Scrotal Cancer Research Articles

Abstract Despite what childhood films suggest, the life of a chimney sweep was not one of glamour and dance routines. Rising to prominence in the aftermath of the Great Fire of London in 1666, when the clearing chimneys of soot became obligatory, young boys from poor families composed much of the workforce needed to fit into the narrow flues most homes had. Doing a predictably dirty job, chimney sweeps often worked naked to ease their manoeuvring into the flue. It was arduous work and, as bathing was rare, sweeps left soot to sit on their skin. Through this, an occupational disease would arise in later life that caused untold suffering, and it took the wisdom of the brilliant Percival Pott to recognize it. Throughout the 17th to 19th centuries, chimney sweeps presented to doctors with lesions of the scrotal skin. A diagnosis of venereal disease was often made, yet these spots and sores did not behave like those expected from sexually transmitted disease. In many cases they progressed to destructive tumours that engulfed the underlying testicle, metastasizing and inevitably killing the patient. Such was the pain that late-stage disease caused, there were reports of self-mutilation in attempts to cut off the affected area. Once it spread to the lymphatics, death was a certainty. Percival Pott was a brilliant 18th century surgeon famed for the discovery of the eponymous Pott’s disease. While investigating an outbreak of scrotal tumours in chimney sweeps he came to the realization that soot trapped within the rugae of the scrotal skin was the causative agent in the development of this disease. Being a child of impoverished surroundings, Pott was famed for the care he provided his patients, and dedication to helping those in poverty. On chimney sweep’s carcinoma he wrote: ‘The fate of these people seems singularly hard…they are thrust up narrow and sometimes hot chimneys, where they are buried, burned and almost suffocated; and when they get to puberty become liable to a most noisome, painful and fatal disease’ (Waldron HA. A brief history of scrotal cancer. Br J Ind Med 1983; 40: 390–401). Pott’s work helped encourage the introduction of legislation, the Chimney Sweepers Act 1788 and its subsequent revisions, to improve the conditions of chimney sweeps. While adherence in England was poor, other nations introduced uniforms to protect sweeps’ skin from the damaging residues. It was not until the 1900s that the carcinogenic mechanisms of chimney soot were elucidated, proving Pott’s hypothesis correct (Dronsfield A. Percival Pott, chimney sweeps and cancer. Education in Chemistry 2006; 40–2).

Squamous cell carcinoma (SCC) is the most common malignant tumour of the penis. The 2022 WHO classification reinforces the 2016 classification and subclassifies precursor lesions and tumours into human papillomavirus (HPV)-associated and HPV-independent types. HPV-associated penile intraepithelial neoplasia (PeIN) is a precursor lesion of invasive HPV- associated SCC, whereas differentiated PeIN is a precursor lesion of HPV-independent SCC. Block-type positivity of p16 immunohistochemistry is the most practical daily utilised method to separate HPVassociated from HPVindependent penile SCC. If this is not feasible, the term SCC, not otherwise specified (NOS) is appropriate. Certain histologies that were previously classified as"subtypes" are now grouped, and coalesced as "patterns", under the rubric of usual type SCC and verrucous carcinoma (e.g. usual-type SCC includes pseudohyperplastic and acantholytic/pseudoglandular carcinoma, and carcinoma cuniculatum is included as a pattern of verrucous carcinoma). If there is an additional component of the usual type of invasive SCC (formerly termed hybrid histology), the tumour would be a mixed carcinoma (e.g. carcinoma cuniculatum or verrucous carcinoma with usual invasive SCC); in such cases, reporting of the relative percentages in mixed tumours may be useful. The consistent use of uniform nomenclature and reporting of percentages will inform the refinement of future reporting classification schemes and guidelines/recommendations. The classification of scrotal tumours is provided for the first time in the fifth edition of the WHO Blue book, and it follows the schema of penile cancer classification for both precursor lesions and the common SCC of the scrotum. Basal cell carcinoma of the scrotum may have a variable clinical course and finds a separate mention.

Scrotal cancer, chimney sweepers and Sir Percival Pott

The epidemiology of scrotal cancer has changed over time away from occupational exposure to soot. The current incidence of scrotal malignancy is approximately 1 per 1 million males per year. This review summarises the current literature on the management of scrotal squamous cell carcinoma (SCC), including pathogenesis, available diagnostic tools, current treatment, and overall management strategies. The rarity of SSC cases makes it difficult to recruit patients for studies of this disease. To date, very few studies have been performed, and those that have been completed were limited by a small sample size. This review analyses all available evidence, which varies from retrospective case series to prospective multicentre trials. Psoralen ultraviolet light A treatment and human papillomavirus infection are significant risk factors for this cancer. Scrotal SCC had lower survival rates compared with other histological subtypes and the 5-year relative survival rate was 77%. Many studies also showed a positive margin, even after wide excision of the lesion. Excision of the primary lesion and a risk-stratified approach for staging and treatment of regional lymph nodes is the mainstay of current management strategies. For patients with clinically negative lymph nodes, sentinel lymph node biopsy and PET scans for patients with suspected pelvic node involvement has improved the diagnostic yield. The new neoadjuvant therapy (both chemotherapy and radiotherapy) has helped to downstage the disease for complete resection. The prognosis of scrotal SCC is determined by margin-free excision, depth of infiltration, and its histologic grade. Future trials focussing on the conjunction of SCC with penile cancer, as well as the creation of a multinational network for ‘virtual’ online multidisciplinary meetings, will help to improve the overall survival for scrotal SCC patients.

Population (epidemiological) and laboratory studies have led to the discovery of many potential environmental factors in the initiation, promotion and progression of cancer. Starting with Pott's observations in the 18th century, certain occupations have been associated with an increased risk of cancer development. The recognition of increased scrotal cancer in chimney sweeps due to coal and tar exposure was followed by an observation in a British factory that all men distilling 2-napthylamine developed bladder cancer.

Background:Squamous cell scrotal carcinoma (SCSC) is an infrequent skin cancer associated historically with occupational carcinogens. Human papillomavirus (HPV) DNA has been associated with SCSC but there is no definitive proof of its oncogenic role.Methods:Human papillomavirus-DNA and –E6*I mRNA were analysed in six invasive histologically typed SCSC. LCM-PCR was used to localise HPV DNA to tumour cells. P16INK4aand p53 expression were studied by immunohistochemistry.Results:In three warty or basaloid SCSC HPV16-DNA and E6*I-mRNA were detected. LCM-PCR confirmed HPV16 was in p16INK4a-positive malignant cells. However, of three usual-type SCSC, all were HPV-negative and two expressed p53 protein but not p16INK4a.Conclusions:Human papillomavirus 16 was present in tumour cells and oncogenically active in basaloid and warty SCSC, whereas usual SCSC was HPV-negative and showed immunostaining, suggesting p53 mutation. The dual pathways of oncogenesis and relation between histological type of SCSC and HPV are similar to that in penile cancers.

Over two centuries ago, Sir Percival Pott, a London surgeon, published a pioneering treatise showing that soot exposure was the cause of high incidences of scrotal cancers occurring in young men who worked as chimney sweeps. Practicing at a time when cellular pathology was not yet recognized, Sir Percival nonetheless observed that the high incidence and short latency of the chimney sweep cancers, was fundamentally different from the rare scrotal cancers typically found in elderly men. Furthermore, his diagnosis that the etiology of these cancers was related to chimney soot exposure, was absolutely accurate, conceptually novel, and initiated the field of "occupational cancer epidemiology." After many intervening years of research focused on mechanisms of chemical carcinogenesis, briefly described here, it is clear that DNA damage, or DNA adduct formation, is "necessary but not sufficient" for tumor induction, and that many additional factors contribute to carcinogenesis. This review includes a synopsis of carcinogen-induced DNA adduct formation in experimental models and in the human population, with particular attention paid to molecular dosimetry and molecular cancer epidemiology. Environ. Mol. Mutagen. 57:499-507, 2016. © 2016 Wiley Periodicals, Inc.

992 Chim Chim Chiree. The rise and fall of scrotal cancer in chimney sweeps

To evaluate the safety and efficacy of epidermal growth factor receptor (EGFR)-targeted therapy in patients with advanced penile or scrotal cancer. We retrospectively reviewed the charts of patients with penile or scrotal squamous cell carcinoma who had visited our tertiary cancer centre between 2002 and 2009, including their subsequent treatment and follow-up. We collected details of EGFR-targeted therapy and clinical outcomes. Treatment-associated time-to-disease-progression (TTP), overall survival (OS), responses to therapy and toxicity were evaluated. A total of 24 patients had received EGFR-targeted therapies, including cetuximab, erlotinib and gefitinib. The most common treatment given (to 67% of patients) was cetuximab combined with one or more cytotoxic drugs. The most common adverse effect was skin rash (71%). The median (range) TTP and OS were 11.3 (1-40) and 29.6 (2-205) weeks, respectively. The OS time for patients with visceral or bone metastases was significantly shorter than it was for those without (24.7 vs 49.9 weeks, P = 0.013). Among 17 patients treated with cetuximab alone or in combination with cisplatin, there were four partial responses (23.5%) including two patients with apparently chemotherapy-resistant tumours. Our results suggest that cetuximab has antitumour activity in metastatic penile cancer, and may enhance the effect of cisplatin-based chemotherapy. Prospective studies of EGFR-targeted therapies in men with these tumours are warranted.

The earliest report linking environmental (occupational) exposure to adverse human male reproductive effects dates back to1775 when an English physician, Percival Pott, reported a high incidence of scrotal cancer in chimney sweeps. This observation led to safety regulations in the form of bathing requirements for these workers. The fact that male-mediated reproductive harm in humans may be a result of toxicant exposures did not become firmly established until relatively recently, when Lancranjan studied lead-exposed workers in Romania in 1975, and later in 1977, when Whorton examined the effects of dibromochloropropane (DBCP) on male workers in California. Since these discoveries, several additional human reproductive toxicants have been identified through the convergence of laboratory and observational findings. Many research gaps remain, as the pool of potential human exposures with undetermined effects on male reproduction is vast. This review provides an overview of methods used to study the effects of exposures on male reproduction and their reproductive health, with a primary emphasis on the implementation and interpretation of human studies. Emphasis will be on occupational exposures, although much of the information is also useful in assessing environmental studies, occupational exposures are usually much higher and better defined.

Scrotal cancer is an epidermoid malignancy of the scrotum, characterized initially by a small sore that may ulcerate. We report a case presented with discharging ulcer at the root of scrotum encroaching root of penis and diagnosed to be squamous cell carcinoma. Patient underwent total peno-scrotectomy with bilateral orchidectomy with perennial urethroplasty. Simultaneously patient was found to be harboring atypical mycobacteria over scrotum.

We report a case of scrotal squamous cell carcinoma in a 67-year-old man that presented as a recurrent nonhealing scrotal abscess. Radical scrotectomy and bilateral simple orchiectomy were performed. A pudendal thigh flap was used for wound closure. To our knowledge, this is the first report of its use after radical surgery for scrotal cancer. The clinical features, staging, and treatment of scrotal squamous cell carcinoma are reviewed. In this report, we highlight the importance of including scrotal cancer in the differential diagnosis when evaluating a scrotal abscess.

Although scrotal cancer is traditionally regarded as an occupational disease, there is increasing evidence that factors which are involved in cutaneous and genital carcinogenesis might play a role in the carcinogenesis of scrotal cancer. This exploratory study aimed to detect exposures that might have an aetiological relation with scrotal cancer. A nationwide population-based case-control study was conducted in the Netherlands. The patients were identified through the Netherlands cancer registry. Controls were recruited among acquaintances of the cancer registry registrars. The participants completed a questionnaire that included questions on occupational exposures, naked sunbathing, use of sunbeds, skin diseases and their treatments, treatments for cancer and sexually transmitted diseases. Age-adjusted odds-ratios (ORs) were calculated. Forty-seven scrotal cancer patients and 125 controls completed the questionnaire. The patients were categorized according to histology of the scrotal tumours. Having had a skin disease (OR = 6.3, 95% CI = 1.8-22), especially psoriasis (OR = 8.7), increased the risk of squamous cell carcinomas (SCC) of the scrotum. A previous cancer diagnosis may affect the risk of scrotal basal cell carcinomas (BCC; OR = 4.9, 95% CI = 0.9-27.3). Furthermore, an association between the number of sexual partners and the occurrence of scrotal sarcoma was found. Scrotal SCCs may be related with skin diseases or skin disease treatments. Having had cancer may be a risk factor for a BCC of the scrotum. Scrotal sarcomas seem to be correlated with the number of sexual partners. This study suggests that scrotal cancer has characteristics of both cutaneous and genital carcinogenesis.

At a meeting of the Royal Society of Medicine in 1965, Sir Bradford Hill proposed to answer the question he himself posed to the assembled audience: “How do we determine what are physical, chemical and psychologic hazards of occupation and in particular those that are rare and not easily recognized?”1 Although the question Hill proposed was directed at problems of occupational medicine, the article subsequently published from this lecture has become the sentinel guide for the assessment of causation in epidemiologic research. Since the publication of the paper, more than a decade ago, in Science by Ikonomidou,2 there has been a steady stream of work convincingly demonstrating that anesthetic agents and other drugs that act as N-methyl-D-aspartate agonists and γ-aminobutyric acid antagonists can produce widespread apoptotic neurodegeneration, with associated cognitive and behavioral decrements in a variety of animal species, including nonhuman primates. Predictably, these studies have prompted a great deal of concern. They have also generated a series of observational studies seeking evidence for similar effects in children, with varying results.3– 8 The study by Block et al. in this month’s issue of Anesthesiology9 is yet another examination of the association between exposure to anesthesia in young children and outcome, in this case performance on a test of academic achievement. The central concern of those who provide anesthesia to children is that of causation: Does anesthetic exposure at a young age cause neurodevelopmental problems? In the hierarchy of study designs, the randomized control trial reigns as the gold standard. Unfortunately, such studies are expensive, time-consuming, and, in this area, may be ethically impossible. An ongoing randomized clinical trial comparing regional and general anesthesia for infants receiving inguinal herniorraphy will be valuable, but in the meantime, the anesthesia community is left to make judgments regarding the potential applicability of animal findings to children based on a growing number of retrospective observational studies. These studies provide insight, but how should they be interpreted? For example, in studies that find an association between anesthesia and subsequent neurodevelopmental problems, is anesthesia merely a marker for another causative factor (e.g., the stress of a surgical procedure, or the underlying condition which makes surgery necessary)? We here present a “users’ guide” of several questions that should be considered when interpreting observational studies of the association between anesthetic exposure and neurodevelopmental or other outcomes. This discussion is by no means exhaustive, but is meant to alert consumers of literature in this area regarding some of the potential strengths and weaknesses of available and to-be-published studies. This guide should not be seen as criticism of Block et al. or others authors who have contributed to this body of work. Indeed, as nicely typified by Block et al., most authors spend a great deal of time injecting caution into the discourse and highlighting study limitations.

Due to the scrotum's multiple layers of different tissues, scrotal cancer can present with several unique histologies. Historically, outcome arising from these different sources has been historically aggregated together. However, it remains unclear whether survival differs by histology of scrotal cancer. We queried the seventeen registries of the Surveillance, Epidemiology, and End Results database for patients diagnosed with primary scrotal cancer from 1973 to 2006. Patients were initially grouped by the following histologies: basal cell carcinoma, Extramammary Paget's Disease (EMPD), sarcoma, melanoma, squamous cell carcinoma, and adnexal skin tumors. For some analyses, the former three histologies were reclassified as Low-Risk scrotal cancer and the latter three histologies as High-Risk scrotal cancer. Kaplan-Meier survival analyses were conducted to assess the impact of histology on overall survival (OS). The cohort consisted of 766 patients. Median (95% CI) OSs by histologies were basal cell carcinoma--143 (116-180), EMPD--165 (139-190), sarcoma--180 (141-219), melanoma--136 (70-203), squamous cell carcinoma--115 (97-133), and adnexal skin tumors--114 (55-174). Patients with Low-Risk scrotal cancer experienced a median (95% CI) OS of 166 (145-188) months, while patients with High-Risk scrotal cancer experienced a median (95% CI) OS of 118 (101-135) months. Survival of scrotal cancer depends on tumor histology. Classification of histologies into Low and High Risk can be clinically useful for counseling and clinical decisions.

Squamous cell carcinoma of scrotum is not common. It was the first cancer directly associated with a specific occupation i.e. chimney sweeps. We report a case of squamous cell carcinoma of scrotum developed in a patient of stricture urethra with multiple perineal urinary fistulas treated with lay open urethra with buccal mucosal graft. Tobacco exposed buccal mucosa graft can act as a carcinogen for scrotal cancer in patients with multiple fistula and poor hygiene.

Background:Since the 1970s there have been few epidemiological studies of scrotal cancer. We report on the descriptive epidemiology of scrotal cancer in the Netherlands.Methods:Data on all scrotal cancer patients were obtained from the Netherlands Cancer Registry (NCR) in the period 1989–2006 and age-standardised incidence rates were calculated also according to histology and stage. Relative survival was calculated and multiple primary tumours were studied.Results:The overall incidence rate varied around 1.5 per 1 000 000 person-years, most frequently being squamous cell carcinoma (27%), basal cell carcinoma (19%) and Bowen's disease (15%). Overall 5-year relative survival was 82%, being 77% and 95% for patients with squamous and basal cell carcinoma, respectively. In all, 18% of the patients were diagnosed with a second primary tumour.Conclusion:The incidence rate of scrotal cancer did not decrease, although this was expected; affected patients might benefit from regular checkups for possible new cancers.

Primary Scrotal Cancer: Disease Characteristics and Increasing Incidence

The American Association for Cancer Research has been the citadel for communicating research on chemical carcinogens for over a century. It therefore seems appropriate that a review of chemical carcinogenesis inaugurates a series of articles highlighting advances in understanding, treating, and

Scrotal Cancer