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Selective production of interferon-alpha subtypes by cultured peripheral blood mononuclear cells and lymphoblastoid cell lines.

The biological significance of the existence of multiple interferon-alpha (IFN-alpha) subtypes is unknown but may represent a finely tuned mechanism whereby different subtypes are produced in response to different stimuli. To investigate the expression of individual IFN-alpha subtypes, polyclonal antipeptide antisera designed to react with all IFN-alpha subtypes, or with a particular subtype, IFN-alpha 2 or IFN-alpha 4, have been produced. In this study we demonstrate the utility of these antisera for the detection, using indirect immunofluorescence staining, of intracellular IFN-alpha produced by human peripheral blood mononuclear cells (PBMC) and lymphoblastoid cells. Secreted IFN-alpha was also investigated by bioassay and a sandwich radioimmunoassay (RIA), using two monoclonal antibodies (mAb) and specific for IFN-alpha 4. The PBMC were shown to produce IFN reactive with all three polyclonal antisera, after stimulation with Sendai virus. The lymphoblastoid cells also produced IFN, including IFN-alpha 2, but IFN-alpha 4 was not detected either intracellularly, by immunofluorescence, or in the medium, by sandwich RIA. The immunofluorescence studies also demonstrate that in the absence of viral stimulation IFN-alpha is found in the cytoplasm of PBMC and lymphoblastoid cells but not secreted in detectable levels. The finding that two lymphoblastoid cell lines do not produce the subtype IFN-alpha 4 raises important questions as to whether other cell lines and cell types produce IFN-alpha subtypes selectively, and whether individual IFN-alpha subtypes have different roles in human physiology and pathology.

Biological Assay↗

[Clinico-pathologic studies of 95 cases of Hodgkin's disease].

From 1961 through 1986, 95 cases of Hodgkin's disease were biopsied in our hospital. Sex distribution: male 70, female 25. Age incidence: 27% were under 20 years and 75% under 40. 93% of lesions had originated from the lymph nodes. Clinical stage: I 14, II 37, III 25 and IV 19 cases. 20 patients were treated by chemotherapy, 26 by radiotherapy and 49 by combined chemotherapy and radiotherapy. The CR + PR rate was 86.2% and the 1-, 3-, 5- and 10-year survival rates were 83.2% (79/95), 57.6% (53/92), 46.4% (32/69) and 31.3% (15/48), respectively. The results showed that the 4 pathological types (LP, NS, MC, LD) and 10 subtypes (D,N in LP; LP, MC, LD in NS; LP, MC, LD in MC; R, DF in LD) and the predominance of reticulum cells (S-R cells, HD cells, histiocytes, lymphocytes, fibrosis, collagenous changes) in the tumor were all irrelevant to the prognosis (P greater than 0.05). However, the clinical stage, immediate response and the method of treatment were very prognostic (P less than 0.05) The authors believe that intensive chemotherapy combined with radiotherapy and intensive radiotherapy could lead to long survival.

Adolescent↗

Role of the pathologist in the management of soft-tissue sarcomas.

The contribution of the pathologist to the management of soft-tissue sarcomas is threefold. First, and most important, is to establish the correct pathological diagnosis which should include the histologic type, subtype and grade of the tumour. This information, correlated with the size, site, clinical and radiologic presentation, is the key factor in determining the biologic behaviour of the tumour. As soft-tissue sarcomas frequently demonstrate histologic variability from one area to another, biopsy with computed tomography or radiologic guidance and adequate sampling is essential. Second, careful marking of the surgical resection margins in consultation with the surgeon is necessary to determine the completeness of excision. Third, examination of the resected specimen may also provide useful information on the sensitivity of the sarcoma to any previous radiation or chemotherapy which the patient may have received.

Biopsy, Needle↗

Sclerosing Sertoli cell tumor of the testis: a distinct histological subtype.

PURPOSE: A case of sclerosing Sertoli cell tumor of the testis is reported. The histological and clinical features are compared to those of other Sertoli cell tumor subtypes. MATERIALS AND METHODS: The current urological and pathological literature was reviewed. RESULTS: The tumor was identified incidentally in a 35-year-old white man. Pathological examination was performed and the patient was well at 9 months. CONCLUSIONS: Sertoli cell tumors are heterogeneous and not accurately considered a uniform entity. The currently recognized variants differ in apparent malignant potential as well as the association with disease processes in other unrelated organ systems.

Adult↗

[A case of spontaneous rupture of renal cell carcinoma].

There have been a few reports on the spontaneous rupture of renal cell carcinoma. A 67-year-old female patient complaining of vomiting and severe abdominal pain was referred to our hospital. Plain computerized tomography demonstrated large heterogenous mass in the right retroperitoneum. We suspected the hemorrhagic shock because of the rupture of the right kidney and therefore emergent laparotomy was performed. Simple nephrectomy for the right kidney was performed. A pathological report revealed renal cell carcinoma, granular cell subtype, grade 1, pT3a. The patient has been followed for one year and five months after the operation, there has been no evidence of local recurrence or distant metastasis of cancer. Thirteen cases of spontaneous rupture of renal cell carcinoma in the Japanese literature are reviewed.

Aged↗

Tumor Mutational Landscape and Its Correlation With Histopathological Characteristics in Breast Cancer.

BACKGROUND/AIM: In breast cancer, knowledge of the associations between clinicopathologic characteristics, genetic changes, and subtype-specific patterns is expanding. This study investigated how pathological and clinical variables affect the actionability of Next Generation Sequencing (NGS)-based tumor molecular data. MATERIALS AND METHODS: 227 breast cancer patients referred to Genekor's laboratory for tumor molecular profile analysis were included in the study. Pathology records were used to assess critical clinicopathological features, including HER2, ER, PR, Ki67, grade, metastatic site, and age. A 1021-gene NGS-based multigene panel was utilized to assess tumor biology alongside tumor mutational burden (TMB) and microsatellite instability (MSI). RESULTS: Comprehensive genomic profiling revealed that 95.6% of the patients harbored at least one oncogenic or likely oncogenic alteration, highlighting the high diagnostic yield of NGS-based testing. Distinct subtype-specific patterns were observed: HR+/HER2- tumors were enriched for PIK3CA and ESR1 gene alterations, whereas triple-negative breast cancer (TNBC) was dominated by TP53 alterations. Clinically actionable alterations were most common in HR+/HER2- tumors (~60% on-label), whereas TNBC more often harbored off-label or trial-associated targets. The inclusion of tumor-agnostic biomarkers (TMB/MSI) increased on-label actionability up to 64.5% in HR+/HER2- tumors, primarily driven by TMB-high cases. Median TMB values were low, and age was the only independent predictor. Furthermore, the presence of actionable alterations was significantly higher in metastatic tumors, and TP53 alterations were associated with aggressive tumor characteristics. CONCLUSION: Comprehensive NGS-based genomic profiling identifies clinically actionable alterations in over half of breast cancer patients, with substantial variability across molecular subtypes. The HR+/HER2- subtype demonstrates the highest prevalence of on-label actionable biomarkers. These findings support the routine implementation of comprehensive genomic profiling, especially in metastatic HER2-negative breast cancer, to guide precision oncology strategies and enable enrollment in biomarker-driven clinical trials.

Humans↗

[Simultaneous and metachronous pelvic bone metastases from renal cell carcinoma necessitating hemipelvectomy: report of two cases].

Two patients, one with and one without a history of nephrectomy for renal cell carcinoma, presented with lower abdominal pain. One of them, a 49-year-old man, had tumors in the right kidney and the right ischiadic bone. He underwent nephrectomy and pathologic findings showed renal cell carcinoma (tubular type, granular cell subtype, INF-gamma, G2). The other patient, a 33-year-old man with a previous history of left nephrectomy for renal cell carcinoma (tubular type, granular cell subtype, INF-alpha, G2), was found to have a large tumor in the pelvis, extending from the pubic and iliac bones to the hip joint. Both patients underwent embolization of the hypervascular mass using a vascular coil followed by hemipelvectomy under general anesthesia. The pathology reports confirmed bone metastases from renal cell carcinoma. Both patients survived surgery and their postoperative courses were uneventful without urinary or bowel incontinence. However, impaired potency was noted in the latter case. Immunotherapy with INF-alpha was resumed immediately after surgery.

Adult↗

[The epidemiology of tumors of the testes in the Netherlands: accurate rendering by the Registry of Histopathology and Cytopathology (PALGA)].

OBJECTIVE: To investigate recent trends in the incidence of testicular cancer and to describe epidemiological characteristics of various subtypes of testicular cancer. DESIGN: Descriptive. METHOD: Using the nationwide registry of pathology reports (PALGA), the incidence of all newly-diagnosed cases of testicular cancer between the years 1991 and 2002 was analyzed according to age and subtype. To test the accuracy of the PALGA figures, a comparison was made with incidence figures (1991-1998) produced by the Netherlands Cancer Registry. RESULTS: 5856 cases of testicular cancer were diagnosed. The age-adjusted incidence increased from 4.8 to 6.6 per 100,000. The incidence of non-seminoma increased to a larger extent than that of seminoma. The incidence of malignant lymphoma of testicular origin did not increase, but it remained the most frequent testicular tumour beyond the age of 65. Non-seminoma was the most common tumour below the age of 30, while seminoma was the most commonly found tumour between the ages of 30 and 65. When PALGA began recording statistics, the incidence figures showed a difference of up to 10% with the figures produced by the cancer registry, but this has decreased to 1-2% in more recent years. CONCLUSION: The incidence of testicular cancer increased from the 1990s up to 2002. The incidence figures of histopathologically confirmed cases of cancer in the PALGA registry were timely and accurate.

Adult↗

Central alpha 1 adrenoceptor subtypes in narcolepsy-cataplexy: a disorder of REM sleep.

The present study suggests the specific involvement within the central nervous system of an alpha 1 adrenoceptor subtype in a behavior, the control of cataplexy, a pathological analogue of rapid eye movement (REM) sleep atonia. Experiments have shown that prazosin, an alpha 1 antagonist, dramatically aggravates canine narcolepsy-cataplexy through a central mechanism, and that [3H]prazosin binding sites are increased in the amygdala of narcoleptic dogs. However, the corresponding Scatchard plots were curvilinear and best fit was obtained with a two-site model, suggesting the existence of two [3H]prazosin binding sites. These two sites (high and low affinity [3H]prazosin binding sites) met the criteria for authentic receptors and were respectively very similar to the alpha 1a and alpha 1b (high and low affinity for WB4101, respectively) subtypes recently described in the rat and rabbit. Our results of in vivo pharmacology and in vitro [3H]prazosin binding in canine narcolepsy now clearly implicate the low affinity [3H]prazosin binding site (alpha 1b) in canine narcolepsy: (1) Prazosin, an alpha 1 antagonist with similar affinity for both subtypes, was much more potent in increasing cataplexy than WB4101, a compound with more affinity for the alpha 1a receptor. (2) Chlorethylclonidine and phenoxybenzamine, two irreversible blockers of the alpha 1 receptors with more affinity for the alpha 1b receptors, aggravate cataplexy for up to two weeks. (3) The alpha 1 receptor upregulation previously reported by our group in the amygdala of narcoleptic dogs was due to a selective increase in the low affinity [3H]prazosin binding sites. A role for noradrenaline in REM sleep regulation has been suspected for many years, but has never been clearly elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

Basal cell carcinoma with mixed histology: a possible pathogenesis for recurrent skin cancer.

BACKGROUND: Basal cell carcinoma with mixed histology (BCC-MH) demonstrates more than one pathologic pattern of tumor. Appropriate therapy for the nonaggressive tumor subtype diagnosed from a superficial biopsy may not be adequate to treat the unsuspected aggressive tumor subtype, resulting in recurrent skin cancer. OBJECTIVE: We prospectively evaluated the incidence and characteristics of BCC-MH. METHODS: Mohs surgical sections were evaluated for BCC-MH. RESULTS: BCC-MH was observed in 43% (49/144) of cancers. Only 10% (5/49) of the biopsy reports from these cancers diagnosed BCC-MH. Most BCC-MH were previously untreated (90% [44/49] of tumors) and were located on the nose. CONCLUSION: More than 40% of basal cell carcinomas referred for removal of the residual tumor were BCC-MH. An unsuspected aggressive pathologic pattern of growth may not be detected after a superficial biopsy. Subsequently, the cancer may recur if the initial treatment for the diagnosed nonaggressive tumor subtype is inadequate for the undiscovered aggressive carcinoma. Mohs micrographic surgery is recommended for BCC-MH treatment.

Adult↗

Early stage uterine papillary serous carcinoma of the endometrium: effect of adjuvant whole abdominal radiotherapy and pathologic parameters on outcome.

BACKGROUND: Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer, behaving like ovarian epithelial cancers and having a predilection for transperitoneal relapse. Within this subtype of uterine cancers, predictors of outcome and the role of adjuvant therapies have not been firmly established, to the authors' knowledge. METHODS: Between 1985-1995, 78 patients who had International Federation of Gynecology and Obstetrics (FIGO) Stage I, II, or IIIa UPSC (based on positive washings only) were seen at the British Columbia Cancer Agency. During this time, the authors had a policy of offering adjuvant pelvic, paraaortic and whole-abdominal radiotherapy (WART) to these patients. Fifty-eight patients received adjuvant WART, and 20 received lesser or no adjuvant therapy. The authors undertook a retrospective analysis of pathology with quantification of the percentage of papillary serous component (% PSC) and p53 expression. Pathology was retrieved and reviewed on 62 patients; p53 staining was performed on blocks from the hysterectomy specimen in 46 cases. Pathologic parameters, stage, and adjuvant therapy were correlated with clinical outcome in a multivariate analysis. RESULTS: Median follow-up was 52 months (3-139 mos) and the 5-year disease-specific survival rate was 66.2%. The 58 patients who received adjuvant WART had a significantly better 5-year disease-specific survival than those 20 patients who did not, 74.9% versus 41.3% (P = 0.04). Multivariate analysis showed that % PSC and p53 were not significant predictors of outcome for early stage UPSC. Of the factors examined, only FIGO stage and WART significantly predicted improved outcome (P = 0.02 and 0.04, respectively). CONCLUSIONS: The current study demonstrated a significant difference in the outcomes of patients who had FIGO Stage I compared with Stage II UPSC. In the current series of patients, the authors were not able to predict outcome based on % PSC or p53 expression. The current study results with WART were promising, and WART merits further study.

Adult↗

MCMI-II profiles of women with eating disorders: a cluster analytic investigation.

A three-factor model of personality pathology was investigated in a clinical sample of 183 female patients in an outpatient eating disorders treatment program. Cluster analysis of MCMI-II personality scales (Millon, 1987) yielded three distinct personality profiles, which were consistent with previous studies. First, 16.9% of the sample comprised a High Functioning cluster, which manifested no clinical elevations on the MCMI-II and had significantly lower scores on the Eating Disorder Inventory (EDI; Garner; 1991) scales than the other two clusters. Second, 49.1% of the sample comprised an Undercontrolled/Dysregulated cluster. Finally, the remaining 34% of the sample comprised an Overcontrolled/Avoidant cluster. This final cluster had significantly higher EDI Ineffectiveness scale scores than the Undercontrolled/Dysregulated cluster group. Cluster membership was not associated with eating disorder subtype, suggesting that there is considerable variance in personality pathology within eating disorder diagnostic categories.

Adult↗

Tubular carcinoma of the breast: a histologic subtype indicative of breast-conserving therapy.

We reviewed the clinical and pathologic features of pure tubular carcinoma of the breast with particular emphasis on the reported risk factors associated with local recurrences and survival following breast-conserving therapy. Of 1653 cases of invasive breast cancer, 12 (0.7%) were identified as pure tubular carcinoma. Clinical/pathologic features of pure tubular carcinoma were compared with those of T1 invasive carcinoma of all other histologic types (T1 IC). Of the 12 patients with pure tubular carcinoma (median tumor diameter 1.4 cm; range 0.5-3.0 cm), a multicentric association was identified in one patient while a multifocal association was seen in two. One patient had nodal metastatic disease out of the ten who underwent axillary dissection. No lymphatic vessel invasion was identified in any tumors (P < 0.1 vs T1 IC). In addition, extensive intraductal spread was not present in any tumors (P < 0.05 vs T1 IC). This study shows that patients with pure tubular carcinoma are appropriate candidates for breast-conserving therapy based on the clinical/ pathologic features. When a multifocal association is suspected preoperatively, either a wide local excision or a quadrantectomy which includes other lesions is thus recommended.

Adenocarcinoma↗

Cutaneous carcinoma with mixed histology: a potential etiology for skin cancer recurrence and an indication for Mohs microscopically controlled surgical excision.

Cutaneous carcinomas with mixed histology describe nonmelanoma skin cancers which have more than one histologic subtype. These include basal cell carcinomas with concurrent aggressive growth patterns (such as sclerosing, infiltrating, micronodular, keratinizing, and tumors with perineural involvement) and nonaggressive growth patterns (such as superficial, nodular, and follicular) and squamous cell carcinomas with concurrent poorly differentiated and well-differentiated components. One mechanism of recurrence of nonmelanoma skin cancer may very well result from the inadequate initial treatment of cutaneous tumors with mixed histology. If the aggressive histologic subtype of the original tumor is initially not suspected based upon the pathology observed from a superficial biopsy specimen, the clinician may initiate therapy that would be appropriate for the less aggressive variant that was diagnosed. Subsequently, the more aggressive tumor may persist and eventually manifest as a clinical recurrence of the cancer. This is particularly important when there is perineural tumor involvement. We describe two patients whose skin cancers had more than one histologic subtype to demonstrate the histologic features of cutaneous malignancies with more than one pathologic pattern and to emphasize how inaccurate a single diagnostic biopsy can be. We also suggest that clinicians consider Mohs surgical excision of nonmelanoma skin cancers since this technique incorporates microscopically controlled removal of the tumor with complete pathologic evaluation of all surgical margins for any residual cancer.

Aged↗

Gastrointestinal pathology in rhesus monkeys with experimental SIV infection.

The updated results of current pathomorphological investigations in SIV-infected rhesus monkeys (Macaca mulatta) are summarized. After experimental infection with several SIVmac251 subtypes and various vaccination trails, 147 rhesus monkeys were morphologically examined until now. The pathology of the gastrointestinal tract in SIV-infected animals resembled those of human cases with HIV and AIDS. Alterations were considered to be primary SIV-induced (SIV enteropathy, giant cell disease) or secondary caused by opportunistic agents. Typical secondary gastrointestinal opportunistic infectious agents were parasites (Cryptosporidium sp., Trichuris sp., Trichomonas sp., Spironucleus sp.), viruses (cytomegalovirus, adenovirus) and bacteria (Mycobacterium simiae). Five animals developed malignant lymphomas involving the intestinal tract. The present observations revealed that SIV infection of rhesus monkeys provide an excellent model for studies on the pathogenesis of HIV in man.

Age Factors↗

Maturity-onset diabetes of the young: an update.

Maturity-onset diabetes of the young (MODY) is a dominantly inherited form of non-ketotic diabetes. It usually develops in childhood, adolescence or young adulthood. The disease is heterogenous regarding the genetic and clinical features. Until now, 6 causal genes have been identified. According to clinical evidence there is at least one further MODY gene. MODY2 is caused by mutations in the glucokinase gene, which encodes the signal protein for insulin secretion. The remaining MODY subtypes are the result of mutations in genes coding for transcription factors. MODY2 and MODY3 are by far the most frequent forms. Patients with MODY2 have mild, asymptomatic and stable hyperglycemia that is present from birth. They rarely develop microvascular disease, and seldom require pharmacologic treatment. MODY3 patients usually develop severe hyperglycemia after puberty, which often leads to the diagnosis of diabetes type 1. Despite the progression of hyperglycemia, sensitivity to sulfonylureas is retained in MODY3 patients for many years. Diabetic retinopathy and nephropathy frequently occur in MODY3 patients. Other risk factors are not present. The frequency of cardiovascular disease is not increased. Due to the pleiotropic character of the transcription factors most MODY subtypes are diseases with multi-organ involvement in addition to diabetes. MODY5 appears to be much more frequent than originally assumed. This form is associated with pancreatic atrophy, renal morphologic and functional abnormalities, genital tract malformations and pathological liver test. Compared to MODY2, 3, and 5, the remaining subtypes of MODY have a much lower prevalence. Molecular diagnosis has important consequences for prognosis, family screening and therapy.

Age Factors↗

Metaplastic breast carcinoma: clinical-pathologic characteristics and HER2/neu expression.

BACKGROUND: Metaplastic breast carcinomas (MBC) are rare primary breast malignancies characterized by the co-existence of carcinoma with non-epithelial cellular elements. They can be classified as monophasic spindle cell (sarcomatoid) carcinoma, biphasic carcinosarcoma, adenocarcinoma with divergent stromal differentiation (osseous, chondroid and rarely rhabdoid) as well as adenosquamous and pure squamous cell carcinomas. There is a paucity of information on clinically relevant pathologic features and clinical outcomes for these rare tumors. The aim of this study was to review the pathologic features and clinical outcomes of all cases of MBC seen at a single institution between 1971 and 2000. METHODS: A computerized search of the Queen Elizabeth II Health Sciences Center (QEII HSC) surgical pathology files was performed for the years 1971-2000. Tumor blocks from identified cases were reviewed and immunohistochemistry was performed for estrogen and progesterone receptors (ER/PR), HER2/neu protein overexpression and cytokeratin profile. Clinical outcome information was obtained from hospital files and telephone contact with treating physicians. RESULTS: Twenty-six (26) cases were retrieved with only one case identified before 1990. All tumors were high grade with a median tumor size of 3.7 cm (range 1.4-9.5 cm). Thirteen cases had lymph node dissections available for evaluation, with 4 demonstrating nodal metastases. Five of 26 cases were ER positive within the adenocarcinomatous component, only two of which also expressed PR. Associated ductal carcinoma in situ (DCIS) was present in 11 cases. HER2/neu over-expression was seen in only one (1/26) adenosquamous carcinoma (3 + membranous staining of the malignant glandular component). At 23 months median follow-up, disease free survival (DFS) for the entire group was 53%. CONCLUSIONS: Although a rare breast cancer subtype, MBC is of considerable interest due to its pathological heterogeneity and differences in clinical behavior compared to typical breast carcinomas. Increasing pathologic recognition of MBC as a discrete entity is suggested by the number of MBC diagnoses in the last decade compared to previous years. The poor DFS associated with MBC suggests that further research exploring mechanisms of carcinogenesis and identifying clinically relevant prognostic factors is needed to direct optimum clinical care. Importantly, MBC variants appear to rarely overexpress the HER2/neu oncoprotein.

Adult↗

Chromophobe renal cell carcinoma: clinical, pathological and molecular biological aspects.

Chromophobe renal cell carcinoma (RCC), a newly established subtype of renal neoplasm, is composed of tumor cells with characteristically cloudy, weakly eosinophilic and reticular cytoplasm. The tumor should be distinguished from the common clear cell RCC, because of the unique clinicopathological and molecular biological features. The tumor does not show gender bias. Patient ages are similar to those of clear cell RCC, but might occur in the 20- to 40-year-old age group. Grossly, the tumor tends to be beige in color, which is different from the yellowish color of common RCC. Electron microscopy and immunohistochemistry indicate the intercalated cell of the collecting duct as the cellular origin. Cytogenetic study shows non-random multiple chromosome loss, with mitochondrial DNA rearrangement. Alteration of the von Hippel-Lindau (VHL) gene, a cancer suppressor gene relating with clear cell RCC, has not yet been observed. In order to adopt the most appropriate treatment, including gene therapy, recognition and correct pathological diagnosis of chromophobe RCC are extremely important.

Adenocarcinoma↗