and hyperchromatic nuclei | 1 month after diagnosis | NR |
Chung et al. (2013) [49] | 1 | Urothelial carcinoma | Bilateral inguinal lymph nodes, both iliac chain lymph nodes | Lungs, brain | Abdominal skin | Multiple erythematic nodular lesions | Abdominal skin | Metastatic urothelial carcinoma | 8 years after diagnosis | Severe dyspnea, dizziness |
Yoshida et al. (2012) [40] | 1 | High-grade urothelial carcinoma with glandular differentiation | Pelvic lymph nodes | Ureter | Around the soma | Painless skin erosion | Skin lesion | Malignant cells suspected of being urothelial carcinoma | 4 years and a half after diagnosis | NR |
Manzelli et al. (2011) [37] | 1 | Sarcomatoid carcinoma invading bladder musculature | Loco-regional node enlargement | Lungs | Right chest wall | Hypodermic nodular lesion | Right chest wall | Epithelial-type cells with nuclear atypias, poorly differentiated neoplastic infiltration with morphologic aspects of urothelial tissue | At the time of diagnosis | NR |
Blalock et al. (2011) [14] | 1 | Minimally invasive TCC | Lymphovascular invasion, inguinal and femoral lymphadenopathy | NR | Left lower abdomen | Firm pink plaque with "frog spawn", with small peripheral papules extending from the edge of the larger plaque | Abdomen | Full-thickness malignant epithelial neoplasm with nests of tumor cells involving the dermis and invading the epidermis | 1 year and a half after diagnosis | NR |
Salemis et al. (2011) [20] | 1 | High-grade TCC | NR | NR | Left lower abdomen | Hard non-tender palpable nodule | Abdomen | Extensive infiltration from high-grade transitional cell bladder carcinoma | 1 year and 2 months after diagnosis | NR |
Swick et al. (2010) [29] | 1 | Superficially invasive TCC | Periaortic and pelvic lymphadenopathy | No | Mid-upper back, left mid-back, lower thoracic spine | The asymptomatic lesion which began as a small flesh-colored nodule became violaceous | Larger nodule | Proliferation of atypical cells infiltrating in nests and cords, collagen bundles through the mid and deep-reticular dermis, no involvement of overlying epidermis, individual cells with abundant cytoplasm and hyperchromatic atypical nuclei with frequent mitoses | 3 months after diagnosis | Acute-onset diplopia, persistent headaches |
Sgambato et al. (2009) [53] | 1 | Bladder adenocarcinoma | NR | NR | Scalp and back | Red firm nodular lesions | Scalp | Epidermotropic tumor cells appear singly and in a cluster as polygonal, large, refractile structures embedded in the epidermis, at the dermal level, tumor nests composed of large, mildly refractile, polymorphic cells arranged in a "palisading" array around a luminal area filled with hyporefractile material. | 7 years after diagnosis | NR |
Atmaca et al. (2007) [46] | 1 | Superficial TCC | NR | Skeletal | Trunk and upper extremities | Multiple subcutaneous nodules | Nodules | TCC metastasis | 3 months after diagnosis | NR |
Zwenzner et al. (2006) [38] | 1 | TCC | Pelvic lymphadenopathy | NR | Neck | Fast-growing poorly demarcated erythematous induration | Neck | Multiple nests of urothelial cells, with cytologic atypia | 3 years after diagnosis | NR |
Kumar et al. (2006) [6] | 1 | Muscle invasive grade II TCC | Pelvic lymphadenopathy | NR | Right arm | Nodular swelling, slightly reddish, smooth-surfaced nodule with central crusting | Arm | Metastatic carcinoma from the bladder | After many cycles of chemotherapy | NR |
1 | Renal cell carcinoma | NR | NR | Left postauricular area | Swelling and purple, smooth-surfaced non-tender nodule | Postauricular area | Metastatic carcinoma from kidney | 4 months before diagnosis | Abdominal pain | |
Pomara et al. (2004) [36] | 1 | TCC | Enlarged pelvic lymph nodes | Upper right pulmonary lobe | Penis glans | Ulcerative swelling, fungating lesion with seropurulent discharge, partially ulcerated, erythematous, and slightly itchy | Glans | Urothelial carcinoma | 8 years after diagnosis | NR |
Gowardhan et al. (2004) [21] | 1 | Extensive muscle-invasive bladder TCC | No | No | Left iliac fossa | Skin nodule | Nodule | Extensive infiltration of the dermis and subcutis by high-grade urothelial carcinoma | 3 months after diagnosis | NR |
Akman et al. (2003) [47] | 1 | Poorly differentiated carcinoma | NR | Liver | Trunk | Multiple, rubbery subcutaneous nodules | Trunk | Metastasis of TCC | 3 months after diagnosis | NR |
Somani et al. (2006) [52] | 1 | Poorly differentiated, muscle-invasive TCC with carcinoma in situ | NR | NR | Left side of neck and chest | Herpetiform-like, multiple reddish nodules | Lesions | Metastatic carcinoma similar to TCC of the bladder | 6 weeks after diagnosis | NR |
Miyamoto et al. (2000) [27] | 1 | Poorly differentiated grade III TCC | No | NR | Penis | Pseudophimosis, a reddish oval tumor on corona glandis, well-demarcated erythema with slight erosion on preputium and glans | Penis | Nest of atypical malignant cells on the surface | 3 years after diagnosis | NR |
Kumar et al. (2000) [54] | 1 | Grade IV TCC | Enlarged para-aortic lymph nodes | NR | Right lumbar paraspinal region | Subcutaneous mass, painful, soft, and nonmobile | Paraspinal | Isolated and clusters of malignant cells, different sizes and shapes, high nuclear/cytoplasmic ratios, hyperchromatic nuclei with prominent nucleoli and abundant, deep, basophilic cytoplasm, plus frequent multinucleated tumor giant cells. Clusters of different sizes and shapes, irregular and papillary in configuration | 6 months after diagnosis | NR |
Saito (1998) [28] | 1 | Grade II TCC | No | NR | Scrotum | Solitary subcutaneous induration, firm, moderately tender | Left testis | TCC metastasis | 1 year and a half after diagnosis | NR |
Stolla et al. (1994) [25] | 1 | NR | 4th and 7th nodes | Liver | Celioscopy puncture scars | NR | Scar | Permeation nodules of a poorly differentiated carcinoma | 9 months after diagnosis | NR |
Roos and Wigg (1993) [24] | 1 | Grade II TCC | Left supraclavicular lymphadenopathy | NR | Left shoulder | Diffuse nodular, violaceous tumor with well-demarcated borders, with C6 neuralgia | Left shoulder | Metastasis of TCC | 1 year after diagnosis | Anorexia, weight loss |
Fujita et al.(1994) [7] | 1 | TCC | Cervical and para-aortic lymphadenopathy | NR | Thighs and lower abdomen | Erysipeloid skin rash | Thigh and cheek | Metastatic TCC | 3 months after diagnosis | NR |
1 | Grade III TCC | Para-aortic lymph nodes enlargement, Virchow nodes, retroperitoneal parapancreatic, mediastinal | Pleura of lungs, liver, bones, GI tract | Thighs and lower abdomen | Erythematous skin eruptions | Thigh | Metastatic TCC | 2 months after diagnosis | NR | |
Rebelakos et al. (1989) [8] | 2 | TCC | NR | NR | Left mid sternum | Painful nodule | Sternum | TCC metastasis | 2 months after diagnosis | NR |
Wyldes and Osborn (1988) [41] | 1 | Solid, poorly differentiated TCC | NR | NR | Right forearm | Painful swelling, firm, moderately tender, not fluctuant, with raised well-demarcated edge, surrounding skin indurated with marked erythema | Forearm | Small group of malignant cells having the appearance of original bladder tumor | 3 months after diagnosis | NR |
Takematsu et al. (1984) [39] | 1 | Adenocarcinoma of the bladder | NR | Lower GI, pelvic wall, liver and spleen | Right inguinal region to the middle right thigh | Papillomatous nodule, with cauliflower-like proliferation with a large quantity of foul-smelling exudate | Nodule | Well-differentiated adenocarcinoma | At the time of diagnosis | NR |
Bachrach and Dahlen (1973) [9] | 1 | Poorly differentiated TCC | NR | Brain, penis | Neck and abdominal wall | Ulcerated lesions | Subcutaneous skin nodule | Anaplastic poorly differentiated metastatic carcinoma with areas of necrosis | At the time of diagnosis | Personality change, priapism, weight loss, left hemiparesis |
1 | Bladder carcinoma | NR | Scalp, lungs, and retina | The right shaft of the penis | Non-tender area of induration | Penis | Fibro-vascular tissue infiltrated by nests of malignant tumor cells consistent with metastatic carcinoma | 2 months after diagnosis | NR | |
Higgins and Hausfeld (1948) [10] | 1 | Highly undifferentiated infiltrating carcinoma | Virchow nodes | NR | End of cystectomy incision, right biceps, left supraclavicular space, under right rib margin | Small lump, firm subcutaneous nodule, freely movable and slightly tender | NR | NR | 2 years after diagnosis | NR |
1 | TCC | Cervical lymphadenopathy | Liver, lungs, posterior peritoneum | Above left iliac crest, left posterior cervical region, abdomen, lower thorax. Left upper extremity | Pitting edema, hard superficial, adherent nodule | NR | Smooth surface, grayish-white color | At the time of diagnosis | Right groin pain, nausea, vomiting | |
Bischoff and Fishkin (1956) [12] | 1 | TCC | Iliac lymphadenopathy | Pericardium | Head, neck, arms, and chest | Subcutaneous nodules, hard, painless, movable with orange peel surface | Right chest wall | Infiltrating nests and cords of transitional epithelial cells (metastatic TCC) | 1 year after diagnosis | Dyspnea, ankle edema |
1 | Grade III TCC with adenocarcinoma features | Bone, liver, adrenals, small bowel, mesentery, lungs | Left deltoid and posterior axillary line over 7th rib | Elevated, dusky red, firm, tender, fixed nodule in subcutaneous tissue | Nodules | Loose cords of polyhedral tumor cells interspersed in a delicate fibrous stroma, containing many inflammatory cells, with finely granular cytoplasm | 3 years after diagnosis | Weight loss | ||
1 | TCC | NR | Pericardium, adrenals, pancreas, cerebellar hemisphere | Left arm, cystotomy scar, right axilla, left axilla, chest, abdomen, shoulders, thighs | Small lump, many nodules | Nodules | Undifferentiated carcinoma with clear cell features | At the time of diagnosis | Abdominal, left flank pain, pitting edema | |
1 | TCC | NR | NR | Mid-epigastrium | Ulcerative lesion | Lesion | Neoplastic involvement of all layers except the epidermis, cells polyhedral shape, containing vesicular nuclear patterns with prominent nucleoli, fibrovascular cores containing polymorphonuclear leukocytes. (metastatic TCC) | A few months after diagnosis | Weight loss, hypertension, left cornea opacification, left indirect inguinal hernia, bilateral spermatoceles, BPH | |
Wormer et al. (1956) [15] | 1 | Undifferentiated carcinoma | NR | NR | Left cheek, left periorbital tissues | Small red spot enlarging progressively and painlessly | Cheek | Undifferentiated carcinoma | 1 year before diagnosis | NR |
Hamer and Nourse (1951) [31] | 1 | Grade III undifferentiated infiltrating carcinoma | NR | Prostate, seminal vesicles | Lateral to ureterostomy incision | Subcutaneous nodules | Nodule | Metastatic carcinoma | 1 month after diagnosis | Weight loss |
McCrea (1949) [11] | 1 | Grade III papillary carcinoma | NR | Lung | Back and shoulders | Several painful nodules | Nodule | Cores and islands of relatively anaplastic cells embedded in hyalinized stroma, pseudo-acinar formation (urinary bladder primary carcinoma) | At the time of diagnosis | NR |
1 | Grade III papillary carcinoma | Inguinal lymph nodes | Right ileum, lung, adrenals | Abdomen | Nodule | Abdomen | Streaks of atypical epithelial cells with large nuclei and vacuolated cytoplasm, very numerous mitotic figures (metastatic carcinoma) | At the time of diagnosis | NR | |
Chin et al. (2011) [30] | 1 | Myeloid sarcoma | Pelvic and inguinal lymphadenopathy | No | Suprapubic region | Hyperemic skin | Suprapubic region | Myeloid sarcoma | At the time of diagnosis | Abdominal pain |
Presentation of cutaneous lesions: The most common site for cutaneous lesions was the abdomen (n=15) followed by the chest (n=12). Cutaneous metastasis on the upper extremities including the shoulders and axillae was present in 18.6% of patients (n=11) and on the back was found in 18.6% of patients (n=11). Neck cutaneous metastasis and inguinal region (including penis and scrotum) were present in 10 patients each. Less common sites of cutaneous spread were the pelvis (n=9), thigh (n=6), and head (scalp or face) (n=4). The site of cutaneous metastasis was not mentioned in only one report. It is noteworthy that lesions arose in areas of previous procedures in many reports: adjacent to ileostomy site [22], celioscopy puncture scars [24], cystectomy incision [9], cystotomy scar [11], lateral to ureterostomy scar [30]. The skin findings in the different reported cases were heterogeneous, but the most recurrent finding in most of the described cases was a nodular component. In some reports, the nodule was painful [7,10]; but in most of them, the nodule was painless [11,19,31]. In many cases, it was accompanied by another finding [32,33]. Moreover, in some cases, the cutaneous metastasis appeared simply as an erythematous flat lesion with no additional characteristics [4,6,14]. Ulceration was seen in some cases [8,34,35].
Cutaneous biopsy: In addition to the above-mentioned macroscopic descriptions, biopsies were performed and showed a wide variety of findings. As expected, nuclear and cellular atypias [36,37], as well as abundant mitoses, were frequently described [5-10]. The urothelial cells were well differentiated in some reports [38] and undifferentiated in others [8-14]. The different layers of the skin, epidermis, dermis, and subcutaneous tissue, were also invaded to variable degrees; in fact, the epidermis was spared in some cases [20,28] and invaded in others [13].
Date of skin manifestations: Out of the 59 patients with bladder cancer, 72.8% had the skin manifestation occurring after the bladder cancer diagnosis (n=43) by months or even years (up to 10 years in two case reports). Interestingly, in 6.7% of the patients (n=4), the skin lesion appeared before the bladder cancer diagnosis, and in the remaining 24.4%, the cutaneous manifestation was identified at the same time as the bladder cancer diagnosis (n=12). The earliest skin lesion identification was made one year before the bladder malignancy diagnosis [14]. Among the non-cutaneous associated symptoms, some of the most mentioned complaints were edema of the lower extremities and genital area (n=4), abdominal distention or pain (n=4), and weight loss (n=5).
Treatment and Prognosis
Treatment of cutaneous lesions: In some cases, the same treatment strategy used to treat urinary tract cancer was aimed at improving skin manifestations too. In other cases, different treatment modalities were added to address the skin lesions. In about 38% of the cases (n=23), the original article did not mention the treatment strategy used for the cutaneous lesions. In another 10% (n=6), no treatment was used for skin manifestations and it was mentioned that in one of these cases, the treatment modality was proposed to the patient but declined. Chemotherapy alone was used in the treatment of skin lesions in 16.9% of the cases (n=10), with some of the mentioned regimens being pembrolizumab (n=2), gemcitabine with cisplatin (n=1), gemcitabine with carboplatin (n=2), vinblastine (n=1), bleomycin ointment (n=1), and methotrexate (n=1). About 15% of cases (n=9) had treatment with radiotherapy with a special mention to Roentgen therapy in one report. Surgery for the organ with affected skin occurred in 8% of the cases (n=5) with resection of the glands in one case and resection of the penis, scrotum, and groin skin in another. A combination of chemotherapy and radiotherapy was used in two cases, resection and chemotherapy together were used in one case, and a combination of radiation and resection was also used in only one case. In addition, one article mentioned using electrotherapy and one article only went for supportive treatment of the skin (Table 3).
Table 3. Treatment and Prognosis Data From Individual Studies.
NR: not recorded; TCC: transitional cell carcinoma; TURBT: transurethral resection of bladder tumor.
Study (year) | Total number of patients | Type of bladder cancer | Treatment of cutaneous lesion | Treatment of bladder cancer | |
Mathew et al. (2021) [32] | 1 | Urothelial carcinoma | NR | Palliative chemotherapy (cisplatin-based) | |
Yajima et al. (2021) [13] | 1 | Invasive high-grade urothelial carcinoma | Chemotherapy (pembrolizumab) | Transurethral resection of tumor and adjuvant chemotherapy (cisplatin and gemcitabine) | |
Endo et al. (2021) [22] | 1 | Renal pelvic urothelial carcinoma UC | NR | NR | |
Elumalai et al. (2020) [35] | 1 | Metastatic bladder carcinoma | NR | Transurethral resection of the tumor, radiotherapy of the pelvis, and chemotherapy | |
Feldmann et al. (2020) [55] | 1 | Transitional cell carcinoma of the bladder | Pembrolizumab | Transurethral resection of tumor, chemotherapy (gemcitabine and cisplatin) | |
Hasan et al. (2020) [33] | 1 | Uroepithelial carcinoma of the bladder | NR | TURBT with palliative chemotherapy (cisplatin and gemcitabine) | |
Ghalleb et al. (2019) [26] | 1 | Urothelial carcinoma of the bladder and renal pelvis | NR | TURBT with palliative chemotherapy (cisplatin and gemcitabine) | |
Garg et al. (2018) [17] | 1 | Adenocarcinoma of bladder | None | Bilateral percutaneous nephrostomy tubes and hemodialysis | |
Cohen et al. (2017) [16] | 1 | High-grade urothelial cell carcinoma with submucosal invasion | None | Multiple TURBTs and BCG immunotherapy | |
Kerkeni et al. (2017) [34] | 1 | Non-metastatic muscle-invasive transitional cell bladder carcinoma | NR | Cysto-prostatectomy with chemotherapy (cisplatin-based adjuvant) | |
Filho et al. (2016) [50] | 1 | High-grade urothelial carcinoma with invasion of the muscle | NR | TURBT with palliative chemotherapy (cisplatin and gemcitabine) | |
Lees (2015) [18] | 1 | High-grade transitional cell carcinoma of the bladder | Palliative radiation of left thigh lesions | Cystectomy and ileostomy | |
Giunchi et al. (2017) [5] | 1 | Urothelial carcinoma of the bladder | NR | NR | |
1 | High-grade urothelial carcinoma of the bladder, prostatic urethra, and membranous urethra | Complete resection of glans | Radical cystectomy | ||
Yang et al. (2015) [42] | 1 | Urachal adenocarcinoma of the bladder with enteric-type differentiation, mucinous adenocarcinoma, and ring cell carcinoma | Total resection of penis, scrotum, and groin skin | Partial cystectomy | |
Schmiedecke et al. (2014) [23] | 1 | Transitional cell carcinoma of the bladder | Declined | NR | |
Agarwal et al. (2014) [19] | 1 | Transitional cell carcinoma of the bladder | NR | TURBT, chemotherapy (gemcitabine, cisplatin, carboplatin) | |
Salmanpoor et al. (2013) [56] | 1 | Urothelial carcinoma | NR | NR | |
Chang et al. (2013) [48] | 1 | High-grade urothelial carcinoma | Chemotherapy | Chemotherapy | |
Chung et al. (2013) [49] | 1 | Urothelial carcinoma | NR | Cystectomy with ileal conduit, chemotherapy (gemcitabine and cisplatin) | |
Yoshida et al. (2012) [40] | 1 | High-grade urothelial carcinoma with glandular differentiation | Chemotherapy (gemcitabine and cisplatin) | Cystectomy | |
Manzelli et al. (2011) [37] | 1 | Sarcomatoid carcinoma invading bladder musculature | Surgical resection | TURBT, chemotherapy (gemcitabine, cisplatin, carboplatin, and paclitaxel) | |
Blalock et al. (2011) [14] | 1 | Minimally invasive TCC | Chemotherapy (carboplatin and gemcitabine) | TURBT, BCG treatment | |
Salemis et al. (2011) [20] | 1 | High-grade TCC | Supportive treatment | Radical cystectomy and bilateral ureterostomy | |
Swick et al. (2009) [22] | 1 | Superficially invasive TCC | NR | TURBT with BCG | |
Sgambato et al. (2009) [53] | 1 | Bladder adenocarcinoma | NR | Surgery and local chemotherapy | |
Atmaca et al. (2007) [46] | 1 | Superficial TCC | Chemotherapy | TRUBT and intravesical mitomycin | |
Zwenzner et al. (2006) [38] | 1 | TCC | None | Cystoprostatovesiculectomy and chemotherapy (gemcitabine, cisplatin, paclitaxel, and carboplatin) | |
Kumar et al. (2006) [54] | 1 | Muscle-invasive grade II TCC | None | Chemotherapy (gemcitabine and cisplatin) | |
1 | Renal cell carcinoma | Chemotherapy (vinblastine) | Chemotherapy (vinblastine) | ||
Pomara et al. (2004) [36] | 1 | TCC | Combination chemotherapy (gemcitabine) and radiotherapy | Nephro-ureterectomy | |
Gowardhan et al. (2004) [21] | 1 | Extensive muscle-invasive bladder TCC | Oral methotrexate | TURBT, radical cystoprostatourethrectomy, and radiotherapy | |
Akman et al. (2002) [47] | 1 | Poorly differentiated carcinoma | Chemotherapy (gemcitabine and carboplatin) | TURBT, chemotherapy (gemcitabine and carboplatin) | |
Somani et al. (2006) [52] | 1 | Poorly differentiated muscle-invasive TCC with carcinoma in situ | Radiotherapy | TURBT, palliative radiotherapy | |
Miyamoto et al. (2000) [27] | 1 | Poorly differentiated grade III TCC | 5-fluorouracil and corticosteroid ointment then resection | Chemotherapy (cisplatin and doxorubicin) | |
Kumar et al. (2000) [6] | 1 | Grade IV TCC | None | Radiotherapy and chemotherapy | |
Saito (1998) [28] | 1 | Grade II TCC | Resection, chemotherapy (MVAC) | TURBT, bladder infiltration with BCG | |
Stolla et al. (1994) [25] | 1 | NR | Electrotherapy | Endourethral resection, chemotherapy (MVAC), radiochemotherapy, with 5-fluorouracil and cis-platinum | |
Roos et al. (1993) [24] | 1 | Grade II TCC | Palliative chemotherapy, radiotherapy | Radiotherapy | |
Fujita et al.(1994) [7] | 1 | TCC | Radiotherapy | TURBT, tegafur | |
1 | Grade III TCC | Ointment (bleomycin) | TURBT, radical cystectomy, nephro-urectomy, chemotherapy (cis-platinum, doxorubicin, cyclophosphamide), radiotherapy | ||
Rebelakos et al. (1989) [8] | 2 | TCC | Radiotherapy with excision (n=1) | NR | |
Radiotherapy without excision | NR | ||||
Wyldes and Osborn (1988) [41] | 1 | Solid, poorly differentiated TCC | Radiotherapy | Pelvic radiotherapy | |
Takematsu et al. (1984) [39] | 1 | Adenocarcinoma of bladder | NR | Chemotherapy (doxorubicin and fluorouracil) | |
Bachrach and Dahlen (1973) [9] | 1 | Poorly differentiated TCC | NR | NR | |
1 | Bladder carcinoma | Radiotherapy | Ileal conduit, radiotherapy | ||
Higgins and Hausfeld (1950) [10] | 1 | Highly undifferentiated infiltrating carcinoma | Radiotherapy | Bilateral ureterosigmoidostomy, cystectomy | |
1 | TCC | NR | TURBT, radiotherapy | ||
Bischoff and Fishkin [12] | 1 | TCC | NR | NR | |
1 | Grade III TCC with adenocarcinoma features | NR | NR | ||
1 | TCC | Roentgen therapy | Transvesical fulguration | ||
1 | TCC | NR | Segmental resection | ||
Wormer et al. (1956) [15] | 1 | Undifferentiated carcinoma | Radiotherapy | TURBT, radiotherapy | |
Hamer and Nourse (1953) [31] | 1 | Grade III undifferentiated infiltrating carcinoma | NR | Cystectomy | |
McCrea (1949) [11] | 1 | Grade III papillary carcinoma | NR | Radiotherapy, fulguration | |
1 | Grade III papillary carcinoma | NR | NR | ||
Chin et al. (2011) [30] | 1 | Myeloid sarcoma | NR | TURBT, palliative chemotherapy (Ara C and Myclotarg) |
Treatment of bladder cancer: As for the treatment of primary urinary tract cancer, it was not mentioned for 16.9% of the cases (n=10). The most common strategy was a combination of surgery and chemotherapy in 23% of the cases (n=14) with cisplatin and gemcitabine being frequently used. Surgery alone was used in 18% of the cases (n=11), chemotherapy alone was used in 10% of the cases (n=6), and radiotherapy alone was used in 3% of the cases (n=2). Note that cystectomy was frequently performed (n=7) and other surgical approaches included transvesical fulguration, nephroureterectomy, segmental resection, and bilateral percutaneous nephrostomy tube placement with subsequent hemodialysis. As for chemotherapy modalities, these included cisplatin, cisplatin+gemcitabine, cisplatin+doxorubicin, vinblastine, and doxorubicin+fluorouracil.
In addition, a combination of radiotherapy and surgery was seen in 10% of the cases, whereas a combination of radiotherapy, surgery, and chemotherapy was seen in 5% of the cases (n=3). Radiotherapy and chemotherapy together were used in only one case. Finally, it is worth mentioning that surgery with BCG injection was the treatment modality used in 8% of the cases (n=5).
Prognosis: Death was the most reported outcome, seen in 33 patients, which is 55.9% of the cases. The date of death was reported heterogeneously in articles with some announcing the date of death from the biopsy date, while others from the cutaneous manifestation date and so on. However, most of the 33 patients survived only for a few months. No information about prognosis was found in 23% of cases (n=14). For the rest of the patients, remarkably, a good prognosis was mentioned in one case [14], and disease-free progression was seen at three months in one case [39], at four months in another [40], at seven months [41], two years [4], 15 months [27], four years [26], and 23 years [20].
Discussion
Skin cancer is the sixth most prevalent cancer in women and the fifth most common cancer in men [42]. The most common primary tumors of skin metastasis are breast cancer (69%) and lung carcinoma (24%), in women and men, respectively [43]. Colorectal carcinoma is the second most common primary malignancy sending skin metastasis in men and women [43]. Metastases from urologic tumors are rare, occurring in around 1% of individuals with advanced illness [41-43]. Lymph nodes, bones, and lungs are the most common organs with urologic metastasis [44,45]. The first cutaneous tumor originating from transitional cell carcinoma of the bladder was reported in 1909 [16].
There are four mechanisms by which visceral tumors can metastasize to the skin: direct invasion, iatrogenic, lymphatics, or hematologic [45-47]. Cutaneous metastasis from urologic conditions may clinically look similar to other prevalent dermatologic conditions that affect people with advanced malignancies. Thus, a skin biopsy and an index of suspicion are needed for a conclusive diagnosis [43].
Punch biopsy from the cutaneous lesions showed an increased mitotic activity with malignant cells in the dermis rather than the epidermis [48-51]. These lesions appear as rapidly growing solitary or multiple flesh-colored lesions, with a necrotic or ulcerated aspect and with erythematous surrounding skin [28,50,52,53]. These findings were similar to the reported data in our text. Primary tumors of the metastatic lesion can be identified histologically. Renal cell carcinoma appears as a pulsatile solitary red nodule [43].
The differential diagnosis is wide, especially for patients taking systemic treatment for bladder cancer. Therefore, the lesions might appear as a possible cutaneous drug reaction or an infected lesion from an opportunistic infection. The differential diagnosis might also include hemangiomas, keratoacanthomas, cysts, pyogenic granuloma, dermatofibroma, pyoderma, and morphea-like lesions herpes zoster and erysipelas [46-48,52,54,55-57].
Conclusions
The most common metastasis of urogenital cancer occurs in the liver, lungs, and bones. Among the various urogenital cancers, bladder cancer is the most common and is the fourth most common malignancy in males and the tenth in females. Cutaneous metastasis of bladder cancer is extremely rare with an incidence of less than 1%. The disease occurs via direct tumor invasion, hematogenous lymphatic spread, or direct seeding due to an iatrogenic implantation.
This paper provides a deeper understanding of the characteristics of bladder cancer spread and would help physicians in their diagnosis and management. Further randomized cohort study assessing the spread of malignancy is now warranted.
Acknowledgments
Mohamad Al Mokdad contributed in the early submission of this manuscript. Lea Daou contributed to the Data Collection.
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:
Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.
Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Author Contributions
Concept and design: Nagham Bazzi, Sally Al Hassan, Sadek Jaber, Wajih A. Saad, Ali Alhousseini
Acquisition, analysis, or interpretation of data: Nagham Bazzi, Samer Dbouk, Wajih A. Saad
Drafting of the manuscript: Nagham Bazzi
Critical review of the manuscript for important intellectual content: Nagham Bazzi, Sally Al Hassan, Sadek Jaber, Samer Dbouk, Wajih A. Saad, Ali Alhousseini
Supervision: Nagham Bazzi, Samer Dbouk
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