Peritumoral immune infiltrates in primary tumours are not associated with the presence of axillary lymph node metastasis in breast cancer: a retrospective cohort study.

BACKGROUND: The axillary lymph nodes (ALNs) in breast cancer patients are the body regions to where tumoral cells most often first disseminate. The tumour immune response is important for breast cancer patient outcome, and some studies have evaluated its involvement in ALN metastasis development. Most studies have focused on the intratumoral immune response, but very few have evaluated the peritumoral immune response. The aim of the present article is to evaluate the immune infiltrates of the peritumoral area and their association with the presence of ALN metastases. METHODS: The concentration of 11 immune markers in the peritumoral areas was studied in 149 patients diagnosed with invasive breast carcinoma of no special type (half of whom had ALN metastasis at diagnosis) using tissue microarrays, immunohistochemistry and digital image analysis procedures. The differences in the concentration of the immune response of peritumoral areas between patients diagnosed with and without metastasis in their ALNs were evaluated. A multivariate logistic regression model was developed to identify the clinical-pathological variables and the peritumoral immune markers independently associated with having or not having ALN metastases at diagnosis. RESULTS: No statistically significant differences were found in the concentrations of the 11 immune markers between patients diagnosed with or without ALN metastases. Patients with metastases in their ALNs had a higher histological grade, more lymphovascular and perineural invasion and larger-diameter tumours. The multivariate analysis, after validation by bootstrap simulation, revealed that only tumour diameter (OR = 1.04; 95% CI [1.00-1.07]; p = 0.026), lymphovascular invasion (OR = 25.42; 95% CI [9.57-67.55]; p < 0.001) and histological grades 2 (OR = 3.84; 95% CI [1.11-13.28]; p = 0.033) and 3 (OR = 5.18; 95% CI [1.40-19.17]; p = 0.014) were associated with the presence of ALN metastases at diagnosis. This study is one of the first to study the association of the peritumoral immune response with ALN metastasis. We did not find any association of peritumoral immune infiltrates with the presence of ALN metastasis. Nevertheless, this does not rule out the possibility that other peritumoral immune populations are associated with ALN metastasis. This matter needs to be examined in greater depth, broadening the types of peritumoral immune cells studied, and including new peritumoral areas, such as the germinal centres of the peritumoral tertiary lymphoid structures found in extensively infiltrated neoplastic lesions.

Roundness variation in JPEG images affects the automated process of nuclear immunohistochemical quantification: correction with a linear regression model.

The volume of digital image (DI) storage continues to be an important problem in computer-assisted pathology. DI compression enables the size of files to be reduced but with the disadvantage of loss of quality. Previous results indicated that the efficiency of computer-assisted quantification of immunohistochemically stained cell nuclei may be significantly reduced when compressed DIs are used. This study attempts to show, with respect to immunohistochemically stained nuclei, which morphometric parameters may be altered by the different levels of JPEG compression, and the implications of these alterations for automated nuclear counts, and further, develops a method for correcting this discrepancy in the nuclear count. For this purpose, 47 DIs from different tissues were captured in uncompressed TIFF format and converted to 1:3, 1:23 and 1:46 compression JPEG images. Sixty-five positive objects were selected from these images, and six morphological parameters were measured and compared for each object in TIFF images and those of the different compression levels using a set of previously developed and tested macros. Roundness proved to be the only morphological parameter that was significantly affected by image compression. Factors to correct the discrepancy in the roundness estimate were derived from linear regression models for each compression level, thereby eliminating the statistically significant differences between measurements in the equivalent images. These correction factors were incorporated in the automated macros, where they reduced the nuclear quantification differences arising from image compression. Our results demonstrate that it is possible to carry out unbiased automated immunohistochemical nuclear quantification in compressed DIs with a methodology that could be easily incorporated in different systems of digital image analysis.

[Nested variant of urothelial carcinoma. A rare histological variant]. / Carcinoma urotelial de vejiga tipo Nested. Una variante histológica poco frecuente.

The nested variant of urothelial carcinoma is a rare histological tumor of urinary bladder. The clinical symptoms are similar to those of the classic urothelial carcinomas. Its macroscopic appearance can be very subtle due to its preference for a submucosal growth leading to a possible delay in diagnosis. Microscopically, it is characterized by nests and tubules formation. While the neoplastic cells exhibit low-grade histological features, the growth pattern is widely infiltrative conferring this neoplasia a bad prognosis even if a radical treatment is performed. We present a case of a patient affected by a nested variant of urothelial carcinoma of urinary bladder to whom a radical cystoprostatectomy was performed and adjuvant chemotherapy was given. He is alive and free of disease one year after the diagnosis.

Carcinoma urotelial de vejiga tipo Nested. Una variante histológica poco frecuente / Nested variant of urothelial carcinoma. A rare histological variant

El carcinoma urotelial de vejiga tipo “nested” o en nidos es una variante histológica rara dentro de los tumores uroteliales de vejiga. Aunque las manifestaciones clínicas son semejantes a los demás tumores de vejiga, su apariencia macroscópica puede ser inexpresiva, con crecimiento submucoso difícil de detectar en la cistoscopia, lo que puede retrasar el diagnóstico. Microscópicamente se caracteriza por la distribución celular en forma de nidos y túbulos. Presentan un bajo grado de atipia citológico que simula un carcinoma urotelial de bajo grado, lo que contrasta con un patrón de crecimiento ampliamente infiltrativo que le confiere un mal pronóstico a pesar de tratamientos radicales. Presentamos el caso de un paciente afecto de un carcinoma urotelial de vejiga tipo nested sometido a cistoprostatectomia radical y tratamiento con quimioterapia adyuvante que se encuentra libre de enfermedad un año después del diagnóstico (AU)

The nested variant of urothelial carcinoma is a rare histological tumor of urinary bladder. The clinical symptoms are similar to those of the classic urothelial carcinomas. Its macroscopic appearance can be very subtle due to its preference for a submucosal growth leading to a possible delay in diagnosis. Microscopically, it is characterized by nests and tubules formation. While the neoplastic cells exhibit low-grade histological features, the growth pattern is widely infiltrative conferring this neoplasia a bad prognosis even if a radical treatment is performed. We present a case of a patient affected by a nested variant of urothelial carcinoma of urinary bladder to whom a radical cystoprostatectomy was performed and adjuvant chemotherapy was given. He is alive and free of disease one year after the diagnosis (AU)

Tumor-infiltrating cells as a prognostic factor in Hodgkin's lymphoma: a quantitative tissue microarray study in a large retrospective cohort of 267 patients.

The present study aimed to describe the general tissular composition of the immune infiltrate observed in Hodgkin's lymphoma (HL) and its possible relationship with clinical and survival prognostic factors. In this retrospective study of 267 HL patients, the relative proportions of infiltrating T lymphocytes (CD4+, CD8+), natural killer cells (CD 56+, CD 57+), cytotoxic cells (Granzyme B+, TIA-1+) and dendritic cells (CD 21+, S-100+) were quantified immunohistochemically with tissue microarray technology. Our results confirm the predominance of CD4 + T lymphocytes in the background of tumoral cells, in addition to a high number of cytotoxic lymphocytes (CD8, CD 57 and TIA-1). Patients with low numbers of infiltrating CD8, CD 56, CD 57+cells and high numbers of Granzyme B and TIA-1+cells presented a significantly unfavourable clinical course (presence of leukocytosis, B symptoms, advanced clinical stage (III/IV), non-responding patients). A reduced infiltration of CD4+T lymphocytes was related with the presence of Epstein - Barr virus. Significantly longer survival times were observed in patients with a high level of infiltrating CD 57, as well as a low level of Granzyme B and TIA-1+cells (log-rank test). When evaluated in a multivariate model, high levels of infiltrating TIA-1 and Granzyme B+cells were shown to be independent prognostic factors that negatively influenced overall survival. The presence of TIA-1+cells was found to be the only unfavorable prognostic factor of event-free survival and disease-free survival. The overall detection of tumor-infiltrating cells in HL confirms the importance of cytotoxic T lymphocyte infiltration (Granzyme B and TIA-1+cells) in these patients. Independently of the classical clinical and pathological features, these cells appear to be an unfavourable prognostic factor in HL and, more particularly, the presence of cytotoxic TIA-1+cells.

Decreased number of granzyme B+ activated CD8+ cytotoxic T lymphocytes in the inflammatory background of HIV-associated Hodgkin's lymphoma.

This study aimed to assess the differences in the cellular composition of the inflammatory reactive background around tumoral cells of classical Hodgkin's lymphomas (cHL) inside and outside the HIV settings. This retrospective study evaluates the infiltrating T lymphocytes (CD4 and CD8), natural killer cells (CD57+ cells), and more especially cytotoxic cells [granzyme B (GrB) and TIA-1+ cells] in the background of 99 EBV+ cHL. Sections from paraffin-embedded tumor samples from nine HIV-infected cHL patients were immunostained, using standard immunohistochemical protocols and were compared to a control group of 90 HIV-noninfected cHL patients. Our clinical and histological data indicate that HIV-infected cHL patients present a higher frequency of mixed cellularity (MC) histological subtypes, more advanced disease stages, a poor response to treatment, and a poor overall survival compared to control patients. In controls, CD4/CD8 and GrB/TIA-1 ratios were determined as 2:1 and 1:2, respectively. The inflammatory infiltrate of HIV-infected patients had a significant reduction of CD4+ T lymphocytes (CD4/CD8 ratio 1:23), a decrease in infiltrating GrB+ cells (activated cytotoxic cells) and an increase in infiltrating TIA+ T cells (mainly nonactivated cytotoxic cells) in these patients (GrB/TIA-1 ratio 1:12). In conclusion, this study highlights an important intratumoral loss of CD4+ T cells (striking inversion in the CD4/CD8 ratio) and a decrease in intratumoral activated cytotoxic T lymphocytes in HIV-associated cHL patients. Further studies are required to confirm these results and to determine the role of these findings on the antitumoral immune response observed in HIV-associated cHL.

Síndrome linfoproliferativo autoinmune / Autoimmune lymphoproliferative syndrome

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