Diagnosis and treatment of extramammary Paget's disease

Extramammary Paget's disease is a malignant tumor with the characteristic bright large atypical cells called Paget's cells, which proliferate within an intraepidermal lesion outside the breast. It occurs most frequently in the external genitalia, followed by perianal and axillary regions. The main clinical symptoms are erythema, erosion, pigmentation and depigmentation. Extramammary Paget's disease is commonly an intraepidermal neoplasm. However, if the tumor cells infiltrate into the dermis and form a clinically manifest nodule, it becomes an invasive carcinoma that can be classified as adnexal adenocarcinoma of the skin. Surgery with wide local excision is the first choice of treatment, and the prognosis is comparatively favorable in the early stages. However, when tumor cells infiltrate into the dermis and advance to Paget's carcinoma, it is referred to as adenocarcinoma of the skin and has a poor prognosis. We report an effective treatment of extramammary Paget's disease in advanced stages' including our case. No standard treatment with a significant effect has yet been established. There are few reports of cases responsive to chemotherapy, and treatment in advanced stages is extremely difficult at present.     

Metastatic extramammary Paget's disease: dramatic response to combined modality treatment

A case of extramammary Paget's disease is reported. The distinguishing features of the case are: (1) localization of the primary lesion to the scrotum, (2) development of metastases in the absence of a recognizable underlying carcinoma, and (3) response of the systemic disease to a combination of radiation therapy and chemotherapy. The histogenesis, clinical behavior, and treatment of extramammary Paget's disease are reviewed.     

An immunohistochemical analysis of extramammary Paget's disease compared with mammary Paget's disease

Fourteen cases of extramammary Paget's disease and five cases of mammary Paget's disease have been studied using stereomorphometric, histochemical, and immunohistochemical methods. The antibodies were anti-CEA, anti-EMA, 115D8 and DF3. Intracytoplasmic mucin was positive in Paget's cells, and both 115D8 and DF3 were detected intensely in all of Paget's cells. 115D8 and DF3 were also positive in the normal apocrine sweat gland, the intercellular canaliculi of the eccrine sweat gland, and the intraductal carcinoma of the breast. Therefore, we have concluded that extramammary Paget's disease is an intraepidermal adenocarcinoma originating in the apocrine sweat gland.     

Oncogenic mutations in extramammary Paget's disease and their clinical relevance

Extramammary Paget's disease (EMPD) is a rare cutaneous malignant neoplasm. The genetic alterations underlying its pathogenesis have less been described. Therefore, we analyzed the possible mutations in the KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, PIK3CA, AKT1, CTNNB1 and APC genes as well as methylation and expression of CDH1 in 144 EMPD cases and 42 matched normal skin tissues. A distinct mutation profile was identified in EMPDs with 27 (19%) cases mutant for RAS and RAF genes and 50 (35%) cases harboring oncogenic mutations in PIK3CA and AKT1. Moreover, a mutually exclusive pattern was observed in the genetic variants in these two signaling pathways. No mutation was detected in CTNNB1 and APC genes. High prevalence of low expression and hypermethylation of CDH1 gene was detected in 33 and 48% of the EMPD cases, respectively. Furthermore, PIK3CA and AKT1 mutations were significantly correlated with CDH1 hypermethylation which could explain why the majority of EMPD cases with mutant PIK3CA and AKT1 were invasive. Our study demonstrates that genetic variants associated with constitutive activation of RAS/RAF and PI3K/AKT pathways are involved in the pathogenesis of EMPD. This may represent novel therapeutic targets for this skin cancer.     

Radiation therapy for locally advanced breast cancer: prognostic factors and complication rate

A retrospective analysis was carried out in 100 patients with locally advanced breast cancer without distant metastases treated by radiotherapy between 1960 and 1979. The primary tumor was irradiated to a total dose of 60 Gy in 76 patients and to doses ranging between 60 and 80 Gy in 24 patients. The regional lymphatics were treated with doses between 50 and 60 Gy. Following radiotherapy, chemotherapy was administered to 58 patients and hormonal therapy to 29, while 13 patients received no further therapy. Locoregional recurrences were documented in 29% and distant metastases in 49% of patients. The actuarial survival was 56% at 5 years, 21% at 10 years and 14% at 15 years. At 10 years 90% of the surviving patients had some degree of radiation damage.     

A case of perineal (extramammary) Paget's disease

A case of perineal Paget's disease in a 67-year-old male patient is reported. The perineal polyp, having shown no increase in size for 3 years, wks resected. The microscopic features of the polyp was comprised of clusters of a pale, large tumor cell (Paget cell) only in the epidermis. The skin that was resected around the polyp showed almost the same histological appearance as the polyp, except for an infiltration of tumor cells forming a small gland structure on the minimal region of the dermis. Both the Paget's cells and these tumor cells showed positive for mucin staining. Ultrastructurally, we confirmed two types of Paget's cells, one containing much granules and the other lacking in these granules but rich in other organelles. Further, the Paget's cells formed lumen and intercellular canaliculus, suggesting a differentiation to the eccrine sweat gland. From our findings and a review of the literature, we favor presuming that extramammary Paget's disease without a cancer of the neighbouring organs originates from the epidermis and extends to the dermis.     

Mammary and extramammary Paget's disease. An immunocytochemical and ultrastructural study

Twenty-one cases of Paget's disease have been studied using histochemical, ultrastructural, and immunohistochemical methods. Eight of the tumors involved the nipple, and 13 were extramammary (11 vulvar and two anal). The antibodies used were directed against different classes of cytokeratin proteins, epithelial membrane antigen, carcinoembryonic antigen, gross cystic disease fluid protein-15, and S-100 protein. The findings of this study provide conclusive evidence that Paget's cells, regardless of their location, are adenocarcinoma cells. Intracytoplasmic mucin is scanty in Paget's cells within the nipple, but typically plentiful in the extramammary sites where the cells are frequently signet-ring cells. The common mechanism for the evolution of Paget's disease is extension of cells from an underlying carcinoma, but the possibility that some cases, particularly in the vulva, develop from intraepithelial precursors cannot be excluded.     

Hodgkin disease: prognostic factors and treatment strategies

Depending on stage and risk factor profile, more than 80% of patients with Hodgkin disease (HD) will be cured with modern treatment strategies. In early-stage, favorable HD, extended field irradiation has been the standard treatment resulting in cure rates of greater than 90%. However, due to the recognition of fatal long-term effects, especially the high rates of second solid tumors, extended field irradiation therapy is now being abandoned by most study groups. Instead, mild chemotherapy for control of occult disease is combined with involved field irradiation. In early-stage, unfavorable (intermediate) HD, for which combined modality treatment is already the treatment of choice, extended field irradiation is replaced by involved field irradiation for the same reasons. A different situation is found in advanced HD. In this case, standard therapy consists of eight cycles of polychemotherapy. Until recently, modifications of the standard chemotherapy regimens had not changed the poor outcome of advanced-stage patients. The development of a new dose-intensified regimen (BEACOPP) now for the first time has significantly improved the prognosis of these patients. Patients who relapse following radiation therapy alone for early stage HD have satisfactory results with combination chemotherapy and are not considered candidates for high-dose chemotherapy with autologous stem cell transplantation. For patients with relapsed HD after combination chemotherapy, the current data support the use of high-dose chemotherapy with autologous stem cell transplantation.     

Radiation therapy for recurrent esophageal cancer after surgery: clinical results and prognostic factors

Objective: To evaluate the outcome of radiotherapy for recurrent esophagealcancer after surgery and to determine the prognostic factors. Methods: From 1987 through 2002, 82 patients treated with radiotherapyfor loco-regional recurrences of esophageal cancer after surgerywere retrospectively reviewed. The stage at initial surgerywas I in 16, II in 41, III or higher in 24 and unknown in 1.The median size of recurrent tumors was 3.5 cm in diameter.Fifty-two patients were treated with radiotherapy alone, and30 were treated with radiotherapy combined with chemotherapy.The median total dose of external radiotherapy given was 50.4Gy in 28 fractions. Results: The median survival period after recurrence was 7.0 months.The 2- and 5-year overall survival rate for all patients was22 and 11%, respectively. In univariate analysis, the patientswith performance status (PS) = 0–1, or tumor size <3.5cm, and those treated with total dose 50 Gy showed a bettersurvival outcome than each the other groups. The patients witha history of previous radiotherapy showed a poorer survivaloutcome in univariate analysis than each the other groups. Inmultivariate analysis, tumor size, PS and radiation dose wereindependent prognostic factors for overall survival. Conclusion: The prognosis of patients with post-operative loco-regionalrecurrence of esophageal cancer is poor. However, a long-termsurvival may be expected by definitive radiotherapy for thepatients with small-size tumors and with a good PS.     

隐匿性乳腺癌的治疗选择及预后因素分析

目的：探讨隐匿性乳腺癌的治疗方法和预后。方法：回顾性分析中国医学科学院肿瘤医院1968年1 月至2014年6 月收治的66例隐匿性乳腺癌患者的临床病理及治疗转归资料。结果：患者中位生存期为75.5（7.0～328.0）个月,仅行腋窝淋巴结清扫的保乳手术与改良根治术者的总生存和无病生存差异无统计学意义（P > 0.05）。 单因素分析提示腋窝淋巴结分期是唯一可能与无病生存（P = 0.035）相关的因素。结论：隐匿性乳腺癌患者保乳术和乳房全切术对于预后无明显影响。腋窝淋巴结转移数目多可能提示预后不良。     

Failure to detect human papillomavirus DNA in extramammary Paget's disease.

Ten genital skin specimens, biopsy proven to be Paget's disease, were examined by human papillomavirus (HPV) in situ hydridization in an effort to detect DNA of HPV types 6, 11, 16, 18, 31, 33, and 35. All ten specimens showed no evidence of DNA of these HPV types. Extra-mammary Paget's disease is probably not a result of infection with HPV types 6, 11, 16, 18, 31, 33, or 35.     

Recurrent retroperitoneal sarcomas: Clinical outcomes of surgical treatment and prognostic factors

Background and purposeLocoregional recurrence after resection of primary retroperitoneal sarcoma (RPS) is a challenging therapeutic issue. The objective of this study was to identify clinicopathological factors predictive of overall survival (OS) and disease specific survival (DSS) after reoperation for recurrent RPS.Patients and methodsWe retrospectively collected data from the medical records of 800 patients who underwent resection for sarcoma at our Institution, from 1983 to 2015. Among these patients, 120 were treated for retroperitoneal sarcoma and 55 had a locoregional recurrence (LR). Four of them did not undergo surgery and thus were excluded from this study leaving 51 cases available for data analysis. Univariate and multivariate survival analyses were performed to identify prognostic factors.ResultsMedian overall survival was 33 months. The 1-year, 3-year and 5-year OS rates were 75.5%, 47.1% and 31.6% respectively. Multivariate Cox regression analysis suggested that extension of surgery (P = 0.026), surgical margin status (P = 0.015) and histological grade of recurrent tumor (P = 0.047) were independent prognostic factors for OS. Median DSS was 48 months. The 1-year, 3-year and 5-year DSS rates were 79.2%, 53.1% and 40.9%, respectively. At multivariate analysis, predictors of DSS were extension of surgery (P = 0.004), margin status (P = 0.011), histological grade of recurrent tumor (P = 0.008), and disease free interval (DFI) (P = 0.020). As regards histological subtype of recurrent RPS, at univariate analysis, well-differentiated liposarcoma (WDLS) was associated with better OS and DSS (P = 0.052 and P = 0.016 respectively) compared to dedifferentiated liposarcoma (DDLS).ConclusionsAccording to our findings, surgery is more beneficial in patients with low-grade sarcoma, WDLS and long DFI. The achievement of clear resection margins, rather than performing a multivisceral resection, appears to be a key factor to improve OS and DSS.     

Radiation therapy in early glottic carcinoma: significance of prognostic factors and dose fractionation

A retrospective analysis of 208 cases with early glottic cancers treated by radiation therapy is presented. Early T1 (156 cases) and T2 (52 cases) lesions accounted for only 43 per cent of all glottic tumours that presented at the Tata Memorial Hospital between 1975-80. A markedly predominant male to female ratio of 22:1 was noted with 66 percent presenting in the fifth and sixth decades of life. Radical Radiation therapy was delivered with two different regimens according to the then prevalent physician preference. Regimen 1 delivered 50 Gy/15 frs. in three weeks and regimen 2 with 60 Gy/24 frs./5 weeks. The actual total survival and disease free survival was 92 per cent and 85 percent for T1 lesions and 82 percent and 67 percent for T2 tumours respectively. Minimal tumour volume involving a unilateral mobile vocal cord had the best prognosis. With extension to more lengths of cord and/or involvement of the anterior commissure or with tethering or fixation of the cord the prognosis was adversely influenced. In T1 lesions, the shorter course with the higher fractionation dosage levels showed improved local controls. However, the results were not statistically significant. This was not so in the T2 lesions probably due to small number of cases. Treatment failure was recorded in 19 per cent cases of which 90 per cent was seen in the first two years after treatment. Persisting laryngeal oedema confirmed a high index of suspicion towards recurrent disease. A radiotherapeutic technique using proper patient positioning and accurate beam direction with total dosage level above 1850 rets and TDF between 101-106 values is the recommended optimal treatment. In conclusion, an understanding of the prognostic features and an appropriate dose fractionation schedule allows optimization to effectively control early glottic tumours and retain function in the majority of patients.     

Photodynamic Therapy for Extramammary Paget＇s Disease： 5 Cases Report

Objective： To study the therapeutic effect of photodynamic therapy for extramammary Paget＇s disease. Methods： DIOMED 630 nm diode laser was used as light source and photofrin as photosensitizer. The patient＇s lesion was irradiated for 24-72 h after administrating of photofrin. The power density was 100-150 mW/cm^2 and energy density was 150-300J/cm^2. Dosage of photofrin was 2 mg/kg. Results： Lesion darkened 24 h after irradiation and formed a scar 96-120 h after irradiation. One patient＇s lesion disappeared, three patients＇ lesion diminished apparently and one patient＇s lesion was not controlled 3 months later. Conclusion： Photodynamic therapy is an effective modality for extramammary Paget＇s disease.     

乳腺外佩吉特病治疗进展

乳腺外佩吉特病是一种少见的恶性皮肤肿瘤。治疗策略应根据不同患者的个体情况,单独或联合应用手术、光动力疗法、外用免疫调制剂、化学疗法和放射疗法等方式。手术通常被认为是首选的治疗方法,但术后仍有较高的复发率,故国内外学者尝试对传统手术方式进行改进,并取得一定进展。也有学者尝试使用其他方法作为手术治疗的辅助或替代。目前Mohs外科手术是最佳治疗方案。     

乳腺外佩吉特病治疗进展

乳腺外佩吉特病是一种少见的恶性皮肤肿瘤。治疗策略应根据不同患者的个体情况,单独或联合应用手术、光动力疗法、外用免疫调制剂、化学疗法和放射疗法等方式。手术通常被认为是首选的治疗方法,但术后仍有较高的复发率,故国内外学者尝试对传统手术方式进行改进,并取得一定进展。也有学者尝试使用其他方法作为手术治疗的辅助或替代。目前Mohs外科手术是最佳治疗方案。     

Haemorrhagic soft-tissue sarcoma: Oncological outcomes and prognostic factors for survival

IntroductionHaemorrhagic soft-tissue sarcomas (HSTS) are characterised by aggressive local growth and highly metastatic behaviour. We aimed to describe oncological outcomes and prognostic factors.Materials and methodsRetrospective review including 64 patients treated with palliation (n = 7), with limb salvage surgery (LSS) (n = 9), with neoadjuvant radiotherapy (RT) + LSS (n = 12), with LSS + adjuvant RT (n = 30) or amputation (n = 6). Kaplan-Meier survival analysis estimated overall survival (OS), metastasis-free survival (MFS) and local recurrence-free survival (LRFS). After uni- and multivariate analysis, prognostic factors affecting OS, MFS and LRFS were identified.ResultsMedian age was 67 years (IQR 23 years) with median follow-up of 11 months (IQR 28 months). All cases were high grade. Eight (13%) had pulmonary metastases at presentation and another 40 (63%) developed metastases after median 9 months (IQR 19 months). Median OS was 12 months (IQR 38 months), and estimated OS after two-years was 15.9% and 52.9% for patients with and without metastatic disease at presentation, respectively. Improved OS was associated with negative resection margins (p = 0.031), RT (p = 0.045), neoadjuvant RT (versus adjuvant RT, p = 0.044) and amputation (versus LSS, p < 0.001). MFS was 35.1% after two-years. LR occurred in 18 of 51 (35.3%) patients with surgically treated localised disease. LRFS was 63.4% after two-years and significantly affected by a negative margin (p = 0.042) and RT (p = 0.001).ConclusionHaemorrhagic soft-tissue sarcomas should be excised, either with amputation or LSS with a clear resection margin. If LSS is attempted, neoadjuvant RT reduces the risk of tumour spillage and early LR, enhances the feasibility of achieving clear resection margins, and offers superior overall survival compared to adjuvant RT.