Indications and results of diagnostic biopsy in pediatric renal tumors: A retrospective analysis of 317 patients with critical review of SIOP guidelines.

OBJECTIVES: According to the Renal Tumor Study Group (RTSG) of the International Society of Paediatric Oncology (SIOP), diagnostic biopsy of renal tumors prior to neoadjuvant chemotherapy is not mandatory unless the presentation is atypical for a Wilms tumor (WT). This study addresses the relevance of this strategy as well as the accuracy and safety of image-guided needle biopsy. METHODS: Clinical, radiological, and pathological data from 317 children (141 males/176 females, mean age: 4 years, range, 0-17.6) consecutively treated in one SIOP-affiliated institution were retrospectively analyzed. RESULTS: Presumptive chemotherapy for WT was decided for 182 patients (57% of the cohort), 24 (8%) were operated upfront, and 111 (35%) were biopsied at diagnosis. A non-WT was confirmed after surgery in 5/182 (3%), 11/24 (46%), and 28/111 (25%), respectively. Age at diagnosis was the most commonly (46%) used criterion to go for biopsy but a nine-year threshold should be retrospectively considered more relevant. Tumor volumes of clear cell sarcoma of the kidney and WT were significantly higher than those of other tumors (P = 0.002). The agreement between core-needle biopsy (CNB) and final histology was 99%. No significant morbidity was associated with CNB. CONCLUSION: The use of SIOP criteria to identify patients eligible for presumptive WT neoadjuvant chemotherapy or upfront surgery avoided biopsy in 65% of children and led to a 97% rate of appropriate preoperative chemotherapy. Image-guided CNB is a safe and accurate diagnostic procedure. The relevance of SIOP biopsy criteria might be improved by using an older age threshold (9 years instead of 6 years) and by adding initial tumor volume.

The RB1 gene is the target of chromosome 13 deletions in malignant fibrous histiocytoma.

Forty-four malignant fibrous histiocytomas (MFHs) were studied by comparative genomic hybridization. Among the observed imbalances, losses of the 13q14-q21 region were observed in almost all tumors (78%), suggesting that a gene localized in this region could act as a tumor suppressor gene and that its inactivation could be relevant for MFH oncogenesis and/or progression. We determined by CA repeat analyses a consensus region of deletion focusing on the RB1 region. The RB1 gene was then analyzed by protein truncation test, direct sequencing, fluorescence in situ hybridization, Southern blotting, and immunohistochemistry. RB1 mutations and/or homozygous deletions were found in 7 of the 34 tumors analyzed (20%). Among the 35 tumors with comparative genomic hybridization imbalances analyzed by immunohistochemistry, 30 (86%) did not exhibit significant nuclear labeling. The high correlation between chromosome 13 losses and absence of RB1 protein expression and the mutations detected strongly suggest that RB1 gene inactivation is a pivotal event in MFH oncogenesis. Moreover, the observation of a high incidence of MFH in patients previously treated for hereditary retinoblastoma fits well this hypothesis.

[Pseudotumoral soft tissue masses in children and adolescents]. / Masses des tissus mous d'allure tumorale de l'enfant et de l'adolescent.

INTRODUCTION: Pseudotumoral soft tissue masses in children and adolescents are a frequent reason for consultation and a diagnostic dilemma. Soft tissue malignancies are relatively uncommon, unlike the large number of benign lesions that may be seen in the superficial tissue and that can be diagnosed with clinical characteristics. MATERIALS AND METHODS: This retrospective study concerns 161 children and adolescents less than 20 years old, referred for a soft tissue mass between 2007 and 2011. It describes their epidemiology, clinical characteristics, and course of care to validate a diagnostic strategy for such masses. RESULTS: Final diagnoses were malignant tumors (44%), benign tumors (32%), and pseudotumoral lesions (24%). Clinical features were similar between these three groups except for age and tumor location, with more benign thoracic masses in younger children. Clinical and radiological association led to an accurate diagnosis for 50% of benign masses and with cytological analysis contribution in 79% of benign tumors and 86% of pseudotumoral lesions. Malignant tumors were suspected in only 39% of cases with radiological exams and in 89% after fine-needle aspiration, an essential additional diagnostic tool. Final diagnoses were formally established through simple standard clinical and radiological evaluation in 19 patients (11.8%; benign tumors, seven patients; malformations, eight patients; post-traumatic lesions, two patients; infection and inflammation, one patient each); ultrasound exam in five patients (3.1%; hemangioendotheliomas, two patients, fascial dehiscence, hemangioma, and vascular malformation, one patient each); MRI in four patients (2.5%; three vascular malformations and one lipoma); CT in two cases (1.2%; vascular malformation and myositis ossificans), and radiological examinations associated with cell aspiration in 15 cases (9.3%; ten benign tumors and five malignant tumors). CONCLUSIONS: A multidisciplinary approach should be requested from oncological, radiological, and pathologic experts to optimize soft tissue mass management as soon as initial investigations start. The authors advise a diagnostic strategy for children with pseudotumoral soft tissue masses.

Treatment of retinoblastoma: The Institut Curie experience on a series of 730 patients (1995 to 2009).

INTRODUCTION: To describe the results of retinoblastoma treatment from 1995-2009 in a single institution. MATERIAL AND METHODS: Retrospective review of the charts of patients treated for retinoblastoma. Clinical characteristics at diagnosis, treatments and outcomes in terms of survival and ocular preservation are described. RESULTS: During the study period 826 children were referred for retinoblastoma and 730 were managed in our institution. Four hundred and eleven children presented with unilateral retinoblastoma and 319 with bilateral retinoblastoma. Median follow-up is of 93 months. Global survival is 98.5% of children, 10 children presented with second tumors, 11 children died (6 of tumor-related causes). Of the 411 children with unilateral retinoblastoma enucleation was needed at diagnosis for 324 (78.8%). Conservative treatments were attempted for 87 patients (21.2%) and ocular preservation obtained for 65 patients (74% of eyes). Three hundred and nineteen patients presented with bilateral retinoblastoma. Three hundred and ten could be treated conservatively for at least one eye. Initial intravenous chemotherapy was necessary for 75% of them. Ocular preservation without external beam radiation was possible for 221 patients (70%). The use of EBR decreased significantly after 2004 (9.1% of eyes vs 25.1%: P<0.001). DISCUSSION: Management and treatment of retinoblastoma are complex, adapted to the extent of the disease. Survival is good. Enucleation is still required for extensive ocular disease, especially for unilateral patients. Intravenous chemotherapy allows good tumor control and eye preservation and decrease the need of EBR. CONCLUSIONS: Retinoblastoma treatment with intravenous chemotherapy and ocular adjuvant therapies is very effective on the local tumor control and eye preservation.

Wide metastatic spreading in infiltrating lobular carcinoma of the breast.

The aim of this study was to determine whether the metastatic potential of breast cancer could be related to phenotypic characteristics of the tumour. Therefore, we compared the metastatic patterns of invasive lobular (ILC) and ductal (IDC) carcinomas. In ILC, we also analysed this pattern according to the histological subtype of the primary and the E-cadherin (EC) expression level. Metastatic ILC cases (n=96) were retrospectively analysed and classified into classical, alveolar, solid, tubulo-lobular, signet ring cells or pleomorphic subtypes. Anatomical distribution of metastases was detailed for every patient and compared with that registered for IDC (n=2749). Immunostaining of EC (HECD1 antibody) was performed in 82 cases. Histologically, 78 of the 96 cases (81%) corresponded to classical ILC. The pleomorphic subtype was observed in 14 cases (15%), a rate that was higher than that expected. Others corresponded to alveolar (2 cases), signet ring cell (1 case) and solid (1 case) subtypes. EC was undetectable in 72/82 cases (88%). The rate of multiple metastases was higher in ILC (25.0%) than in IDC (15.8%) (P=0.016). Metastases were found more frequently in ILC than in IDC in the bone (P=0.02) and/or in various other sites (peritoneum, ovary, digestive tract, skin em leader ) (P<0.001). In ILC, no significant link was found between the localisation(s) of metastases, the histological subtype and the EC status in the primary. In conclusion, in breast carcinomas, the frequency of multiple metastasis was found to be higher in ILC than IDC. This fact may be related to the phenotypic trait of discohesive small cells which characterises ILC. EC loss, observed in most cases of ILC, may result in alterations in cell-cell adhesion and a preferential growth at metastatic sites. A high rate of pleomorphic tumours was observed in the group of metastatic ILC, but the pattern of metastatic site(s) was not related to the histological subtype of the primary.

ERBB2 overexpression in breast carcinomas: no positive correlation with complete pathological response to preoperative high-dose anthracycline-based chemotherapy.

The predictive value of ERBB2 amplification/expression to doxorubicin use is controversial. Preoperative chemotherapy, followed by the pathological assessment of tumour response to treatment provide optimal conditions for the evaluation of the predictive value of biological parameters. We report here data on the predictive value of ERBB2 in a series of 54 cases of breast cancer treated by preoperative high-dose anthracycline-based chemotherapy. Our series consisted of 26 women presenting an inflammatory breast cancer (IBC) and of 28 women with poor prognosis primary cancer (PPPC). Patients received a total of four cycles with doxorubicin (75 mg/m(2) for IBC or 70 mg/m(2) for PPPC) and cyclophosphamide (6 g/m(2) for IBC or 1400 mg/m(2) for PPPC), every 21 days. ERBB2 expression was determined by immunohistochemistry (clone CB11) performed on a tumour biopsy taken before chemotherapy. All patients underwent surgery as a second step of treatment, and the tumour response was assessed on pathological specimens. A complete pathological response was observed in 24 of the 54 cases (44%) (95% confidence interval (CI), 31-57). Pathological complete response was positively correlated with high histological grade (P=0. 02) and with the absence of oestrogen (P=0.003) or progesterone (P=0. 02) receptor expression. ERBB2 overexpression was found in 18 of the 54 cases (33%). A complete pathological response was observed in 33% of these cases (6/18). This figure was not significantly different from the 50% rate of complete response observed for tumours with no detectable ERBB2 expression (18/36). In this small series, ERBB2 overexpression was not a significant predictive marker of the pathological response to high-dose doxorubicin-based chemotherapy.

Sonographic, CT, and MR imaging findings in diffuse infiltrative retinoblastoma: report of two cases with histologic comparison.

SUMMARY: Diffuse infiltrating retinoblastoma is a rare form of retinoblastoma. We report two cases of this disease in which sonographic, CT, and MR imaging findings were compared with histologic studies obtained after enucleation. Although nonspecific, MR imaging provides valuable morphologic data for the diagnosis of diffuse infiltrating retinoblastoma and may help in decisions regarding enucleation.

Analysis of correlation between mitotic index, MIB1 score and S-phase fraction as proliferation markers in invasive breast carcinoma. Methodological aspects and prognostic value in a series of 257 cases.

BACKGROUND: The study was designed in order to evaluate the degree of correlation of mitotic index (MI), Ki67 (MIB1) score and S-phase fraction (SPF) as markers of cell proliferation and prognosis in breast cancer. MATERIALS AND METHODS: The series analysed corresponded to 257 consecutive invasive breast carcinoma, treated at the Institut Curie, France, in 1995. Nottingham histological grade and MIB1 semiquantitative and quantitative score were assessed on histological sections, whereas SPF was calculated using flow cytometry analysis of fine-needle aspiration products. Proliferation indices were compared to pathological data and to overall survival (OS) and disease-free survival (DFS) (minimum follow-up: 72 months). RESULTS: The median values for the proliferation markers were 9/10 HPF for MI, 32.4% for MIB1 and 3.7% for SPF. A high rate of correlation (r=0.96; p<0.001) was observed between semi-quantitative and quantitative MIBI evaluation. A positive correlation was found between the three markers (r ranging from 0.54 to 0.61;p<0.001). Univariate analysis of markers associated to disease outcome showed that MIB1, axillary node status (N) and progesterone receptor (PR) status were significantly associated with OS and that MIB1 and SPF were associated with DFS, together with node and hormone receptor status. In multivariate analysis, when proliferation markers were adjusted on the N and PR status, only MIB1 retained a prognostic value for OS (RR= 1.83) [1.00;3.35] and SPF for DFS (RR= 1.58) [1.02-2.44] (p=0.04). CONCLUSION: A good level of correlation was observed between the values of the three markers of tumour cell proliferation analysed. In this series of invasive breast cancers, MIB1 immunostaining was found to be a prognostic marker of both OS and DFS. The median (32.4%) was a valuable cut-off value for prognostic assessment. Semi-quantitative and quantitative evaluations provided very similar values. MIB1 can thus be considered as a reliable prognostic maker, usable in small size tissue specimens which are inappropriate for MI or SPF analysis. The impact of MIB1 compared to that of the other proliferative markers will be further assessed in a subgroup of T1N0M0 for which the prognostic assessment is of major interest.

[Identification of sentinel lymph node in breast cancer: experience from the Institut Curie]. / Individualisation du ganglion sentinelle en cas de cancer du sein: expérience de l'Institut Curie.

Sentinel lymph node (SN) biopsy is a recently developed, minimally invasive technique for staging the axilla in breast cancer. This new procedure of selective lymphadenectomy has been the subject of several studies, but there is not currently a consensus of opinion to define which is the best method of identification. At the Institut Curie since 1996, we have been using the Patent blue dye. The current series present the result of 122 patients with T1, T2, N0 or N1a breast cancer consecutively operated between december 1997 and august 1998. Sentinel nodes were identified in 107 out of 122 (87.7%) and accurately predicted axillary nodal status in 104 out of 107 (97.1%) cases. Three out of 35 node positive patients would have been missed with sentinel node biopsy alone, for a false negative rate of 8.5%. In all 3 cases, one lymph node presented with a micrometastases. In 15 cases out of 35 with metastatic axillary nodes, the only positive node was the SN (43%). The encouraging results of this study shows that it is possible to identify, in a large number of cases, the sentinel node by means of Patent blue dye only. This article detailed the technique used and reviews the literature concerning other methods of identification.

[Histological margin and residual disease assessment for breast carcinoma]. / Evaluation des limites d'exérèse chirurgicale en pathologie mammaire. Risque de maladie résiduelle.

Margin and histological size of ductal in situ carcinoma or intraductal component of an infiltrative carcinoma are important prognostic factors to predict presence/absence as well as amount of residual tumor burden. Their evaluation requires standardized pathological analysis. These factors should be interpreted in clinical and radiological context.

[Value of macroscopic analysis for authentification of axillary sentinel nodes detected by Patent Blue dye alone during breast cancer surgery]. / Intérêt de l'examen macroscopique pour l'authentification des ganglions sentinelles axillaires repérés par le Bleu Patenté seul au cours de la chirurgie des cancers du sein.

Assessment sentinel node coloration by the patent blue dye technique during breast carcinoma surgery largely depends upon the surgeon. It would therefore be valuable to define a procedure to validate the quality of the surgical specimen. With this aim, we have analyzed a series of 141 cases of sentinel nodes and determined whether the blue color of the node persisted after formalin fixation and could be assessed by examination of the tissue blocks. The pathologist's macroscopic control confirmed blue coloring in 114/141 cases (81%). This rate was similar when the sentinel node was metastatic (82.5%) (40 cases) or non metastatic (81%) (101 cases). Checking the color of the lymph node is a simple method to verify the quality of the surgical specimen. This item should be included in the pathologist's report. Several mechanisms can account for the lack of coloring of true sentinel nodes.

[Sentinel lymph node detection in breast cancer. Experience of the Institut Curie]. / Détection du ganglion sentinelle dans les cancers du sein.

Sentinel lymph node biopsy is a recently developed, minimally invasive technique for staging the axilla in breast cancer. This new procedure of selective lymphadenectomy has been the subject of several studies, and a consensus of opinion is starting to form to define indications and methods of identification concerning the use of this technique. At the Institut Curie since 1996, we have been using the Patenté blue dye technique and from 1998 we have used the combination of blue dye and technetium labeled sulfur colloid. This article summarizes the principales aspect of this technique.

[Sentinel node biopsy in breast cancer. Improving reliability of results]. / Ganglion sentinelle et cancer du sein. Amélioration de la fiabilité des prélèvements.

OBJECTIVES: Sentinel node (SN) biopsy in breast cancer has a relatively high false negative rate, frequently exceeding 10%, for predicting the axillary nodal status. When the SN is identified using the patent blue dye technique, we advocate subjecting it to a verification of its blue colour by the pathologist as quality control. PATIENTS AND METHODS: One hundred and twenty-two consecutive patients with an operable breast cancer underwent a SN biopsy procedure with patent blue dye injected peritumourally. The SN biopsy was routinely followed by an axillary dissection. Initially each SN was examined histopathologically in a standard fashion. Then the non metastatic SNs were checked to ensure that they were blue by macroscopic examination of the paraffin blocks in which they had been embeded. Finally, a search for micrometastasis using immunohistochemistry was performed on all SNs which were non metastatic and confirmed to be blue. RESULTS: In 107 (88%) of 122 patients a SN was identified by the surgeon. After standard histological examination, 32 of 107 SNs proved to contain metastatic tumour. 75 SNs were not metastatic, of which 3 were false negative which would have given a false negative rate of 8.5%(3/35). After checking the paraffin blocks of the 75 non metastatic SN, 62 of the 75 were confirmed blue from which there were 2 false negatives giving a false negative rate of 5.8% (2/34). The 62 confirmed blue nodes were then assessed for micrometastasis. 20 nodes proved to be micrometastatic and there remained one false negative. This gave a final false negative rate of 1.8% (1/53). The false negative rate was thus reduced from 8.5% to 1.8% after colour quality control and identification of micrometastasi. DISCUSSION: In this series the procedure of histopathological quality control of the SN identified with the patent blue only technique resulted in a valuable reduction in the false negative rate.

HER2 status of bone marrow micrometastasis and their corresponding primary tumours in a pilot study of 27 cases: a possible tool for anti-HER2 therapy management?

Discrepancies have been reported between HER2 status in primary breast cancer and micrometastatic cells in bone marrow. The aim of this study was to assess HER2 gene status in micrometastatic cells in bone marrow and corresponding primary tumour. Micrometastatic cells were detected in bone marrow aspirations in a prospective series of 27 breast cancer patients by immunocytochemistry (pancytokeratin antibody). HER2 status of micrometastatic cells was assessed by fluorescence in situ hybridisation (FISH), respectively in 24 out of 27. Primary tumour HER2 status was assessed by immunohistochemistry (CB11 antibody) and by FISH in 20 out of 27 of the cases. HER2 was amplified or overexpressed in five out of 27 (18.5%) primary tumours and in four out of 27 (15%) micrometastatic cells. In two cases, HER2 was overexpressed and amplified in primary tumour, but not in micrometastatic cells, whereas, in one case, HER2 presented a low amplification rate (six copies) in micrometastatic cells not found in the primary tumour. We demonstrated that negative and positive HER2 status remained, in the majority of the cases, stable between the bone marrow micrometastasis and the primary tumour. Therefore, the efficiency of anti-HER2 adjuvant therapy could be evaluated, in a clinical trial, by sequential detection of HER2-positive micrometastatic cells within the bone marrow, before and after treatment.

hSNF5/INI1-deficient tumours and rhabdoid tumours are convergent but not fully overlapping entities.

Rhabdoid tumours (RTs) are rare but highly aggressive tumours of childhood. Their rarity and their miscellaneous locations make the diagnosis particularly challenging for pathologists. Central nervous system and peripheral RTs have been associated with biallelic inactivation of the hSNF5/INI1/SMARCB1 (hSNF5/INI1) tumour suppressor gene. Immunohistochemistry (IHC) with a monoclonal anti-hSNF5/INI1 antibody has recently been proposed as an efficient diagnostic tool for RTs. We have conducted a retrospective study of 55 tumours referred to our institution with a suspicion of RT. This analysis included pathological review, IHC with anti-hSNF5/INI1 antibody, and molecular investigation using quantitative DNA fluorescent analysis and sequencing of the nine exons of hSNF5/INI1. The molecular lesion could be detected in 37 of the 39 cases exhibiting negative staining for hSNF5/INI1. In the two discrepant cases, the lack of detection of genetic abnormality was probably owing to the presence of a high number of non-tumour cells in the samples. This indicates that hSNF5/INI1 IHC is very sensitive and highly specific for the detection of hSNF5/INI1 loss-of-function. Among the 38 cases with typical RT histological features, six failed to exhibit hSNF5/INI1 mutation and stained positive for hSNF5/INI1. This strongly supports the evidence of a second genetic locus, distinct from hSNF5/INI1, associated with RT. Conversely, seven tumours with histological features poorly compatible with RT stained negative for hSNF5/INI1; they nevertheless exhibited an age of onset and a clinical behaviour similar to RT. This suggests that hSNF5/INI1 inactivation is not strictly limited to typical RT but characterizes a wider family of hSNF5/INI1-deficient tumours. Consequently, we believe that anti-hSNF5/INI1 IHC should be performed widely, even when the pathological characteristics are not typical. The molecular investigation should be performed in infants when a rhabdoid predisposition syndrome is suspected.

Prediction of tumour involvement in remaining axillary lymph nodes when the sentinel node in a woman with breast cancer contains metastases.

BACKGROUND: In a significant proportion of women with breast cancer, the sentinel node is the only involved node in the axilla. The purpose of this study was to identify factors associated with histologically positive non-sentinel lymph nodes. METHODS: Between 1997 and 2002, 800 women with early breast cancer underwent sentinel node biopsy. In 263 patients the node contained metastases, including 83 with micrometastases detected by immunohistochemistry (IHC), 40 micrometastases detected on haematoxylin, eosin and safranine (HES) staining, and 140 macrometastases. All clinical and histological criteria were recorded and analysed with reference to histology of the non-sentinel node. RESULTS: The risk of metastasis in the non-sentinel lymph node was related to the volume of the tumour in the sentinel node. Non-sentinel nodes were involved in five (6.0 per cent) of 83 women when the sentinel node contained only micrometastatic cells detected on IHC, and in three (7.5 per cent) of 40 women when micrometastases were detected by HES, compared with 55 (39.3 per cent) of 140 when the sentinel node contained macrometastases on HES staining. Univariate analysis revealed a significant association between non-sentinel node involvement and type of metastasis within the sentinel node, clinical primary tumour size, palpable axillary lymph nodes before operation, pathological primary tumour size and the presence of peritumoral lymphovascular invasion. On multivariate analysis, the type of metastasis within the sentinel node (P < 0.001), histological tumour size greater than 20 mm (P = 0.017) and the presence of palpable axillary nodes before operation (P = 0.014) remained significant. CONCLUSION: Clinical and pathological factors associated with sentinel node histology can reliably predict women for whom further axillary clearance is recommended, but it is not yet possible to determine a subgroup of patients in whom the sentinel node is the only involved node and for whom further axillary treatment may be unnecessary.

Sentinel lymph node detection for breast cancer: which patients are best suited for the patent blue dye only method of identification?

BACKGROUND: The objectives of this study were, first, to define the preoperative criteria for using solely the blue dye method and, second, to decrease its operator dependence in predicting axillary lymph node status. METHODS: Two hundred fifty-three women consecutively identified with operable breast cancer underwent sentinel lymph node (SLN) detection by the patent blue dye method followed by completion axillary lymph node dissection. A standard pathological examination was performed for all SLN. Then, a pathological color quality assessment (PCQA), which checked for the presence of the blue dye, was performed on the paraffin blocks of the nonmetastatic SLN. Six preoperative identifiable variables likely to influence the detection rate were examined. RESULTS: The surgical detection (sd) rate was 84% (213 of 253) and the PCQA rate was 73% (185 of 253). Only breast size (sd, P = .0005; PCQA, P = .0007) and body mass index < or =30 (sd, P = .005; PCQA, P = .0007) were significant for SLN identification. Multivariate analysis revealed two independent factors influencing SLN identification: breast size (sd, P = .0001; PCQA, P = .002) and the timing of injection-injection prior to lumpectomy (sd, P = .04). CONCLUSIONS: The optimal patient features for identifying the SLN by the patent blue dye method are small or medium-sized breasts, low body fat, and that the procedure is carried out prior to tumor excision. The PCQA offers a useful second assessment of the surgically removed SLN, introducing an independent element of quality control.