Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma.

BACKGROUND: Src is a non-receptor tyrosine kinase involved in signalling and crosstalk between growth-promoting pathways. We aim to investigate the relationship of active Src in response to trastuzumab of HER2-positive breast carcinomas. METHODS: We selected 278 HER2-positive breast cancer patients with (n=154) and without (n=124) trastuzumab treatment. We performed immunohistochemistry on paraffin-embedded tissue microarrays of active Src and several proteins involved in the PI3K/Akt/mTOR pathway, PIK3CA mutational analysis and in vitro studies (SKBR3 and BT474 cancer cells). The results were correlated with clinicopathological factors and patients' outcome. RESULTS: Increased pSrc-Y416 was demonstrated in trastuzumab-resistant cells and in 37.8% of tumours that correlated positively with tumour size, necrosis, mitosis, metastasis to the central nervous system, p53 overexpression and MAPK activation but inversely with EGFR and p27. Univariate analyses showed an association of increased active Src with shorter survival in patients at early stage with HER2/hormone receptor-negative tumours treated with trastuzumab. CONCLUSIONS: Src activation participates in trastuzumab mechanisms of resistance and indicates poor prognosis, mainly in HER2/hormone receptor-negative breast cancer. Therefore, blocking this axis may be beneficial in those patients.

Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas.

BACKGROUND: Trastuzumab resistance hampers its well-known efficacy to control HER2-positive breast cancer. The involvement of PI3K/Akt pathway in this mechanism is still not definitively confirmed. METHODS: We selected 155 patients treated with trastuzumab after development of metastasis or as adjuvant/neoadjuvant therapy. We performed immunohistochemistry for HER2, ER/PR, epidermal growth factor 1-receptor (EGFR), α-insulin-like growth factor 1-receptor (IGF1R), phosphatase and tensin homologue (PTEN), p110α, pAkt, pBad, pmTOR, pMAPK, MUC1, Ki67, p53 and p27; mutational analysis of PIK3CA and PTEN, and PTEN promoter hypermethylation. RESULTS: We found 46% ER/PR-positive tumours, overexpression of EGFR (15%), α-IGF1R (25%), p110α (19%), pAkt (28%), pBad (22%), pmTOR (23%), pMAPK (24%), MUC1 (80%), PTEN loss (20%), and PTEN promoter hypermethylation (20%). PIK3CA and PTEN mutations were detected in 17% and 26% tumours, respectively. Patients receiving adjuvant trastuzumab with α-IGF1R or pBad overexpressing tumours presented shorter progression-free survival (PFS) (all P≤0.043). Also, p110α and mTOR overexpression, liver and brain relapses implied poor overall survival (OS) (all P≤0.041). In patients with metastatic disease, decreased PFS correlated with p110α expression (P=0.024), whereas for OS were the presence of vascular invasion and EGFR expression (P≤0.019; Cox analysis). CONCLUSION: Our results support that trastuzumab resistance mechanisms are related with deregulation of PTEN/PI3K/Akt/mTOR pathway, and/or EGFR and IGF1R overexpression in a subset of HER2-positive breast carcinomas.

Doxorubicin and cyclophosphamide followed by weekly docetaxel as neoadjuvant treatment of early breast cancer: analysis of biological markers in a GEICAM phase II study.

INTRODUCTION: To evaluate the sequential administration of doxorubicin (A) and cyclophosphamide (C) followed by weekly docetaxel in women with stage II to IIIA breast cancer. PATIENTS AND METHODS: Patients received 60 mg/m(2) of A and 600 mg/m(2) of C every three weeks for four cycles followed by 12 infusions of weekly docetaxel at a dose of 36 mg/m(2) and with a 2-week resting period. RESULTS: Sixty-three women were included. On an intention-to- treat basis, clinical response rate was 90% (95% CI: 83-98), with 46% complete responses. Breast-conserving surgery could be performed in 43 patients (68%). Complete pathological responses in the breast were confirmed in 17% of patients. No correlations between levels of expression of topoisomerase II alpha, survivin or p27 and the pathological response were detected. The study treatment was generally well tolerated. CONCLUSION: Neoadjuvant AC followed by weekly docetaxel is a feasible regimen for patients with early-stage breast cancer.

Liquid chromatography-multistage tandem mass spectrometry for the quantification of dihydroxynonene mercapturic acid (DHN-MA), a urinary end-metabolite of 4-hydroxynonenal.

The mercapturic acid conjugate of 1,4-dihydroxynonene (DHN-MA) is a urinary metabolite of 4-hydroxynonenal (4-HNE), one of the main lipid peroxidation products occurring in vivo. To determine its level in urine, a combination of liquid chromatography with positive electrospray-multistage tandem mass spectrometry has been developed. A deuterated analog of the target compound (DHN-MA) with six deuterium atoms was synthesized and used as the internal standard. Three-stage tandem mass spectrometry was used, providing good selectivity for the detection of DHN-MA. The response of the system to DHN-MA was linear in the 5-100 ng range. Urine samples spiked with different levels of standard DHN-MA were used to evaluate the influence of matrix effects on the linearity. The repeatability of the method was also determined by using repeated 5 ng injections of DHN-MA, providing a RSD of 10%. The method was then applied to the determination of DHN-MA in rat urine samples; increased levels of urinary DHN-MA in urine from rats treated with BrCCl3 indicates that lipid peroxidation processes take place in such rats.

Analysis of HER-2/neu amplification in endometrial carcinoma by chromogenic in situ hybridization. Correlation with fluorescence in situ hybridization, HER-2/neu, p53 and Ki-67 protein expression, and outcome.

Fluorescence in situ hybridization (FISH) is the most widely used technique to detect HER-2/neu gene amplification; however, it is only available in some institutions. In contrast, chromogenic in situ hybridization (CISH) can be evaluated by routine light microscopy. In endometrial carcinoma there are few data concerning HER-2/neu status and prognosis. Therefore, we determined HER-2/neu gene status by CISH using a digoxigenin-labelled probe on 60 formalin-fixed paraffin-embedded endometrial carcinomas. The data were compared with the immunohistochemistry of HER-2/neu (A0485, TAB250), p53, Ki-67, clinicopathological factors, and survival. By conventional light microscopy, HER-2/neu amplification (>/=6 copies >50% cancer cells) was detected in 14% (8/59) tumours, HER-2/neu overexpression (>10% cells moderate/strong complete membrane staining) in 22% (13/60) for A0485, and 18% (11/60) for TAB250, p53 (>10% +cells) in 61% (36/59), and Ki-67 (>50% +cells) in 50% (30/60). Discordant cases for CISH and immunohistochemistry, as well as all (2+) were further analysed by FISH (Vysis). Among 10 cases (2+) and not amplified by CISH, two showed low-level amplification by FISH. Significant correlation was found between amplification and protein overexpression (P

Cellular apoptosis susceptibility gene expression in endometrial carcinoma: correlation with Bcl-2, Bax, and caspase-3 expression and outcome.

Deregulation of proliferation and apoptosis is known to contribute to neoplastic transformation and growth. Using specific antibodies for the cellular apoptosis susceptibility (CAS) gene, caspase-3, Bcl-2, and Bax, we examined the protein expression in 89 endometrial carcinomas and in 56 samples of nonneoplastic adjacent endometrium for comparison. Immunostaining results were scored with regard to approximate percentage of positive tumor cells (< 10%, 10% to 50%, > 50%) and relative immunostaining intensity (1+, 2+, 3+). In nonneoplastic endometrium, CAS protein was expressed in 70.6%, Bax in 64%, caspase-3 in 52%, and Bcl-2 in 87%. In neoplastic tissue, CAS was present in 93% of the tumors, Bax in 88%, caspase-3 in 77%, and Bcl-2 in 51%. Bcl-2:Bax ratio was > 1 in 9 cases (10%). In cases of atrophy (n = 24) and simple (n = 10) and complex (n = 22) hyperplasia in the adjacent endometrium, lower levels of expression compared with carcinoma were observed for CAS (p = 0.003), caspase-3 (p = 0.034), and Bax (p = 0.04) and higher levels for Bcl-2, although for this protein the results were not statistically significant (p = 0.32). There was no association between immunoscores and FIGO stage. High caspase-3 levels were seen in endometrioid tumor type (p = 0.017). CAS expression was higher in grade 3 tumors (p = 0.002) and older patients (p = 0.013). All tumors of younger patients (< 50 years) were Bcl-2 negative (p = 0.037). Caspase-3 correlated positively with CAS (p = 0.008), Bax (p = 0.04), and low Bcl-2:Bax ratio (p = 0.043), and inversely (as a trend) with Bcl-2 (p = 0.056). Survival analysis (Kaplan-Meier and Cox regression) established a strong association between prognosis and stage, grade, and histologic type (all p < or = 0.0036). In addition, shorter survival was observed for patients whose tumors contained > 50% of positive cells for caspase-3 (p = 0.024) or for CAS (p = 0.04). Age, Bcl-2, Bax, and Bcl-2:Bax ratio did not provide prognostic information. Our results suggest a role of CAS, Bcl-2, Bax, and caspase-3, which are apparently involved in the progressive deregulation of proliferation and apoptosis leading from simple and complex hyperplasia to carcinoma. In addition, CAS and caspase-3 protein levels may be useful markers in predicting the outcome of the patients.

Prognostic relevance of hMLH1, hMSH2, and BAX protein expression in endometrial carcinoma.

Endometrial carcinoma is the most common gynecologic malignancy in perimenopausal and postmenopausal women. A role of mismatch repair genes, like hMLH1 and hMSH2 in their pathogenesis, has been suggested. Loss of their function leads to the accumulation of replication errors (mutator phenotype), which are responsible for further mutations in genes with microsatellite sequences in their coding region, such as Bax. We analyzed the expression of hMLH1, hMSH2, and Bax genes in 89 formalin-fixed paraffin-embedded endometrial carcinomas. The immunostains were scored with regard to percentage of positive tumor cells (0%, <10%, 10 to 50%, >50%), and relative staining intensity (1+, 2+, 3+). The staining results were correlated with clinicopathologic features and survival. Loss of hMSH2 expression (0% positive cells) was observed in 1.1% (1/89) of the tumors; loss of hMLH1 was seen in 12.4% (11/89) of the cases, particularly in endometrioid tumors with mucinous differentation (5/11; 45%; P =.03). No significant association was found between the immunoscores and grade, stage criteria of the International Federation of Obstetrics and Gynecology (FIGO), or age of the patients. Among 11 tumors with loss of Bax expression (12.4%), 4 had also loss of hMLH1 (4/11; 36.4%; P =.017). In multivariate analysis (Cox model), significantly longer survival was found for patients with tumors in FIGO Stage I-II (P <.0001), endometrioid type (P =.001), low grade (P =.001), and absence of hMLH1 expression (P =.027). Our results suggest that loss of function of hMLH1 and Bax occur in a subgroup of endometrial carcinoma. In addition to the classical prognostic factors, absence of hMLH1 expression is associated with better outcome of patients.

Prognostic value of HER-2/neu and p53 expression in node-positive breast cancer. HER-2/neu effect on adjuvant tamoxifen treatment.

HER-2/neu and p53 expression, conventional clinical and pathologic prognostic factors, were evaluated in a retrospective series of 283 node-positive breast cancer patients. Overexpression was determined by immunohistochemistry in formalin-fixed paraffin-embedded tissue blocks. Twenty one percent were HER-2/neu positive and 40% p53 positive. HER-2/neu expression was related to axillary lymph node metastasis (P=0.014), inflammatory infiltrates (P=0.004), and the absence of oestrogen (ER) (P=0.0026) and progesterone (P=0.01) receptors (PR). p53 expression was related to lymph node involvement (P=0.03), necrosis (P=0.036), absence of ER (P=0.028) and PR (P=0.065). p53 was not associated with outcome. HER-2/neu was an unfavourable prognostic factor for disease-free (DFS) (P=0.05) and overall survival (OS) (P=0.02) in univariate analysis. Multivariate analysis showed that the number of involved axillary nodes (P<0.00001), age (P=0.004), grade (P=0.04), and PR (P=0.04) were independent predictors for OS. ER-positive patients treated with adjuvant tamoxifen had shorter DFS and OS when they were HER-2/neu positive.

The influence of infiltrating lobular carcinoma on the outcome of patients treated with breast-conserving surgery and radiation therapy.

BACKGROUND: The role of conservative surgery and radiation therapy (CS and RT) in the treatment of patients with infiltrating ductal carcinoma is well established. However, the efficacy of CS and RT for patients with infiltrating lobular carcinoma is less well documented. The goal of this study was to examine treatment outcome after CS and RT for patients with infiltrating lobular carcinoma and to compare the results to those of patients with infiltrating ductal carcinoma and patients with mixed ductal-lobular histology. METHODS: Between 1970 and 1986, 1624 patients with Stage I or II invasive breast cancer were treated with CS and RT consisting of a complete gross excision of the tumor and > or = 6000 cGy to the primary site. Slides were available for review for 1337 of these patients (82%). Of these, 93 had infiltrating lobular carcinoma, 1089 had infiltrating ductal carcinoma, and 59 had tumors with mixed ductal and lobular features; these patients constitute the study population. The median follow-up time for surviving patients was 133 months. A comprehensive list of clinical and pathologic features was evaluated for all patients. Additional histologic features assessed for patients with infiltrating lobular carcinoma included histologic subtype, multifocal invasion, stromal desmoplasia, and the presence of signet ring cells. RESULTS: Five and 10-year crude results by site of first failure were similar for patients with infiltrating lobular, infiltrating ductal, and mixed histology. In particular, the 10-year crude local recurrence rates were 15%, 13%, and 13% for patients with infiltrating lobular, infiltrating ductal, and mixed histology, respectively. Ten-year distant/regional recurrence rates were 22%, 23%, and 20% for the three groups, respectively. In addition, the 10-year crude contralateral breast cancer rates were 4%, 13% and 6% for patients with infiltrating lobular, infiltrating ductal and mixed histology, respectively. In a multiple regression analysis which included established prognostic factors, histologic type was not significantly associated with either survival or time to recurrence. CONCLUSIONS: Patients with infiltrating lobular carcinoma have a similar outcome following CS and RT to patients with infiltrating ductal carcinoma and to patients with tumors that have mixed ductal and lobular features. We conclude that the presence of infiltrating lobular histology should not influence decisions regarding local therapy in patients with Stage I and II breast cancer.

20q13 and cyclin D1 in ovarian carcinomas. Analysis by fluorescence in situ hybridization.

In ovarian carcinomas, alterations of the chromosomal region 20q13 and the cyclin D1 gene have been described. This study has sought to determine their prognostic significance. Fluorescence in situ hybridization (FISH) on dissociated nuclei and paraffin sections with DNA probes for 20q13.2 and cyclin D1, as well as immunohistochemistry (cyclin D1), were applied to formalin-fixed tissue of 69 invasive ovarian carcinomas, mainly of serous type. On dissociated nuclei 33/47 cases (70%) and on tissue sections 13/66 cases (20%) demonstrated an increase of 20q13.2 copies. The presence of > or =4 copies per nucleus (isolated nuclei) and > or =3 copies per nucleus (sections) was associated with an adverse prognosis (Kaplan-Meier for FIGO stage III after stratification for residual tumour: p=0.0049 and p=0.03, respectively). Thirty-four out of 47 cases (72%) showed an increase of cyclin D1 copies. Kaplan-Meier analysis for FIGO stage III after stratification for residual tumour>2 cm or < or =2 cm revealed an unfavourable outcome for cases with more than two cyclin D1 copies (p=0.04). No correlation was seen between FISH and immunohistochemistry. Multivariate analysis identified residual tumour (p=0.0002), 20q13.2 gain (p=0.0004) and cyclin D1 gain (p=0.0343) as independent prognostic factors. It is concluded that gains of chromosomal region 20q13.2 and the cyclin D1 gene are frequent and biologically important events, with prognostic relevance, in advanced ovarian carcinomas.

p53 oncoprotein as a prognostic indicator in patients with breast cancer.

UNLABELLED: p53 is a tumor suppressor gene located on the human chromosome 17 that is thought to regulate (suppress) the proliferation of normal cells. The mutant protein accumulates in the nuclei of tumor cells that may then have a proliferative advantage over normal cells. The purpose of this study was to investigate the relationship between levels of mutant p53 expression and the clinical outcome of patients with node-positive and node-negative breast cancer. Expression of mutant p53 was evaluated in 655 human breast carcinomas (349 node-positive and 306 node-negative patients) with long-term clinical follow-up by immunohistochemistry in sections from paraffin embedded tumors. RESULTS: Immunoreactivity was found in 37.3% of breast tumors. There was no significant correlation between the expression of p53 and tumor size, nodal involvement, age or histological type. However, p53 overexpression was clearly related to histological grade and steroid receptors, with a trend to higher overexpression in ER-tumors or in those with a high histological grade (p < 0.01). On univariate analysis positive tumors were associated with reduced DFS in the total group (p < 0.001) as well as in node-positive patients (p < 0.05) and in node-negative patients (p < 0.01). In conclusion, these results suggest that the immunoreactivity of p53 may be a biologic marker of prognostic significance in both node-positive and node-negative patients.

Predictors of breast recurrence after conservative surgery and radiation therapy for invasive breast cancer.

The majority of women with breast cancer are adequately treated with breast-conserving surgery and radiation therapy. Although most women need very limited surgery, some require a larger volume of resection to attain a high level of local control, and some might even require a mastectomy. This article summarizes the current state of knowledge concerning the assessment of the adequacy of excision.

Correlation of tumor size and axillary lymph node involvement with prognosis in patients with T1 breast carcinoma.

BACKGROUND: The prognosis of patients with T1 breast carcinoma remains controversial. Some studies have shown a low risk of lymph node metastasis and distant failure whereas others have not, possibly due to differences in the definition of tumor size. In this study, the authors assessed the relation between macroscopic tumor size, microscopic invasive tumor size, axillary lymph node involvement, and prognosis in a group of patients with clinically lymph node negative disease. METHODS: Between 1968 and 1986, 1865 women with American Joint Committee on Cancer clinical Stage I or II infiltrating carcinoma of the breast were treated at the Joint Center for Radiation Therapy with conservative surgery and radiation therapy. The study population was limited to 118 patients with clinically negative axillary lymph nodes for whom the macroscopic pathologic tumor size was identified unambiguously as being < or = 2.0 cm, who underwent an axillary lymph node dissection with at least 6 lymph nodes sampled, and for whom the microscopic size of the invasive component could be determined. The median follow-up time for surviving patients was 134 months (range, 90-208 months). No patients with pathologically negative axillary lymph nodes received systemic therapy. RESULTS: Macroscopic and microscopic tumor sizes differed by > 5 mm in 17 patients (14%), by 3-5 mm in 24 patients (20%), and by < or = 2 mm in 77 patients (65%). The macroscopic tumor size was smaller than the microscopic size in 37 patients (31%), larger in 55 patients (47%), and equal in 26 patients (22%). Pathologic axillary lymph node involvement was present in 21% of all patients. The risk of lymph node involvement was not significantly different for those patients with tumors < or = 1 cm compared with patients with tumors > or = 1.1 cm, regardless of whether tumor size was measured by macroscopic or microscopic examination. The 10-year actuarial rate of freedom from distant recurrence (FFDR) was 91% for lymph node negative patients with macroscopic tumors measuring < or = 1.0 cm compared with 77% for patients with macroscopic tumors measuring > or = 1.1 cm (P = 0.07). When measured microscopically, the rates were 96% and 72%, respectively (P = 0.001). CONCLUSIONS: There often is a discrepancy between microscopic tumor size and macroscopic tumor size. T1 tumors have a substantial risk of axillary lymph node metastasis whether measured macroscopically or microscopically. Among those patients with pathologic lymph node negative tumors who are not treated with systemic adjuvant therapy, microscopic invasive tumor size is a better predictor of 10-year FFDR than macroscopic tumor size. There is a substantial risk of distant failure for patients with tumors whose invasive component microscopically measure > or = 1.1 cm, whereas the prognosis for patients with tumors that microscopically measured < or = 1 cm is excellent. These results suggest that the microscopic size of the invasive component of breast carcinomas < or = 2.0 cm routinely should be reported.

Breast-conserving therapy for stage I-II synchronous bilateral breast carcinoma.

BACKGROUND: Synchronous bilateral breast carcinoma (SBBC) is an uncommon presentation, and the management of patients with this disease is not well established. METHODS: In order to evaluate whether patients with early-stage SBBC could be safely and effectively treated with bilateral breast-conserving therapy (BCT), the authors retrospectively reviewed the records of 24 patients with clinical Stage I-II SBBC treated during the period 1977-1989 with bilateral BCT. SBBC was defined as bilateral invasive carcinomas diagnosed no more than 1 month apart. The median age at diagnosis was 56 years (range, 32-85 years), and the median follow-up for surviving patients was 95 months (range, 68-157 months). Pathology slides were available for review in 19 cases. Cosmetic results and complications after BCT were scored. Outcome was compared with that of 1314 patients with unilateral Stage I or II breast carcinoma, within the same age range, treated during the same time period. RESULTS: There were no significant differences between the SBBC and unilateral groups in actuarial disease free survival (70% and 74%, respectively, at 5 years), overall survival (88% and 87%, respectively, at 5 years), or crude distribution of sites of first failure. Multivariate analysis of overall survival and disease free survival also did not show bilaterality to be a significant factor. The cosmetic results for the SBBC group were not significantly different from those for the unilateral group. Physician assessment of cosmetic outcome was excellent in 57% and good in 43% of SBBC patients evaluated 25-48 months after BCT. Long term complications were rare in both groups. CONCLUSIONS: Patients with early-stage SBBC can be safely treated with carefully planned, bilateral BCT, with outcome that appears to be comparable to that of patients with early-stage unilateral breast carcinoma.

Prognostic value of S-phase fraction in lymph-node-negative breast cancer by image and flow cytometric analysis.

Cellular DNA content and proliferation rates have been suggested as prognostic factors in breast carcinomas. A series of 271 lymph-node negative breast carcinoma patients without adjuvant therapy was reviewed (mean follow-up, 108 mo). Tumor cells from the same paraffin-embedded block tissue (Hedley's method) were analyzed by image analysis (IA) in Feulgen-stained smears and by flow cytometric analysis (FC). Clinicopathologic features, ploidy, S-phase fraction, and percentage of tumor cells with more than 5n DNA content (in diploid tumors, by IA) were related to outcome. The results of IA and FC were compared in 115 cases. Tumor size, histologic grade, desmoplasia and S-phase fraction were significant predictors of survival in multivariate analysis (Cox proportionate regression) (P < or = 0.03). Ploidy by the two methods showed agreement in 100 carcinomas (87%). Of the 15 discordant cases, FC detected 6 multiploid and 4 aneuploid-peridiploid. In contrast, IA detected more tetraploid carcinomas. Tumor size, histologic grade, desmoplasia, and S-phase fraction were independent predictors of long-term prognosis in our patients. Ploidy and percentage of tumor cells with more than 5n DNA content were not prognostic indicators. FC detected aneuploidy more frequently than did IA.

Proliferative activity in C-cell hyperplasia and medullary thyroid carcinoma. Evaluation by PCNA immunohistochemistry and AgNORs staining.

C cell hyperplasia (CCH) is a preneoplastic lesion that precedes the development of medullary thyroid carcinoma (MTC) in familial cases. It has been hypothesized that CCH progressively acquires the neoplastic phenotype after presenting some genetic changes that involve oncogenes and tumor suppressor genes. The proliferative activity of nodular C cell hyperplasia (NCCH) and early MTC has been assessed by PCNA (Proliferating Cell Nuclear Antigen) immunohistochemistry and nucleolar organizer regions silver staining (AgNOR) in surgical specimens of seven patients with familial MTC. The ratios of PCNA-positive nuclei in NCCH (mean 1.2, range 0.2-4) were lower than in MTC (mean 2, range 1-7%). The AgNOR scores for NCCH (mean 1.53, range 1.10-1.90) were also lower than for MTC (mean 2.10, range 1.90-2.64). The results suggest that C cells progressively acquire a higher proliferative activity in agreement with the severity of the morphologic changes in the process of hyperplasia-neoplasia that leads to widely invasive MTC.

Detection of steroid receptors in breast cancer: relationship between EIA and IHC methods.

The efficiency of EIA and IHC (frozen tissue) in the detection of ER and PR in 51 breast cancers were compared. ER were detected in 51% of cases by IHC and in 49% of tumours by EIA. PR were detected in 56.8% of cases by IHC and in 54.8% of tumours by EIA. Concordance of the results of IHC and EIA reached 78.4% in ER and 82.4% in PR detection. Discordance between IHC and EIA seems to be related to minor changes in sensibility of methods, but we cannot conclude that one of the two techniques is superior to the other in the detection of hormonal receptors. There is a common trend of association between low grade of histologic or nuclear malignancy and a high expression of hormonal receptors.

[Gastric carcinoma with a lymphoid stroma]. / Carcinoma gástrico con estroma linfoide.

Carcinomas with lymphoid stroma have been described in different locations: breast, uterine cervix, nasopharynx, esophagus and stomach. These neoplasms have a better prognosis probably due to the lymphoid reaction that takes place in the tumoral stroma. For this reason many authors prefer to consider this entity separate from the rest of gastric carcinomas. We present a case of gastric carcinoma with lymphoid stroma and neuroendocrine features. Such association has not been previously described in the Spanish literature.