Ca15-3在乳腺外Paget病鉴别诊断中的价值
作者：孔祥田 涂平 李竞贤 曾荔 夏同礼 郭应禄
单位：孔祥田 曾荔 夏同礼 郭应禄 北京医科大学第一医院泌尿外科研究所；涂平 皮肤科；李竞贤 病理科，北京 100034
关键词：佩吉特病；乳腺外；诊断；Ca15-3☆；诊断；鉴别；Bowen病；诊断
北京医科大学学报990512 摘 要 目的：探讨Ca15-3在Paget病鉴别诊断中的价值。方法：对11例阴囊Paget病回顾性地做Ca15-3、EMA、CEA和HMB45免疫组化染色，并以4例Bowen病和1例恶性黑色素瘤做对照。结果：Ca15-3、EMA在Paget病和大、小汗腺及皮脂腺均有较强的表达，4例Bowen病均无Ca15-3表达，但其中2例有EMA表达。CEA在6例(54.5%)Paget病中有表达。HMB45只在恶性黑色素瘤中表达。结论：Ca15-3在Paget细胞的相对特异性表达提示它可作为Paget病与Bowen病鉴别诊断的标志物，其对诊断的敏感性与EMA相同，但特异性高于EMA。同时还说明Paget病的发生可能与汗腺有关。
, 百拇医药
中国图书资料分类法分类号 R711.72
The value of Ca15-3 in differential diagnosis of Paget's disease
KONG Xiang-Tian#， TU Ping, LI Jing-Xian, ZENG Li, XIA Tong-Li, GUO Ying-Lu
(#Institute of Urology, the First Hospital, Beijing Medical University, Beijing 100034)
MeSH Paget's disease, extramammary/diag Ca15-3☆ Diagnosis, differential Bowen's disease/diag
, 百拇医药
ABSTRACT Objective: To probe the value of Ca15-3, an antibody to human milk-fat globule membrane and to the membranous component of mammary cancer cells, in differential diagnosis of Paget's disease. Methods: A retrospective study of 11 cases of scrotal Paget's disease from 1984 to 1997 in our hospital was carried out, and 4 cases of Bowen's disease and 1 of malignant melanoma were studied as control. Ca15-3, EMA, CEA, HMB45 were immunostained in all cases. Results: Paget's cells stained strongly with antibodies Ca15-3 and EMA, and staining with Ca15-3 and EMA was also observed in the ductal and secretory portions of the eccrine and apocrine glands, and in the sebaceous gland cells. Staining with the antibody CEA was observed in 54.5% of the cases in Paget's disease, and none in Bowen's disease. Expression of EMA was also observed in 2 out of 4 cases in Bowen's disease. HMB45 was the only antigen expressed in malignant melanoma. Conclusion: Ca15-3 was specifically expressed in Paget's cells. This result demonstrated that Ca15-3 can be used as a marker in the differential diagnosis between Paget's disease and Bowen's disease. It has the same sensitivity as EMA and higher specificity than EMA in differential diagnosis. The coexpression of Ca15-3 in Paget cells and in cutaneous adenexal organs suggests that the origin of Paget cells may be the secretory cells of sweat glands.
, 百拇医药
(J Beijing Med Univ, 1999,31:426-428)
在Paget病病理诊断中,除常规HE染色外，还发现Paget细胞表达许多上皮和癌基因产物，如低分子量细胞角蛋白、上皮膜抗原(EMA)、癌胚抗原(CEA)和Ca15-3等[1]。但是，需与Paget病相鉴别的Bowen病也表达其中部分产物,所以找到Paget细胞特异的标志物对鉴别诊断十分必要。我们对我院1984～1997年间收治的11例阴囊Paget病全部做Ca15-3、EMA、CEA和HMB45 4种抗体的免疫组化染色，并以4例Bowen病和1例恶性黑色素瘤做对照研究，发现Ca15-3在Paget细胞呈相对特异性表达。报告如下。
1 材料与方法
对1984～1997年间我院收治的11例阴囊Paget病进行回顾性研究，复查病理切片并做免疫组化染色。选取4例Bowen病和1例皮肤恶性黑色素瘤(以下简称恶黑)做对照研究。所用抗体鼠抗人Ca15-3(1∶50)、EMA(1∶100)、HMB45(1∶75)和CEA(工作液)均为美国Zymed公司产品，由北京中山生物制品公司提供。SP法染色。采用微波进行抗原修复。设阳性和阴性对照。染色结果根据强度判断为-～+++不等。
, 百拇医药
2 结果
2.1 上述抗体在表皮及其附属器中的表达
Ca15-3在正常皮肤的大、小汗腺导管和分泌腺的管腔表面和分泌上皮细胞胞浆表达较强(++～+++, 图1), 而导管的基底细胞和分泌腺的肌上皮细胞无表达。皮脂腺有较强表达。EMA的表达情况同Ca15-3, 但表达强度强于Ca15-3(表1)。CEA只在小汗腺导管和分泌腺的管腔表面有弱表达(+/-)。HMB45只在表皮黑色素细胞表达。
图1 皮肤小汗腺管腔表面和分泌上皮Ca15-3有较强的表达 ×50
Figure 1 Strong expression of Ca15-3 in eccrine sweat glands ×50
, 百拇医药
表1 正常表皮及皮肤附属器几种标志物的表达
Table 1 Expression of antibodies in normal epidermis and its adenexal structures
Ca15-3+
EMA+
CEA+
HMB45+
Epidermal keratinocytes
-
-
, 百拇医药
-
-
Melanocytes
-
-
-
++
Eccrine sweat glands
Ducts luminal surface
++
+++
+/-
-
, 百拇医药
luminal cells
++
+++
+/-
-
basal cells
-
-
-
-
Secretary elements
luminal surface
, 百拇医药 ++
+++
+/-
-
secretary cells
++
+++
+/-
-
myoepithelial cells
-
-
-
, http://www.100md.com
-
Apocrine sweat glands
Ducts luminal surface
+++
+++
-
-
luminal cells
+++
+++
-
-
, 百拇医药 basal cells
-
-
-
-
Secretary elements
luminal surface
+++
+++
-
-
secretary cells
+++
, http://www.100md.com
+++
-
-
myoepithelial cells
-
-
-
-
Sebaceous glands
+++
+++
-
-
, 百拇医药
+, immunohistochemical staining positive.
2.2 皮肤肿瘤免疫组织化学染色结果
本组皮肤肿瘤Ca15-3和EMA在11例Paget病中均表达(图2)，其中包括1例转移至腹股沟淋巴结的Paget病(图3)。而CEA只在其中的6例中有表达(54.5%)。EMA在Paget病和Bowen病间有交叉反应，4例Bowen病中2例有EMA的表达。而Ca15-3在Bowen病呈阴性反应。HMB45只在恶黑中表达(表2)。
图2 Paget细胞Ca15-3阳性表达，而角化上皮细胞阴性 ×50
Figure 2 Staining is positive for Ca15-3 in Paget cells and negative in keratinocytes ×50
, 百拇医药
表2 皮肤肿瘤免疫组织化学染色结果
Table 2 Immunohistochemical staining results of skin tumors Tumors
Cases
Ca15-3+
EMA+
CEA+
HMB45+
Paget's disease
11
11/11
, 百拇医药
11/11
6/11
0/11
Bowen's disease
4
0/4
2/4
0/4
0/4
Malignant melanoma
1
0/1
0/1
, 百拇医药
0/1
1/1
3 讨论
在皮肤肿瘤中，Paget病、Bowen病和恶黑是需要仔细进行鉴别的，尤其是Paget样Bowen病(Pagetoid Bowen's disease)、表皮内表浅扩散的恶黑(Intraepidermal superficial spreading malignant melanoma)和Paget样无色素性恶黑(Pagetoid amelanotic malignant melanoma),在HE染色切片上极易与Paget病混淆[2]，但它们的预后差别很大。恶黑易浸润和转移，预后最差。而Bowen病为皮肤原位癌或称鳞状上皮表皮内瘤，不易浸润转移，预后好。Paget病尽管大多数病例预后较好，但少数病例有真皮浸润(图4)和远处转移(图3)，偶尔有伴有内脏器官恶性肿瘤的可能[2]，预后介于Bowen病和恶黑间。所以明确诊断具有实际的临床意义。
, 百拇医药
图3 转移至腹股沟淋巴结的Paget细胞Ca15-3强阳性表达 ×50
Figure 3 Paget cells metastasized to inguinal lymph node strongly express Ca15-3 ×50
图4 Paget细胞浸润真皮，EMA免疫组化染色 ×50
Figure 4 Invasive Paget cells in dermis are demonstrated by EMA immunohistochemistry ×50
除上述肿瘤所特有的组织病理学表现外，免疫组织化学方法是一种简便可行的鉴别手段。研究显示Paget细胞表达EMA、GCDFP-15(gross cystic disease fluid protein-15,)、人乳脂肪球蛋白(human milk-fat globule protein)Ca15-3等；而Bowen病通常不表达CEA、GCDFP-15和低分子质量细胞角蛋白。恶黑与前两者鉴别的标志物为S-100和HMB45强阳性[2]。我们的研究表明，CEA在Paget病54.5%(6/11)表达; 而EMA 100%表达，但它也在少数Bowen病有表达，说明它的特异性还不能满足鉴别诊断的要求。近几年，科学家从转移的乳腺癌中提纯的人乳脂肪球蛋白，其抗体Ca15-3是相对分子质量为300×103～450 ×103的糖蛋白[1]。不仅发现乳腺癌患者的血清Ca15-3水平增高[3]，还发现在Paget病中有较强的表达[1]。
, http://www.100md.com
本研究表明，Ca15-3在乳腺外Paget病中有特异性表达，而在Bowen病、恶黑中则检测不到。不仅如此，Ca15-3在大、小汗腺和皮脂腺中也有较强的表达。Tsuji[1]检测了7例乳腺Paget病、5例外阴Paget病、2例阴囊Paget病和2例腋窝Paget病，发现所有的Paget病均有Ca15-3的表达。说明无论是乳腺Paget病还是乳腺外Paget病Ca15-3都有稳定的表达。我们的研究结果与文献[1]相符，并且显示Ca15-3可以作为鉴别Paget病和Bowen病的标志物。当然，还需在更多的病例上研究证实。
Ca15-3在皮肤附属器上也有较强的表达，故皮肤附属器肿瘤也会有Ca15-3的表达，有学者甚至把Ca15-3作为皮肤附属器肿瘤的标志物[4]。Ca15-3在大、小汗腺和Paget病的同步表达，提示Paget病的发生可能和汗腺有关。此结果与乳腺外Paget病的“汗腺演化学说”相符，何况组织化学、免疫组织化学和超微结构研究显示Paget细胞和顶浆分泌腺的表型非常相似[1，2，5]，提示乳腺外Paget病可能主要来源于汗腺，或向汗腺分化。此学说可以解释Paget病易发生于汗腺分布多的区域以及这些部位多处同时发病的现象。
, http://www.100md.com
注：☆ 自由词。
参考文献
1 Tsuji T. Mammary and extramammary Paget's disease: expression of Ca15-3, Ka-93, Ca19-9 and CD44 in paget cells and adjacent normal skin. Br J Dermatol, 1995, 132:7
2 Suster S. Clear cell tumors of the skin. Semin Diag Pathol, 1996, 13:40-59
3 Sofi F, Kohler I, Rottinger E, et al. The value of the tumor marker Ca15-3 in diagnosing and monitoring breast cancer. Cancer, 1991, 68:574-582
4 Yasui S, Ando I, Kukita A, et al. DF3(Ca15-3) antibody as a marker of cutaneous adenexal tumors. Acta Derm Venereol, 1994, 74:98-100
5 Jones RZ Jr, Ackerman AB. Extramammary Paget's disease: A critical reappraisal. Am J Dermatopathol, 1979, 1:101-103
(1998-10-18收稿), 百拇医药
单位：孔祥田 曾荔 夏同礼 郭应禄 北京医科大学第一医院泌尿外科研究所；涂平 皮肤科；李竞贤 病理科，北京 100034
关键词：佩吉特病；乳腺外；诊断；Ca15-3☆；诊断；鉴别；Bowen病；诊断
北京医科大学学报990512 摘 要 目的：探讨Ca15-3在Paget病鉴别诊断中的价值。方法：对11例阴囊Paget病回顾性地做Ca15-3、EMA、CEA和HMB45免疫组化染色，并以4例Bowen病和1例恶性黑色素瘤做对照。结果：Ca15-3、EMA在Paget病和大、小汗腺及皮脂腺均有较强的表达，4例Bowen病均无Ca15-3表达，但其中2例有EMA表达。CEA在6例(54.5%)Paget病中有表达。HMB45只在恶性黑色素瘤中表达。结论：Ca15-3在Paget细胞的相对特异性表达提示它可作为Paget病与Bowen病鉴别诊断的标志物，其对诊断的敏感性与EMA相同，但特异性高于EMA。同时还说明Paget病的发生可能与汗腺有关。
, 百拇医药
中国图书资料分类法分类号 R711.72
The value of Ca15-3 in differential diagnosis of Paget's disease
KONG Xiang-Tian#， TU Ping, LI Jing-Xian, ZENG Li, XIA Tong-Li, GUO Ying-Lu
(#Institute of Urology, the First Hospital, Beijing Medical University, Beijing 100034)
MeSH Paget's disease, extramammary/diag Ca15-3☆ Diagnosis, differential Bowen's disease/diag
, 百拇医药
ABSTRACT Objective: To probe the value of Ca15-3, an antibody to human milk-fat globule membrane and to the membranous component of mammary cancer cells, in differential diagnosis of Paget's disease. Methods: A retrospective study of 11 cases of scrotal Paget's disease from 1984 to 1997 in our hospital was carried out, and 4 cases of Bowen's disease and 1 of malignant melanoma were studied as control. Ca15-3, EMA, CEA, HMB45 were immunostained in all cases. Results: Paget's cells stained strongly with antibodies Ca15-3 and EMA, and staining with Ca15-3 and EMA was also observed in the ductal and secretory portions of the eccrine and apocrine glands, and in the sebaceous gland cells. Staining with the antibody CEA was observed in 54.5% of the cases in Paget's disease, and none in Bowen's disease. Expression of EMA was also observed in 2 out of 4 cases in Bowen's disease. HMB45 was the only antigen expressed in malignant melanoma. Conclusion: Ca15-3 was specifically expressed in Paget's cells. This result demonstrated that Ca15-3 can be used as a marker in the differential diagnosis between Paget's disease and Bowen's disease. It has the same sensitivity as EMA and higher specificity than EMA in differential diagnosis. The coexpression of Ca15-3 in Paget cells and in cutaneous adenexal organs suggests that the origin of Paget cells may be the secretory cells of sweat glands.
, 百拇医药
(J Beijing Med Univ, 1999,31:426-428)
在Paget病病理诊断中,除常规HE染色外，还发现Paget细胞表达许多上皮和癌基因产物，如低分子量细胞角蛋白、上皮膜抗原(EMA)、癌胚抗原(CEA)和Ca15-3等[1]。但是，需与Paget病相鉴别的Bowen病也表达其中部分产物,所以找到Paget细胞特异的标志物对鉴别诊断十分必要。我们对我院1984～1997年间收治的11例阴囊Paget病全部做Ca15-3、EMA、CEA和HMB45 4种抗体的免疫组化染色，并以4例Bowen病和1例恶性黑色素瘤做对照研究，发现Ca15-3在Paget细胞呈相对特异性表达。报告如下。
1 材料与方法
对1984～1997年间我院收治的11例阴囊Paget病进行回顾性研究，复查病理切片并做免疫组化染色。选取4例Bowen病和1例皮肤恶性黑色素瘤(以下简称恶黑)做对照研究。所用抗体鼠抗人Ca15-3(1∶50)、EMA(1∶100)、HMB45(1∶75)和CEA(工作液)均为美国Zymed公司产品，由北京中山生物制品公司提供。SP法染色。采用微波进行抗原修复。设阳性和阴性对照。染色结果根据强度判断为-～+++不等。
, 百拇医药
2 结果
2.1 上述抗体在表皮及其附属器中的表达
Ca15-3在正常皮肤的大、小汗腺导管和分泌腺的管腔表面和分泌上皮细胞胞浆表达较强(++～+++, 图1), 而导管的基底细胞和分泌腺的肌上皮细胞无表达。皮脂腺有较强表达。EMA的表达情况同Ca15-3, 但表达强度强于Ca15-3(表1)。CEA只在小汗腺导管和分泌腺的管腔表面有弱表达(+/-)。HMB45只在表皮黑色素细胞表达。
图1 皮肤小汗腺管腔表面和分泌上皮Ca15-3有较强的表达 ×50
Figure 1 Strong expression of Ca15-3 in eccrine sweat glands ×50
, 百拇医药
表1 正常表皮及皮肤附属器几种标志物的表达
Table 1 Expression of antibodies in normal epidermis and its adenexal structures
Ca15-3+
EMA+
CEA+
HMB45+
Epidermal keratinocytes
-
-
, 百拇医药
-
-
Melanocytes
-
-
-
++
Eccrine sweat glands
Ducts luminal surface
++
+++
+/-
-
, 百拇医药
luminal cells
++
+++
+/-
-
basal cells
-
-
-
-
Secretary elements
luminal surface
, 百拇医药 ++
+++
+/-
-
secretary cells
++
+++
+/-
-
myoepithelial cells
-
-
-
, http://www.100md.com
-
Apocrine sweat glands
Ducts luminal surface
+++
+++
-
-
luminal cells
+++
+++
-
-
, 百拇医药 basal cells
-
-
-
-
Secretary elements
luminal surface
+++
+++
-
-
secretary cells
+++
, http://www.100md.com
+++
-
-
myoepithelial cells
-
-
-
-
Sebaceous glands
+++
+++
-
-
, 百拇医药
+, immunohistochemical staining positive.
2.2 皮肤肿瘤免疫组织化学染色结果
本组皮肤肿瘤Ca15-3和EMA在11例Paget病中均表达(图2)，其中包括1例转移至腹股沟淋巴结的Paget病(图3)。而CEA只在其中的6例中有表达(54.5%)。EMA在Paget病和Bowen病间有交叉反应，4例Bowen病中2例有EMA的表达。而Ca15-3在Bowen病呈阴性反应。HMB45只在恶黑中表达(表2)。
图2 Paget细胞Ca15-3阳性表达，而角化上皮细胞阴性 ×50
Figure 2 Staining is positive for Ca15-3 in Paget cells and negative in keratinocytes ×50
, 百拇医药
表2 皮肤肿瘤免疫组织化学染色结果
Table 2 Immunohistochemical staining results of skin tumors Tumors
Cases
Ca15-3+
EMA+
CEA+
HMB45+
Paget's disease
11
11/11
, 百拇医药
11/11
6/11
0/11
Bowen's disease
4
0/4
2/4
0/4
0/4
Malignant melanoma
1
0/1
0/1
, 百拇医药
0/1
1/1
3 讨论
在皮肤肿瘤中，Paget病、Bowen病和恶黑是需要仔细进行鉴别的，尤其是Paget样Bowen病(Pagetoid Bowen's disease)、表皮内表浅扩散的恶黑(Intraepidermal superficial spreading malignant melanoma)和Paget样无色素性恶黑(Pagetoid amelanotic malignant melanoma),在HE染色切片上极易与Paget病混淆[2]，但它们的预后差别很大。恶黑易浸润和转移，预后最差。而Bowen病为皮肤原位癌或称鳞状上皮表皮内瘤，不易浸润转移，预后好。Paget病尽管大多数病例预后较好，但少数病例有真皮浸润(图4)和远处转移(图3)，偶尔有伴有内脏器官恶性肿瘤的可能[2]，预后介于Bowen病和恶黑间。所以明确诊断具有实际的临床意义。
, 百拇医药
图3 转移至腹股沟淋巴结的Paget细胞Ca15-3强阳性表达 ×50
Figure 3 Paget cells metastasized to inguinal lymph node strongly express Ca15-3 ×50
图4 Paget细胞浸润真皮，EMA免疫组化染色 ×50
Figure 4 Invasive Paget cells in dermis are demonstrated by EMA immunohistochemistry ×50
除上述肿瘤所特有的组织病理学表现外，免疫组织化学方法是一种简便可行的鉴别手段。研究显示Paget细胞表达EMA、GCDFP-15(gross cystic disease fluid protein-15,)、人乳脂肪球蛋白(human milk-fat globule protein)Ca15-3等；而Bowen病通常不表达CEA、GCDFP-15和低分子质量细胞角蛋白。恶黑与前两者鉴别的标志物为S-100和HMB45强阳性[2]。我们的研究表明，CEA在Paget病54.5%(6/11)表达; 而EMA 100%表达，但它也在少数Bowen病有表达，说明它的特异性还不能满足鉴别诊断的要求。近几年，科学家从转移的乳腺癌中提纯的人乳脂肪球蛋白，其抗体Ca15-3是相对分子质量为300×103～450 ×103的糖蛋白[1]。不仅发现乳腺癌患者的血清Ca15-3水平增高[3]，还发现在Paget病中有较强的表达[1]。
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本研究表明，Ca15-3在乳腺外Paget病中有特异性表达，而在Bowen病、恶黑中则检测不到。不仅如此，Ca15-3在大、小汗腺和皮脂腺中也有较强的表达。Tsuji[1]检测了7例乳腺Paget病、5例外阴Paget病、2例阴囊Paget病和2例腋窝Paget病，发现所有的Paget病均有Ca15-3的表达。说明无论是乳腺Paget病还是乳腺外Paget病Ca15-3都有稳定的表达。我们的研究结果与文献[1]相符，并且显示Ca15-3可以作为鉴别Paget病和Bowen病的标志物。当然，还需在更多的病例上研究证实。
Ca15-3在皮肤附属器上也有较强的表达，故皮肤附属器肿瘤也会有Ca15-3的表达，有学者甚至把Ca15-3作为皮肤附属器肿瘤的标志物[4]。Ca15-3在大、小汗腺和Paget病的同步表达，提示Paget病的发生可能和汗腺有关。此结果与乳腺外Paget病的“汗腺演化学说”相符，何况组织化学、免疫组织化学和超微结构研究显示Paget细胞和顶浆分泌腺的表型非常相似[1，2，5]，提示乳腺外Paget病可能主要来源于汗腺，或向汗腺分化。此学说可以解释Paget病易发生于汗腺分布多的区域以及这些部位多处同时发病的现象。
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注：☆ 自由词。
参考文献
1 Tsuji T. Mammary and extramammary Paget's disease: expression of Ca15-3, Ka-93, Ca19-9 and CD44 in paget cells and adjacent normal skin. Br J Dermatol, 1995, 132:7
2 Suster S. Clear cell tumors of the skin. Semin Diag Pathol, 1996, 13:40-59
3 Sofi F, Kohler I, Rottinger E, et al. The value of the tumor marker Ca15-3 in diagnosing and monitoring breast cancer. Cancer, 1991, 68:574-582
4 Yasui S, Ando I, Kukita A, et al. DF3(Ca15-3) antibody as a marker of cutaneous adenexal tumors. Acta Derm Venereol, 1994, 74:98-100
5 Jones RZ Jr, Ackerman AB. Extramammary Paget's disease: A critical reappraisal. Am J Dermatopathol, 1979, 1:101-103
(1998-10-18收稿), 百拇医药