Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

Consistency in recognizing microinvasion in breast carcinomas is improved by immunohistochemistry for myoepithelial markers.

Microinvasion is the smallest morphologically identifiable stage of invasion. Its presence and distinction from in situ carcinoma may have therapeutic implications, and clinical staging also requires the recognition of this phenomenon. Microinvasion is established on the basis of several morphological criteria, which may be difficult and not perfectly reproducible among pathologists. The aim of this study was to assess the consistency of diagnosing microinvasion in the breast on traditional haematoxylin and eosin (HE) stained slides and to evaluate whether immunohistochemistry (IHC) for myoepithelial markers could improve this. Digital images were generated from representative areas of 50 cases stained with HE and IHC for myoepithelial markers. Cases were specifically selected from the spectrum of in situ to microinvasive cancers. Twenty-eight dedicated breast pathologists assessed these cases at different magnifications through a web-based platform in two rounds: first HE only and after a washout period by both HE and IHC. Consistency in the recognition of microinvasion significantly improved with the use of IHC. Concordance rates increased from 0.85 to 0.96, kappa from 0.5 to 0.85, the number of cases with 100% agreement rose from 9/50 to 25/50 with IHC and the certainty of diagnosis also increased. The use of IHC markedly improves the consistency of identifying microinvasion. This corroborates previous recommendations to use IHC for myoepithelial markers to clarify cases where uncertainty exists about the presence of microinvasion. Microinvasive carcinoma is a rare entity, and seeking a second opinion may avoid overdiagnosis.

The role of obesity in the immune response during sepsis.

BACKGROUND/OBJECTIVES: Sepsis is one of the most important causes of mortality in the developed world, where almost two-thirds of the population suffer from obesity. Therefore, the coexistence of both conditions has become frequent in clinical practice and a growing number of clinical studies attempts to examine the potential effect of obesity on sepsis with controversial results up to now. The present study investigates how obesity influences the immune response of septic patients, by assessing the number and activation state of adipose tissue macrophages, serum and adipose tissue tumor necrosis factor-alpha (TNFα) levels and plasma oxidative stress markers. SUBJECTS/METHODS: The study included 106 patients, divided into four groups (control n=26, obesity n=27, sepsis n=27 and sepsis and obesity n=26). The number of macrophages in subcutaneous and visceral adipose tissue (SAT and VAT) and their subtypes (M1 and M2) were defined with immunohistochemical staining techniques under light microscopy. TNFα mRNA levels were determined in SAT and VAT using real-time reverse transcription-PCR. Serum levels of TNFα were determined with sandwich enzyme-linked immunosorbent assay. Plasma oxidative stress was evaluated using selective biomarkers (thiobarbituric acid-reactive substances (TBARS), protein carbonyls and total antioxidant capacity (TAC)). RESULTS: Sepsis increased the total number of macrophages and their M2 subtype in (VAT), whereas obesity did not seem to affect the concentration of macrophages in fat. Obesity increased TNFα mRNA levels (P<0.05) in VAT as well as the plasma TBARS (P<0.001) and protein carbonyls (P<0.001) in septic patients. The plasma TAC levels were decreased and the serum TNFα levels were increased in sepsis although they were not influenced by obesity. CONCLUSIONS: Obesity is associated with elevated TNFα adipose tissue production and increased oxidative stress biomarkers, promoting the proinflammatory response in septic patients.

Toxic peripheral neuropathy associated with commonly used chemotherapeutic agents.

Peripheral neuropathy ranks among the most common non-haematological adverse effects of a number of effective chemotherapeutic agents, including platinum compounds, taxanes and vinca alkaloids. Newer agents, such as bortezomib, thalidomide and lenalidomide, frequently exert similar neurotoxic effects on peripheral nerves. Chemotherapy-induced peripheral neuropathy (CIPN) may result from a variety of mechanisms and may be related to causal factors, such as single dose per course, cumulative dose and risk factors including treatment schedule, prior or concomitant administration of other neurotoxic agents, age and pre-existing peripheral neuropathy of other causes. The symptoms usually begin during chemotherapy and they may even worsen after cessation of treatment. In most of the cases, patients experience positive (pain, paresthesias) or negative (numbness) sensory symptoms in distal extremities in a stocking-and-glove distribution with less prominent motor and autonomic involvement. To date, several neuroprotective agents including thiols, neurotrophic factors, anticonvulsants and antioxidants have been tested in preclinical models and clinical open label or randomized controlled trials for their ability to prevent or treat symptoms of CIPN. Although several of these agents hold promise as possible neuroprotective factors, clinical data are still controversial and none have as yet robustly been proven effective against CIPN. This review critically looks at the pathogenesis, incidence, risk factors, diagnosis, characteristics and management of peripheral neuropathy associated with commonly used chemotherapeutic agents. We also highlight areas of future research to pursue.

Miliary pattern due to occupational lung disease in a patient with laryngeal cancer.

Inhalation of metal dusts and fumes can induce a wide range of respiratory disorders, including granulomatosis, chemical pneumonitis and pulmonary interstitial disease. Laryngeal cancer is the most common cancer of the upper aerodigestive tract. We present a patient with occupational lung disease whose chest CT showed miliary nodular pattern, with concurrent laryngeal cancer who had been engaged in type printing for 22 years. Histology of the laryngeal lession showed squamous cell laryngeal cancer. Histology of the nodules showed a foreign body granulomatous response with several foreign body cells, most probably due to exposure to numerous inorganic (lanthanides, elements such us La, Ce, Nd, Sm, EU, Tb, Lu) and organic particles (such us acrylates, epoxy- and urethane-acrylates).

Solitary fibrous tumor of the urinary bladder: report of a case with long-term follow-up and review of the literature.

Solitary fibrous tumor (SFT) is a neoplasm typically arising in the pleura. Yet, extrapleural cases have been described and are a common cause of diagnostic pitfalls, especially when met in unusual sites. We report the clinical and pathological features of a case of SFT arising in a rather unusual site, the urinary bladder, the seventh reported to date in the English literature and the first with long term follow-up. Differential diagnosis from other spindle cell neoplasms of the bladder can be problematic. Prognosis of this neoplasm is obscure and long-term follow-up is required for all cases of solitary fibrous tumor. Solitary fibrous tumor is a rare mesenchymal tumor of the urinary bladder, but should always be considered in the differential diagnosis of spindle cell neoplasms encountered in the lower genital tract.

Bcl-2, bax and p53 expression in rectal adenocarcinoma. Correlation with classic pathologic prognostic factors and patients' outcome.

BACKGROUND: Bcl-2 oncoprotein inhibits apoptosis, whereas bax protein promotes apoptosis by enhancing cell susceptibility to apoptotic stimuli. This study examined the bcl-2, bax and p53 expression in rectal adenocarcinomas and their relationship with tumor prognosis. PATIENTS AND METHODS: Paraffin-embedded 4-microm tumor sections obtained from patients with rectal adenocarcinoma who underwent colectomy for therapeutic reasons, were analyzed with a standard streptavidin biotin peroxidase method, using polyclonal and monoclonal antibodies. Patients were followed up for 1.5-83 (mean +/- SD: 47.19 +/- 6.2) months. RESULTS: Positive immunoreactivity for bcl-2, bax and p53 was detected in 21 (37%), 28 (50%) and 45 (80%) tumors, respectively. Bax was co-expressed in 17 out of 21 bcl-2(+) cases, whereas p53 was co-expressed in 18 out of 21 bcl-2(+) and 17 out of 28 bax(+) cases. Loss of bax expression was associated with advanced stage and high grade tumors (p < 0.01). Local (n = 6) or distant (n = 5) tumor recurrence was established in 11 cases. All these cases were bax(+), bcl-2(-) and p53(+). Bax and p53 expressions were correlated with adverse outcome (p < 0.05) while bcl-2 presence did not influence survival. Bcl-2(-)/bax(+)/p53(+) cases showed lower survival than bax(+)/bcl-2(+)/p53(+) cases (p < 0.001). CONCLUSION: In rectal adenocarcinoma, bax and bcl-2 proteins co-express frequently with p53. Co-expression of bax with p53 protein is associated with poor clinical outcome, especially in cases without concomitant expression of bcl-2.

Fetus amorphous acardious: report of a rare case and differential diagnosis from placental teratoma with review of the literature.

Fetus amorphous acardious is a rare fetal malformation, lacking a functional heart and bearing no resemblance to human embryos. The main differential diagnosis is with placental teratoma and is based on the degree of skeletal organization and umbilical cord formation. A 27-year old woman delivered a healthy newborn at 37 weeks' gestation. An amorphous mass, covered with healthy looking skin, was connected to the placenta with a short pendicle. X-ray examination of the mass revealed the presence of vertebral column associated with ribs and pelvic bones. Histopathologic examination demonstrated the presence of spinal tube inside the vertebral column. Microscopy of the pedicle was consistent with umbilical cord. Various other tissues were also discovered, such as adipose tissue, gastric and large.

Increased mast cell infiltration in familial varicose veins: pathogenetic implications?

AIM: Increased infiltration of activated mast cells has been recently implicated in the pathophysiology of varicose veins. The aim of the present study was to investigate a possible association between mast cell infiltration of primary varicose veins and clinical features, which could clarify further varicose vein pathophysiology. METHODS: Seventeen patients, operated on for primary varicose veins and greater saphenous vein incompetence, participated in the study. Mast cells, distributed within the adventitia of grossly abnormal segments of the greater saphenous vein and calf varicosities removed during surgery, were identified and measured in stained tissue sections. The mast cell count, expressed as mast cells per 10 high-power fields, was subsequently associated with clinical features, including age, gender, body mass index, familial varicose veins, duration of varicose vein disease and relation to previous pregnancies, leg symptoms and findings on physical examination, clinical class and score of chronic venous insufficiency (CEAP classification). RESULTS: Patients with family history of varicose veins (n=7) had a significantly increased mast cell infiltration (median, interquartile range) of the abnormal venous segments (16, 8.4) in comparison with those (n=10) without such a history (9.2, 7.3), p=0.005. Mast cell infiltration had a significant inverse association with age (r= -0.49, p=0.046), but not with the remaining clinical features. CONCLUSION: Our findings support the hypothesis that the increased mast cell infiltration in varicose veins is not a consequence of venous hypertension. Furthermore, the increased mast cell infiltration in familial varicose veins implies a rather primary role and therefore the presence of a distinct pathophysiology. Further investigation testing the activity of mast cells in cases of family history might reveal another step in the pathogenic mechanism of varicose veins, leading to a more rational treatment.

Determination of plasma cell secreting potential as an index of maturity of myelomatous cells and a strong prognostic factor.

According to the widely accepted myeloma staging system, the bulk of paraprotein is the main determinant of disease stage. However, myelomatous plasma cells differ considerably in their ability to synthesize and secrete monoclonal paraprotein. We determined plasma cell secreting potential (PCSP) as the amount of M-component, divided by the percentage of marrow plasmacytic infiltration, in 240 patients with myeloma, and correlated our results with chain isotype, plasma cell morphology, severity of bone disease, well-recognized prognostic factors, such as serum LDH, CRP, albumin and beta2-microglobulin, treatment response and overall survival. PCSP was higher in IgG than in other myeloma types, and was an almost constant parameter for each individual patient, in 134/166 cases. A > 10% decrease of PCSP in 26 patients was associated with disease aggressiveness and treatment failure. Patients with MGUS had significantly higher PCSP than those with myeloma of the same chain type. Higher PCSP was associated with stage I, absence of Bence-Jones proteinuria and indolent forms of disease with lower proliferating cell nuclear antigen (PCNA) positivity, serum LDH, alpha2-globulins, CRP and beta2-microglobulin and higher albumin levels. Conversely, patients with immature/plasmablastic morphology and those with severe bone disease had lower PCSP. Good responders to treatment had significantly higher PCSP than moderate and poor responders and PCSP was strongly correlated with overall survival in IgG and IgA myeloma. In conclusion, PCSP reflects the maturation status of myelomatous cells and therefore can be used as a prognostic factor, since patients with high secreting potential represent a lower malignancy group, in comparison to those with a low secreting potential.

S-100 protein-positive dendritic cells and CD34-positive dendritic interstitial cells in palatine tonsils.

Dendritic cells (DCs) are effective antigen-presenting cells and have been shown to mature from precursor CD34-positive stromal cells (dendritic interstitial cells, DICs) or monocytes. To gain insight into the local immune response in human tonsils, we investigated immunohistochemically the presence of DCs and DICs in 17 non-hyperplastic and 13 hyperplastic tonsils. Dense infiltrates of S-100-positive DCs were noted in the majority of hyperplastic tonsils, while there were fewer in non-hyperplastic tonsils. DICs were noted specifically at the periphery in the dense hemi-capsule cap that separates the tonsil from the underlying muscle. In addition, their small number suggests that the accumulation of S-100 dendritic cells in hyperplastic palatine tonsils is achieved through migration from other sites rather than through maturation from precursors locally.

Unusual presentation of pancreatic mucinous cystadenocarcinoma by spontaneous splenic rupture.

BACKGROUND: Mucinous cystic neoplasms of the pancreas are uncommon tumors with varying potential for malignancy. Although traumatic splenic rupture is common, spontaneous rupture is a rare event. CADE REPORT: We present an unusual case of spontaneous splenic rupture, due to an otherwise asymptomatic mucinous cystadenocarcinoma of the tail of the pancreas. CONCLUSION: A tumor of the tail of the pancreas may uncommonly present as spontaneous splenic rupture, probably due to venous congestion and infiltration of the spleen, requiring emergency surgical treatment.

Papillary serous adenocarcinoma of the endocervix: A rare neoplasm. Immunohistochemical profile.

Serous adenocarcinoma of the endocervix is a rare carcinoma similar to the serous carcinoma of the ovary and the endometrium. We report a case of a 63-year-old woman with papillary serous adenocarcinoma arising within the endocervix, describing the clinical presentation and the morphologic characteristics of this rare neoplasm. A detailed immunohistochemical analysis on the expression of low- and high-molecular weight cytokeratins (AE1 and AE3), EMA, CEA, vimentin, B72.3, nm23, estrogen and progesterone receptors, LeuM1 (CD15), p53, Ki-67 antigen, and PCNA by tumor cells has also been carried out, which to our knowledge has not been previously reported.

Autoimmune cholangitis in a patient with celiac disease: a case report and review of the literature.

Autoimmune cholangitis is a rare chronic cholestatic liver disease. We describe the case of a 65-year-old woman with celiac disease who presented to us with fever, jaundice and weight loss. Serum biochemical study showed marked increase in alkaline phosphatase and gammaGT levels. Antinuclear antibodies were positive, while antimitochondrial and anti-smooth-muscle antibodies were negative. Liver biopsy was compatible with primary autoimmune cholangitis. The patient was successfully treated with azathioprine and methylprednisolone. We describe here the uncommon association of autoimmune cholangitis with celiac disease and review the prevalence of liver diseases in patients with celiac disease.

Microvessel density, proliferating activity, p53 and bcl-2 expression in in situ ductal carcinoma of the breast.

BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of lesions that show important differences in biologic behavior. New vessel formation has been reported as a prognostic indicator in breast carcinoma, but little information is available about its significance in DCIS. This study was planned to examine angiogenesis in DCIS in relation to histologic subtype, proliferation activity, p53 and bcl-2 expression. MATERIALS AND METHODS: Paraffin sections from 24 cases of DCIS (9 comedo and 15 non comedo type) were studied immunohistochemically using polyclonal and monoclonal antibodies to von Willebrand factor, Ki-67, p53 (clone 1801) and bcl-2 proteins. The streptavidine-biotin technique with microwave antigen retrieval was employed. RESULTS: Most cases showed enhanced microvessel formation around ducts with DCIS compared to normal ducts. Comedo carcinomas (CCs) showed enhanced neovascularization compared to non comedo carcinomas (NCCs). Growth fraction determination with Ki-67 antibody showed that 78% of the CCs expressed high proliferating activity compared to 27% of the NCCs. p53 immunoexpression was noted in 78% of the CCs and 20% of the NCCs. Bcl-2 immunoreactivity was observed in 67% of the total cases in 58% of which there was no association with p53 expression. However, an association was found between neovascularization and overexpression of Ki-67 and p53. CONCLUSIONS: This study suggests that neovascularization is an early phenomenon in breast neoplasia and is apparent as early as the in situ stage. CCs express a more aggressive immunophenotype, compared to the other DCIS subtypes, characterized by increased stromal interaction, high proliferating activity, p53 overexpression and a near lack of bcl-2 immunostaining.

Assessment of angiogenesis in human cervical lesions.

Angiogenesis has been extensively studied in several types of invasive carcinomas and has been correlated-with tumor growth and metastasis. In some of these studies it has been shown that angiogenesis preceeds neoplastic transformation. A correlation is evident between microvessel density and conditions that exist much before the onset of tumor formation (i.e. dysplastic lesions). In this study, tumor vascularity was quantified in a series of cervical lesions: 92 dysplasias (31 mild, 24 moderate and 36 severe) and 11 infiltrating squamous cell carcinomas. Microvessels were visualized by a polyclonal antibody against factor VIII-related antigen (DAKO), using a streptavidin-peroxidase immunohistochemical method. Vessel density was quantified in 3 high power fields (hpf) of the most vascular areas, by two independent observers. Mean vascular counts were 13 +/- 5 vessels per unit area in CIN I lesions, 17 +/- 4 in CIN II, 20 +/- 6 vessels in CIN III and 17 +/- 5 in infiltrating carcinomas. There was a progressive increase of vascularity in the dysplastic lesion in the samples with increasing atypia in relation to controls. No significant differences were noted between severe cervical dysplasias and infiltrating carcinomas. Our findings suggest that angiogenesis may be an important event in tumor initiation and the conversion of the normal epithelium into cancer.

Immunohistochemical detection of ras p21 and c-myc p62 in colonic adenomas and carcinomas.

In the present paper we review the results of our study on the use of monoclonal antibodies Y13,259 to the ras p21 and MYC1 9E10 to the c-myc p62 oncoprotein products in human tumors and tumorlike conditions of the colorectum. A total of 78 tissue sections were analyzed immunohistochemically and revealed the following: 42 adenocarcinomas with 8 normal mucosae adjacent to the tumor, 25 adenomas (with or without dysplasia and with in situ carcinoma) and 3 hyperplastic polyps. Parallel tissue sections were used in order to compare ras and c-myc oncoproteins. Reviewing our results we made the following remarks: 1. All adenocarcinomas but one were expressed with both oncoproteins, most of them being strongly positive. 2. All adenomas were positive for ras p21, and all but two were also positive for c-myc p62. An interesting point is that the degree of staining intensity increased in accordance with the degree of dysplasia and/or in situ carcinoma association. 3. The hyperplastic polyps, as well as all normal mucosae were negative.