Abstract
Metastasizing adnexal carcinomas are rare; thus, currently there is no uniform treatment guideline. Chemotherapeutic drugs that selectively target cancer-promoting pathways may complement conventional therapeutic approaches. We performed immunohistochemistry (epidermal growth factor receptor (EGFR), HER2, and CD117), EGFR and ERBB2 fluorescence in situ hybridization (FISH), and multiplexed SNaPshot® genotyping (testing for recurrent mutations in 15 cancer genes including BRAF, EGFR, KRAS, PIK3CA, and TP53) on primary tumors and corresponding metastases of 14 metastasizing adnexal carcinomas (three apocrine, six eccrine, two hidradenocarcinomas, two porocarcinomas, and one aggressive digital papillary adenocarcinoma). Metastasis to regional lymph node was most common, followed by skin and then lungs. Follow-up was available in 12 patients (5 months to 8 years) with 1 died of widespread metastases. Although EGFR overexpression was a prevalent feature in this cohort, seen in 7/11 (64%) primary tumors and 10/14 (71%) metastases; FISH for EGFR gene amplification was negative in 9 tested primary tumors and 12 metastases. FISH of the one primary tumor and three metastases with 2+ HER2 overexpression revealed a low level of ERBB2 gene amplification in one apocrine carcinoma and corresponding metastasis. CD117 expression was seen only in rare cases. PIK3CA (2/12, 17%) and TP53 (3/12, 25%) mutations were detected in two (one hidradenocarcinoma, one porocarcinoma) and three (one eccrine, one hidradenocarcinoma, and one aggressive digital papillary adenocarcinoma) cases, respectively. The role of EGFR inhibitor therapy in metastasizing adnexal carcinomas with protein overexpression remains unclear. Targeted therapy including PI3K pathway inhibitors might be a potential treatment for rare cases of adnexal carcinomas with metastases.
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Adnexal carcinomas are rare and associated with poor prognosis. Currently, there is no uniform guideline concerning their treatment, especially for those with metastases. Wide surgical excision remains the treatment of choice; but treatment success has been documented only in isolated case reports.1, 2, 3 Three of nine cases of clear cell eccrine carcinomas reported by Wong et al4 developed metastases despite local excision, radiation, and chemotherapy.
Targeted therapy may be a potential treatment option in patients whose tumors are characterized by a relevant oncogene mutation. In a growing number of tumor types including breast and colorectal and lung cancer, selective agents that target critical cancer-promoting pathways are now the treatment of choice for those patients carrying the genetic changes recognized by the drugs.4, 5, 6, 7
ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2) gene amplification and response to trastuzumab were documented in a case of metastasizing hidradenocarcinoma.2 Members of the ERBB receptor tyrosine kinase family, including epidermal growth factor receptor (EGFR), HER2, HER3, and HER4, present possible targeted therapeutic options.8 The membranous expression of these markers has therapeutic implications and second-generation EGFR tyrosine kinase inhibitors such as HKI-272, XL647, and BIBW2992 have dual activity, inhibiting both EGFR and HER2 receptors.9, 10
Another case of metastasizing clear cell hidradenocarcinoma was reported to be stabilized over 8 months with Sunitinib treatment, an oral multi-targeted tyrosine kinase inhibitor.3 KIT (CD117) is known to be expressed in normal adnexal tissue.11 Moreover, KIT-activating (v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homolog) mutations are reported to be associated with a variety of malignant neoplasms and specific chemotherapeutic agents (imatinib and sorafenib) are available.12, 13 Clinical experience in patients with gastrointestinal stromal tumor indicates that the presence and location of specific KIT mutations can predict sensitivity and resistance patterns to KIT kinase inhibitors.14
To investigate whether metastasizing adnexal carcinomas possess activation of oncogenic pathways that can be targeted by available chemotherapeutic agent, we performed immunohistochemistry for EGFR, HER2, and CD117 (KIT) expression; fluorescence in situ hybridization (FISH) for EGFR and ERBB2 gene amplification; and molecular analyses for recurrent mutations in 15 cancer genes including BRAF, EGFR, KRAS, PIK3CA, and TP53 on cases of adnexal carcinomas with metastases.15
Materials and methods
The study has been approved by the Massachusetts General Hospital institutional review board (IRB No. 2009P001738). Archival materials of all metastasizing adnexal carcinomas including aggressive digital papillary adenocarcinoma, apocrine carcinomas, eccrine ductal carcinoma, hidradenocarcinoma, and porocarcinoma, diagnosed between 1987 and 2010 were retrieved from the pathology files of the Massachusetts General Hospital, Boston, MA, USA. Age, gender, tumor site, tumor size, and clinical follow-up information (such as local recurrence or metastasis) were extracted from the patients’ medical records. All patient data were de-identified. The histological sections of all cases were re-examined and the diagnoses were confirmed.
Immunohistochemistry
Immunohistochemical studies were performed on 5-μm-thick sections of formalin-fixed, paraffin-embedded tissue, using the standard techniques, heat-induced epitope retrieval buffer, and primary antibodies against CD117 (1:200, Dakocytomation, Carpinteria, CA, USA), EGFR (3C6, 1:2, Ventana Medical Systems, Tucson, AZ, USA), and HER2 (4B5, predilute, Ventana Medical Systems). Appropriate positive and negative controls were included.
Evaluation of the membranous EGFR expression was performed using a combined scoring system based on both the staining intensity (0=no staining, 1=weak, 2=moderate, and 3=strong staining) as well as the percentage of positive cells (0%=0, <25%=1, 26–50%=2, 51–75%=3, and >75%=4), similar to that outlined by Janisson-Dargaud et al.16 The sum of these two scores yielded a total score from 0 to 7 (1–3=weak and 4–7=strong).
Overexpression of HER2 was defined as positive membranous staining in >10% of the neoplastic cells. Partial and faint, weak or thin, and intense or thick circumferential membrane staining in >10% of the tumor cells were scored as 1+ (negative), 2+ (equivocal), and 3+ (positive), respectively. Evaluation of CD117-positive cells were recorded as <10%=negative, 10–50%=1+, 51–75%=2+, and >75%=3+.17
Mutational Analysis and EGFR and ERBB2 FISH
A SNaPshot® genotyping assay recently developed by our group was performed on primary tumors and corresponding metastases of 14 metastasizing adnexal carcinomas with available archival materials.15 This assay consists of multiplexed PCR followed by a single-base extension reaction and uses the commercially available SNaPshot platform (Applied Biosystems). The original tumor genotyping panel described by Dias-Santagata et al15 was expanded to include three additional assays (AKT1.49, testing for the AKT1 E17K mutation; IDH1.394 and IDH1.395, testing for hotspot mutations in IDH1, which affect codon R132). The full panel and tests for common mutations in 15 cancer genes are outlined in Table 1. SNaPshot® genotyping was performed using previously described conditions,15 and included the following additional primers for AKT1 and IDH1 (PCR: AKT1 exon 3 Forward, 5′-ACGTTGGATGGGTAGAGTGTGCGTGGCTCT-3′; AKT1 exon 3 Reverse, 5′-ACGTTGGATGAGGTGCCATCATTCTTGAGG-3′; IDH1 exon 4 Forward, 5′-ACGTTGGATGGGCTTGTGAGTGGATGGGTA-3′, IDH1 exon 4 Reverse 5′-ACGTTGGATGgcaaaatcacattattgccaac-3′. Extension: AKT1.49 extR 5′-CTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGCCAGGTCTTGATGTACT-3′IDH1.394 extR 5′-GACTGACTGGACTGACTGACTGACTGACTGGACTGACTGACTGAGATCCCCATAAGCATGAC-3′, IDH1.395 extR 5′-TGATCCCCATAAGCATGA-3′). EGFR gene copy number was assessed in 9 primary tumors and 12 metastases by FISH as previously published.18 ERBB2 gene copy number was also assessed in four cases with HER2 IHC overexpression.
Results
A total of 14 cases were identified: 3 apocrine carcinomas, 6 eccrine ductal carcinomas, 2 hidradenocarcinomas, 2 porocarcinomas, and 1 aggressive digital papillary adenocarcinoma (Table 2). The age of the patients ranged from 38 to 85 years (median, 68.5 years). The male to female ratio was 6:1. The majority of the patients received excision and regional lymph node dissection. Three patients received chemotherapy and one received radiotherapy. One patient received both radiotherapy and chemotherapy. Follow-up was available in 12 patients ranging from 5 months to 8 years (Table 2). Recurrences developed in two patients. Metastasis to regional lymph node is most commonly observed. Widespread metastases were observed in two patients that resulted in death in one patient, 7 years status post diagnosis. Metastases to both lymph node and skin were observed in four cases. Metastases to both lymph node and lung were observed in two cases.
Immunohistochemistry
Immunohistochemistry was performed on 11 primary tumors and 14 metastases. The immunohistochemical results are summarized in Table 3. Overexpression of EGFR was seen in 7/11 (64%) primary tumors and 10/14 (71%) metastases (Figure 1a–c). All cases exhibited strong membranous EGFR expression (Figure 1c). Overexpression of HER2 (2+) was seen in 2/11 (18%) apocrine carcinomas and 3/14 (21%) metastases (from two apocrine carcinomas and one aggressive digital papillary adenocarcinoma) (Figure 1d–f). Weak (1+) CD117 expression was noted in 1/9 (11%) primary tumors and 1/14 (7%) metastases (Figure 1g–i).
Mutational Analysis and FISH
The molecular results are summarized in Table 3. We have recently developed a multiplexed tumor genotyping clinical assay that uses the SNaPshot platform from Applied Biosystems.15 This assay performs well with archived tissue and tests for recurrent mutations in 15 cancer genes, including BRAF, EGFR, KRAS, PIK3CA, and TP53 (Table 1). The genes included in this panel were selected based on their clinical significance and on the availability of therapeutic agents (either FDA-approved or under clinical testing) targeting these cancer pathways.15 SNaPshot genotyping identified somatic mutations in 42% (n=5) of the 12 available paired tumor samples (Table 3). Activating mutations in PIK3CA mutations were detected in one hidradenocarcinoma (c.1624G>A; p.Glu542Lys) and one porocarcinoma (c.1633G>A; p.Glu545Lys) (Figure 2). TP53 mutations were detected in one eccrine (c.743G>A; p.Arg248Gln), one hidradenocarcinoma (c.817C>T; p.Arg273Cys), and one aggressive digital papillary adenocarcinoma (c.818G>A; p.Arg273His) (Figure 2). The PIK3CA tumor mutations were found in two older males of this cohort (Tables 2 and 3), but given the sample size correlative analysis is limited.
FISH for EGFR gene amplification was negative in 9 tested primary tumors and 12 metastases, including 7 primaries and 7 metastases with strong EGFR expression. Low level of ERBB2 gene amplification was seen in one apocrine carcinoma and its corresponding metastasis (Table 3).
Discussion
Adnexal carcinomas and breast carcinomas are analogous tumors often with similar histology. It is interesting that in this study we detected mutations in PIK3CA and TP53 in a subset of metastasizing adnexal carcinomas, as both of these genes are known to be frequently mutated in breast carcinomas. TP53 mutations have been previously described in adnexal carcinomas (Table 4), but to our knowledge this is the first report of PIK3CA mutations in these tumors, which is a therapeutically relevant finding. There was concordant detection of PIK3CA and TP53 mutations in both the primary tumors and the corresponding metastases from patients with metastasizing adnexal carcinomas with the exception of one case (case 11). One possible explanation is that the metastasis had a distinct primary origin. Alternatively, it is conceivable that the primary tumor was heterogeneous and the component without PIK3CA mutation gave rise to the metastasis. Larger studies will be needed to determine whether loss of an activating PIK3CA mutation during tumor progression and metastasis is a common occurrence. Such a finding would have therapeutic implications for patients with metastatic disease and argue for molecular testing of the metastasis before clinical decision-making.
The phosphatidylinositol 3 kinase (PIK3) signaling pathway is an important regulator of cell growth, proliferation, cell motility, angiogenesis, and survival and it has been shown that PIK3CA (phosphatidylinositol 3-kinase, catalytic, α polypeptide) is the most frequently mutated gene in breast cancer.19, 20 It is thought that in breast cancer, oncogenic mutations in PIK3CA or low levels of PTEN expression may confer resistance to treatment with trastuzumab, a monoclonal antibody that targets the HER2/NEU receptor.21 ERBB2 amplification and PIK3CA mutation were validated as biomarkers for sensitivity to the single-agent PIK3 inhibitor, GDC-0941, in breast cancer models.22 Other studies have shown that cancers with PIK3CA mutations were sensitive to single-agent PI3K inhibitors and dual PI3K-mammalian target of rapamycin inhibitors.23, 24
In breast carcinomas, the majority of mutations have been identified in the helical domain (exon 9, 37%) and in the kinase domain (exon 20, 63%) of PIK3CA.25 All mutations were single-based substitutions.25 Similarly, we detected two mutations, c.1624G>A:p.Glu542Lys and c.1633G>A:Glu545Lys, in exon 9 of PIK3CA, in one hidradenocarcinoma and one porocarcinoma, respectively. These two mutations are among the three most frequently reported mutations in breast cancer.25 Mutations in codon 545 are mutational hotspots reported in ovarian and colorectal carcinomas as well.26, 27 The clustering of mutations within PIK3CA may prove useful for therapeutic purpose.
Tumor suppressor gene, TP53, located on the short arm of chromosome 17p13 has been implicated in the regulation of cell growth, DNA repair, and apoptosis. The TP53 gene is frequently (14–52%) altered in human breast carcinomas and is the most commonly mutated gene in human tumors.28, 29, 30 Mutations are usually clustered within the most conserved regions of exons 4, 5, 7, and 8.31 TP53 mutations have been previously documented in nine cases of adnexal carcinomas (Table 4).32, 33, 34, 35 Similar to findings reported by Biernat et al,32 we found TP53 mutations within codon 248 of exon 7 and codon 273 of exon 8 in 25% of our cases. Interestingly, these mutations have also been reported in breast carcinomas.36, 37, 38
EGFR/erbB-1 belongs to a receptor family with tyrosine kinase activity whose gene is located on chromosome 7p12. The EGFR signaling that mediates proliferation, migration, invasion, and suppression of apoptosis, can be blocked by a growing number of drug inhibitors. The role of EGFR inhibitor therapy in metastasizing adnexal carcinomas with protein overexpression remains unclear. Although 64% of the primary tumors and 71% of the metastases in our series demonstrated EGFR protein overexpression, the EGFR FISH studies were negative. This is not an unexpected finding; as similar results were noted in our recent study of hidradenocarcinomas.39 In addition, increased EGFR expression has been shown in various epithelial malignancies with or without gene amplification and the underlying mechanisms of EGFR protein overexpression are still unclear at this time.40 The lack of gene amplification does not entirely exclude the role of EGFR inhibitors in the treatment of metastasizing adnexal carcinomas; as there are conflicting results in the literature regarding the role of IHC, FISH, and/or PCR in treatment decision of various tumors.41, 42, 43 There is frequent discrepancy between the EGFR protein expression and gene amplification in other tumors in the literature.44 Furthermore, inconsistent results have also been reported regarding the correlation between EGFR gene mutations and EGFR gene amplification/polysomy detected by FISH (Bell et al, 2005; Sone et al, 2005). In a recent series of 100 patients with advanced pulmonary adenocarcinoma, Gupta et al41 proposed that tumors should be evaluated by more than one method to identify patients that may benefit from tyrosine kinase inhibitors therapy.
One of three metastasizing adnexal carcinomas in our series with (2+) HER2 overexpression had low level of ERBB2 gene amplification. This is consistent with prior published results indicating that high level ERBB2 gene amplification is unlikely in the setting of 2+ HER2 overexpression.35 Strong (3+) overexpression of HER2 (3+) and gene amplification have been documented in one case of metastasizing malignant hidradenoma.2 These findings suggested that ERBB2 may be a relevant therapeutic target in rare cases of adnexal carcinoma.
KIT (CD117) is a transmembrane tyrosine kinase whose alterations are of interest as it is a target for STI571 (Glivec) therapy. In our study, only one case weakly overexpressed CD117. KIT mutational analyses have not been reported in adnexal carcinomas. KIT mutations were found in none of 10 CD117-positive breast carcinomas and in none of 30 adenoid cystic carcinomas of the major and minor salivary glands.45, 46 These findings suggest that KIT activation may not be a major driving mechanism in adnexal carcinomas and their analogous tumors (breast and salivary gland).
In summary, we report mutations in PIK3CA and TP53 in a subset of metastasizing adnexal carcinomas. The role of EGFR inhibitor therapy in metastasizing adnexal carcinoma cases with protein overexpression remains unclear. The lack of correlation between the protein expression and polysomy/gene amplification suggests that molecular mechanisms other than gene amplification have a role in EGFR overexpression in metastasizing adnexal carcinomas. Targeted therapy including PI3K pathway inhibitors, which is currently in clinical testing, might be a potential treatment for rare cases of adnexal carcinomas with metastases. Actual therapeutic trials will be of interest in seeing whether these results will translate to therapeutic response.
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A patent application for the SNaPshot® genotyping methods used in this study was submitted by DDS and AJI and is currently pending.
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The results have been presented in part at the 31st Symposium of the International Society of Dermatopathology, Barcelona, Spain on October 2010.
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Dias-Santagata, D., Lam, Q., Bergethon, K. et al. A potential role for targeted therapy in a subset of metastasizing adnexal carcinomas. Mod Pathol 24, 974–982 (2011). https://doi.org/10.1038/modpathol.2011.48
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DOI: https://doi.org/10.1038/modpathol.2011.48
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