Carcinoma arising within fibroadenomas of the breast. A clinicopathologic study of 105 patients.

The authors report the clinicopathologic features of 105 carcinomas arising within fibroadenomas (FAs) of the breast. The mean age of the patients was 44 years. The presentation and gross characteristics of these tumors rarely differed from those of uncomplicated FAs. Carcinoma in situ (CIS) was the predominant type of malignancy (95%) found to arise in FAs, and lobular and ductal types occurred with equal frequency. Nine of ten FAs harboring an invasive carcinoma also contained CIS supporting the origin of the infiltrative component in the FAs. CIS within FAs was associated with in situ malignancy in surrounding breast tissue in 21% of cases. Age, fibroadenoma size, and type and extent of CIS were similar in patients with disease limited to the FA and in those with associated malignant disease in the remainder of the breast. Axillary nodal metastases were not detected. Sixty-three patients were observed for a mean period of 8.4 years. Only one of 26 patients with CIS within an FA who was treated conservatively developed an ipsilateral carcinoma. None of the 26 developed contralateral carcinoma; however, 3 of 23 with similar lesions, who were treated by mastectomy, did so. The contralateral carcinomas were invasive in two patients, one of whom died with distant metastases. Seven patients with FAs harboring lobular CIS underwent bilateral mastectomy. Their postoperative course was uneventful. None of seven patients with invasive carcinoma arising in an FA, two of whom were treated conservatively, succumbed to disease. However, one developed contralateral carcinoma. The authors recommend breast-conserving therapy for CIS arising in an FA.     

Carcinoma arising within mammary fibroadenomas. A study of six patients

We report six cases of carcinomas arising within fibroadenomas. Fibroadenoma is a benign neoplasm occurring in young women. Its association with carcinomas is unfrequent and particularly reported in older women. Few data are available on the histologic features of fibroadenomas harboring malignant lesions. In this study, most cases of fibroadenomas showed cysts, sclerosing adenosis, epithelial calcifications or papillary apocrine changes. These fibroadenomas are classified as complex and are a long-term risk factor for breast cancer. The complex fibroadenoma may be specific of fibroadenoma associated with carcinoma.     

Multiple fibroadenomas harbouring carcinoma in situ in a woman with a family history of breast/ovarian cancer

A 46 year old woman with a family history of breast and ovarian cancer presented with multiple fibroadenomas in both breasts. From three fibroadenomas removed from the left breast carcinoma in situ (CIS) had developed. One fibroadenoma gave rise to ductal CIS, whereas the other two harboured lobular CIS. This is the first report of three fibroadenomas simultaneously giving rise to CIS. In addition, synchronous fibroadenomas harbouring different types of CIS from one fibroadenoma to the other have never been described. Direct sequencing revealed a mutation (5075G-->A) in the BRCA1 gene, but retention of BRCA1 immunohistochemical staining and no loss of heterozygosity at the BRCA1 locus by polymerase chain reaction made a pathogenic mutation in BRCA1 unlikely. Furthermore, in this family no cosegregation of breast cancer with this BRCA1 mutation was seen. Indeed, this mutation is now regarded as a polymorphism. This case stresses the need for histological evaluation of all breast masses in women with a strong positive family history for breast and/or ovarian cancer.     

Myxomatous fibroadenoma of the breast: correlation with clinicopathologic and radiologic features

Fibroadenoma is a frequently encountered benign tumor that must be differentiated from carcinoma. Fibroadenomas often exhibit myxedematous changes (myxomatous fibroadenoma). We focused on myxomatous fibroadenomas and evaluated their diagnostic imaging and clinicopathologic findings. We examined the (1) clinicopathologic findings of myxomatous fibroadenomas out of 113 fibroadenomas among 592 needle biopsy cases and (2) clinical findings of 27 patients with fibroadenoma who underwent surgical resection. One hundred thirteen (19%) of 592 cases were fibroadenoma, of which 45 cases (40%) were myxomatous fibroadenoma. Based on ultrasonography findings, the depth to width ratio was significantly higher in the myxomatous fibroadenoma group (0.79 ± 0.26) compared with the non-myxomatous fibroadenoma group (0.64 ± 0.26) (P < .01). Forty-two patients were subjected to needle biopsy to differentiate fibroadenoma from carcinomas based on ultrasonography and clinical findings, of which 13 cases (31%) were myxomatous fibroadenoma. These lesions showed a relatively round shape and increased posterior echo enhancement with internal hyperechogenicity on ultrasonography. Among 17 resected cases suspected of malignancy that showed rapid growth and/or size greater than 3 cm, 16 cases were myxomatous fibroadenoma. Tumors showing rapid growth and a relatively large size, a high depth to width ratio, a relatively round shape, and posterior echo enhancement with internal hyperechogenicity on ultrasonography require differentiation from (mucinous) carcinoma but are histologically more likely to be myxomatous fibroadenoma. Understanding the histologic features and combining the ultrasonography findings of myxomatous fibroadenomas may permit reduction in the number of unnecessary needle biopsies for tumor-forming lesions.     

Adenomas of the breast and ectopic breast under lactational influences

The tubular adenomas, lactating adenomas, and ectopic lactation- or gestation-associated benign lesions of the breast diagnosed during a 22-year period are reported. Forty-two breast adenomas (in 28 patients) that demonstrated lactational changes are reviewed, with special attention to classification and clinical presentation. Five ectopic lactating adenomas--three axillary or in the chest wall and two vulvar, the latter occurring in the same patient--were identified in three patients. The lesions in the remaining cases were fibroadenomas with lactational changes (16 patients) and lactating or tubular adenomas (nine patients). Striking histologic and clinical similarities between the tubular and lactating adenomas and the lesions identified as lactational changes within a fibroadenoma were observed, with foci of tubular adenomatous change present within otherwise typical fibroadenomas. The overlapping morphologic spectrum and the strong association with pregnancy or lactational influences blur the distinction between these entities and suggest a common pathogenesis. The cytologic features of lactational lesions of the breast and ectopic breast pose special problems in diagnosis by fine needle aspiration.     

Analysis of the progression of fibroepithelial tumours of the breast by PCR-based clonality assay

Fibroadenoma and phyllodes tumour of the breast are both fibroepithelial tumours. Although progression to epithelial malignancy has been described, the behaviour of most fibroadenomas is benign. Phyllodes tumours, on the other hand, can display locally destructive growth and can even metastasize. A relationship between the two tumours has been suggested in the literature. This study investigated the clonality of both the stroma and the epithelium of these fibroepithelial tumours and attempted to construct a model in which fibroadenoma can progress in both an epithelial and a stromal direction. Fibroadenomas (n=25) and phyllodes tumours (n=12) were selected for analysis. Tissue was microdissected and analysed for clonality using a polymerase chain reaction (PCR)-based assay targeted at an X-linked polymorphic marker, the human androgen receptor gene (HUMARA). Nineteen fibroadenomas and nine phyllodes tumours could be analysed. Normal-appearing epithelium, hyperplastic epithelium, and stroma removed from fibroadenomas were polyclonal. As expected, carcinoma in situ (CIS) removed from four fibroadenomas was monoclonal. Three areas of apparent stromal expansion within fibroadenoma were monoclonal, suggesting stromal progression. Mostly, the stroma of phyllodes tumours was monoclonal and the epithelium polyclonal. In two cases, however, the epithelium seemed to be monoclonal, whereas in three other cases the stromal component was polyclonal. These findings indicate that fibroadenoma can progress in an epithelial direction to CIS and in a stromal direction to phyllodes tumour.     

Fibroepithelial lesions with cellular stroma on breast core needle biopsy: are there predictors of outcome on surgical excision?

Fibroepithelial lesions with cellular stroma (FELCS) in breast core needle biopsy (CNB) specimens may result in either fibroadenoma or phyllodes tumor at excision. We evaluated histologic features, proliferation indices (by Ki-67 and topoisomerase II a immunostaining) and p53 expression in 29 cases of FELCS in CNB specimens and correlated these with excision findings in a blinded manner. On excision, 16 patients had fibroadenomas and 12 had phyllodes tumors. All CNB specimens with mildly increased stromal cellularity were fibroadenomas on excision (n=4), and all with markedly cellular stroma were phyllodes tumors (n=4). Among CNB specimens with moderate cellularity (12 fibroadenomas and 8 phyllodes tumors), only stromal mitoses were discriminatory histologically. Stromal proliferation indices were significantly higher in CNB that were phyllodes tumors vs fibroadenomas. Assessment of stromal cellularity, mitoses, and proliferation indices might help determine the probability of phyllodes tumor occurring and guide management of these cases.     

Cell proliferation in normal human breast ducts,fibroadenomas, and other ductal hyperplasias measured by nuclear labeling with tritiated thymidine: Effects of menstrual phase,age, and oral contraceptive hormones

The proliferative rates of terminal duct cells were studied by tritiated thymidine labeling in vitro in 104 specimens of benign breast tissue from 92 women. The tritiated thymidine labeling index showed a cyclic pattern consistent with regulation by female sex hormones. It was low during the segment of the menstrual cycle encompassing days 2 through 15 (early cycle) and often was elevated during the segment encompassing days 16 through 1 (late cycle). The early cycle geometric mean index for morphologically normal terminal ducts was 0.19, and for ducts of fibroadenomas it was 0.77. The geometric means for late cycle were 1.03 and 1.67 respectively. The difference for normal ducts between early and late cycles was highly significant (P<0.001). For both normal ducts and fibroadenomas the tritiated thymidine labeling index correlated negatively with the age of the patient, and the higher index value of fibroadenoma ducts relative to normal ducts was entirely accounted for by the younger mean age of the fibroadenoma patients. Oral use of contraceptive hormones could not be shown to change the index in either normal ducts or fibroadenoma ducts. Based on a postulated duration of DNA synthesis of 12 hours, the mean turnover time of the cells of normal terminal ducts would be approximately 22 days for 20 year old women with regular menstrual cycles, and would increase to 147 days at age 40. the mean potential doubling times of fibroadenomas would be approximately 33 days. The index values of other benign ductal proliferative lesions of the breast were similar to those of fibroadenomas and normal terminal ducts.     

Cellular fibroepithelial lesions of the breast: A long term follow up study

Some fibroepithelial lesions (FEL) of the breast are difficult to classify as cellular fibroadenoma (CFA) or benign phyllodes tumor (BPT) due to overlapping histologic features. This indeterminate group is histologically characterized by prominent stromal cellularity, mild atypia, and mitotic activity. The local recurrence potential of cellular FEL (CFEL) has been insufficiently studied. The objective of this study was to evaluate the histologic features, characterize the long-term follow-up and recurrence rate of CFEL, and compare this data with the recurrence rate of definitive BPT. Ninety CFEL that were <4 cm were recovered from the benign breast disease cohort. The control group comprised of 10 randomly selected patients with BPT. Cases were classified based on a combination of mitotic activity, intracanalicular growth, stromal atypia, stromal prominence, and fat infiltration. None of the CFEL was widely excised. Of the 90 CFEL cases, there were 22 BPT-like, 35 CFA, and 33 indeterminate. The mean age of the patients was 40.1 years. The mean tumor size was 2.4 cm. All patients had at least two years of follow-up (median 27). None of the patients with BPT-like CFEL showed ipsilateral recurrence. Five of the 35 patients with CFA had recurrent ipsilateral CFA. This occurred within 1 to 11 years after the initial diagnosis. One of 33 patients with indeterminate type had a recurrent ipsilateral lesion five years after the initial diagnosis with histologic features of CFA. None of the patients in control group had any recurrence. In conclusion, as a group, CFEL have a low proclivity for recurrence, even when enucleated with close or positive margins. The presence of histologic features of BPT did not correlate with an increased potential for recurrence.     

Fibroadenomas with stromal cellularity. A clinicopathologic study of 21 patients

Data on clinical and pathologic features of tumors from 21 patients who had breast tumors compatible with juvenile (cellular) fibroadenomas (JCF) were reviewed. All patients were black females ranging in age at time of presentation from 10 to 39 years, with a median age of 15 years. Follow-up (median period, six years) was obtained for 20 patients. Patients were categorized into two groups; 13 had solitary lesions and eight had multiple and successive lesions. No histologic differences were observed between JCF occurring as solitary or multiple tumors or between lesions occurring in patients younger and older than age 20 years. The JCF was shown to be a fairly distinct clinicopathologic entity that characteristically occurred in adolescents, but which was occasionally seen in young adults. It had a benign course, characterized by synchronous and metachronous multicentricity, rather than local recurrence.     

Long-term prognosis of teenagers with breast cancer

We report 4 new cases of breast carcinoma in teenage girls diagnosed by use of histochemical and immunohistochemical methods. These cases of breast carcinoma in women under 20 years of age were found in the files of our department in the last 24 years (1976-2000). The patients had operable breast carcinomas corresponding to various histologic types (1 invasive ductal carcinoma associated with fibroadenoma, 2 secretory carcinomas, and 1 invasive lobular-type carcinoma). Simple mastectomy with low axillary lymph node dissection was performed in 2 postpubertal patients. Only 1 patient received adjuvant chemotherapy (case 4). After follow-up ranging from 76 to 126 months, 3 patients are alive and disease-free and 1 has disseminated metastatic disease. The correlations with prognosis-related risk factors (stage, age, previous benign lesions, family history, histologic types, hormonal receptors, and pregnancy) were examined.     

"Missed" diagnoses of phyllodes tumor on breast biopsy: pathologic clues to its recognition

Fibroadenoma and phyllodes tumors of the breast exhibit a continuum of pathologic features. We examined phyllodes tumors initially called fibroadenoma for features that may accurately classify the tumor as phyllodes tumor on the first biopsy specimen. The phyllodes tumors initially called fibroadenoma for features that may accurately classify the tumor as phyllodes tumors on the first biopsy specimen are examined. Fifteen patients with phyllodes tumors were studied, initially called FA or another term short of PT. These tumors were compared with 16 true fibroadenomas, all with needle-core biopsy followed by excision. Resected phyllodes tumors were larger on average than fibroadenoma, 6.8 cm (range = 1.7-16.2 cm) versus 2.6 cm (range = 1.0-4.8 cm). In needle-core biopsy cases, sampling was limited, even in large breast masses. p53 and cleaved caspase-3 were noncontributory. Ki-67 showed higher proliferation indices in phyllodes tumors versus fibroadenoma (4.8% vs 0.6%). Features suggesting phyllodes tumors include tissue fragmentation, increased stromal cellularity especially around glands, stromal overgrowth, and increased mitoses. Increased sampling of a large tumor will likely yield more correct diagnoses.     

Breast cancer in young women: clinicopathologic correlation.

It has been suggested that early-onset breast carcinomas may be different from those that occur in older women. The clinicopathologic characteristics of 191 young female patients (under 40 years of age) diagnosed with breast carcinoma (BC) were studied. Clinical history, staging, treatment and outcome were reviewed. Histology was assessed for tumor subtypes, invasive and in situ components, nuclear and histologic grades and lymph node status. Adjacent nontumoral breast tissue was evaluated. Clinically, 11 patients were stage 0, 21 stage I, 94 stage II, 38 stage III, 6 stage IV, and in 21 no information was obtained. Sixty five percent of patients had positive lymph nodes at diagnosis; 102 patients (54%) relapsed at a median of 29 months after diagnosis. Histologically, 180 cases were infiltrating BC, 150 ductal (83%), 19 lobular (11%) and 11 of special types (6%); 11 cases were ductal carcinoma in situ. We found no cases of medullary carcinoma. High nuclear grade and vascular invasions were frequent (68% and 67%, respectively) even in patients who remained disease-free at least 5 years after diagnosis (61% and 60%, respectively). Our study demonstrates that the histologic types of early-onset breast cancer are not different from other BC. However, BC in young women is often associated with histologic features of high-grade malignancy even in patients with better survival. Our results suggest that BCs in young women are different from those that occur in older women.     

Fibroadenoma of the breast: diagnostic pitfalls of fine-needle aspiration.

On fine-needle aspiration (FNA), fibroadenomas have a characteristic cytological appearance, although occasional cases are misinterpreted as carcinomas and vice versa. In a review of 521 breast aspirates correlated with the subsequent histology, six of 87 fibroadenomas (7%) were malignant or suspicious of malignancy on FNA (false positives). Following cytological review, four were still suspicious of malignancy because of cellular dyscohesion and prominent nucleoli, while two were fibroadenomas. On FNA, four of 145 carcinomas (3%) were diagnosed as fibroadenomas (false negatives). On review, three were malignant or suspicious of malignancy, while one was consistent with a fibroadenoma. Three false negative diagnoses were due to underappreciation of single malignant cells present between epithelial groupings typical of a fibroadenoma, while one was due to undersampling of the carcinoma. Cytologically, some fibroadenomas are sufficiently atypical that histological confirmation is necessary to exclude a malignancy. Misinterpreting carcinomas as fibroadenomas could be avoided by careful study of the morphology of isolated cells.     

乳腺神经内分泌型导管内癌

目的对乳腺神经内分泌型导管内癌（E-DCIS）的临床病理特点、预后和鉴别诊断进行探讨。方法用光镜、免疫组织化学EnVision法行嗜铬素A、突触素和神经元特异性烯醇化酶（NSE）染色和消化PAS、消化阿辛蓝和嗜银染色,对18例具有E-DCIS特征的乳腺癌进行观察。结果具有E-DCIS特征的乳腺癌具有以下特点：（1）好发于老年女性,平均年龄71岁。最常见的临床症状为乳腺肿块或乳头溢液。（2）E-DCIS呈导管内肿瘤细胞的膨胀性生长,在肿瘤周边常可见导管内乳头状瘤。（3）肿瘤细胞呈多边形,卵圆形或梭形,胞质丰富,嗜酸性或细颗粒状。细胞核往往只有轻一中度异型,消化PAS或AB染色显示细胞内或细胞外存在黏液,有些肿瘤细胞呈印戒细胞样。（4）〉50％的肿瘤细胞表达嗜铬素A、突触素和NSE中的至少两种,部分病例CD56和CD57染色阳性。（5）E-DCIS中常可见到肿瘤细胞向邻近导管的派杰样扩散,且在膨胀性生长的导管内不存在肌上皮成分。这两点有助于E-DCIS与导管上皮增生的鉴别。结论E-DCIS是一种低度恶性的乳腺导管内癌,有其独特的组织形态、免疫组织化学特征,应作为一种独立的导管内癌类型加以认识。     

Significance of TLR4/MyD88 expression in breast cancer

Objective: To investigate the expression of TLR4/MyD88 in breast cancer, and explore the relationship between their expression and breast cancer tumor growth and invasion. Methods: We examined the protein expression of TLR4 and MyD88 in 60 cases of histologically confirmed breast cancer. The relationship of their protein expressions with clinical features including age at diagnosis, tumor size and stage, lymph node metastasis and distant metastasis were analyzed. Results: The IHC results showed that TLR4 and MyD88 were expressed in 63.3% (38/60) and 58.3% (35/60) of malignant breast tumors respectively. TLR4 expression in breast cancer were significantly higher than in fibroadenoma (n = 4, 20.0%) and adjacent normal tissues (n = 2, 10.0%) (P < 0.001). MyD88 expression in breast cancer were also significantly higher than in fibroadenoma (n = 4, 20.0%) and adjacent normal tissue (n = 3, 15.0%) (P < 0.001). The gene expressions of TLR4 and MyD88 were significantly higher in breast cancer than in fibroadenoma and adjacent normal tissues (P < 0.05). The protein expressions of TLR4 and MyD88 were also significantly associated with poor clinical features (P < 0.05). Conclusion: TLR4 and MyD88 expression might be associated with breast cancer growth and regional and distant metastases.     

Epstein-Barr virus infection is not associated with fibroadenomas of the breast in immunosuppressed patients after organ transplantation.

Epstein-Barr virus has been linked to an increasing number of nonhematolymphoid conditions. Epstein-Barr virus was recently described in association with fibroadenomas of the breast occurring in immunosuppressed patients. To further investigate the potential association of Epstein-Barr virus with fibroadenoma in the context of immune dysfunction, 11 cases of fibroadenoma of the breast in immunosuppressed organ transplant recipients were examined. Cases were evaluated for the presence of Epstein-Barr virus by polymerase chain reaction, in situ hybridization, and immunohistochemical methods. The presence of Epstein-Barr virus genomic DNA was studied by polymerase chain reaction amplification using primers flanking the BamHI-W fragment of the Epstein-Barr virus genome, as well as the Epstein-Barr virus nuclear antigen-4 and latent membrane protein-1 genes. Cases were also evaluated for the presence of defective heterogeneous Epstein-Barr virus DNA. In addition, morphologic analysis by in situ hybridization for Epstein-Barr virus-encoded RNA-1 and immunohistochemistry for latent membrane protein-1 were performed. Epstein-Barr virus DNA was detected in 4 of 11 (36%) cases with BamHI-W polymerase chain reaction. Polymerase chain reaction studies for Epstein-Barr virus nuclear antigen-4 and latent membrane protein-1 genes were positive in two and four cases, respectively. No defective Epstein-Barr virus genomes were identified in any of the cases. Quantitative polymerase chain reaction demonstrated low levels of Epstein-Barr virus in the fibroadenomas studied. Despite the detection of Epstein-Barr virus genomes in a subset of the cases examined, the constituent epithelial and stromal components of all fibroadenomas demonstrated no evidence of Epstein-Barr virus-encoded RNA-1 by in situ hybridization or latent membrane protein-1 expression by immunohistochemistry. Rare Epstein-Barr virus-encoded RNA-1-positive lymphocytes were observed in some cases, which may account for the positive polymerase chain reaction results. The findings of the present study argue against a significant relationship between Epstein-Barr virus and fibroadenomas of the breast in the setting of transplant-associated immunosuppression.     

Gene expression in fibroadenomas of the rat mammary gland in contrast to spontaneous adenocarcinomas and normal mammary gland.

Fibroadenomas are considered a benign lesion in rodent carcinogenicity studies. However, the entity adenocarcinoma arising in fibroadenoma does exist and in humans there is evidence of certain forms of fibroadenomas to confer greater risk of subsequent breast cancer. In this study, we aim to elucidate the molecular features of both spontaneous fibroadenomas and adenocarcinomas. The gene expression of the two tumour types is examined and compared to mammary gland in the same developmental state and examined for similarities which might indicate common molecular pathways. In the present study no similarities were discovered. We conclude that in the tumours examined here, no progression to adenocarcinoma is likely. Further studies are needed, examining a greater number of tumours and including cases of adenocarcinoma arising in fibroadenoma.     

Morphology of testicular parenchyma adjacent to germ cell tumours. An interim report

A comparative morphological analysis of parenchyma adjacent to testicular germ cell tumours (TGCT) was performed in a series of 181 orchidectomy specimens: 86 with seminomas (Se), 72 with nonseminomatous germ cell tumours (NS) and 23 with combined tumours (CT, which have a Se and a NS component). The following morphological features were semiquantitatively scored: spermatogenesis (modified Johnsen score); amount of tubular atrophy; amount of carcinoma in situ (CIS); amount of intertubular tissue. Absence and presence was scored for the following features: lymphocytic infiltrate surrounding and invading CIS; intratubular seminoma (ISe); intratubular nonseminoma (INS); microlithiasis; diffuse and nodular hyperplasia of Leydig cells; angioinvasiveness; testicular angiopathy. Using non-parametric statistics these features were correlated with each other and with tumour type, tumour size and age of the patient. Se-patients presented at significantly higher age than NS-patients (36 vs 29 years, p=0.001). The age of patients with CT (32 years) was in between that of Se- and NS-patients. No correlation was found between patient age and tumour size. Parenchyma adjacent to Se, compared to parenchyma adjacent to NS had the following significant differences: a lower Johnsen score (5.6 vs 7.2, p=0.005); less frequent (85% vs 97% of specimens, p=0.016) and a lesser amount of CIS (26% vs 32% of tubules, p=0.015); more frequent peri- (80% vs 60% of specimens, p=0.001) and intratubular (68% vs 30% of specimens, p=0.001) lymphocytic infiltrates; more extensive tubular atrophy (36% vs 15% of tubules, p=0.001); and a larger area of intertubular tissue (42% vs 34% of parenchyma area, p=0.016). The pooled Se and CT had a significantly higher frequency of ISe than the NS (31% vs 17% of specimens, p=0.036). With one exception INS was only found adjacent to NS or CT, with a frequency of 16%, and 20% of the specimens, respectively. It was significantly associated with angio-invasiveness. In specimens lacking angio-invasion the frequency of INS was 6%. The correlation of INS with tumour size and patient age was studied in a series of 145 NS and CT (95 from the original series supplemented by 50 newer cases). In this series INS was significantly associated with smaller tumours and younger patients. Extensive tubular atrophy was significantly correlated with higher age, the diagnosis of Se, a low Johnsen score, and the presence of angiopathy. The more tubular atrophy, the less CIS (both in incidence and amount). Inversely, a higher Johnsen score is associated with smaller tumours, the diagnosis of NS or CT, a higher incidence and a larger amount of CIS, and little tubular atrophy. Tubules with mature spermatogenesis were found in 42% of the specimens regardless of tumour type. We conclude that ISe and INS are probably frequent intermediate stages between CIS and Se and NS, respectively. The features of parenchyma adjacent to Se are probably due to the host response elicited by the invasive Se, which secondarily also affects CIS. The long time to clinical presentation allows the host to eradicate most of the CIS by the time the tumour is surgically removed. The much less extensive morphological features of a host response in parenchyma adjacent to NS support the contention that NS originates as INS, behind the blood/testis barrier, without exposure of the host to tumour cells with a seminomatous phenotype (CIS- or Se cells). Microlithiasis and testicular angiopathy are frequent, but not specific findings in parenchyma next to TGCT. Their relationship with the development with TGCT is unexplained.     

Estrogen receptor-beta is expressed in stromal cells of fibroadenoma and phyllodes tumors of the breast.

An estrogen dependency has been suggested for the growth of fibroadenomas: however, thus far, none of the steroid hormone receptors acting on breast tissues has been demonstrated in the stroma of breast fibroepithelial lesions. In this study, the expression of estrogen receptor (ER)-alpha and -beta was investigated by immunohistochemistry in 33 fibroadenomas and in 30 benign, three borderline and seven malignant phyllodes tumors, all with spindle cell growth and in one distant metastasis. In addition, the presence of ER-beta mRNA and its variants was evaluated by RT-PCR in microdissected stroma. The possible correlation between hormone receptor expression and differentiation processes of stromal cells was investigated by smooth muscle actin and calponin immunostaining. ER-beta was the only hormone receptor expressed by stroma of fibroadenomas and phyllodes tumors, both at protein and mRNA level. The highest percentage of ER-beta was observed in fibroadenomas with cellular stroma and in phyllodes tumors. In both lesions, ER-beta-positive stromal cells showed expression of smooth muscle actin and/or calponin, as demonstrated by double immunostaining. In addition, the mean age at diagnosis was significantly lower in patients with ER-beta-positive vs ER-beta-negative fibroadenomas. In contrast, in phyllodes tumors, ER-beta expression was higher in older patients. In conclusion, (i) only ER-beta is detected in the stroma of fibroadenomas and phyllodes tumors; (ii) its expression correlates with the expression of smooth muscle markers and suggests a role of ER-beta in myofibroblastic differentiation of stromal cells. These two results, together with the young age of patients carrying fibroadenomas with highly ER-beta-positive stroma cells, may further indicate a hormone-receptor mechanism involved in regulating the growth of fibroadenomas. Conversely, the older age of patients with ER-beta-rich phyllodes tumors suggests that mechanisms, probably independent from estrogen stimulation, act on the growth of these tumors.