Eruptive nevi associated with medications (ENAMs).

Eruptive melanocytic nevi have been reported in association with severe blistering diseases, renal transplantation, malignancy, AIDS, and medications. Eruptive nevi associated with medications have been reported with increasing frequency. Of particular interest are eruptive nevi associated with medications developing in association with biologic therapies, which we anticipate will continue to become more common as use of these medications continues to increase. We searched the databases PubMed/MEDLINE, Cochrane, and Cumulative Index to Nursing and Allied Health Literature for associated medications using the terms "eruptive nevi," "melanocytic + medications," and "nevi + medications" for relevant articles. We report the summary of our findings, which were used in defining what constitutes an eruptive nevi associated with medication and developing a classification system by medication type.

Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: clinical characteristics and outcomes.

Aristolochic acid (AA), a component of all Aristolochia-based herbal medicines, is a potent nephrotoxin and human carcinogen associated with upper urinary tract urothelial carcinoma (UUC). To investigate the clinical and pathological characteristics of AA-induced UUC, this study included 152 UUC patients, 93 of whom had been exposed to AA based on the presence of aristolactam-DNA adducts in the renal cortex. Gene sequencing was used to identify tumors with A:T-to-T:A transversions in TP53, a mutational signature associated with AA. Cases with both aristolactam-DNA adducts and A:T-to-T:A transversions in TP53 were defined as AA-UUC, whereas patients lacking both of these biomarkers were classified as non-AA-UUC. Cases with either biomarker were classified as possible-AA-UUC. Forty (26%), 60 (40%), and 52 (34%) patients were classified as AA-UUC, possible-AA-UUC and non-AA-UUC, respectively. AA-UUC patients were younger (median ages: 64, 68, 68 years, respectively; p=0.189), predominately female (65%, 42%, 35%, respectively; p=0.011), had more end-stage renal disease (28%, 10%, 12%, respectively; p=0.055), and were infrequent smokers (5%, 22%, 33%, respectively; p=0.07) compared to possible-AA-UUC and non-AA-UUC patients. All 14 patients who developed contralateral UUC had aristolactam-DNA adducts; ten of these also had signature mutations. The contralateral UUC-free survival period was shorter in AA-UUC compared to possible- or non-AA-UUC (p=0.019 and 0.002, respectively), whereas no differences among groups were observed for bladder cancer recurrence. In conclusion, AA-UUC patients tend to be younger and female, and have more advanced renal disease. Notably, AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC.

The rapid onset of multiple squamous cell carcinomas in two patients commenced on ustekinumab as treatment of psoriasis.

We report the cases of two patients who developed eruptive cutaneous squamous cell carcinomas (SCC) soon after commencement of ustekinumab, as treatment of moderate to severe plaque type psoriasis. Ustekinumab is a human monoclonal antibody with a novel mechanism, selectively targeting the shared p40 subunit of interleukin-12 (IL-12) and IL-23. Its efficacy has been well documented in three large phase-III trials (PHOENIX I, PHEONIX 2, ACCEPT). Safety data on this new biological agent continue to grow. To date, no link between ustekinumab and cutaneous carcinogenesis has been demonstrated and, to our knowledge, these cases are the first of their kind. Importantly, both these patients had independent risk factors for developing non-melanoma skin cancers; however, the specific time correlation with the administration of ustekinumab is of note. Our report suggests that ustekinumab may allow the development of cutaneous carcinomata in predisposed individuals.

Composite cutaneous lymphoma in a patient with rheumatoid arthritis treated with methotrexate.

Patients with rheumatoid arthritis, whether treated or not with immunosuppressive agents including methotrexate, have an increased risk of lymphoproliferative disorders. Termed "iatrogenic immunodeficiency-associated lymphoproliferative disorders" in the 2008 World Health Organization classification of lymphoid neoplasms, they include Hodgkin and non-Hodgkin lymphomas. Composite lymphomas are rare, particularly in skin, with none reported in immunodeficiency states. We report the case of a 67 year-old woman with a long history of rheumatoid arthritis, on methotrexate treatment, who developed multiple skin lesions exhibiting a malignant infiltrate displaying both B- and T-cell phenotypes and dual clonal gene rearrangement by polymerase chain reaction, consistent with a cutaneous composite lymphoma. The patient received chemotherapy including rituximab with partial response, but the T-cell component recurred. To the best of our knowledge, this is the first case report of a cutaneous composite lymphoma in a patient with an iatrogenic immunodeficiency representing a dual challenge, diagnostic for the pathologist and therapeutic for the hematologist.

Pathology Working Group review and evaluation of proliferative lesions of mammary gland tissues in female rats fed ammonium perfluorooctanoate (APFO) in the diet for 2 years.

Perfluorooctanoate (PFO) is a perfluorinated carboxylate that is widely distributed in the environment. A 2-year chronic study was conducted in rats fed either 30 or 300 ppm of ammonium perfluorooctanoate (APFO). To investigate the possible relationship of APFO exposure to proliferative mammary lesions, a Pathology Working Group (PWG) review of the original slides was performed. The consensus reached by the PWG was that the incidence of mammary-gland neoplasms was not affected by chronic dietary administration of APFO. Therefore, feeding female rats up to 300 ppm of APFO resulted in no increase in proliferative lesions of the mammary tissue.

Letter: Iatrogenic lipomatosis: a rare manifestation of treatment with a peroxisome proliferator-activated receptor gamma agonist.

Lipomas are common benign neoplasms of adipose tissue. Lipomatosis, the progressive appearance of multiple lipomas, is most often associated with specific congenital, familial, or idiopathic syndromes. In one reported case, the development of multiple lipomas occurred as a result of treatment with rosiglitazone, a peroxisome proliferator-activated receptor (PPAR) gamma agonist. We report a second case of lipomatosis occurring as a result of treatment with a PPAR gamma agonist. This case occurred in a 77-year-old woman who developed multiple lipomas two years after beginning treatment with pioglitazone, a PPAR gamma agonist. Histopathologic examination confirmed these lesions to be lipomas. Within four weeks of discontinuation of pioglitazone, regression of the lipomas began. We describe a case of PPAR agonist-induced lipoma formation, review relevant literature, and provide a molecular mechanism for this side effect.

Circadian disruption accelerates liver carcinogenesis in mice.

BACKGROUND: The circadian timing system rhythmically controls behavior, physiology, cellular proliferation and xenobiotic metabolism over the 24-h period. The suprachiasmatic nuclei in the hypothalamus coordinate the molecular clocks in most mammalian cells through an array of circadian physiological rhythms including rest-activity, body temperature, feeding patterns and hormonal secretions. As a result, shift work that involves circadian disruption is probably carcinogenic in humans. In experimental models, chronic jet-lag (CJL) suppresses rest-activity and body temperature rhythms and accelerates growth of two transplantable tumors in mice. CJL also suppresses or significantly alters the expression rhythms of clock genes in liver and tumors. Circadian clock disruption from CJL downregulates p53 and upregulates c-Myc, thus favoring cellular proliferation. Here, we investigate the role of CJL as a tumor promoter in mice exposed to the hepatic carcinogen, diethylnitrosamine (DEN). METHODS: In experiment 1 (Exp 1), the dose-dependent carcinogenicity of chronic intraperitoneal (i.p.) administration of DEN was explored in mice. In Exp 2, mice received DEN at 10 mg/kg/day (cumulative dose: 243 mg/kg), then were randomized to remain in a photoperiodic regimen where 12 h of light alternates with 12 h of darkness (LD 12:12) or to be submitted to CJL (8-h advance of light onset every 2 days). Rest-activity and body temperature were monitored. Serum liver enzymes were determined repeatedly. Mice were sacrificed and examined for neoplastic lesions at 10 months. RESULTS: In Exp 1, DEN produced liver cancers in all the mice receiving 10 mg/kg/day. In Exp 2, mice on CJL had increased mean plasma levels of aspartate aminotransferase and more liver tumors as compared to LD mice at approximately 10 months (p = 0.005 and 0.028, respectively). The mean diameter of the largest liver tumor was twice as large in CJL vs LD mice (8.5 vs 4.4 mm, p = 0.027). In LD, a single histologic tumor type per liver was observed. In CJL, up to four different types were associated in the same liver (hepatocellular- or cholangio-carcinomas, sarcomas or mixed tumors). DEN itself markedly disrupted the circadian rhythms in rest-activity and body temperature in all the mice. DEN-induced disruption was prolonged for >or= 3 months by CJL exposure. CONCLUSIONS: The association of circadian disruption with chronic DEN exposure suggests that circadian clocks actively control the mechanisms of liver carcinogenesis in mice. Persistent circadian coordination may further be critical for slowing down and/or reverting cancer development after carcinogen exposure.

Surgical outcome in patients with oral verrucous carcinoma: long-term follow-up in an endemic betel quid chewing area.

BACKGROUND/AIMS: To evaluate the clinical features and prognosis of patients with oral verrucous carcinoma (OVC) in an endemic betel quid chewing area. METHODS: A retrospective review was conducted in 39 patients with OVC treated surgically from 1991 to 2002. RESULTS: Thirty-seven patients (94.9%) were male. The median age at diagnosis was 53.8 years. All patients had been exposed to betel quid, cigarette smoking, and/or alcohol. The most common site of tumor origin was the buccal mucosa (64.1%). The tumor control rate was 97.4% after the first surgical procedure. Second/multiple primary tumors (SPTs/MPTs) were found in 21 patients. There were 13 deaths during the follow-up period, with SPTs/MPTs being the most common cause. The cancer-specific survival rate was 89.1% at 5 years, but continued to decrease thereafter. CONCLUSION: Surgery was effective for controlling OVC. However, long-term follow-up was necessary because of the high incidence of SPTs/MPTs and its impact on patient survival.

Coexistence of different tissue tumourigenesis in an N-methyl-N-nitrosourea-induced mammary carcinoma model: a histopathological report in Sprague-Dawley rats.

N-methyl-N-nitrosourea (MNU), a highly potent carginogen, is widely used to generate mammary tumours in murine species. In a model of MNU-induced mammary carcinogenesis using immature female Sprague-Dawley rats, large mammary tumours (largest dimension > or =0.5 cm) were obtained within a very short period of time. In addition, in the rats bearing MNU-induced mammary carcinomas, there were a number of tumours whose origins were not from mammary tissue but from several different tissues and from mammary non-epithelial tissue. The tumours were of mesenchymal or epithelial origin and they were located in the inguinal region. These tumours were diagnosed as fibroadenoma, combined tubular adenoma and fibroadenoma, hyperkeratotic papilloma, keratinous cyst and malignant peripheral nerve sheath tumour (MPNST) with smooth muscle differentiation. The occurrence of these other tumours in addition to the development of the mammary carcinomas may be attributed to a direct local effect of the intraperitoneal administration of MNU during the sexual development of the immature rats. In the MNU-induced mammary tumour model, coexistence of tumourigenesis in various non-mammary tissues should be considered an important factor that may interfere with experimental procedures and results and also the quality of life of the tumour-bearing animals.

[Multiple skin cancers in a patient treated with hydroxyurea]. / Multiple kutane Neoplasien nach Therapie mit Hydroxyurea.

A 62-year-old patient treated for 9 years with hydroxyurea for chronic myeloproliferative disease developed multiple cutaneous neoplasms. Hydroxyurea minimizes DNA synthesis via inhibition of the enzyme ribonucleotide reductase and is used to treat hematological malignancies. The most important and severe side-effect is a dose-dependent myelodepression. An association with multiple skin tumors has been reported. The presented case emphasizes this potential risk of hydroxyurea therapy. Continuous dermatologic monitoring of patients treated with hydroxyurea is recommended.

Case-control study and meta-analysis of SULT1A1 Arg213His polymorphism for gene, ethnicity and environment interaction for cancer risk.

Cytosolic sulphotransferase SULT1A1 plays a dual role in the activation of some carcinogens and inactivation of others. A functional polymorphism leading to Arg(213)His substitution (SULT1A1*2) affects its catalytic activity and thermostability. To study the association of SULT1A1*2 polymorphism with tobacco-related cancers (TRCs), a case-control study comprising 132 patients with multiple primary neoplasm (MPN) involving TRC and 198 cancer-free controls was carried out. One hundred and thirteen MPN patients had at least one cancer in upper aerodigestive tract including lung (UADT-MPN). SULT1A1*2 showed significant risk association with UADT-MPN (odds ratio (OR)=5.50, 95% confidence interval (CI): 1.09, 27.7). Meta-analysis was conducted combining the data with 34 published studies that included 11 962 cancer cases and 14 673 controls in diverse cancers. The SULT1A1*2 revealed contrasting risk association for UADT cancers (OR=1.62, 95% CI: 1.12, 2.34) and genitourinary cancers (OR=0.73, 95% CI: 0.58, 0.92). Furthermore, although SULT1A1*2 conferred significant increased risk of breast cancer to Asian women (OR=1.91, 95% CI: 1.08, 3.40), it did not confer increased risk to Caucasian women (OR=0.92, 95% CI: 0.71, 1.18). Thus risk for different cancers in distinct ethnic groups could be modulated by interaction between genetic variants and different endogenous and exogenous carcinogens.

Low-dose dietary chlorophyll inhibits multi-organ carcinogenesis in the rainbow trout.

We recently reported that chlorophyll (Chl) strongly inhibits aflatoxin B(1) preneoplasia biomarkers in rats when administered by co-gavage (Simonich et al., 2007. Natural chlorophyll inhibits aflatoxin B1-induced multi-organ carcinogenesis in the rat. Carcinogenesis 28, 1294-1302.). The present study extends this by examining the effects of dietary Chl on tumor development, using rainbow trout to explore ubiquity of mechanism. Duplicate groups of 140 trout were fed diet containing 224 ppm dibenzo[a,l]pyrene (DBP) alone, or with 1000-6000 ppm Chl, for 4 weeks. DBP induced high tumor incidences in liver (51%) and stomach (56%), whereas Chl co-fed at 2000, 4000 or 6000 ppm reduced incidences in stomach (to 29%, 23% and 19%, resp., P<0.005) and liver (to 21%, 28% and 26%, resp., P<0.0005). Chlorophyllin (CHL) at 2000 ppm gave similar protection. Chl complexed with DBP in vitro (2Chl:DBP, K(d1)=4.44+/-0.46 microM, K(d2)=3.30+/-0.18 microM), as did CHL (K(d1)=1.38+/-0.32 microM, K(d2)=1.17+/-0.05 microM), possibly explaining their ability to inhibit DBP uptake into the liver by 61-63% (P<0.001). This is the first demonstration that dietary Chl can reduce tumorigenesis in any whole animal model, and that it may do so by a simple, species-independent mechanism.

Hepatocellular adenoma in a woman who was undergoing testosterone treatment for gender identity disorder.

A 32-year-old Japanese woman was admitted to our hospital for the diagnosis and treatment of multiple liver tumors. She had been receiving 125 mg testosterone enanthate every 2 weeks following female-to-male gender identity disorder (GID) diagnosis at 20 years of age. Ultrasonography, computed tomography, and magnetic resonance imaging showed 11 hepatic nodular tumors with a maximum diameter of 28 mm. Liver tumors with hepatocellular adenoma (HCA) were diagnosed with needle biopsy. Segmentectomy of the left lateral lobe including two lesions, subsegmentectomy of S6 including two lesions, enucleation of each tumor in S5 and S7, and open surgical radiofrequency ablation for each tumor in S4 and S7 were performed. Immunohistochemical specimens showed that the tumor cells were diffusely and strongly positive for glutamine synthetase and that the nuclei were ectopically positive for ß-catenin. Thus, the tumors were diagnosed as ß-catenin-activated HCA (b-HCA). Transcatheter arterial chemoembolization plus subsequent radiofrequency ablation was performed for the 3 residual lesions in S4 and S8. Although testosterone enanthate was being continued for GID, no recurrence was observed until at least 22 months after the intensive treatments. HCA development in such patients receiving testosterone should be closely monitored using image inspection.

Rapid onset of multiple concurrent squamous cell carcinomas associated with the use of an arsenic-containing traditional medicine for chronic plaque psoriasis.

We report a case of a 46-year-old Vietnamese man who developed widespread, numerous and concurrent cutaneous squamous cell carcinomas (SCCs) in non-sun exposed skin areas after taking a traditional medicine (TM) formulation for chronic plaque psoriasis. The SCC lesions began to develop within 12-15 months after beginning the arsenic-containing TM. The patient experienced both acute and chronic symptoms consistent with arsenic exposure. Laboratory investigation of a collected hair sample showed a significant arsenic level. The TM formulation used by the patient was tested and demonstrated an extremely high concentration of arsenic.

Primary Breast Lymphoma with cutaneous involvement in a patient with Rheumatoid Arthritis - a complication of infliximab therapy?

It is well established that rheumatoid arthritis is associated with an increased risk of lymphoma. The use of tumor-necrosis factor-α inhibitors as a therapy in rheumatoid arthritis has been related to higher incidence of lymphoma arising at atypical and/or unusual locations; however, recent data shows their safety. We report the case of a 79 year-old woman with rheumatoid arthritis treated with infliximab, who presented a primary breast lymphoma with cutaneous involvement.

Modification by ozone of lung tumor development in mice.

Mice, either strain A/J or Swiss Webster, were exposed for 18 weeks either to filtered air or to 0.4 or 0.8 ppm ozone for 8 hours daily. Subgroups in each test group received a single ip injection of 1,000 mg urethan/kg or 0.9% sodium chloride vehicle 1 day prior to initiation of the exposure regimen. Tumor incidence in Swiss Webster mice was 0-3% in groups not receiving urethan and was 61-74% in groups receiving urethan. In A/J mice, the corresponding values were 9-38% and 100%, respectively. Exposure to ozone caused a decrease in the number of tumors per lung in urethan-treated mice of both strains, in a dose-dependent manner. There seemed to be a specific decrease in tumors derived from alveolar type II cells in the A/J mice given urethan plus ozone. Most interesting, perhaps, was a significant increase in the number of tumors per lung in A/J mice exposed to 0.8 ppm ozone without urethan, confirming a previous report by others. The corresponding ozone effect on lung tumor development was not observed in Swiss Webster mice.

Mammary tumor induction in male and female Sprague-Dawley rats by adriamycin and daunomycin.

Male and female noninbred Sprague-Dawley rats 30-36 days of age were given single iv injections of 10 or 5 mg adriamycin (Ad)/kg or 10 mg daunomycin (DM)/kg. Multiple mammary tumors (MT), mostly adenocarcinomas, were observed in 29 and 67% of the females given 10 and 5 mg Ad/kg, respectively, and in 64% of those given 10 mg DM/kg. The mean induction time for females receiving 10 mg Ad/kg was 135 days, for those receiving 5 mg/kg it was 114 days, and for those receiving DM it was only 80 days. Single MT, also mostly adenocarcinomas, were observed an average of 279 days from injection in 31% of the males given 5 mg Ad/kg and an average of 91 days from injection in 37% of the males given 10 mg DM/kg. No tumors were observed in the males given 10 mg Ad/kg, but these survived for only 79 days after treatment.

Experimental pancreatic carcinogenesis. II. Lifetime carcinogenesis studies in the outbred Syrian golden hamster with N-nitroso-bis(2-hydroxypropyl)amine.

A high incidence of pancreatic duct neoplasms was induced in outbred male Syrian golden hamsters following weekly sc injection of N-nitroso-bis(2-hydroxypropyl)amine for life. The first such tumors appeared as early as 16 experimental weeks; the maximum incidence reached 100% by the termination of the study. Tumors in the respiratory tracts and angiosarcomas of the livers of the hamsters were also observed in high frequency. Latency of the induced neoplasms was significantly decreased by the substitution of distilled water for olive oil as the vehicle for the carcinogen.

Synergism of diethylstilbestrol and other carcinogens in concurrent development of hepatic, mammary, and pituitary tumors in castrated male rats.

Castrated male WF rats, given implants of pellets containing 5.0 mg diethylstilbestrol (DES), were given N-butyl-N-nitrosourea (NBU) in small amounts, which alone produced no mammary tumors in intact female rats. Treatment resulted in the high yield of hepatic tumors (HT), mammary tumors (MT), and pituitary tumors (PT) concurrently in each rat. If animals were further treated with prolactin, the development of HT and MT was accelerated, whereas that of PT was suppressed. None of the intact or castrated rats receiving NBU and/or prolactin developed tumors in any tissues if DES treatment was omitted. Exposure of male rats, preconditioned similarly to NBU treatment, to 200 rads of 14.1-MeV fast-neutron radiation also elicited HT, MT, and PT with an efficiency comparable to that of NBU-treated rats. These findings indicate that DES played an essential role in the whole carcinogenic process in each tissue and that castrated male rats, if conditioned properly with estrogens, are useful for the study of the carcinogenesis mechanism in these tissues.