Grading of neuroendocrine neoplasms: mitoses and Ki-67 are both essential.

BACKGROUND: The current WHO classification for neuroendocrine neoplasms (NEN) of the gastrointestinal tract requires Ki-67 and mitotic index for grading. However, both indexes might be conflicting as far as grade is concerned. In this study, we investigate which of the two indexes is most informative to predict survival. METHODS: We assessed 362 patients with NEN of gastrointestinal (n = 148), pancreatic (n = 29), lung (n = 77), unknown primary site (n = 102) and of miscellaneous (n = 6) origin. Follow-up and proliferative indexes were recorded. RESULTS: Survival was clearly correlated with both proliferative indexes (p < 0.001). One hundred and nineteen samples (34%) showed discordance in grading between the Ki-67 and the mitotic index, of which 74 (62%) were biopsies and 45 (38%) resection specimens (p = 0.001). In 86% of these cases, survival matched with the highest proliferative index, which was the Ki-67 index in 87% of these cases. Seventeen cases had a mitotic index of 2 (threshold grade 2) and a Ki-67 index of <3% (grade 1). For these cases, survival curve matched that of patients with concordant indexes of grade 1. CONCLUSION: Grading NEN using two proliferative markers results in discordance between these indexes in one third of cases, more often in biopsy material than in resection specimens. If results are discordant, survival is for the most part associated with the grade of the highest index, for the most part Ki-67. Thus, grading with two proliferative indexes is useful as it highlights cases where one of these indexes may be incongruent.

Somatic mosaicism caused by monoallelic reversion of a mutation in T cells of a patient with ADA-SCID and the effects of enzyme replacement therapy on the revertant phenotype.

Patients with adenosine deaminase (ADA) deficiency exhibit spontaneous and partial clinical remission associated with somatic reversion of inherited mutations. We report a child with severe combined immunodeficiency (T-B- SCID) due to ADA deficiency diagnosed at the age of 1 month, whose lymphocyte counts including CD4+ and CD8+ T and NK cells began to improve after several months with normalization of ADA activity in Peripheral blood lymphocytes (PBL), as a result of somatic mosaicism caused by monoallelic reversion of the causative mutation in the ADA gene. He was not eligible for haematopoietic stem cell transplantation (HSCT) or gene therapy (GT); therefore he was placed on enzyme replacement therapy (ERT) with bovine PEG-ADA. The follow-up of metabolic and immunologic responses to ERT included gradual improvement in ADA activity in erythrocytes and transient expansion of most lymphocyte subsets, followed by gradual stabilization of CD4+ and CD8+ T (with naïve phenotype) and NK cells, and sustained expansion of TCRγδ+ T cells. This was accompanied by the disappearance of the revertant T cells as shown by DNA sequencing from PBL. Although the patient's clinical condition improved marginally, he later developed a germinal cell tumour and eventually died at the age of 67 months from sepsis. This case adds to our current knowledge of spontaneous reversion of mutations in ADA deficiency and shows that the effects of the ERT may vary among these patients, suggesting that it could depend on the cell and type in which the somatic mosaicism is established upon reversion.

Anthropometry, physical activity and cancer of unknown primary (CUP) risk: Results from the Netherlands cohort study.

BACKGROUND: Cancer of Unknown Primary (CUP) is a metastatic disease for which the primary tumour origin could not be identified during life. Few studies have investigated the risk factors associated with this disease. This study investigates anthropometry, physical activity and CUP risk. METHODS: Data is used from the Netherlands Cohort Study, which includes 120,852 participants aged 55-69 years. All cohort members completed a self-administered questionnaire on cancer risk factors at baseline in 1986. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and the Dutch Pathology Registry. After a follow-up of 20.3 years, 926 incident CUP cases and 4099 subcohort members were available for case-cohort analyses. Proportional hazards models were used to compute multivariable adjusted hazard ratios (HRs). RESULTS: We found no associations between height, body mass index (BMI) at baseline, BMI at age 20 years, change in BMI since age 20 years, clothing size (trouser/skirt size), or non-occupational physical activity and CUP risk. CONCLUSION: Our findings indicate that neither anthropometry nor physical activity are associated with the development of CUP.

Unknown primary Merkel cell carcinoma with cutaneous spread.

The authors present the case of a woman in the seventh decade of life with medical history of: left nephrectomy for renal tuberculosis and non-Hodgkin's lymphoma treated with chemotherapy (QT) and radiotherapy. She presented with a 2-month history of non-tender, left inguinal lymph node enlargement. Positron Emission Tomography (PET)-CT -scanshowed hypermetabolic inguinal and retroperitoneal lymphadenopathies, no primary tumour. On the second dermatological examination a pink, 2 cm plaque on the anterior left knee was noted. The histopathological analysis revealed Merkel cell carcinoma. The patient underwent two lines of systemic QT, with life-threatening toxicities limiting treatment. Followed overwhelming disease progression with lymphoedema and numerous skin metastases in the left lower limb. The patient received palliative care until death. The rare incidence of such neoplasia and its uncommon clinical presentation justifies reporting this case and highlights the importance of multidisciplinary teams in the management of cancer patients.

CUP Syndrome-Metastatic Malignancy with Unknown Primary Tumor.

BACKGROUND: 2-4% of newly diagnosed cases of malignant disease involve cancer of unknown primary (CUP). This mixed entity is one of the 6 most common types of malignant disease in Germany. Highly refined treatment strategies can now be offered to patients with CUP. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed with an emphasis on articles from the past decade. The current guidelines and recommendations of specialty societies were also considered in the evaluation. RESULTS: CUP most commonly manifests itself as metastases to the lymph nodes, lungs, liver, or bones. With the aid of imaging studies, including functional hybrid imaging and further medical examination, a primary tumor can be discovered in up to 40% of patients initially diagnosed with CUP. Immunohistochemistry guided by histomorphology often enables precise characterization of the lesion and can be supplemented, in selected cases, by molecular-genetic diagnostic evaluation. The most commonly detected types of primary tumor are cancers of the lung, pancreas, liver, and biliary system. For patients with local metastases, surgical resection or radiotherapy with curative intent is usually indicated, sometimes in the framework of a multimodal treatment concept. The median 2-year survival of patients with disseminated CUP is only 20%. For such patients, specific types of systemic therapy are recommended on the basis of the diagnostic characterization of the disease. Immune-modulatory antibodies can be effective, particularly in the treatment of CUP that has been characterized with biomarkers, but should still be considered experimental at present. CONCLUSION: A combination of conventional and innovative diagnostic methods enables the provision of highly refined therapeutic strategies to patients with CUP who are undergoing treatment in interdisciplinary cancer centers.

[Bone Metastases - Pathophysiology, Diagnostic Testing and Therapy (Part 1)]. / Knochenmetastasen ­ Pathophysiologie, Diagnostik und Therapie (Teil 1).

In Germany and other European countries, cancer is the second most common cause of death after cardiovascular disease. Although 5-year survival rates for several types of cancer have significantly improved over the last 30 years, metastasis to the bone almost always leads to incurable disease. Aside from the rare primary bone tumours, the treatment of bone metastases now accounts for a major part of tumour orthopaedic workload and requires close interdisciplinary coordination between specialists in oncology, radiology and the discipline of the primary tumour entity. Due to improvements in oncological treatment regimes, long survival times can be achieved. Therefore, the management of so-called "SRE" (skeletal-related events) has gained importance, even in palliative situations. On the basis of a selective literature review, the following article points out the underlying pathophysiological processes of bone metastases and outlines different diagnostic approaches and their relevance in the current clinical setting.

Circadian breast skin temperature rhythms: overt and occult benign and occult primary malignant breast disease.

Circadian variations of breast surface temperature have been measured in patients with overt or occult benign breast disease, or in those with occult breast cancer. Subjects were studied in a hospital ward environment well-controlled with respect to ambient temperature. Using manual techniques temperatures were recorded half-hourly for 96 hr from replicate sensors placed on quadrants of the left and right breasts inclusive of tumour areas and similar sites on the contralateral breast. Application of time series analysis failed to consistently demonstrate differences in values for the rhythm parameters for the tumour area and contralateral site. It was apparent, however, that the tumour area was generally associated with a reduced initial variance of the series in addition to a reduced percentage variance explained by a time series model with two rhythmic components when compared to the control site. These data suggest that efforts to identify early breast disease from signals of breast temperature should, at least, be directed to studies of temperature variance.

Metastasis of unknown origin.

Evaluation of the patient with metastasis of unknown origin should be structured to quickly identify treatable tumors or the need for palliation while avoiding prolonged hospital stays and testing that will result in neither improved treatment nor better prognosis. The evaluation should be symptom-directed and pathologically oriented. It is the responsibility of the family physician in caring for a patient with MUO to ensure that communication is facilitated between surgeon, oncologist, pathologist, and patient. The physical examination should include thyroid, breasts, pelvic, and rectal examinations. General lab analyses should include fecal occult blood testing, complete blood count, urinalysis, serum calcium, and liver function studies. Men should have assays for prostate-specific antigen and serum prostatic acid phosphatase. Women should undergo mammography and pelvic ultrasound. Undifferentiated carcinoma is likely to originate from either small cell bronchogenic, lymphoma, or germ cell, and thus, serum should be assayed for HCG and AFP. Further radiologic studies, in the absence of specific symptoms, should be limited to chest radiographs and abdominal CT. Contrast studies should be included only if there is organ dysfunction. Biopsy of the malignant tissue should be done early, and studies should include histochemistry, immunohistology, and electron microscopy. Tissues from female patients should be studied for estrogen and progesterone receptors. When a biopsy is planned, advance communication between the family physician or surgeon and the pathologist greatly increases the chance of identifying a primary site. It is important that the surgeon obtain sufficient material to enable study, not only by standard histologic techniques, but also by electron microscopy, special stains, estrogen receptor activity, hormonal markers, and tumor markers. Treatment of patients for whom a primary tumor remains undiscovered must include toxic therapies only for those with good functional status who are likely to respond. Therapy must be pursued for palliation of symptoms when they develop. As physicians, we must control the urge to do something at those times when doing nothing is more appropriate. We must provide continuous support for both the patient and family, protecting to the best of our ability their quality of life. A physician should never convey the impression that it is "not cost-effective" to look for the source of a patient's malignancy. It can be emphasized that further search for a primary tumor carries both medical risk and expense, yet is unlikely to locate the primary tumor or improve the response to therapy or the quality of life.(ABSTRACT TRUNCATED AT 400 WORDS)

Cancer of unknown primary site. Deciding how far to carry evaluation.

Management of most patients who present with metastatic cancer from an unknown primary site is challenging. These patients often are debilitated from the onset of their disease, have symptoms that are hard to control, and respond poorly to systemic therapy. The decision regarding the extent of a frequently unrewarding diagnostic evaluation, especially in these days of cost containment, is difficult. Knowing that few will benefit from aggressive therapy, the treating physician should make quality of life the most important goal in caring for these patients.

Paraneoplastic muscle disease.

In paraneoplastic muscle disease, the malignancy may remotely affect neuromuscular transmission or incite muscle inflammation or necrosis. In several of these diseases, an autoimmune basis for the muscle disease has been established and has become a defining feature. These paraneoplastic muscle diseases may be the first manifestation of a malignancy, and their diagnosis thus demands a vigilant search for an underlying tumor. This article is focused on inflammatory and necrotizing myopathies and disorders of neuromuscular transmission that may arise in the setting of malignancy and are considered paraneoplastic phenomena.

Development and validation of a bedside score to predict early death in cancer of unknown primary patients.

BACKGROUND: We have investigated predictors of 90-day-mortality in a large cohort of non-specific cancer of unknown primary patients. METHODS: Predictors have been identified by univariate and then logistic regression analysis in a single-center cohort comprising 429 patients (development cohort). We identified four predictors that produced a predictive score that has been applied to an independent multi-institutional cohort of 409 patients (validation cohort). The score was the sum of predictors for each patient (0 to 4). RESULTS: The 90-day-mortality-rate was 33 and 26% in both cohorts. Multivariate analysis has identified 4 predictors for 90-day-mortality: performance status>1 (OR = 3.03, p = 0.001), at least one co-morbidity requiring treatment (OR = 2.68, p = 0.004), LDH>1.5 x the upper limit of normal (OR = 2.88, p = 0.007) and low albumin or protein levels (OR = 3.05, p = 0.007). In the development cohort, 90-day-mortality-rates were 12.5%, 32% and 64% when the score was [0-1], 2 and [3]-[4], respectively. In the validation cohort, risks were 13%, 25% and 62% according to the same score values. CONCLUSIONS: We have validated a score that is easily calculated at the beside that estimates the 90-days mortality rate in non-specific CUP patients. This could be helpful to identify patients who would be better served with palliative care rather than aggressive chemotherapy.

The value of postmortem examination in cases of metastasis of unknown origin-20-year retrospective data from a tertiary care center.

BACKGROUND: Metastasis of unknown origin (MUO) is a diagnostic challenge in clinical practice even with the state of current advanced diagnostic technology. To evaluate the value of autopsy in determining the primary site of MUO, this study reviewed the Hamilton experience-over the last 20 years-with patients autopsied with clinical diagnosis of MUO. METHODS: All autopsy diagnoses from cases performed at the Hamilton Health Sciences Center and St Joseph's Healthcare from 1980 to 2000 were reviewed. Fifty-three cases of MUO were identified (MUO was defined as a patient with pathological and/or radiological diagnosis of a metastatic tumor for which the primary site of malignancy was unknown). The clinical history and gross and microscopic diagnoses for these cases were reviewed. RESULTS: There were 31 men (58.5%) and 22 women (41.5%) in the study. Their mean age was 66 years. Pathological diagnoses at autopsy were adenocarcinoma (n = 37), small cell carcinoma (n = 6), anaplastic carcinoma (n = 3), and undifferentiated carcinoma (n = 3). Primary tumors were identified in 27 patients (51%), most commonly in the lung (n = 8), large bowel (n = 6), and pancreas (n = 4). Histochemical and immunohistochemical stains were helpful in reaching the diagnosis of a primary tumor in 4 of 27 cases. CONCLUSIONS: The following were observed: (1) in this series, autopsy was helpful in establishing the diagnosis of a primary tumor in 51% of the cases, reaffirming the value of postmortem examination in these instances; (2) adenocarcinoma was the most frequent tumor presenting as MUO; (3) the lung and the large bowel were the most frequent sites for primary tumors; and (4) careful gross and histological examinations remain the most important tools in identifying the primary site.

Pilocytic astrocytoma presenting as primary diffuse leptomeningeal gliomatosis: report of a unique case and review of the literature.

We describe a 25-year-old male patient with primary diffuse leptomeningeal gliomatosis (PDLG) presenting with gait ataxia, positive Lhermitte's sign, double vision, and right abducens nerve palsy. Spinal magnetic resonance imaging showed extended intradural, extramedullary, contrast-enhancing masses with compression of the myelon. Spinal leptomeningeal biopsy revealed a pilocytic astrocytoma WHO grade I. Despite chemotherapy with vincristin and carboplatin, the patient died 2 months after admission. A thorough autopsy showed no evidence for primary neoplasms in brain, spine and optic nerve. Sequence analysis of tumor protein 53 gene (TP53) revealed a missense mutation in exon 5, and expression of phosphatase and tensin homolog (mutated in multiple advanced cancers 1) (PTEN) protein was not detected, which may have contributed to astrocytoma development. To our knowledge, this is the first definitive case of pilocytic astrocytoma presenting as PDLG.

The unknown biology of the unknown primary tumour: a literature review.

The unknown primary tumour (UPT) is an intriguing clinical phenomenon found in approximately 5% of all newly diagnosed patients with cancer. It is unclear whether UPT forms a distinct biological entity with specific genetic and phenotypic characteristics, or whether it is merely a clinical presentation of metastases in patients in whom the primary tumour cannot be detected and does not result in any visible clinical signs. Understanding the basic biology of UPT may shed light on this issue and, moreover, may have a direct impact on clinical care. A review of the literature revealed only a limited number of publications describing the genetic and phenotypic features of UPT, most of which focus only on the potential of these markers to predict prognosis. The question as to whether the biology of UPT is different from tumours of known primaries therefore remains unanswered. Further insight into the molecular mechanisms underlying the oncogenesis of UPT, e.g. by applying newly available DNA and gene profiling microarray techniques, will be necessary to understand its specific biology and to develop more effective treatments.

Raynaud's phenomenon and positive antinuclear antibodies in a malignancy.

Both Raynaud's phenomenon and the presence of antinuclear antibodies are uncommon features of malignant disease and the association of both with a malignancy extremely rare. The case is reported of a 78 year old woman who presented with Raynaud's phenomenon and positive antinuclear antibodies related to adenocarcinoma of unknown primary site.

Intrapulmonary shunting causing hypoxaemia in a case of carcinoid syndrome.

A case of metastatic carcinoid syndrome with hypoxaemia is described. The hypoxaemia appeared to be due to intrapulmonary shunting. There was improvement in resting and exercise arterial oxygen saturations following chemotherapy with streptozotocin and 5-fluorouracil. This was followed by a decrease in the tumour bulk which may have led to a reduction in the secretion of the vasodilator products responsible for shunting. Some features of this case suggest that the hypoxaemia might have been due to dilatation of precapillary and capillary vessels of the pulmonary micro-circulation. These features are part of the so-called 'hepatopulmonary syndrome', of which this case appears to represent a less severe form.

Liver-specific imaging with SHU 563A: diagnostic potential of a new class of ultrasound contrast media.

The purpose of this study was to evaluate the imaging properties and diagnostic potential of the novel polymeric ultrasound contrast agent SHU 563 A. After i. v. injection, the agent circulates in the blood pool for about 10 min and is then subsequently sequestered by the RES cells predominantly in the liver. The acoustic emission capabilities enable a very sensitive detection during the blood pool phase and after uptake in the RES cells, contributing to differential diagnosis as well as detection of liver lesions. During a multicenter study, 28 patients with liver lesions were examined. In all patients the results were compared to baseline ultrasound and Contrast enhanced Spiral CT. With respect to lesion size and location, very good agreement between SHU 563 A ultrasound and Spiral CT was achieved. Additional lesions could be shown in the RES phase by SHU 563 A enhanced ultrasound. 26 further patients were examined in other indications. The results in all 54 patients indicate good safety and tolerance of SHU 563 without limitations for diagnostic use. SHU 563 A enhanced ultrasound adds significantly to the detection and delineation of focal liver lesions by improving conspicuity due to RES based contrast after uptake.

Aspectos fundamentales del diagnóstico del cáncer de origen desconocido / Diagnostic approach to cancer of unknown primary site

El cáncer de origen desconocido (COD) es una entidad heterogénea definida por la presencia de enfermedad metastásica documentada histológicamente, sin evidencia de neoplasia primaria tras un estudio diagnóstico dirigido. Los protocolos actuales de manejo del COD se basan no en la búsqueda de la neoplasia primaria, sino en la identificación de los pacientes que pueden beneficiarse de un tratamiento que prolongue su supervivencia, de acuerdo a las características clínicas e histopatológicas de cada caso. Al optimizar el estudio diagnóstico, evitaremos además pruebas infructuosas en pacientes con escasas posibilidades terapéuticas y mal pronóstico a corto plazo (AU)

Cancer of unknown primary site (CUPS) is a heterogeneous entity defined by the presence of a histologically-proven metastatic neoplasm, in which the original tumor cannot be identified after a targeted study. The current guidelines for CUPS focus is not based on the search for the primary neoplasm but rather on the identification of patients who may benefit from a treatment that will prolong their survival, based on the clinical and histological characteristics of each case. By improving the diagnostic study, we avoid using fruitless tests in patients with limited therapeutic possibilities and poor short-term prognosis (AU)