Human Pathology (2014) 45, 1078–1083
www.elsevier.com/locate/humpath
Original contribution
p40 exhibits better specificity than p63 in distinguishing primary skin adnexal carcinomas from cutaneous metastases☆ Jonathan J. Lee BA a,1 , Mark C. Mochel MD b,1 , Adriano Piris MD a,b , Chakib Boussahmain BS b , Meera Mahalingam MD c , Mai P. Hoang MD a,b,⁎ a
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA Massachusetts General Hospital, Boston, MA 02114, USA c Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA b
Received 25 October 2013; revised 2 January 2014; accepted 8 January 2014
Keywords: p40; p63; Cytokeratin 5/6; Adnexal neoplasm; Cutaneous metastasis
Summary The histopathologic distinction between primary adnexal carcinomas and metastatic adenocarcinoma to the skin from sites such as the breast, lung, and others often presents a diagnostic dilemma. Current markers of diagnostic utility include p63 and cytokeratin 5/6; however, their expression has been demonstrated in 11% to 22% and 27% of cutaneous metastases, respectively. Furthermore, the immunoreactivity of p40 and GATA3 in various cutaneous adnexal carcinomas has not been previously reported. In the present study, we compared the expression of p40, p63, cytokeratin 5/6, and GATA3 in a total of 143 cases, including 67 primary adnexal carcinomas and 76 cutaneous metastases. p40, p63, cytokeratin 5/6, and GATA3 expression was observed in 80%, 84%, 86%, and 47% of primary adnexal carcinoma, respectively, and in 8%, 17%, 26%, and 40% of cutaneous metastases, respectively. χ2 Analysis revealed statistically significant P values (b.0001) for p40, p63, and cytokeratin 5/6 in distinguishing primary adnexal carcinoma from cutaneous metastases. In summary, while p63 and cytokeratin 5/6 have similar sensitivity (84% and 86%, respectively) in detecting primary adnexal carcinomas, p40 appeared to be the most specific marker (92%) with the best positive predictive value (90%). Since breast and lung are the most common sites of origin for cutaneous metastases, p40 is the best distinguishing marker in these settings. None of the four studied markers (p40, p63, cytokeratin 5/6, and GATA3) are helpful in distinguishing between primary adnexal carcinomas from cutaneous metastases of salivary gland or bladder malignancies. © 2014 Elsevier Inc. All rights reserved.
1. Introduction ☆
The authors have no conflicts of interest to disclose. ⁎ Corresponding author. Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. E-mail address: [email protected] (M. P. Hoang). 1 These authors contributed equally to this work. 0046-8177/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.humpath.2014.01.006
Cutaneous metastasis of a visceral malignancy is often a hallmark of a widely disseminated neoplasm and confers a poor prognosis. Survival after detection and/or diagnosis of a cutaneous metastatic lesion typically does not exceed 12 months [1]. The frequency of cutaneous metastases
p40 exhibits better specificity than p63 ranges from 0.7% to 10% in patients with visceral tumors. The most common sites for cutaneous metastases are the head and neck region as well as the trunk [2]. The most common primaries associated with cutaneous metastasis include malignancies of the breast, lung, gastrointestinal system and kidney [2]. Distinguishing between primary adnexal carcinoma and metastatic adenocarcinoma from breast, lung, and other primaries frequently presents a histopathologic challenge [3–13]. Currently, the most helpful immunohistochemical markers as diagnostic adjuncts include p63 and cytokeratin 5/6, both of which are preferentially expressed in primary sweat gland carcinomas [3–6,9–12]. Prior studies have investigated the role of p63 in distinguishing primary adnexal tumors with ductal differentiation from metastatic adenocarcinoma to skin [3–6,11,13]. These markers, however, lack specificity. p63 is also expressed in 11% to 22% of cutaneous metastases [3,6,9], and cytokeratin 5/6 expression can also be seen in 9% to 27% of adenocarcinomas of various primary sites [3,14,15]. The immunoreactivity of p40 and GATA3 in various cutaneous adnexal carcinomas has not been previously reported. p40 is an antibody that recognizes only the ΔNp63 isoform of p63, which is highly specific for squamous or basal epithelia [16,17]. Bishop et al [18] have recently demonstrated that p40 nuclear staining is equally sensitive but more specific for squamous cell carcinomas of the lung than p63, which also stains a consistent percentage of adenocarcinomas, small cell lung carcinoma, lymphoma, and other tumor types. GATA3 is a zinc transcription factor that regulates the normal development of a variety of tissues and cell types, including the skin [19]. GATA3 immunoreactivity has recently been reported to be specific for carcinomas of the breast, bladder and salivary gland [20–22]. In our previous study, we demonstrated that p63 is a sensitive and specific marker for primary adnexal carcinomas [11]. In the present study, we expanded and updated the same data, including additional cases of cutaneous apocrine carcinomas as well as cutaneous metastases from liver, prostate, salivary gland, and bladder malignancies and compare the sensitivities and specificities of p63 to p40, cytokeratin 5/6, and GATA3 in distinguishing between primary adnexal carcinoma and cutaneous metastases.
2. Materials and methods The study was approved by the institutional review boards of the Massachusetts General Hospital (2011-P-002489) and Boston University Medical Center (H-28387). Archival materials from 1990 to 2013 with a diagnosis of primary adnexal carcinomas or metastatic adenocarcinoma to the skin were retrieved from the database of both institutions. Approximately 270 cutaneous metastases were identified. Cases with equivocal primary sites or “unknown primary”;
1079 squamous cell carcinomas; and metastases from colorectal, biliary, and gallbladder primaries were excluded. One hundred forty-three cases (67 primary adnexal carcinomas and 76 cutaneous metastases) with available archival materials were retrieved from the pathology files (Table 1). Cutaneous metastases from stomach, endometrium, ovary, and lung included in our study were adenocarcinomas. Fiftynine primary adnexal carcinomas and 54 cutaneous metastases were included from our prior study [11]. The histologic sections of all cases were re-reviewed, and the diagnoses were confirmed. Clinical information was extracted from the medical records. All patient data were de-identified.
2.1. Immunohistochemical analysis Five-micrometer-thick whole tissue sections were obtained for immunohistochemical studies, which were performed on formalin-fixed, paraffin-embedded tissue using standard peroxidase immunohistochemistry techniques, heat-induced epitope retrieval buffer, and primary antibodies against p40 (Biocare Medical, Concord, MA), p63 (BC4A4, prediluted, Biocare Medical), cytokeratin 5/6 (B4, 1:100; Dako, Carpinteria, CA), and GATA3 (L50823, 1:250, Biocare Medical). Appropriate positive and negative controls were included. Positive staining of p40, p63, cytokeratin 5/6, and GATA3 were scored as 3+ (51%100% of the tumor cells), 2+ (26-50%), 1+ (6-25%), and 0/ negative (5% or less).
2.2. Statistical analysis The statistical association of p40, p63, cytokeratin 5/6, and GATA3 immunohistochemical expression in primary cutaneous adnexal carcinomas versus metastatic carcinoma to the skin was analyzed by χ2 analysis, with respect to each immunostain assessed in this study. A 2-tailed P b .05 was considered to be statistically significant.
3. Results 3.1. Immunohistochemical evaluation The immunohistochemical results for p40, p63, cytokeratin 5/6, and GATA3 are summarized in Tables 1 and 2, and Fig. The p63 staining of 59 primary adnexal carcinomas and 54 cutaneous metastases was included from our prior study [11]. Positive staining of cytokeratin 5/6 was noted by ascertaining expression in the cytoplasm and any nuclear staining was considered to be background artifact. Cytokeratin 5/6 highlights the entire epidermis, follicular epithelium, and eccrine glands. Nuclear p40, p63, and GATA3 staining was seen within basal keratinocytes, sebocytes, and eccrine glands.
1080 Table 1
J. J. Lee et al. Immunohistochemical results of p40, p63, cytokeratin 5/6, and GATA3 in primary adnexal carcinomas and cutaneous metastases N
p40
Primary adnexal carcinoma Eccrine carcinoma Apocrine carcinoma Hidradenocarcinoma Porocarcinoma Microcystic adnexal carcinoma Trichilemmal carcinoma Mucinous carcinoma Adenoid cystic carcinoma Total
13 9 9 16 14 3 2 1 67
10/12 0/9 9/9 16/16 14/14 3/3 0/2 1/1 53/66
Primary site of cutaneous metastases Liver Prostate Lung Ovary Endometrium Stomach Pancreas Thyroid Kidney Salivary gland Bladder Breast Paget's disease Extramammary Paget's disease Total
1 3 8 2 5 5 5 5 5 3 4 16 5 9 76
(83%) (0%) (100%) (100%) (100%) (100%) (0%) (100%) (80%)
0/1 (0%) 0/3 (0%) 0/8 (0%) 0/2 (0%) 0/5 (0%) 0/5 (0%) 2/5 (40%) 0/5 (0%) 0/5 (0%) 2/3 (67%) 2/4 (50%) 0/16 (0%) 0/5 (0%) 0/8 (0%) 6/75 (8%)
3.1.1. Primary adnexal carcinoma P40, p63, and cytokeratin 5/6 exhibit similar sensitivities in detecting primary adnexal carcinomas (80%, 84% and 86%, respectively) (Tables 1–3, Fig.). With the exception of apocrine and mucinous carcinomas, p40 and p63 staining was seen in the majority of the cases. Two of nine (22%) apocrine carcinomas were positive for p63 while all cases of apocrine carcinoma were negative for p40. This accounted for the 84% sensitivity of p63 versus the 80% sensitivity of p40. Cytokeratin 5/6 exhibited the best sensitivity for apocrine carcinoma (78%) and the best overall sensitivity (86%) in detecting primary adnexal carcinomas. Although GATA3 stained all of the included cutaneous apocrine and
Table 2
p63
Cytokeratin 5/6
GATA3
11/13 (85%) 2/9 (22%) 9/9 (100%) 16/16 (100%) 14/14 (100%) 3/3 (100%) 0/2 (0%) 1/1 (100%) 56/67 (84%)
8/12 7/9 7/7 16/16 14/14 2/3 0/2 1/1 55/64
(67%) (78%) (100%) (100%) (100%) (67%) (0%) (100%) (86%)
28/59 (47%)
0/1 (0%) 0/3 (0%) 2/8 (25%) 0/2 (0%) 1/5 (20%) 2/5 (40%) 2/5 (40%) 1/5 (20%) 0/5 (0%) 2/3 (67%) 2/4 (50%) 1/15 (7%) 0/5 (0%) 0/9 (0%) 13/75 (17%)
0/1 0/3 1/7 2/2 3/5 2/4 2/4 2/5 0/4 3/3 4/4 0/16 0/5 0/9 19/72
(0%) (0%) (14%) (100%) (60%) (50%) (50%) (40%) (0%) (100%) (100%) (0%) (0%) (0%) (26%)
0/1 (0%) 0/3 (0%) 0/8 (0%) 0/1 (0%) 0/5 (0%) 0/5 (0%) 0/5 (0%) 0/4 (0%) 0/5 (0%) 1/3 (33%) 4/4 (100%) 12/16 (75%) 4/4 (100%) 8/8 (100%) 29/72 (40%)
4/11 (36%) 9/9 (100%) 2/7 (29%) 3/15 (20%) 5/12 (42%) 3/3 (100%) 2/2 (100%)
mucinous carcinomas, its sensitivity for the remaining subtypes of adnexal carcinomas was poor and its overall sensitivity was only 47%. 3.1.2. Cutaneous metastases The expression of the four studied markers was most often seen in salivary gland and urothelial carcinomas (Tables 1–3, Fig.). Both p40 and p63 stained 40% to 67% of cutaneous metastases from the pancreas, salivary gland, and bladder. p63 stained additional cases of cutaneous metastases from lung, endometrium, stomach, thyroid, and breast. Thus, p63 exhibited 83% specificity versus 92% specificity with p40. The specificity of cytokeratin 5/6 is only 74% with staining of
Scoring summary of p40, p63, cytokeratin 5/6, and GATA3 immunohistochemical stains Primary adnexal carcinoma
Metastatic adenocarcinoma to skin
Grade of reactivity
Grade of reactivity
Markers
+ cases (%)
P40 p63 CK5/6 GATA3
53 56 55 28
(80) (84) (86) (47)
0 (%) 13 11 9 31
(20) (16) (14) (53)
1+ (%)
2+ (%)
3+ (%)
2 (3) 8 (12) 5 (8) 0 (0)
1 (2) 9 (13) 3 (5) 14 (24)
50 39 47 14
(76) (58) (73) (24)
+ cases (%)
0 (%)
1+ (%)
6 13 19 29
69 (92) 63 (83) 53 (74) 43 (60)
2 (3) 5 (7) 7 (10) 0 (0)
0/negative (5% or less of the tumor cells), 1+ (6%-25%), 2+ (26%-50%) and 3+ (51%-100%).
(8) (17) (26) (40)
2+ (%) 1 3 4 1
(1) (4) (6) (1)
3+ (%) 3 5 8 28
(4) (7) (11) (39)
p40 exhibits better specificity than p63
1081 Table 3 Sensitivities, specificities, positive predictive values, and negative predictive values of p40, p63, cytokeratin 5/6, and GATA3 with respect to the diagnosis of primary adnexal carcinoma
p40 p63 CK5/6 GATA3
Sensitivity
Specificity
PPV
NPV
P
80 84 86 47
92 83 74 60
90 81 74 49
84 85 85 58
b .0001 ⁎ b .0001 ⁎ b .0001 ⁎ .48
Abbreviations: NPV, negative predictive value; PPV, positive predictive value. ⁎ Statistically significant.
observed for p40, p63, and cytokeratin 5/6 in distinguishing primary adnexal carcinoma from cutaneous metastases.
4. Discussion
Fig. In a hidradenocarcinoma (A), the tumor cells exhibited strong staining for p40 (B), GATA3 (C), p63 (D), and cytokeratin 5/ 6 (E). On the contrary, in a case of metastatic gastric carcinoma (F), the tumor cells were negative for p40 (G) and GATA3 (H), while the adjacent epidermis was positive. The tumor cells were focally positive for p63 (I) and cytokeratin 5/6 (J).
all the metastases from the ovary and salivary gland. GATA3 stained all the metastases from the bladder and breast, and all the mammary and extramammary Paget disease cases. The overall specificity of GATA3 was only 60%.
3.2. Statistical analysis The sensitivity, specificity, positive predictive value and negative predictive value of each immunostain were calculated and listed in Table 3. Statistically significant P values were
Cutaneous metastases occur in up to 10% of all cancer patients and represent 2% of all skin tumors [1,23]. Cutaneous metastases may be the first manifestation of underlying visceral malignancy and may also be the first sign of extranodal disease, mandating alterations in therapy. In one study, these patients typically had a poor prognosis with an average reported survival of 7.5 months after diagnosis of the primary tumor [24]. Whereas local surgical or radiation therapies may provide long-term disease-free survival for patients with primary malignancies of the skin, cutaneous metastases require further systemic work-up and management of the underlying visceral malignancy in addition to the local treatment [25]. The most common primary sources of cutaneous metastases are the breast and ovary in women as opposed to the lung and large intestine in men [26]. However, cases of cutaneous metastatic disease from malignancies of the hepato-pancreaticobiliary, genitourinary, gynecologic, endocrine, neuroendocrine, cardiovascular, musculoskeletal, and central nervous systems as well as other primary sites have been reported in the literature, albeit, more rarely [26]. Cutaneous metastases may clinically and/or histologically mimic primary tumors of the skin. Thus, specific diagnosis of the lesion typically requires further immunohistochemical study as the histologic features may not be diagnostic. p63, a transcription factor belonging to the p53 gene family, plays a distinct role in the development, differentiation, and specialization of skin and cutaneous appendages and is believed to help maintain the proliferative capacity of the basal layer [27]. Nuclear expression of p63 in normal human multilayered epithelia has been documented in the respiratory tract, prostatic basal cells, uterine cervix, and urogenital tract in addition to the basal cells of the epidermis and cutaneous appendages, including the basal/myoepithelial cells of sweat glands [28]. Primary cutaneous adnexal
1082 neoplasms, squamous cell carcinomas of various sites, basal cell carcinoma, as well as urothelial carcinomas express p63 [28]. The sensitivity of p63 in our current study is 84% versus 91% observed in our previous study [11]. This is likely due to the fact that 9 cutaneous apocrine carcinomas were included in the current whereas only 2 were included in the prior. The sensitivity and specificity of p63 has been reported to range from 89-100% and 89-100%, respectively [3–6,11]. Kanitakis and Chouvet [6] reported that 5 (11%) of 45 cutaneous metastases expressed p63, emphasizing that the expression of p63 does not rule out metastatic origin of a carcinoma present in the skin. In the present study, cytokeratin 5/6 exhibited the best overall sensitivity (86%) in detecting primary adnexal carcinomas as well as the best sensitivity for apocrine carcinoma (78%). Cytokeratin 5/6 is a basic, high-molecularweight cytokeratin with an expression profile similar to that of p63 [28]. The expression of cytokeratin 5/6 in adnexal carcinomas versus cutaneous metastases has been studied previously by Plumb et al [12] and Qureshi et al [3]. Qureshi et al [3] found that cytokeratin 5/6 had a nearly identical staining profile to p63 in their comparison of primary cutaneous adnexal neoplasms and metastatic carcinomas. Furthermore, they reported that 20 of 22 primary cutaneous adnexal neoplasms whereas only 4 of 15 metastatic carcinomas stained positively for cytokeratin 5/6 (sensitivity 91%, specificity 73%) [3]. In a larger series, Plumb et al [12] reported similar results but clarified that metastatic breast carcinoma may express cytokeratin 5/6 in up to 47% (8 of17) of cases. Similar to the previous findings, cytokeratin 5/6 staining was seen in only 26% of cutaneous metastases in this series for a specificity of 74%. Our results indicate p40, an isoform of p63, shows better specificity than p63 for ruling out cutaneous metastases, especially from tumors of the breast, lung, endometrium, stomach, and thyroid. Bishop et al [18] recently reported similar results, demonstrating that p40 nuclear staining is equally sensitive but more specific for squamous cell carcinomas of the lung than is p63, which also stains a consistent percentage of adenocarcinomas, small cell lung carcinoma, lymphoma, and other tumor types. In our study, both p40 and p63 stained 40% to 67% of cutaneous metastases from pancreatic, salivary gland, and bladder malignancies, thereby highlighting the limitation of these stains in ruling out metastases from these organs. In their comparative study of cutaneous metastases from 12 cases of breast carcinomas and 13 cases of primary sweat gland neoplasms, Rollins-Raval et al [13] reported an overall sensitivity of 100% and specificity of 91% when using a panel of stains including p63, cytokeratin 5/ 6, CK14, CK17, and mammaglobin. Therefore, the overall sensitivity and specificity may be improved when both p40 and p63 are used together. According to our results, GATA3 does not appear to be specific for carcinomas of the breast, bladder and salivary gland as previously reported [20–22] because it also stains carcinomas of cutaneous adnexae. Indeed, GATA3 was
J. J. Lee et al. recently shown to stain occasional squamous cell carcinomas of the anus, cervix, and lung as well as more than half of all salivary gland neoplasms [20–22]. While present in tumors arising from the breast, bladder, mammary, and extramammary Paget’s disease, GATA3 immunoreactivity was absent in cutaneous metastases from the liver, prostate, lung, ovary, endometrium, stomach, pancreas, thyroid, and kidney. The expression of GATA3 in tumors of salivary gland, breast, and cutaneous adnexal carcinomas is likely due to the similar embryologic development of these ectodermally derived, exocrine, and secretory structures [22,29]. A panel of immunostains is helpful in the work up of cutaneous metastases. The differential expression of CK7 and CK20 is not completely specific [14]. Thus, a panel of CK7, CK20, TTF-1 (thyroid transcription factor-1), CDX2, CEA, MUC2, MUC5AC, estrogen receptor, and gross cystic disease fluid protein-15 has been proposed by Park et al [30] to improve prediction of the primary site. Approximately two-thirds of lung adenocarcinoma expresses TTF-1 [30]. The nuclear expression of CDX-2 would be seen in almost all colorectal carcinomas but only in a few cases of gastric, pancreaticobiliary, and mucinous ovarian adenocarcinomas [31]. In summary, although statistically significant P values (b.0001) were observed for p40, p63, and cytokeratin 5/6 in distinguishing primary adnexal carcinomas from cutaneous metastases, p40 appears to be the most specific marker. Since malignancies of the breast and lung are the most common site of origin for cutaneous metastases, p40 is the best distinguishing marker in these settings. None of the four studied markers (p40, p63, cytokeratin 5/6, and GATA3) are helpful in distinguishing between primary adnexal carcinomas and cutaneous metastases of salivary gland or bladder carcinomas.
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www.elsevier.com/locate/humpath
Original contribution
p40 exhibits better specificity than p63 in distinguishing primary skin adnexal carcinomas from cutaneous metastases☆ Jonathan J. Lee BA a,1 , Mark C. Mochel MD b,1 , Adriano Piris MD a,b , Chakib Boussahmain BS b , Meera Mahalingam MD c , Mai P. Hoang MD a,b,⁎ a
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA Massachusetts General Hospital, Boston, MA 02114, USA c Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA b
Received 25 October 2013; revised 2 January 2014; accepted 8 January 2014
Keywords: p40; p63; Cytokeratin 5/6; Adnexal neoplasm; Cutaneous metastasis
Summary The histopathologic distinction between primary adnexal carcinomas and metastatic adenocarcinoma to the skin from sites such as the breast, lung, and others often presents a diagnostic dilemma. Current markers of diagnostic utility include p63 and cytokeratin 5/6; however, their expression has been demonstrated in 11% to 22% and 27% of cutaneous metastases, respectively. Furthermore, the immunoreactivity of p40 and GATA3 in various cutaneous adnexal carcinomas has not been previously reported. In the present study, we compared the expression of p40, p63, cytokeratin 5/6, and GATA3 in a total of 143 cases, including 67 primary adnexal carcinomas and 76 cutaneous metastases. p40, p63, cytokeratin 5/6, and GATA3 expression was observed in 80%, 84%, 86%, and 47% of primary adnexal carcinoma, respectively, and in 8%, 17%, 26%, and 40% of cutaneous metastases, respectively. χ2 Analysis revealed statistically significant P values (b.0001) for p40, p63, and cytokeratin 5/6 in distinguishing primary adnexal carcinoma from cutaneous metastases. In summary, while p63 and cytokeratin 5/6 have similar sensitivity (84% and 86%, respectively) in detecting primary adnexal carcinomas, p40 appeared to be the most specific marker (92%) with the best positive predictive value (90%). Since breast and lung are the most common sites of origin for cutaneous metastases, p40 is the best distinguishing marker in these settings. None of the four studied markers (p40, p63, cytokeratin 5/6, and GATA3) are helpful in distinguishing between primary adnexal carcinomas from cutaneous metastases of salivary gland or bladder malignancies. © 2014 Elsevier Inc. All rights reserved.
1. Introduction ☆
The authors have no conflicts of interest to disclose. ⁎ Corresponding author. Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. E-mail address: [email protected] (M. P. Hoang). 1 These authors contributed equally to this work. 0046-8177/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.humpath.2014.01.006
Cutaneous metastasis of a visceral malignancy is often a hallmark of a widely disseminated neoplasm and confers a poor prognosis. Survival after detection and/or diagnosis of a cutaneous metastatic lesion typically does not exceed 12 months [1]. The frequency of cutaneous metastases
p40 exhibits better specificity than p63 ranges from 0.7% to 10% in patients with visceral tumors. The most common sites for cutaneous metastases are the head and neck region as well as the trunk [2]. The most common primaries associated with cutaneous metastasis include malignancies of the breast, lung, gastrointestinal system and kidney [2]. Distinguishing between primary adnexal carcinoma and metastatic adenocarcinoma from breast, lung, and other primaries frequently presents a histopathologic challenge [3–13]. Currently, the most helpful immunohistochemical markers as diagnostic adjuncts include p63 and cytokeratin 5/6, both of which are preferentially expressed in primary sweat gland carcinomas [3–6,9–12]. Prior studies have investigated the role of p63 in distinguishing primary adnexal tumors with ductal differentiation from metastatic adenocarcinoma to skin [3–6,11,13]. These markers, however, lack specificity. p63 is also expressed in 11% to 22% of cutaneous metastases [3,6,9], and cytokeratin 5/6 expression can also be seen in 9% to 27% of adenocarcinomas of various primary sites [3,14,15]. The immunoreactivity of p40 and GATA3 in various cutaneous adnexal carcinomas has not been previously reported. p40 is an antibody that recognizes only the ΔNp63 isoform of p63, which is highly specific for squamous or basal epithelia [16,17]. Bishop et al [18] have recently demonstrated that p40 nuclear staining is equally sensitive but more specific for squamous cell carcinomas of the lung than p63, which also stains a consistent percentage of adenocarcinomas, small cell lung carcinoma, lymphoma, and other tumor types. GATA3 is a zinc transcription factor that regulates the normal development of a variety of tissues and cell types, including the skin [19]. GATA3 immunoreactivity has recently been reported to be specific for carcinomas of the breast, bladder and salivary gland [20–22]. In our previous study, we demonstrated that p63 is a sensitive and specific marker for primary adnexal carcinomas [11]. In the present study, we expanded and updated the same data, including additional cases of cutaneous apocrine carcinomas as well as cutaneous metastases from liver, prostate, salivary gland, and bladder malignancies and compare the sensitivities and specificities of p63 to p40, cytokeratin 5/6, and GATA3 in distinguishing between primary adnexal carcinoma and cutaneous metastases.
2. Materials and methods The study was approved by the institutional review boards of the Massachusetts General Hospital (2011-P-002489) and Boston University Medical Center (H-28387). Archival materials from 1990 to 2013 with a diagnosis of primary adnexal carcinomas or metastatic adenocarcinoma to the skin were retrieved from the database of both institutions. Approximately 270 cutaneous metastases were identified. Cases with equivocal primary sites or “unknown primary”;
1079 squamous cell carcinomas; and metastases from colorectal, biliary, and gallbladder primaries were excluded. One hundred forty-three cases (67 primary adnexal carcinomas and 76 cutaneous metastases) with available archival materials were retrieved from the pathology files (Table 1). Cutaneous metastases from stomach, endometrium, ovary, and lung included in our study were adenocarcinomas. Fiftynine primary adnexal carcinomas and 54 cutaneous metastases were included from our prior study [11]. The histologic sections of all cases were re-reviewed, and the diagnoses were confirmed. Clinical information was extracted from the medical records. All patient data were de-identified.
2.1. Immunohistochemical analysis Five-micrometer-thick whole tissue sections were obtained for immunohistochemical studies, which were performed on formalin-fixed, paraffin-embedded tissue using standard peroxidase immunohistochemistry techniques, heat-induced epitope retrieval buffer, and primary antibodies against p40 (Biocare Medical, Concord, MA), p63 (BC4A4, prediluted, Biocare Medical), cytokeratin 5/6 (B4, 1:100; Dako, Carpinteria, CA), and GATA3 (L50823, 1:250, Biocare Medical). Appropriate positive and negative controls were included. Positive staining of p40, p63, cytokeratin 5/6, and GATA3 were scored as 3+ (51%100% of the tumor cells), 2+ (26-50%), 1+ (6-25%), and 0/ negative (5% or less).
2.2. Statistical analysis The statistical association of p40, p63, cytokeratin 5/6, and GATA3 immunohistochemical expression in primary cutaneous adnexal carcinomas versus metastatic carcinoma to the skin was analyzed by χ2 analysis, with respect to each immunostain assessed in this study. A 2-tailed P b .05 was considered to be statistically significant.
3. Results 3.1. Immunohistochemical evaluation The immunohistochemical results for p40, p63, cytokeratin 5/6, and GATA3 are summarized in Tables 1 and 2, and Fig. The p63 staining of 59 primary adnexal carcinomas and 54 cutaneous metastases was included from our prior study [11]. Positive staining of cytokeratin 5/6 was noted by ascertaining expression in the cytoplasm and any nuclear staining was considered to be background artifact. Cytokeratin 5/6 highlights the entire epidermis, follicular epithelium, and eccrine glands. Nuclear p40, p63, and GATA3 staining was seen within basal keratinocytes, sebocytes, and eccrine glands.
1080 Table 1
J. J. Lee et al. Immunohistochemical results of p40, p63, cytokeratin 5/6, and GATA3 in primary adnexal carcinomas and cutaneous metastases N
p40
Primary adnexal carcinoma Eccrine carcinoma Apocrine carcinoma Hidradenocarcinoma Porocarcinoma Microcystic adnexal carcinoma Trichilemmal carcinoma Mucinous carcinoma Adenoid cystic carcinoma Total
13 9 9 16 14 3 2 1 67
10/12 0/9 9/9 16/16 14/14 3/3 0/2 1/1 53/66
Primary site of cutaneous metastases Liver Prostate Lung Ovary Endometrium Stomach Pancreas Thyroid Kidney Salivary gland Bladder Breast Paget's disease Extramammary Paget's disease Total
1 3 8 2 5 5 5 5 5 3 4 16 5 9 76
(83%) (0%) (100%) (100%) (100%) (100%) (0%) (100%) (80%)
0/1 (0%) 0/3 (0%) 0/8 (0%) 0/2 (0%) 0/5 (0%) 0/5 (0%) 2/5 (40%) 0/5 (0%) 0/5 (0%) 2/3 (67%) 2/4 (50%) 0/16 (0%) 0/5 (0%) 0/8 (0%) 6/75 (8%)
3.1.1. Primary adnexal carcinoma P40, p63, and cytokeratin 5/6 exhibit similar sensitivities in detecting primary adnexal carcinomas (80%, 84% and 86%, respectively) (Tables 1–3, Fig.). With the exception of apocrine and mucinous carcinomas, p40 and p63 staining was seen in the majority of the cases. Two of nine (22%) apocrine carcinomas were positive for p63 while all cases of apocrine carcinoma were negative for p40. This accounted for the 84% sensitivity of p63 versus the 80% sensitivity of p40. Cytokeratin 5/6 exhibited the best sensitivity for apocrine carcinoma (78%) and the best overall sensitivity (86%) in detecting primary adnexal carcinomas. Although GATA3 stained all of the included cutaneous apocrine and
Table 2
p63
Cytokeratin 5/6
GATA3
11/13 (85%) 2/9 (22%) 9/9 (100%) 16/16 (100%) 14/14 (100%) 3/3 (100%) 0/2 (0%) 1/1 (100%) 56/67 (84%)
8/12 7/9 7/7 16/16 14/14 2/3 0/2 1/1 55/64
(67%) (78%) (100%) (100%) (100%) (67%) (0%) (100%) (86%)
28/59 (47%)
0/1 (0%) 0/3 (0%) 2/8 (25%) 0/2 (0%) 1/5 (20%) 2/5 (40%) 2/5 (40%) 1/5 (20%) 0/5 (0%) 2/3 (67%) 2/4 (50%) 1/15 (7%) 0/5 (0%) 0/9 (0%) 13/75 (17%)
0/1 0/3 1/7 2/2 3/5 2/4 2/4 2/5 0/4 3/3 4/4 0/16 0/5 0/9 19/72
(0%) (0%) (14%) (100%) (60%) (50%) (50%) (40%) (0%) (100%) (100%) (0%) (0%) (0%) (26%)
0/1 (0%) 0/3 (0%) 0/8 (0%) 0/1 (0%) 0/5 (0%) 0/5 (0%) 0/5 (0%) 0/4 (0%) 0/5 (0%) 1/3 (33%) 4/4 (100%) 12/16 (75%) 4/4 (100%) 8/8 (100%) 29/72 (40%)
4/11 (36%) 9/9 (100%) 2/7 (29%) 3/15 (20%) 5/12 (42%) 3/3 (100%) 2/2 (100%)
mucinous carcinomas, its sensitivity for the remaining subtypes of adnexal carcinomas was poor and its overall sensitivity was only 47%. 3.1.2. Cutaneous metastases The expression of the four studied markers was most often seen in salivary gland and urothelial carcinomas (Tables 1–3, Fig.). Both p40 and p63 stained 40% to 67% of cutaneous metastases from the pancreas, salivary gland, and bladder. p63 stained additional cases of cutaneous metastases from lung, endometrium, stomach, thyroid, and breast. Thus, p63 exhibited 83% specificity versus 92% specificity with p40. The specificity of cytokeratin 5/6 is only 74% with staining of
Scoring summary of p40, p63, cytokeratin 5/6, and GATA3 immunohistochemical stains Primary adnexal carcinoma
Metastatic adenocarcinoma to skin
Grade of reactivity
Grade of reactivity
Markers
+ cases (%)
P40 p63 CK5/6 GATA3
53 56 55 28
(80) (84) (86) (47)
0 (%) 13 11 9 31
(20) (16) (14) (53)
1+ (%)
2+ (%)
3+ (%)
2 (3) 8 (12) 5 (8) 0 (0)
1 (2) 9 (13) 3 (5) 14 (24)
50 39 47 14
(76) (58) (73) (24)
+ cases (%)
0 (%)
1+ (%)
6 13 19 29
69 (92) 63 (83) 53 (74) 43 (60)
2 (3) 5 (7) 7 (10) 0 (0)
0/negative (5% or less of the tumor cells), 1+ (6%-25%), 2+ (26%-50%) and 3+ (51%-100%).
(8) (17) (26) (40)
2+ (%) 1 3 4 1
(1) (4) (6) (1)
3+ (%) 3 5 8 28
(4) (7) (11) (39)
p40 exhibits better specificity than p63
1081 Table 3 Sensitivities, specificities, positive predictive values, and negative predictive values of p40, p63, cytokeratin 5/6, and GATA3 with respect to the diagnosis of primary adnexal carcinoma
p40 p63 CK5/6 GATA3
Sensitivity
Specificity
PPV
NPV
P
80 84 86 47
92 83 74 60
90 81 74 49
84 85 85 58
b .0001 ⁎ b .0001 ⁎ b .0001 ⁎ .48
Abbreviations: NPV, negative predictive value; PPV, positive predictive value. ⁎ Statistically significant.
observed for p40, p63, and cytokeratin 5/6 in distinguishing primary adnexal carcinoma from cutaneous metastases.
4. Discussion
Fig. In a hidradenocarcinoma (A), the tumor cells exhibited strong staining for p40 (B), GATA3 (C), p63 (D), and cytokeratin 5/ 6 (E). On the contrary, in a case of metastatic gastric carcinoma (F), the tumor cells were negative for p40 (G) and GATA3 (H), while the adjacent epidermis was positive. The tumor cells were focally positive for p63 (I) and cytokeratin 5/6 (J).
all the metastases from the ovary and salivary gland. GATA3 stained all the metastases from the bladder and breast, and all the mammary and extramammary Paget disease cases. The overall specificity of GATA3 was only 60%.
3.2. Statistical analysis The sensitivity, specificity, positive predictive value and negative predictive value of each immunostain were calculated and listed in Table 3. Statistically significant P values were
Cutaneous metastases occur in up to 10% of all cancer patients and represent 2% of all skin tumors [1,23]. Cutaneous metastases may be the first manifestation of underlying visceral malignancy and may also be the first sign of extranodal disease, mandating alterations in therapy. In one study, these patients typically had a poor prognosis with an average reported survival of 7.5 months after diagnosis of the primary tumor [24]. Whereas local surgical or radiation therapies may provide long-term disease-free survival for patients with primary malignancies of the skin, cutaneous metastases require further systemic work-up and management of the underlying visceral malignancy in addition to the local treatment [25]. The most common primary sources of cutaneous metastases are the breast and ovary in women as opposed to the lung and large intestine in men [26]. However, cases of cutaneous metastatic disease from malignancies of the hepato-pancreaticobiliary, genitourinary, gynecologic, endocrine, neuroendocrine, cardiovascular, musculoskeletal, and central nervous systems as well as other primary sites have been reported in the literature, albeit, more rarely [26]. Cutaneous metastases may clinically and/or histologically mimic primary tumors of the skin. Thus, specific diagnosis of the lesion typically requires further immunohistochemical study as the histologic features may not be diagnostic. p63, a transcription factor belonging to the p53 gene family, plays a distinct role in the development, differentiation, and specialization of skin and cutaneous appendages and is believed to help maintain the proliferative capacity of the basal layer [27]. Nuclear expression of p63 in normal human multilayered epithelia has been documented in the respiratory tract, prostatic basal cells, uterine cervix, and urogenital tract in addition to the basal cells of the epidermis and cutaneous appendages, including the basal/myoepithelial cells of sweat glands [28]. Primary cutaneous adnexal
1082 neoplasms, squamous cell carcinomas of various sites, basal cell carcinoma, as well as urothelial carcinomas express p63 [28]. The sensitivity of p63 in our current study is 84% versus 91% observed in our previous study [11]. This is likely due to the fact that 9 cutaneous apocrine carcinomas were included in the current whereas only 2 were included in the prior. The sensitivity and specificity of p63 has been reported to range from 89-100% and 89-100%, respectively [3–6,11]. Kanitakis and Chouvet [6] reported that 5 (11%) of 45 cutaneous metastases expressed p63, emphasizing that the expression of p63 does not rule out metastatic origin of a carcinoma present in the skin. In the present study, cytokeratin 5/6 exhibited the best overall sensitivity (86%) in detecting primary adnexal carcinomas as well as the best sensitivity for apocrine carcinoma (78%). Cytokeratin 5/6 is a basic, high-molecularweight cytokeratin with an expression profile similar to that of p63 [28]. The expression of cytokeratin 5/6 in adnexal carcinomas versus cutaneous metastases has been studied previously by Plumb et al [12] and Qureshi et al [3]. Qureshi et al [3] found that cytokeratin 5/6 had a nearly identical staining profile to p63 in their comparison of primary cutaneous adnexal neoplasms and metastatic carcinomas. Furthermore, they reported that 20 of 22 primary cutaneous adnexal neoplasms whereas only 4 of 15 metastatic carcinomas stained positively for cytokeratin 5/6 (sensitivity 91%, specificity 73%) [3]. In a larger series, Plumb et al [12] reported similar results but clarified that metastatic breast carcinoma may express cytokeratin 5/6 in up to 47% (8 of17) of cases. Similar to the previous findings, cytokeratin 5/6 staining was seen in only 26% of cutaneous metastases in this series for a specificity of 74%. Our results indicate p40, an isoform of p63, shows better specificity than p63 for ruling out cutaneous metastases, especially from tumors of the breast, lung, endometrium, stomach, and thyroid. Bishop et al [18] recently reported similar results, demonstrating that p40 nuclear staining is equally sensitive but more specific for squamous cell carcinomas of the lung than is p63, which also stains a consistent percentage of adenocarcinomas, small cell lung carcinoma, lymphoma, and other tumor types. In our study, both p40 and p63 stained 40% to 67% of cutaneous metastases from pancreatic, salivary gland, and bladder malignancies, thereby highlighting the limitation of these stains in ruling out metastases from these organs. In their comparative study of cutaneous metastases from 12 cases of breast carcinomas and 13 cases of primary sweat gland neoplasms, Rollins-Raval et al [13] reported an overall sensitivity of 100% and specificity of 91% when using a panel of stains including p63, cytokeratin 5/ 6, CK14, CK17, and mammaglobin. Therefore, the overall sensitivity and specificity may be improved when both p40 and p63 are used together. According to our results, GATA3 does not appear to be specific for carcinomas of the breast, bladder and salivary gland as previously reported [20–22] because it also stains carcinomas of cutaneous adnexae. Indeed, GATA3 was
J. J. Lee et al. recently shown to stain occasional squamous cell carcinomas of the anus, cervix, and lung as well as more than half of all salivary gland neoplasms [20–22]. While present in tumors arising from the breast, bladder, mammary, and extramammary Paget’s disease, GATA3 immunoreactivity was absent in cutaneous metastases from the liver, prostate, lung, ovary, endometrium, stomach, pancreas, thyroid, and kidney. The expression of GATA3 in tumors of salivary gland, breast, and cutaneous adnexal carcinomas is likely due to the similar embryologic development of these ectodermally derived, exocrine, and secretory structures [22,29]. A panel of immunostains is helpful in the work up of cutaneous metastases. The differential expression of CK7 and CK20 is not completely specific [14]. Thus, a panel of CK7, CK20, TTF-1 (thyroid transcription factor-1), CDX2, CEA, MUC2, MUC5AC, estrogen receptor, and gross cystic disease fluid protein-15 has been proposed by Park et al [30] to improve prediction of the primary site. Approximately two-thirds of lung adenocarcinoma expresses TTF-1 [30]. The nuclear expression of CDX-2 would be seen in almost all colorectal carcinomas but only in a few cases of gastric, pancreaticobiliary, and mucinous ovarian adenocarcinomas [31]. In summary, although statistically significant P values (b.0001) were observed for p40, p63, and cytokeratin 5/6 in distinguishing primary adnexal carcinomas from cutaneous metastases, p40 appears to be the most specific marker. Since malignancies of the breast and lung are the most common site of origin for cutaneous metastases, p40 is the best distinguishing marker in these settings. None of the four studied markers (p40, p63, cytokeratin 5/6, and GATA3) are helpful in distinguishing between primary adnexal carcinomas and cutaneous metastases of salivary gland or bladder carcinomas.
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