Tumor metabolism assessed by FDG-PET/CT and tumor proliferation assessed by genomic grade index to predict response to neoadjuvant chemotherapy in triple negative breast cancer.

PURPOSE: Survival is increased when pathological complete response (pCR) is reached after neoadjuvant chemotherapy (NAC), especially in triple-negative breast cancer (TNBC) patients. Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) and the genomic grade index (GGI), each separately, showed good potential to predict pCR. Our study was designed to evaluate the predictive value for the therapeutic response of a combination of parameters based on FDG-PET, histoclinical features and molecular markers of proliferation. METHODS: Molecular parameters were measured on pre-treatment biopsy. Tumor metabolic activity was measured using two PET/CT scans, one before and one after 2 cycles of NAC. The pCR was determined on specimen after NAC. Event-free survival (EFS) was estimated using the Kaplan Meier method. RESULTS: Of 55 TNBC patients, 19 (35%) reached pCR after NAC. Tumor grade and Ki67 were not associated with pCR whereas GGI (P = 0.04) and its component KPNA2 (P = 0.04) showed a predictive value. The change of FDG uptake between PET1 and PET2 (ΔSUVmax) was highly associated with pCR (P = 0.0001) but the absolute value of baseline SUVmax was not (P = 0.11). However, the AUC of pCR prediction increased from 0.63 to 0.76 when baseline SUVmax was combined with the GGI (P = 0.016). The only two parameters associated with EFS were ΔSUVmax (P = 0.048) and pathological response (P = 0.014). CONCLUSIONS: The early tumor metabolic change during NAC is a powerful parameter to predict pCR and outcome in TNBC patients. The GGI, determined on pretreatment biopsy, is also predictive of pCR and the combination GGI and baseline SUVmax improves the prediction.

Long-term survival of advanced triple-negative breast cancers with a dose-intense cyclophosphamide/anthracycline neoadjuvant regimen.

BACKGROUND: Triple-negative (TN) breast cancers exhibit major initial responses to neoadjuvant chemotherapy, but generally have a poor outcome. Because of the lack of validated drug targets, chemotherapy remains an important therapeutic tool in these cancers. METHODS: We report the survival of two consecutive series of 267 locally advanced breast cancers (LABC) treated with two different neoadjuvant regimens, either a dose-dense and dose-intense cyclophosphamide-anthracycline (AC) association (historically called SIM) or a conventional sequential association of cyclophosphamide and anthracycline, followed by taxanes (EC-T). We compared pathological responses and survival rates of these two groups and studied their association with tumours features. RESULTS: Although the two regimens showed equivalent pathological complete response (pCR) in the whole population (16 and 12%), the SIM regimen yielded a non-statistically higher pCR rate than EC-T (48% vs 24%, P=0.087) in TN tumours. In the SIM protocol, DFS was statistically higher for TN than for non-TN patients (P=0.019), although we showed that the TN status was associated with an increased initial risk of recurrence in both regimens. This effect gradually decreased and after 2 years, TN was associated with a significantly decreased likelihood of relapse in SIM-treated LABC (hazard ratio (HR)=0.25 (95% CI: 0.07-0.86), P=0.028). CONCLUSIONS: AC dose intensification treatment is associated with a very favourable long-term survival rate in TN breast cancers. These observations call for a prospective assessment of such dose-intense AC-based regimens in locally advanced TN tumours.

Immunohistochemical and molecular analyses of HER2 status in breast cancers are highly concordant and complementary approaches.

BACKGROUND: Immunohistochemistry (IHC) and fluorescent in situ hybridisation (FISH) are currently the most commonly used methods to assess HER2 status. PCR-based assays allow quantitative determination of HER2 amplification (Q-PCR) or overexpression (Q-RT-PCR), but are not routinely used. We evaluated the relevance of Q-RT-PCR for HER2 status determination. METHODS: We compared IHC and Q-RT-PCR in 466 breast tumours. In discordant or equivocal cases, five additional methods (IHC with two other antibodies, FISH, silver in situ hybridisation (SISH) and Q-PCR) were combined to determine HER2 status. Two cases with HER2 intra-tumour heterogeneity were further explored by allelic profiles analysis and HUMARA clonality determination after microdissection. RESULTS: We observed 97.3% concordance between Q-RT-PCR and non-equivocal IHC. Twelve out of 466 cases (3%) revealed discordances between the two methods. The power of Q-RT-PCR to predict HER2 status (defined by seven methods) was similar to that of IHC. Although rare, some discordances between techniques might be due to HER2 intra-tumour heterogeneity and we report two examples, one tumour containing two distinct clones, another tumour consisting of HER2 amplified and non-amplified subclones. CONCLUSION: Q-RT-PCR and IHC are highly concordant methods for HER2 status assessment, and Q-RT-PCR allows a highly reliable quantitative assessment and could be a useful adjunct to IHC.

Multifocal Epstein-Barr virus-associated smooth muscle tumor in adults with AIDS: case report and review of the literature.

OBJECTIVES: The aim of this study was to provide a systematic review of Epstein-Barr virus-associated smooth muscle tumors (EBV-SMT) in human immunodeficiency virus (HIV)-infected adults, focusing on clinical and histopathologic features and outcome. METHODS: A literature search was performed using Medline, Embase and the Cochrane Library. RESULTS: We reviewed 35 cases including our case of a patient with a progressive multifocal EBV-SMT. Patients were mainly men (n = 24) with a mean age of 35.5 years. Median CD4 count was 21/mm(3). Main locations were brain (n = 12), liver (n = 8), spinal cord (n = 7) and adrenal gland (n = 6). The tumors were multifocal in 34% of cases, whereas analysis of clonality showed different clones in tumors from different sites. Treatment included removal surgery in 17 cases and/or radiotherapy in 9 and therapeutic abstention in 4. Mean follow-up after diagnosis was 12.3 months. Nine patients died during this period essentially from opportunistic infection and only 2 from the disease. CONCLUSION: EBV-SMT should be added to the list of virally induced tumors in severely immunocompromised HIV-infected adults. Multifocality of independent tumor clones, especially in liver, brain, spinal cord and adrenal gland, and a slow disease progression seem to be the key features of these tumors, the treatment of which remains poorly defined.

Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency.

BACKGROUND: Patients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis. We aimed to evaluate the relevance of distinguishing sporadic from Lynch syndrome (LS)-like mCRCs. PATIENTS AND METHODS: MSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation. Sporadic cases were molecularly defined as those displaying MLH1/PMS2 loss of expression with BRAFV600E and/or MLH1 hypermethylation and no MMR germline mutation. RESULTS: Among 129 MSI/dMMR mCRC patients, 81 (63%) were LS-like and 48 (37%) had sporadic tumours; 22% of MLH1/PMS2-negative mCRCs would have been misclassified using an algorithm based on local medical records (age, Amsterdam II criteria, BRAF and MMR statuses when locally tested), compared to a systematical assessment of MMR, BRAF and MLH1 methylation statuses. In univariate analysis, parameters associated with better overall survival were age (P < 0.0001), metastatic resection (P = 0.001) and LS-like mCRC (P = 0.01), but not BRAFV600E. In multivariate analysis, age (hazard ratio (HR) = 3.19, P = 0.01) and metastatic resection (HR = 4.2, P = 0.001) were associated with overall survival, but not LS. LS-like patients were associated with more frequent liver involvement, metastatic resection and better disease-free survival after metastasectomy (HR = 0.28, P = 0.01). Median progression-free survival of first-line chemotherapy was similar between the two groups (4.2 and 4.2 months; P = 0.44). CONCLUSIONS: LS-like and sporadic MSI/dMMR mCRCs display distinct natural histories. MMR, BRAF mutation and MLH1 methylation testing should be mandatory to differentiate LS-like and sporadic MSI/dMMR mCRC, to determine in particular whether immune checkpoint inhibitors efficacy differs in these two populations.

C-erbB-2, p53, and nm23 gene product expression in breast cancer in young women: immunohistochemical analysis and clinicopathologic correlation.

We studied c-erbB-2, p53, and nm23 gene products in 112 primary breast carcinomas. Fifty patients were aged 35 years or younger, and 62 were aged 36 to 50. Clinicopathological criteria including clinical stage, hormone receptor status, histological types, histological grades, and lymph node status, were reviewed. Disease-free survival (DFS) and overall survival (OS) were analyzed. Immunohistochemical findings were assessed semiquantitatively. Correlation between clinicopathological criteria, survival data, and immunohistochemical findings have been made. Patients aged younger than 35 years with stage I to II disease had a shorter DFS (P = .03) than older patients. However, no other clinicopathological finding was associated with age. Neither was there association between age and c-erbB-2, p53, or nm23 patterns of expression. p53 positivity was associated with high histological grade (P = .003) and with progesterone receptor negativity (P = .045). Nm23 nuclear positivity was associated with early clinical stages (P = .011) and with absence of axillary lymph node metastasis (P = .007). p53 and c-erbB-2 overexpression were associated with shorter OS while nm23 nuclear positivity was associated with longer OS in univariate and multivariate analyses. Univariate analyses showed that c-erbB-2 or nm23 were potentially important prognostic factors in women aged 35 years or younger while p53 was associated with prognosis in women aged 36 to 50. Cox model analysis indicated that c-erbB-2 alone was associated with prognosis in women 35 years and younger, whereas p53 alone was associated with prognosis in 36- to 50-year-old women. These results suggest that breast cancer in the youngest women has some biological specificity.

Fulminant adenovirus hepatitis after allogeneic bone marrow transplantation.

Adenoviruses may cause severe infections in bone marrow transplant recipients. We report the case of a patient who developed fulminant hepatitis 5 months after bone marrow transplantation. Adenovirus type 2 was cultured from stool and blood samples. The patient died from liver failure. Histologic examination of post-mortem liver samples showed extensive necrosis with nuclear inclusions. Adenovirus was identified in liver cells by electron microscopy and immunohistochemical staining using a monoclonal anti-adenovirus antibody. No other pathogen was identified.

Chronic cholestasis in patients after allogeneic bone marrow transplantation: several diseases are often associated.

From 1984 to 1991, 514 patients were treated by BMT in 1 center. 254 patients survived more than 3 months and, in 38 patients, 47 liver biopsies were performed for chronic liver dysfunction characterized by cholestasis. The aim of the present study was to evaluate the possible causes of liver disease at the time of biopsy. One clinician analyzed clinical data and was able to propose up to 3 diagnoses including GVHD, viral hepatitis, drug-related hepatitis, chronic veno-occlusive disease (VOD) or other. Two pathologists reviewed histologic sections and were also able to propose up to 3 diagnoses. Clinically, 1, 2 or 3 diagnoses were proposed in 30, 60 and 10% of cases, respectively. Pathologically, 1, 2 or 3 diagnoses were proposed in 13, 62 and 25%, respectively. Histologic changes of GVHD were present in 40 of 47 biopsies and concordance between the clinician and the pathologists on the presence of GVHD lesions was found in 77% of biopsies. Viral hepatitis was proposed 22 times by the clinician and 19 times by pathologists. Viral hepatitis, usually hepatitis C, was associated with GVHD in 16 cases. Diagnoses of chronic VOD and drug-related hepatitis were proposed less often. In summary, more than 1 diagnosis was suggested for many of the patients studied, GVHD being the most frequent. The simultaneous presence of GVHD, viral diseases, chronic VOD and drug-induced diseases could explain the high incidence of cholestasis in the long-term post-BMT.

Variability of immunohistochemical reactivity on stored paraffin slides.

AIMS: To investigate the effects of slide storage on immunohistochemical staining, since recent reports have indicated that storage of unstained paraffin slides for up to 12 weeks may lead to false negative immunostaining of tumour markers. METHODS: 11 antibodies (anti-cytokeratin, epithelial membrane antigen (EMA), vimentin, smooth muscle actin, PS100, chromogranin, CD45, CD20, CD3, CD30, and oestrogen receptor (OR) were tested on unstained paraffin slides of breast carcinomas, lymphomas, and neuroendocrine tumours that had been stored for three to 10 years. All the paraffin blocks were recut less than one week before immunostaining. Immunostainings of years old slides were compared with those of recent slides in at least five cases for each antibody. For three antibodies (antichromogranin, anti-CD3, and anti-OR) we also tested one year old and three months old slides. RESULTS: Intensity of staining on years old slides was strikingly reduced for chromogranin and CD3 in several cases and was slightly stronger for vimentin. In some cases a significant decrease of OR positivity was observed after three months storage, and a complete loss of OR immunostaining after 12 months. No significant difference was noted with the other antibodies. CONCLUSIONS: Immunohistochemical detection of some antigens located either in the nucleus, in the cytoplasm, or on the cytoplasmic membrane could be impaired by storage of paraffin slides as short a time as three months. One should be cautious of doing retrospective immunohistochemical studies on stored unstained slides.

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.

[Fatal fulminant hepatitis induced by nilutamide (Anandron)]. / Hépatite fulminante mortelle imputable au nilutamide (Anandron).

The first case of fatal fulminant hepatitis probably caused by nilutamide, a non steroidal antiandrogen derivative, is reported. Nilutamide administration had been continued for 6 days after the occurrence of jaundice, 52 days after beginning of treatment. The rapidly fatal outcome might have been promoted by coadministration of phenobarbital.

[Leiomyosarcoma of the larynx. Histological, immunohistochemical and ultrastructural study of a case with review of the literature]. / Léiomyosarcome du larynx. Etude histologique, immunohistochimique et ultrastructurale d'une observation avec revue de la littérature.

Laryngeal leiomyosarcoma: histological, immunohistochemical and ultrastructural study of one case with review of the literature. Leiomyosarcoma of the larynx have rarely been reported and a review of the literature has yielded only 8 cases. Authors report a case in a 45-year-old patient. Histological exam of the surgical specimen showed a malignant spindle cell tumor. Ultrastructurally, neoplastic cells presented some features of smooth-muscle cells. Immunohistochemical studies revealed that most tumor cells coexpressed vimentin and smooth-muscle actin.

[Inflammatory pseudo-tumor of the lung. Clinico-pathologic report of a case]. / Pseudo-tumeur inflammatoire du poumon. Etude anatomo-clinique d'une observation.

One case of a solitary pulmonary nodule occurring in a 54-year-old woman with history of breast carcinoma is presented. Histological examination of the surgical specimen excluded breast carcinoma metastasis and revealed an inflammatory pseudotumor. Principal clinico-pathological findings in previously reported cases are described. Inflammatory pseudotumors may exhibit, as in our case, some nuclear atypia making the diagnosis sometimes difficult with malignancy.

[Internet, a new resource for anatomopathology?]. / Internet, une nouvelle ressource pour l'anatomie pathologique?

The Internet network is the largest computer network in the world. It can be accessed by a telephone line and a modem. Its different functions are the electronic mail (e-mail), the discussion forums ("newsgroups"), the transfer of files and the navigation between "hypertext" pages ("World Wide Web"). This network offers multiple services for pathology: access to databases, consultation of image banks or electronic journals, teleteaching, informations about congresses and societies, participation to thematic forums. We have connected to this network on October 1995 a french-english web site called "Anapath Web" (http://www.anapath.necker.fr) devoted to pathology. Its purpose is to collect information useful to pathologists and to develop specific applications. We are conceiving several projects for teleteaching.

[Benign non-parasitic splenic cysts. 9 cases]. / Kystes spléniques bénins non parasitaires. 9 observations.

Benign non-parasitic splenic cysts are uncommon. Their diagnosis can benefit from ultrasounds and computed tomography. However, it may be difficult, before surgery, to distinguish between true cysts, which are congenital with epidermal lining, and false cysts, which are consecutive to a trauma, inflammatory or degenerative, without epidermal lining. We report nine cases of non-parasitic splenic cysts and try to determine the preoperative diagnostic approach. To prevent the overwhelming post-splenectomy infection syndrome, conservative surgical treatment is mandatory. Various surgical methods are discussed.

[Cytomegalovirus enteritis in AIDS. 2 cases]. / Entérite à cytomégalovirus au cours du SIDA. 2 observations.

BACKGROUND: It is uncommon for manifestations of cytomegalovirus infection to be limited to the small bowel in AIDS patients. CASE REPORTS: Two HIV-positive patients developed cytomegalovirus infection involving the small bowel with no other visceral localization. Recurrences were frequent despite medical therapy. DISCUSSION: The clinical manifestations, diarrhea, fever, vomiting and abdominal pain, suggest the diagnosis of cytomegalovirus enteritis in AIDS patients. Confirmation is obtained from the small bowel study and pathology examination of biopsy specimens. Treatment is generally based on medical and surgical management using intravenous anti-cytomegalovirus drugs and partial resection. Prognosis often remains less than satisfactory in this condition which is often diagnosed late.

Challenging single- and multi-probesets gene expression signatures of pathological complete response to neoadjuvant chemotherapy in breast cancer: experience of the REMAGUS 02 phase II trial.

This study was designed to identify predictive signatures of pathological complete response (pCR) in breast cancer treated by taxane-based regimen, using clinicopathological variables and transcriptomic data (Affymetrix Hgu133 Plus 2.0 devices). The REMAGUS 02 trial (n = 153,training set) and the publicly available M.D. Anderson data set (n = 133, validation set) were used. A re-sampling method was applied. All predictive models were defined using logistic regression and their classification performances were tested through Area Under the Curve (AUC) estimation. A stable set of 42 probesets (31 genes) differentiate pCR or no pCR samples. Single-or 2-probesets signatures, mainly related to ER pathway, were equally predictive of pCR with AUC greater then 0.80. Models including probesets associated with ESR1, MAPT, CA12 or PIGH presented good classification performances. When clinical variables were entered into the model, only CA12 and PIGH, remained informative (p = 0.05 and p = 0.005) showing that a combination of a few genes provided robust and reliable prediction of pCR.

A refined molecular taxonomy of breast cancer.

The current histoclinical breast cancer classification is simple but imprecise. Several molecular classifications of breast cancers based on expression profiling have been proposed as alternatives. However, their reliability and clinical utility have been repeatedly questioned, notably because most of them were derived from relatively small initial patient populations. We analyzed the transcriptomes of 537 breast tumors using three unsupervised classification methods. A core subset of 355 tumors was assigned to six clusters by all three methods. These six subgroups overlapped with previously defined molecular classes of breast cancer, but also showed important differences, notably the absence of an ERBB2 subgroup and the division of the large luminal ER+ group into four subgroups, two of them being highly proliferative. Of the six subgroups, four were ER+/PR+/AR+, one was ER-/PR-/AR+ and one was triple negative (AR-/ER-/PR-). ERBB2-amplified tumors were split between the ER-/PR-/AR+ subgroup and the highly proliferative ER+ LumC subgroup. Importantly, each of these six molecular subgroups showed specific copy-number alterations. Gene expression changes were correlated to specific signaling pathways. Each of these six subgroups showed very significant differences in tumor grade, metastatic sites, relapse-free survival or response to chemotherapy. All these findings were validated on large external datasets including more than 3000 tumors. Our data thus indicate that these six molecular subgroups represent well-defined clinico-biological entities of breast cancer. Their identification should facilitate the detection of novel prognostic factors or therapeutical targets in breast cancer.