Serum cytokeratin 19 fragment 21-1 and carcinoembryonic antigen combination assay as a biomarker of tumour progression and treatment response in extramammary Paget disease

Extramammary Paget's disease (EMPD) is a rare skin cancer affecting the genitals and armpit regions. EMPDs occur mainly in Caucasian women and Asian men over the age of 60, in less than 0.6 per 100,000 people. Basic treatment is excision (removal) by operation, yet metastasis, meaning that it has spread, is seen in around 10% of patients. If the cancer is spreading, it is really important to detect this and start treatment as early as possible, since in late stages the disease can be hard to treat. A biomarker, or marker, is a molecule found in blood, different levels of which correspond with how well the body responds to a treatment, or to how the disease will progress. Carcinoembryonic antigen (CEA) and cytokeratin 19 fragment 21-1 (CYFRA 21-1) are both biomarkers for certain other cancers, and it has been suggested that they might also be markers for monitoring tumour progression in EMPD; however, neither the accuracy of, nor correlation between, these markers have been examined in EMPD patients. This study from Japan aimed to find out the usefulness and relationship of CEA and CYFRA21-1 levels in blood of EMPD patients in various progression states of the disease. A total of 30 EMPD cases were included in this study. In all early-stage patients, CEA and CYFRA were within normal levels. In advanced-stage patients, CEA and CYFRA were elevated in 79% and 63%, respectively. Either CEA or CYFRA was found to be elevated in 95% of the advanced patients, indicating that a certain number of patients have raised levels of only one of the markers. In addition, both of the markers also correlated well with the treatment responses in all patients. This study revealed that examining both CEA and CYFRA may help to detect advanced-stage EMPD patients, and that they are useful for monitoring treatment responses.     

Combined serum carcinoembryonic antigen and cytokeratin 19 fragment levels provide a sensitive biomarker for lymph node metastasis in extramammary Paget’s disease

Most cases of extramammary Paget’s disease are diagnosed at an early stage. For advanced cases, few effective treatments are available and the prognosis is poor. Therefore, developing sensitive biomarkers for metastatic cases is a critical challenge. Carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA) are two potentially useful biomarkers. In the present retrospective large-scale study, we identified other potential biomarkers of lymph node metastasis. Patients with extramammary Paget’s disease who visited our dermatology clinic between April 2004 and March 2019 (n = 138; mean age, 73.4 years; 85 men and 53 women) were enrolled in the study. The patients were divided into three groups according to the presence of regional lymph node metastasis and distant metastasis to evaluate the relationship between metastasis and various tumor markers: serum CEA, carbohydrate antigen (CA)19-9, CA125, CA15-3 and CYFRA. For distal metastasis, each biomarker had high sensitivity and specificity. The sensitivities and specificities for regional lymph node metastasis were as follows: CEA, 50.0% and 88.6%; CA19-9, 50% and 89.5%; CA125, 0% and 98.2%; CA15-3, 0% and 96.0%; and CYFRA, 66.7% and 95.0%, respectively. We also analyzed biomarker combinations. The sensitivity and specificity of the combination of all five biomarkers (CEA, CA19-9, CA125, CA15-3 and CYFRA) were 83.3% and 70.9%, respectively. The sensitivity of the combination of just CEA and CYFRA was also 83.3%. Screening for combinations of these biomarkers will facilitate the detection of early lymph node metastasis in patients with extramammary Paget’s disease.     

乳房外Paget病19例临床与随访分析

目的探讨乳房外Paget病的临床、病理特点及影响生存率的因素。方法回顾性分析2000-2010年间本院收治的19例乳房外Paget病患者的临床资料。结果 19例中女4例,男15例,平均年龄(70.26±8.90)岁。确诊时病程1月~6.5年,平均43月。临床表现主要为红斑、糜烂及湿疹、皮炎样皮损。手术治疗13例,其中2例复发;光动力治疗5例;未治疗1例。随访期间死亡7例,5年生存率61.20%。单因素变量分析显示淋巴结转移、肿瘤细胞侵袭至真皮、伴发其他肿瘤或远处转移、CEA水平升高与患者生存率有关。结论乳房外Paget病早期诊断困难,复发率高,淋巴结转移、伴发肿瘤或远处转移者预后差,需长期随访。迁延不愈的"湿疹"患者应尽早行皮肤活检,免疫组化检查可提高早期诊断率并指导早期治疗。     

Clinicopathological characteristics, management and outcome of metastatic penoscrotal extramammary Paget's disease

Background  Metastatic penoscrotal extramammary Paget's disease (EMPD) has seldom been reported in the literature.
Objectives  To improve the knowledge of the clinicopathological characteristics, management and outcome in patients with this disease.
Methods  The medical records and pathological slides of 10 patients with metastatic EMPD and 33 patients with nonmetastatic disease were reviewed. Immunohistochemical staining for epithelial cadherin (E-cadherin) was performed in the primary skin disease. All the 10 patients received 5-fluorouracil- or docetaxel-based chemotherapy.
Results  The most common sites of metastases were lymph nodes followed by bone. Patients with metastatic EMPD were more likely to be young and had elevated carcinoembryonic antigen (CEA) levels. Dermal or deeper invasion, lymphovascular embolization and negative expression of E-cadherin were important pathological predictors of metastatic potential. In invasive EMPD, lymphovascular embolization but not expression of E-cadherin was significantly associated with the risk of metastases. In three patients, ¹⁸F-fluorodeoxyglucose positron emission tomography (PET)–computed tomography (CT) scans revealed occult lymph node metastases which were overlooked at conventional CT examinations. Two patients had complete response to the chemotherapy, three had partial response and five had progressive disease. The 2-year overall survival rate was 48% in patients with metastatic EMPD. In those patients with significantly elevated CEA level, the value of CEA paralleled the disease course.
Conclusions  Metastatic EMPD tended to have dermal invasion and lymphovascular embolization. PET–CT scans were helpful in detecting distant metastases. 5-Fluorouracil- or docetaxel based-chemotherapy was effective in some patients. Serum CEA level can be a useful biomarker for monitoring disease course.     

Extramammary Paget's disease: treatment, prognostic factors and outcome in 76 patients

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare cutaneous carcinoma usually presenting as a genital erythematous lesion in the elderly. Although most EMPD tumours are in situ, invasive EMPD has a poor prognosis. OBJECTIVE: To evaluate the clinical and pathological features of EMPD and determine prognostic factors for survival. METHODS: The medical records of 76 patients with EMPD were retrospectively reviewed. RESULTS: Of the 66 patients who underwent curative surgical excision, five (8%) developed local recurrence, but surgical margin (2 cm) was not correlated with local recurrence. Thirteen of the 76 patients (17%) developed systemic metastases and 10 of these died of disease. On univariate analysis, the presence of nodules in the primary tumour, clinical lymph node swelling, elevated serum carcinoembryonic antigen (CEA) levels, tumour invasion level and lymph node metastasis were significant prognostic factors. On multivariate analysis, invasion level and elevated serum CEA were the only factors that were significantly associated with reduced survival. CONCLUSIONS: Invasion level and lymph node metastasis are important prognostic factors in EMPD. In patients with in situ tumour, local tumour control is the major aim of treatment; however, wide surgical margins are not associated with a lower risk of local recurrence.     

恶性胸膜间皮瘤病例报告和分析

目的分析恶性胸膜间皮瘤的临床病例特点,以探讨早期诊断、治疗的方法。方法1998年～2008年收入院11例恶性胸膜间皮瘤患者,男7例,女4例,年龄（63．7±12．6）（41～79）岁,均经病理资料确诊;对其临床资料进行回顾性分析。结果11例患者中10例（90．91％）有呼吸困难和胸痛的症状。11例（100％）患者均有胸腔积液。5例（45．45％）CT表现为胸膜肥厚,3例（27．27％）表现为胸膜结节影。对其中7例患者的胸腔积液的分析表明,7例胸水CEA水平均在正常范围,其中2例行CYFRA21—1检查,CYFRA21—1均升高;7例患者血清学肿瘤标记物CEA检查均在正常范围,其中6例（85．71％）行血清学CYFRA21—1检查提示均升高。结论恶性胸膜间皮瘤最常见的症状是呼吸困难和胸痛。CT对于恶性胸膜间皮瘤的诊断价值高于胸部X线：胸腔积液肿瘤标记物CYFRA21—1水平高而CEA水平正常对于恶性胸膜间皮瘤的诊断具有提示意义．     

Serum carcinoembryonic antigen level in Paget''s disease

Serum carcinoembryonic antigen (CEA) levels were examined in ten patients with genital Paget's disease, using radioimmunoassay. Three of the patients showed elevated serum CEA levels, but the other seven patients had normal levels. All three patients with increased CEA levels had widespread metastases. The seven patients with normal levels had no metastasis or had only a very small metastasis in one lymph node. Elevated serum CEA levels are associated with Paget's disease only when it shows widespread metastases.     

Fluorodeoxyglucose positron emission tomography fails to detect distant metastases at initial staging of melanoma patients with metastatic involvement of sentinel lymph node

Background Positron emission tomography (PET) using fluorodeoxyglucose (FDG) has proven to be more sensitive and accurate than other imaging modalities for the detection of distant metastases in patients with melanoma. Sentinel lymph node (SLN) status is the most important prognostic factor in melanoma patients with no evidence of distant metastasis. Objectives To assess the rate of distant metastases in patients with a positive SLN biopsy (SLNB). Methods Forty‐six consecutive patients with a positive SLNB underwent PET or PET–computed tomography within 6 weeks of the SLNB procedure. The patients did not present any clinical sign of nodal involvement or of distant metastasis. PET findings were classified as positive, negative or nonconclusive. Results No patient had a positive PET scan for distant metastasis. Six patients (13%) had a nonconclusive PET scan; none of them presented distant metastasis within 12 months. Forty patients (87%) had a negative PET scan; among them five (12%) presented with distant metastasis within 12 months. Conclusions Fluorodeoxyglucose positron emission tomography failed to detect distant metastases at initial staging in patients with a positive SLNB, even in patients who presented with distant metastases within 12 months after the FDG PET scan. These results could be explained by the low prevalence of macroscopic metastatic disease at this stage and by the important delay between the onset of the spread of microscopic metastatic disease and the identification by PET scan of macroscopic metastatic disease.     

Usefulness of docetaxel as first‐line chemotherapy for metastatic extramammary Paget's disease

In invasive extramammary Paget's disease (EMPD), distant metastases may develop and the condition may become fatal; however, no standardized treatment has been established. Although based on only a few cases, several chemotherapy regimens were reported to be promising. We conducted a multicenter, retrospective study to evaluate the efficacy of docetaxel for metastatic EMPD. We retrospectively collected data on 18 metastatic EMPD patients treated using docetaxel from 1998 to 2012 in 12 institutes in Japan. The following clinical data were collected: tumor response, time to progression, overall survival and adverse effects. Of those, three patients treated combined with S‐1, one patient treated with weekly schedule and one patient treated combined with radiotherapy were excluded from the further analysis. All 13 patients received monthly docetaxel as the first‐line treatment. The average number of treatment cycles was 9.1. Among the 12 patients with a confirmed response, seven (58%) showed a partial response, three (25%) stable disease and two (17%) progressive disease. The disease control rate (partial response + stable disease) was as high as 83%. The time to progression and median overall survival were 7.1 and 16.6 months, respectively. The 1‐year overall survival rate determined by the Kaplan–Meier method was 75.0%. All adverse effects were manageable and no treatment‐related deaths were observed. The high disease control rate and overall survival shown by this study suggest that first‐line use of docetaxel may be a promising treatment for metastatic EMPD. A prospective clinical trial is required to confirm our results.     

Cutaneous melanoma: baseline and ongoing laboratory evaluation

Numerous laboratory tests and imaging methods are available that can be used in patients who are diagnosed with cutaneous melanoma. The downside risks related to testing are cost and patient anxiety. Therefore, it must be critically considered which examinations are useful and feasible. After a diagnosis of primary cutaneous melanoma, many physicians in Germany perform lymph node ultrasound to detect occult regional metastasis. Whole-body imaging techniques, except the physical examination, are unlikely to detect distant occult metastasis. In tumors that have an intermediate or high risk of recurrence (> 1 mm tumor thickness), baseline whole-body imaging may serve as a reference for ongoing evaluation. During follow-up care, physical examination alone is appropriate when there is a low risk for recurrence (up to 1-mm tumor thickness). In patients whose tumors are > 1 mm thickness, regular lymph node ultrasound examinations and determination of serum tumor marker S-100beta protein are commonly used by physicians in Germany. Whole-body imaging techniques are useful in patients who have locoregional and/or distant metastasis. For consideration of surgical resections in stage IV disease, more advanced examinations techniques such as positron emission tomography-computed tomography or whole body magnetic resonance imaging may be used. Early detection of limited disease using these methods may be helpful for patients who have locoregional metastases and for 10-20% of patients who have distant metastases and whose limited disease may be amenable to surgical resection.     

乳房外Paget病的治疗进展

乳房外Paget病好发于老年人,多发生于肛门及外生殖器周围,由于早期皮损与湿疹、皮炎类似,容易误诊。乳房外Paget病的首选治疗方法为手术治疗,由于皮损边界不清、有多处病灶、肿瘤组织呈跳跃性生长,很难保证切除干净致术后复发率高。其他治疗方法有：放射治疗、化学治疗、光动力疗法、免疫调节剂治疗、分子靶向治疗等。乳房外Paget病预后主要与肿瘤的浸润深度、区域淋巴结转移、淋巴血管转移相关。前哨淋巴结活检对淋巴结清扫有指导意义,选择性淋巴结清扫有助于后续治疗,提高患者生存率。     

Conjunctival melanoma: local–regional control rates,and impact of high‐risk histopathologic features

Background: Conjunctival melanoma is an uncommon malignancy with the potential for significant morbidity. Ulceration is known to be an indicator of more aggressive cutaneous melanoma. This factor has not been previously evaluated in conjunctival melanoma. Methods: Twenty‐six patients with conjunctival melanoma who underwent excision by a single surgeon at a cancer referral center treated between June 2003 and July 2008 were included. The medical records were reviewed for clinical and pathological data. Outcomes assessed included local recurrence, regional lymph node metastasis, distant metastasis, use of adjuvant topical chemotherapy or adjuvant radiation therapy, final visual acuity and death. Results: Local recurrence was seen in three patients (12%). Regional lymph node metastasis and distant metastasis were each seen in four patients (15%). Tumors >2.0 mm thick were more likely to develop distant metastasis than those with a thickness of <2.0 mm (p = 0.0331). Ulceration was noted in 10 of 26 patients. Regional lymph node metastasis and distant metastasis were each seen in 4 of 10 patients with ulceration, and none of the patients without ulceration. Conclusions: Ulceration in conjunctival melanoma may be an important histopathologic predictor of a more aggressive tumor. Globe‐sparing multi‐modality management of conjunctival melanoma can yield acceptable rates of local–regional recurrence. Savar A, Esmaeli B, Ho H, Liu S, Prieto VG. Conjunctival melanoma: local–regional control rates, and impact of high‐risk histopathologic features.     

Modified weekly regimen of cisplatin,epirubicin and paclitaxel induced a durable response in two cases of metastatic extramammary Paget's disease

Metastatic extramammary Paget's disease (EMPD) is a rare cancer with no standardized treatment. We report two cases of metastatic EMPD treated with a modified weekly PET (cisplatin, epirubicin and paclitaxel) regimen given biweekly (i.e. 2 weeks on/2 weeks off) that had durable responses. Case 1 was a 74‐year‐old man with EMPD metastatic to lymph nodes, lung, and bone who presented with a hemorrhagic tumor on the scrotum. We tried the PET regimen weekly, but adjusted the interval to biweekly after two doses because of hematological side‐effects. After five doses, he showed a partial response (PR) on imaging, including the bone lesions. The lesions have remained the same size for 1 year. Case 2 was a 65‐year‐old man with EMPD metastatic to a right inguinal lymph node who presented with an erosive tumor on the scrotum. He was started on weekly docetaxel. However, the lymph node grew and iliac lymph node metastasis developed. Therefore, we tried the PET regimen with a 2 weeks on/2 weeks off schedule. After five doses, he showed a PR. In both cases, all adverse effects were manageable and this modified regimen could be administrated on an outpatient basis. With no current validated chemotherapy regimen, clinicians may consider a modified weekly PET regimen in future treatment of metastatic EMPD.     

Metastatic extramammary Paget's disease treated with paclitaxel and trastuzumab combination chemotherapy

In the treatment of metastatic breast cancer, trastuzumab, a recombinant monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is effective when tumor cells overexpress HER2 protein. Although some cases of extramammary Paget's disease (EMPD) also express HER2 protein, no case of EMPD has been reported to be treated with trastuzumab. A 75-year-old man who suffered from EMPD of the scrotum and inguinal region underwent a local excision and lymph node dissection. Tumor cells invaded the dermis and lymph nodes. Although he was postoperatively treated with adjuvant chemotherapies, metastatic skin lesions appeared and spread over his left thigh, rapidly and widely. Tumor cells disseminated along lymph vessels in the dermis and overexpressed HER2 protein. We administered paclitaxel and trastuzumab according to a protocol for HER2-positive metastatic breast cancers. The skin metastasis dramatically decreased during the regimen and a histopathological examination showed that most of HER2-positive tumor cells diminished. Six months later, metastases were found in the central nervous system (CNS), but no other metastases were found in the skin, visceral organs or lymph nodes. Trastuzumab and paclitaxel-combination with the assessment of central nervous system lesions should be considered as an option for the treatment of HER2-positive EMPD.     

Outcomes of lymph node dissection in the treatment of extramammary Paget’s disease: A single-institution study

Extramammary Paget’s disease (EMPD) often invades the dermis and metastasizes to the lymph nodes. Patients with EMPD associated with lymph node metastases have poor prognosis; to date, effective treatment has not yet been established. Lymph node dissection, aiming to control the local disease, is a standard form of management for EMPD patients with lymph node metastases (LNM). We investigated the clinical and pathological features, treatment strategies and prognostic factors of patients with metastatic EMPD who underwent lymph node dissection. We retrospectively evaluated 38 cases of extramammary Paget’s disease with lymph node metastasis over 10 years. All patients underwent wide resection of the primary lesion and lymph node dissection. Univariate analysis revealed the number of metastatic nodes and lymphadenopathy as prognostic factors. In multivariate analysis, the number of metastatic lymph nodes retained statistical significance (hazard ratio, 35.3; 95% confidence interval, 3.23–387.0; P = 0.003). The 5-year survival rate was 100% and 19.1% in patients with two or less LNM and with three or more LNM, respectively. In patients with three or more LNM, the 5-year survival rate after adjuvant radiation therapy was better than that after surgery alone (75% vs 0%). In conclusion, patients with two or less LNM can be expected to have long-term survival with lymph node dissection only, while patients with three or more LNM may require adjuvant radiation therapy to improve prognosis. These results suggest that lymph node dissection may be a strategy to treat EMPD with regional LNM.     

Efficacy of low‐dose 5‐fluorouracil/cisplatin therapy for invasive extramammary Paget's disease

Extramammary Paget's disease (EMPD) is one of the cutaneous adenocarcinomas. The effective chemotherapy for advanced EMPD has not been established. This study was designed to evaluate the efficacy of combination 5‐fluorouracil (500 mg/body, 7 days/week) and cisplatin (5 mg/body 5 days/week) for invasive EMPD. Seventeen EMPD patients with multiple metastases who visited our dermatology clinic between October 2004 and May 2016 (mean age, 76.9 years; 10 men, seven women) were retrospectively analyzed. Eight EMPD patients underwent low‐dose 5‐fluorouracil/cisplatin therapy and nine patients chose best supportive care. The average number of treatment cycles was 12.3. All patients had a confirmed response, four (50%) showed a partial response, two (25%) stable disease and two progressive disease. The median times to progression‐free and overall survival were 25.0 and 77.4 weeks, respectively. There was no severe (grade 3 and 4) adverse event. Although not significant, the survival of the patients treated with low‐dose 5‐fluorouracil/cisplatin therapy showed a trend toward improved survival as compared with best supportive care (P = 0.08, log–rank test). This regimen had low risk and relatively high disease control rate, suggesting that this regimen be recommended as one of the treatment options for advanced EMPD.     

Multiple lymphadenopathy as an initial sign of extramammary Paget disease

Extramammary Paget disease (EMPD) often develops in external genitalia. Paget cells can, however, adopt an invasive phenotype and metastasize to regional lymph nodes and beyond, leading to poor patient outcomes. Based on this clinical observation, multiple lymphadenopathy may represent an initial sign of EMPD. To address the potential significance of multiple lymph node swelling in EMPD, we report two patients with cutaneous primary EMPD who showed multiple lymphadenopathy as an initial sign during the clinical course of the disease as well as tumour metastasis. Significantly, marked lymphatic vessel growth was observed in regional lymph nodes that underwent massive tumour cell invasion. Therefore, nodal lymphangiogenesis may promote tumour cell invasion and metastasis to distant organs, including the lymph nodes, emphasizing the clinical relevance of multiple lymphadenopathy.     

Decreased serum tryptophan concentration predicts poor prognosis in malignant melanoma patients

BACKGROUND: Indoleamine (2,3)-dioxygenase (IDO) catalyses the initial, rate-limiting step in the degradation of the essential amino acid tryptophan. Via tryptophan deprivation, IDO activity suppresses T cell proliferation and differentiation and is thought to be a fundamental immune escape mechanism for tumor cells. OBJECTIVE AND METHODS: To investigate the potential role of tryptophan degradation as a prognostic marker, serum tryptophan and kynurenine concentrations and the kynurenine-to-tryptophan ratio (kyn/trp) in 87 patients with malignant melanoma were compared to the course of the disease and to concentrations of the immune activation marker neopterin. RESULTS: Compared to 49 healthy volunteers, the melanoma patients presented with lower tryptophan levels due to accelerated degradation. This was especially true for the subgroups of patients with distant metastases (p = 0.01), though not in patients with lymph node metastases or in patients who had not yet progressed. There existed a positive correlation between kyn/trp and neopterin concentrations (r(s) = 0.587, p <0.001). In patients who died due to dissemination of the tumor, median tryptophan concentrations were significantly decreased (p = 0.006) and kyn/trp (p = 0.03) and neopterin concentrations (p = 0.002) were higher compared to survivors. In addition, lower tryptophan concentrations as well as higher kyn/trp and neopterin concentrations predicted a shorter survival. CONCLUSION: Decreased serum tryptophan concentrations and elevated serum neopterin levels can be used as predictive markers for the future course in melanoma patients. Moreover, our data support previous speculations that a higher degree of IDO expression could play a crucial role for tumor progression.     

Evaluation of positron emission tomography imaging to detect lymph node metastases in patients with extramammary Paget's disease

Patients with extramammary Paget's disease (EMPD) have a relatively good prognosis, when spread of the tumor cells is limited to the epidermis. However, invasive EMPD has a poor prognosis, when the patients have regional lymph node metastasis. Detection of nodal metastasis is thus mandatory to manage EMPD. To evaluate the ¹⁸F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) imaging to assess lymph node metastasis, 15 patients with histologically proven primary EMPD were enrolled in this study. All patients underwent whole‐body PET prior to sentinel lymph node biopsy (SLNB). The maximum standardized uptake value (SUVmax) of more than 2.5 was evaluated as positive PET indicative of malignancy. Among 14 cases with the primary genital lesions, 11 cases underwent bilateral SLNB of the inguinal nodal basin and the remaining three cases unilateral SLNB. One case with a primary axillary lesion underwent unilateral SLNB of the axillary nodal basin. Therefore, a total of 26 regional basins were investigated. In general, nodal basins can be categorized into four groups: (i) histologically negative and PET negative (true negative); (ii) histologically positive and PET negative (false negative); (iii) histologically positive and PET positive (true positive); and (iv) histologically negative and PET positive (false positive) groups. In the 26 nodal basins, there were 19 true negative and seven true positive cases, and neither false negative nor false positive cases were observed. The mean SUVmax was significantly higher in the true positive basins (8.03 ± 3.34) than in the true negative basins (0.26 ± 0.56). The SUVmax value may be useful for detection of nodal metastasis.