The expression of p63 in normal human epidermis, cutaneous appendages and skin carcinomas has been recently assessed. Cutaneous metastases may be the initial manifestation of some neoplasms, including adenocarcinomas. The distinction between such metastases and primary cutaneous neoplasms, especially adnexal tumors, on histologic grounds alone, may be difficult. The purpose of this study was to investigate the pattern of p63 expression in cutaneous adnexal neoplasms, including adenocarcinomas and to assess its possible value in the differential diagnosis of primary cutaneous neoplasms vs adenocarcinomas metastatic to the skin.
The pathology database at the University of Texas MD Anderson Cancer Center was retrospectively reviewed to identify cases of primary adnexal carcinomas and metastatic adenocarcinomas to the skin between January and July There were retrieved 20 benign adnexal tumors six poromas, three syringomas, nine trichoepitheliomas, one spiradenoma, one papillary eccrine adenoma , 10 malignant adnexal tumors four microcystic adnexal carcinomas, two eccrine adenocarcinomas, one hidradenocarcinoma, two tricholemmal carcinomas and one mucinous sweat gland adenocarcinoma , and 14 metastatic adenocarcinomas to the skin 12 from breast, two from the gastrointestinal tract.
Clinical information was obtained from the medical records. Immunohistochemical analysis for p63 was performed on formalin-fixed, paraffin-embedded archival tissue using the streptavidin—biotin-peroxidase technique. A mouse antihuman monoclonal antibody that reacts with all p63 isoforms clone 4A4, dilution ; Santa Cruz, Biotechnology Inc.
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Positive and negative controls were included in each slide run. The distribution of the immunoreactivity in the neoplastic cells was analyzed by quantifying nuclear staining, following previous methodology. Positivity of cells was defined regardless of staining intensity. Two investigators VGP and DI have independently reviewed and scored slides by estimating the percentage of cells exhibiting characteristic nuclear staining.
Interobserver variation was addressed by averaging the individual values. The distribution of p63 expression in the basal and suprabasal cells of normal epidermis, hair follicles, sweat glands and sebaceous glands was evaluated in normal skin adjacent to the neoplasms. It was also assessed the pattern of p63 expression in endothelial cells, dermal mesenchymal cells, pilar erector muscles, nerve bundles, adipocytes or inflammatory infiltrates. At least 10 high-power fields were chosen randomly, and cells were counted in each field.
The outer root sheath cells and the hair bulb of the hair follicle exhibited positivity for p63 whereas the inner root sheath cells and the hair matrix were negative for p A variable p63 nuclear staining was identified in the pilar erector muscles. The germinative cells of the secretory portion of the sebaceous glands, as well the duct cells, strongly expressed p No immunoreactivity was seen in the mature sebocytes. The myoepithelial cells of the eccrine coils and the basal cells of the eccrine glands ducts were positive for p The myoepithelial cells of the secretory component of the apocrine glands and the outer layer cells of the apocrine ducts did also express p No differences in the labeling pattern were observed between the epidermis and adnexal structures of the skin.
The other three cases were also positive for p63 and had a nuclear score 2.
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Immunohistochemical staining for p63 reveals strong and diffuse nuclear reactivity in the basaloid cells of trichoepitheliomas a and eccrine poromas b. The myoepithelial cells of the ductal structures of the syringomas expressed p63 ; the inner layer of cuboidal epithelium did not c. Also, strong p63 positivity was identified in the outer cells of the basaloid nodules of the eccrine spiradenomas d. The pattern of expression of p63 in six eccrine poromas Figure 1b included in our study revealed that the cords of proliferating basaloid cells were strongly positive nuclear score 3 in three cases and had a nuclear score 2 in the remaining three cases.
Only the luminal cells in the tumor nests did not expressed p The myoepithelial cells of the ductal structures of the syringomas Figure 1c were positive for p63 ; two cases had nuclear score 3 and one case, score 2. The inner layer of cuboidal epithelium did not express p The papillary eccrine adenoma case had a similar pattern of p63 immunostaining with strong positivity nuclear score 3 of the outer cells. Both cases of eccrine adenocarcinoma Figure 2a were strongly positive nuclear score 3 for p63 , as well as the hidradenocarcinoma Figure 2b.
The eccrine adenocarcinomas a and the hidradenocarcinoma b were strongly positive for p The microcystic adnexal carcinomas c also expressed p63 , as well as the infiltrating lobules of tricholemmal carcinoma d. No differences in the labeling pattern were observed between the superficial and the deeper nests or cords of neoplastic cells.
Pathology Outlines - Adnexal tumors - general
The infiltrating lobules of tricholemmal carcinoma Figure 2d were also positive for p63 nuclear score 3. No cytoplasmic labeling with p63 was observed in any of the primary adnexal carcinomas included in the study. A total of 14 metastatic adenocarcinomas to the skin 12 from breast, two from the gastrointestinal tract were included in our study and they were all negative for p63 Figure 3.
The majority of the metastatic breast carcinomas did not express p63 in any of the cells. The skeletal muscle that was included in some of the studied slides was strongly positive for p63 and the muscle striations were evident. Similar to this case of breast metastatic carcinoma to the skin, none of the metastatic adenocarcinomas expressed p The apical cells revealed mild cytoplasmic staining. The patient follow-up had been negative for four years, when magnetic resonance imaging revealed a neoplastic lesion measuring approximately 5 cm in diameter, with irregular borders and infiltration into the adjacent tissues of the left inguinal region.
The patient started a combined chemotherapy with 5-fluorouracil, cisplatin and docetaxel and underwent a single-fraction radiation therapy for a vertebral collapse. But the patient died due to neoplastic cachexia several months later. This aggressive EPC showed no response to any treatment and intrinsic chemoresistance. EPC is a rare tumor of sweat glands with a high local recurrence rate and tendency to metastatic spread. No standard therapy protocols for metastatic and locally advanced disease exist.
Our suggestion is that these chemoresistant tumors can benefit only from a targeted-therapy. As far as the immunohistochemical expression of specific markers is concerned, the cells of eccrine sweat glands express low and high molecular weight keratins, epithelial membrane antigen EMA , carcinoembryonic antigen CEA , S protein, smooth muscle actin SMA , p63, calponin, cytokeratin 14 and B-cell lymphoma-2 BCL2 2. Some eccrine carcinomas express estrogen and progesterone receptors, which have important clinical implications for hormone therapy.
When eccrine carcinomas exhibit positive immunohistochemical staining for estrogen and progesterone receptors, the differential diagnosis from cutaneous metastasis of breast cancer is very difficult 2 , 3. Androgen receptor evaluation is very important in the differential diagnosis between these two tumor types since these receptors are typically expressed at a higher frequency in metastatic breast cancer and are expressed only in a subset of SATs Human epidermal growth factor receptor-2 HER2 is expressed in only 3.
The molecular pathogenesis of malignant adnexal tumors is still not well understood. Since it was first described, only little information about molecular alterations in EPC have been discovered. Gu et al. In metastatic EPC, p16 overexpression is associated with loss of RB function, since RB protein can induce transcriptional down-regulation of p The positive expression of Ki and p53 can help differentiate benign from malignant tumors Akalin et al.
Cutaneous Adnexal Neoplasms
P53 is a tumor-suppressor protein that regulates cell growth; its mutations and loss of function are involved in the carcinogenetic pathway of EPC, but are not sufficient for its development. Therefore, aberrant p53 expression cannot be accepted as a valuable parameter for malignancy without other oncogene alterations It is interesting that mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha PIK3CA and p53 , expressed by a subset of metastasizing SATs, are also frequently present in breast cancer.
Targeted-therapy, including PI3K pathway inhibitors, could be a potential treatment for rare cases of SATs with metastases, and further investigations are needed Due to the described analogies between breast carcinomas and SATS, using the same chemotherapeutic agents and the same targeted therapy can be effective.
Only one successful case of anti-hormonal therapy of eccrine gland tumors is described: a patient with distal metastasis secondary to an eccrine tumor responded well to tamoxifen Therefore, an anti-estrogen therapy in metastasizing SAT with positive hormone receptor immunohistochemistry should be taken into consideration 46 , Only two experiences of treatment with a targeted therapy for metastatic SATs are described. The first is with sunitinib, an oral tyrosine kinase inhibitor; its efficacy in adnexal carcinomas was recently reported in two cases.
Certainly, sunitinib should be considered in further studies of these rare tumors The second clinical experience is with lapatinib, an oral anti-HER2 targeted-therapy, successfully utilized for a patient with metastatic apocrine carcinoma Metastatic SATs are rare and aggressive tumors which have the potential for distant metastasis and are very resistant to conventional chemotherapies. Longer follow-up and several clinical trials are necessary to evaluate new therapeutic strategies in relation to new possible targets. Considering the differential diagnosis between a primary SAT and a secondary neoplasm, skin metastasis of breast cancer is very difficult, hence we suggest the utilization of all available immunohistochemical markers, additionally to clinical and radiological evaluations Yet, due to the sharing of some molecular alterations in breast cancer and SATs, we suggest that using the same chemotherapeutic agents and the same target therapy for metastatic SAT could be effective, considering also the high rate of chemoresistance of these types of neoplasms.
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Previous Section. Hautarzt 65 : - , Medline Google Scholar. An approach to tumours of cutaneous sweat glands. J Clin Pathol 60 : - , Diagnostic Pathology 8 : 15 - 16 , Am Surg 70 : 63 - 66 , J Cutan Pathol 34 : 49 - 54 , Metastatic eccrine porocarcinoma.
Report of a case and review of the literature. World J Surg Oncol 9 : 32 - 34 , CrossRef Medline Google Scholar. Int Med Case Rep J 5 : 45 - 48 , A clinicopathologic study of 69 cases. Am J Surg Pathol 25 : - , Google Scholar. Arch Dermatol : - , Arch Dermatol 88 : - , Dermatol Surg 23 : - , Clinics 65 : - , J Urol : - , Ann Dermatol Venereol : - , Br J Dermatol : - , Notably, human skin appendage tumors also often exhibit overlapping features with follicular and sebaceous gland differentiation.
Therefore, we believe that this mouse will be a very suitable model for the pathological properties of human appendage tumors.