Variability in distribution and use of tuberculosis diagnostic tests in Kenya: a cross-sectional survey.

BACKGROUND: Globally, 40% of all tuberculosis (TB) cases, 65% paediatric cases and 75% multi-drug resistant TB (MDR-TB) cases are missed due to underreporting and/or under diagnosis. A recent Kenyan TB prevalence survey found that a significant number of TB cases are being missed here. Understanding spatial distribution and patterns of use of TB diagnostic tests as per the guidelines could potentially help improve TB case detection by identifying diagnostic gaps. METHODS: We used 2015 Kenya National TB programme data to map TB case notification rates (CNR) in different counties, linked with their capacity to perform diagnostic tests (chest x-rays, smear microscopy, Xpert MTB/RIF®, culture and line probe assay). We then ran hierarchical regression models for adults and children to specifically establish determinants of use of Xpert® (as per Kenyan guidelines) with county and facility as random effects. RESULTS: In 2015, 82,313 TB cases were notified and 7.8% were children. The median CNR/100,000 amongst 0-14yr olds was 37.2 (IQR 20.6, 41.0) and 267.4 (IQR 202.6, 338.1) for ≥15yr olds respectively. 4.8% of child TB cases and 12.2% of adult TB cases had an Xpert® test done, with gaps in guideline adherence. There were 2,072 microscopy sites (mean microscopy density 4.46/100,000); 129 Xpert® sites (mean 0.31/100,000); two TB culture laboratories and 304 chest X-ray facilities (mean 0.74/100,000) with variability in spatial distribution across the 47 counties. Retreatment cases (i.e. failures, relapses/recurrences, defaulters) had the highest odds of getting an Xpert® test compared to new/transfer-in patients (AOR 7.81, 95% CI 7.33-8.33). Children had reduced odds of getting an Xpert® (AOR 0.41, CI 0.36-0.47). HIV-positive individuals had nearly twice the odds of getting an Xpert® test (AOR 1.82, CI 1.73-1.92). Private sector and higher-level hospitals had a tendency towards lower odds of use of Xpert®. CONCLUSIONS: We noted under-use and gaps in guideline adherence for Xpert® especially in children. The under-use despite considerable investment undermines cost-effectiveness of Xpert®. Further research is needed to develop strategies enhancing use of diagnostics, including innovations to improve access (e.g. specimen referral) and overcoming local barriers to adoption of guidelines and technologies.

Accuracy of giant African pouched rats for diagnosing tuberculosis: comparison with culture and Xpert® MTB/RIF.

SETTING: Enhanced tuberculosis (TB) case finding using detection rats in Tanzania. OBJECTIVES: To assess the diagnostic accuracy of detection rats compared with culture and Xpert® MTB/RIF, and to compare enhanced case-finding algorithms using rats in smear-negative presumptive TB patients. DESIGN: A fully paired diagnostic accuracy study in which sputum of new adult presumptive TB patients in Tanzania was tested using smear microscopy, 11 detection rats, culture and Xpert. RESULTS: Of 771 eligible participants, 345 (45%) were culture-positive for Mycobacterium tuberculosis, and 264 (34%) were human immunodeficiency virus (HIV) positive. The sensitivity of the detection rats was up to 75.1% (95%CI 70.1-79.5) when compared with culture, and up to 81.8% (95%CI 76.0-86.5) when compared with Xpert, which was statistically significantly higher than the sensitivity of smear microscopy. Corresponding specificity was 40.6% (95%CI 35.9-45.5) compared with culture. The accuracy of rat detection was independent of HIV status. Using rats for triage, followed by Xpert, would result in a statistically higher yield than rats followed by light-emitting diode fluorescence microscopy, whereas the number of false-positives would be significantly lower than when using Xpert alone. CONCLUSION: Although detection rats did not meet the accuracy criteria as standalone diagnostic or triage testing for presumptive TB, they have additive value as a triage test for enhanced case finding among smear-negative TB patients if more advanced diagnostics are not available.

Bottom-up or top-down: unit cost estimation of tuberculosis diagnostic tests in India.

SETTING: Of 18 sites that participated in an implementation study of the Xpert® MTB/RIF assay in India, we selected five microscopy centres and two reference laboratories. OBJECTIVE: To obtain unit costs of diagnostic tests for tuberculosis (TB) and drug-resistant TB. DESIGN: Laboratories were purposely selected to capture regional variations and different laboratory types. Both bottom-up and the top-down methods were used to estimate unit costs. RESULTS: At the microscopy centres, mean bottom-up unit costs were respectively US$0.83 (range US$0.60-US$1.10) and US$12.29 (US$11.61-US$12.89) for sputum smear microscopy and Xpert. At the reference laboratories, mean unit costs were US$1.69 for the decontamination procedure, US$9.83 for a solid culture, US$11.06 for a liquid culture, US$29.88 for a drug susceptibility test, and US$18.18 for a line-probe assay. Top-down mean unit cost estimates were higher for all tests, and for sputum smear microscopy and Xpert these increased to respectively US$1.51 and US$13.58. The difference between bottom-up and top-down estimates was greatest for tests performed at the reference laboratories. CONCLUSION: These unit costs for TB diagnostics can be used to estimate resource requirements and cost-effectiveness in India, taking into account geographical location, laboratory type and capacity utilisation.

The potential of a multiplex high-throughput molecular assay for early detection of first and second line tuberculosis drug resistance mutations to improve infection control and reduce costs: a decision analytical modeling study.

BACKGROUND: Molecular resistance detection (MRD) of resistance to second-line anti-tuberculous drugs provides faster results than phenotypic tests, may shorten treatment and allow earlier separation among patients with and without second-line drug resistance. METHODS: In a decision-analytical model we simulated a cohort of patients diagnosed with TB in a setting where drug resistant TB is highly prevalent and requires initial hospitalization, to explore the potential benefits of a high-throughput MRD-assay for reducing potential nosocomial transmission of highly resistant strains, and total costs for diagnosis of drug resistance, treatment and hospitalization. In the base case scenario first-line drug resistance was diagnosed with WHO-endorsed molecular tests, and second-line drug resistance with culture and phenotypic methods. Three alternative scenarios were explored, each deploying high-throughput MRD allowing either detection of second-line mutations in cultured isolates, directly on sputum, or MRD with optimized markers. RESULTS: Compared to a base case scenario, deployment of high-throughput MRD reduced total costs by 17-21 %. The period during which nosocomial transmission may take place increased by 15 % compared to the base case if MRD had currently reported suboptimal sensitivity and required cultured isolates; increased by 7 % if direct sputum analysis were possible including in patients with smear-negative TB, and reduced by 24 % if the assay had improved markers, but was still performed on cultured isolates. Improved clinical sensitivity of the assay (additional markers) by more than 35 % would be needed to avoid compromising infection control. CONCLUSIONS: Further development of rapid second-line resistance testing should prioritize investment in optimizing markers above investments in a platform for direct analysis of sputum.

Cost-effectiveness of rapid susceptibility testing against second-line drugs for tuberculosis.

BACKGROUND: Drug susceptibility testing (DST) against second-line tuberculosis drugs (SLDs) is essential for improving outcomes among multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) cases. OBJECTIVE: To evaluate the potential cost-effectiveness of rapid DST for SLDs. DESIGN: We constructed a decision analysis model of Xpert MTB/RIF-based TB diagnosis in East and South-East Asia to compare culture-based DST vs. a hypothetical rapid SLD DST system for specimens resistant to rifampin. Our primary outcomes were the effectiveness and incremental cost-effectiveness of a rapid SLD DST assay relative to culture-based DST. RESULTS: For rapid SLD DST to be more effective than culture-based DST, treating individuals with pre-XDR/XDR-TB with a standardized MDR-TB regimen while awaiting culture-based DST must incur at least 30% excess XDR-TB mortality (100% = treatment with first-line drugs); rapid SLD DST should attain an aggregate sensitivity and specificity for all pre-XDR/XDR mutations of 88% and 96%, respectively. The unit cost of the rapid SLD DST assay must approach that of culture to achieve common thresholds for cost-effectiveness in low-income countries. CONCLUSION: Rapid SLD DST has the potential to be cost-effective, but must meet stringent criteria for accuracy and costs, and requires that standardized second-line treatment for pre-XDR/XDR-TB incur substantial excess mortality before the return of culture results.

Risk factors for excess mortality and death in adults with tuberculosis in Western Kenya.

OBJECTIVES: To evaluate excess mortality and risk factors for death during anti-tuberculosis treatment in Western Kenya. METHODS: We abstracted surveillance data and compared mortality rates during anti-tuberculosis treatment with all-cause mortality from a health and demographic surveillance population to obtain standardised mortality ratios (SMRs). Risk factors for excess mortality were obtained using a relative survival model, and for death during treatment using a proportional hazards regression model. RESULTS: The crude mortality rate during anti-tuberculosis treatment was 18.0 (95%CI 16.8-19.2) per 100 person-years. The age and sex SMR was 8.8 (95%CI 8.2-9.4). Excess mortality was greater in human immunodeficiency virus (HIV) positive TB patients (excess hazard ratio [eHR] 2.1, 95%CI 1.5-3.1), and lower in patients who were female or started treatment in a later year. Mortality was high in patients with unknown HIV status (HR 2.9, 95%CI 2.2-3.8) or, if HIV-positive, not on antiretroviral treatment (ART; HR 3.3, 95%CI 2.5-4.5) or not known to be on ART (HR 2.8, 95%CI 2.1-3.7). The attributable fraction of incomplete uptake of HIV testing and ART on mortality was 31% (95%CI 15-45) compared to HIV-positive patients on ART. CONCLUSION: Increasing the uptake of HIV testing and ART would further reduce mortality during anti-tuberculosis treatment by an estimated 31%.

Measuring socio-economic data in tuberculosis prevalence surveys.

Addressing social determinants in the field of tuberculosis (TB) has received great attention in the past years, mainly due to the fact that worldwide TB incidence has not declined as much as expected, despite highly curative control strategies. One of the objectives of the World Health Organization Global Task Force on TB Impact Measurement is to assess the prevalence of TB disease in 22 high-burden countries by active screening of a random sample of the general population. These surveys provide a unique opportunity to assess socio-economic determinants in relation to prevalent TB and its risk factors. This article describes methods of measuring the socio-economic position in the context of a TB prevalence survey. An indirect measurement using an assets score is the most feasible way of doing this. Several examples are given from recently conducted prevalence surveys of the use of an assets score, its construction, and the analyses of the obtained data.

High sensitivity of chest radiograph reading by clinical officers in a tuberculosis prevalence survey.

BACKGROUND: Chest radiographs (CXRs) are used in tuberculosis (TB) prevalence surveys to identify participants for bacteriological examination. Expert readers are rare in most African countries. In our survey, clinical officers scored CXRs of 19 216 participants once. We assessed to what extent missed CXR abnormalities affected our TB prevalence estimate. METHODS: Two experts, a radiologist and pulmonologist, independently reviewed 1031 randomly selected CXRs, mixed with lms of confirmed TB cases. CXRs with disagreement on 'any abnormality' or 'abnormality consistent with TB' were jointly reviewed during a consensus panel. We compared the nal expert and clinical of cer classifications with bacteriologically confirmed TB as the gold standard. RESULTS: After the panel, 199 (19%) randomly selected CXRs were considered abnormal by both expert reviewers and another 82 (8%) by one reviewer. Agreement was good among the experts (κ 0.78, 95%CI 0.73-0.82) and moderate between the clinical officers and experts (κ range 0.50-0.62). The sensitivity of 'any abnormality' was 95% for the clinical officers and 83% and 81% for the respective experts. The specificities were respectively 73%, 74% and 80%. TB prevalence was underestimated by 1.5-5.0%. CONCLUSIONS: Acceptable CXR screening can be achieved with clinical officers. Reviewing a sample of CXRs by two experts allows an assessment of prevalence underestimation.

Modelling local and global effects on the risk of contracting Tuberculosis using stochastic Markov-chain models.

For some diseases, the transmission of infection can cause spatial clustering of disease cases. This clustering has an impact on how one estimates the rate of the spread of the disease and on the design of control strategies. It is, however, difficult to assess such clustering, (local effects on transmission), using traditional statistical methods. A stochastic Markov-chain model that takes into account possible local or more dispersed global effects on the risk of contracting disease is introduced in the context of the transmission dynamics of tuberculosis. The model is used to analyse TB notifications collected in the Asembo and Gem Divisions of Nyanza Province in western Kenya by the Kenya Ministry of Health/National Leprosy and Tuberculosis Program and the Centers for Disease Control and Prevention. The model shows evidence of a pronounced local effect that is significantly greater than the global effect. We discuss a number of variations of the model which identify how this local effect depends on factors such as age and gender. Zoning/clustering of villages is used to identify the influence that zone size has on the model's ability to distinguish local and global effects. An important possible use of the model is in the design of a community randomised trial where geographical clusters of people are divided into two groups and the effectiveness of an intervention policy is assessed by applying it to one group but not the other. Here the model can be used to take the effect of case clustering into consideration in calculating the minimum difference in an outcome variable (e.g. disease prevalence) that can be detected with statistical significance. It thereby gauges the potential effectiveness of such a trial. Such a possible application is illustrated with the given time/spatial TB data set.

Increased ratio of mRNA expression of the genes CYP17 and CYP11B1 indicates autonomous cortisol production in adrenocortical tumors.

OBJECTIVE: Due to increased use of imaging techniques, adrenal incidentalomas are frequently detected. The majority are non-hyperfunctioning adrenocortical tumors. We have previously shown that expression of the gene CYP17, coding for the enzyme in the cortisol pathway, correlates with cortisol release from adrenocortical tumors in vitro. The aim of this study was to compare clinical data with mRNA expression of CYP17 and CYP11B1 in adrenocortical tumors from patients with and without Cushing's syndrome and to identify adrenal tumors that may cause subclinical Cushing's syndrome. DESIGN: A retrospective study of 34 patients undergoing adrenalectomy due to an adrenal tumor. METHODS: Clinical data were collected. In the adrenal gland the mRNA expression of the genes CYP17 and CYP11B1 was studied with in situ hybridisation technique. RESULTS: The median ratio of CYP17/CYP11B1 expression in tumors from patients with Cushing's syndrome was significantly higher than the median ratio in the non-hyperfunctioning tumors. Tumors from 2 patients with subclinical Cushing's syndrome had ratios within the upper range for non-hyperfunctioning tumors. CONCLUSIONS: The ratio between the expression of the genes CYP17 and CYP11B1 in tumors from patients with Cushing's syndrome is significantly higher than in the non-hyperfunctioning tumors. This indicates that 17alpha-hydroxylase is a major determinant of cortisol overproduction. The patients with subclinical Cushing's syndrome in this study are too few to draw any firm conclusions although the results suggest that subclinical Cushing's syndrome may be identified post-operatively with this method.

Methylation of the p16INK4A promoter is associated with malignant behavior in abdominal extra-adrenal paragangliomas but not pheochromocytomas.

Pheochromocytomas and abdominal extra-adrenal paragangliomas are related to endocrine tumors of the sympathetic nervous system. Studies in animal models have shown that inactivation of the products of the cyclin dependent kinase inhibitor 2A (CDKN2A) gene locus, p16INK4A and p14ARF, promotes the development of pheochromocytoma, especially in malignant form. The present study evaluated the involvement of CDKN2A in human pheochromocytomas and abdominal extra-adrenal paragangliomas from 55 patients. Promoter methylation was assessed using quantitative Pyrosequencing and methylation-specific PCR, and mRNA expression was measured by quantitative real-time PCR. For p16, western blot analysis and sequencing were also performed. succinate dehydrogenase complex subunit B (SDHB) sequencing analysis included extra-adrenal paragangliomas, all tumors classified as malignant, and cases diagnosed at 30 years or younger. The p16INK4A promoter was heavily methylated in a subset of paragangliomas, and this was significantly associated with malignancy (P<0.0043) and SDHB mutation (P<0.002). p16INK4A mRNA expression showed moderate suppression in malignant cases (P<0.05). In contrast, very little p14ARF promoter methylation was seen and there was no significant difference in p14ARF expression between tumors and normal samples. The p16 protein expression was reduced in 16 tumors, and sequence variations were observed in four tumors including the missense mutation A57V and the single nucleotide polymorphism (SNP) A148T. The results suggest that p16INK4A, and not p14ARF, is a subject of frequent involvement in these tumors. Importantly, hypermethylation of the p16INK4A promoter was significantly associated with malignancy and metastasis, and SDHB gene mutations. This finding suggests an etiological link and could provide a clinical utility for diagnostic purposes.

Evaluation of TB and HIV services prior to introducing TB-HIV activities in two rural districts in western Kenya.

SETTING: Health facilities providing tuberculosis (TB) treatment in two districts in rural western Kenya with a high TB and human immunodeficiency virus (HIV) burden. OBJECTIVE: To evaluate TB and HIV/acquired immune-deficiency syndrome (AIDS) services at the facilities and identify barriers to providing quality diagnostic HIV testing and counseling (DTC) and HIV treatment for TB patients in anticipation of the introduction of TB-HIV collaborative services. METHODS: We performed a standard interview with health workers responsible for TB care, inspected the facilities and collected service delivery data. A self-administered questionnaire on training attended was given to all health workers. Results were shared with stakeholders and plans for implementation were developed. RESULTS: Of the 59 facilities, 58 (98%) provided TB treatment, 19 (32%) offered sputum microscopy and 24 (41%) HIV testing. Most facilities (72%) advised HIV testing only if TB patients were suspected of having AIDS. Barriers identified included unaccommodating TB clinic schedules and lack of space, which was an obstacle to holding confidential discussions. The need to refer for HIV testing and/or HIV care was a perceived barrier to recommending these services. Activities implemented following the assessment aimed 1) to provide HIV testing and cotrimoxazole prophylaxis at all TB treatment clinics, 2) to increase availability of HIV treatment services, and 3) to address structural needs at each facility. CONCLUSION: This evaluation identified barriers to the implementation of HIV testing and care services within facilities providing TB treatment.

Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification.

Parafibromin is a protein product derived from the hyperparathyroidism 2(HRPT2) tumor suppressor geneand its inactivation has been coupled to familial and sporadic forms of parathyroid malignancy. In this study, we have conducted immunohistochemistry on 33 parathyroid carcinomas (22 unequivocal and 11 equivocal) using four parafibromin antibodies directed to different parts of the protein. Furthermore, for a fraction of cases, the immunohistochemical results were compared with known HRPT2 mutational status. Our findings show that 68% (15 out of 22) of the unequivocal carcinomas exhibited reduced expression of parafibromin while the 25 sporadic adenomas used as controls were entirely positive for parafibromin expression. Additionally, three out of the six carcinomas with known HRPT2 mutations showed reduced expression of parafibromin. Using all four antibodies, comparable results were obtained on the cellular level in individual tumors suggesting that there exists no epitope of choice in parafibromin immunohistochemistry. The results agree with the demonstration of a approximately 60 kDa product preferentially in the nuclear fraction by western blot analysis. We conclude that parafibromin immunohistochemistry could be used as an additional marker for parathyroid tumor classification, where positive samples have low risk of malignancy, whereas samples with reduced expression could be either carcinomas or rare cases of adenomas likely carrying an HRPT2 mutation.

Lymphocytic hypophysitis: report of two biopsy-proven cases and one suspected case with pituitary autoantibodies.

Lymphocytic hypophysitis (LyH) is a rare inflammatory disease, considered to be autoimmune. LyH has mainly been reported in females and in relation to pregnancy or the post-partum period. We describe a 73-yr-old woman and a 63-yr-old male who were evaluated at our clinic because of pituitary hormone deficits. Both patients had pituitary masses suggestive of a pituitary adenoma on magnetic resonance imaging (MRI). Transsphenoidal pituitary surgery was performed and histopathological examinations revealed LyH in both cases. Clinical, laboratory, radiological and the histopathological findings in these two patients are discussed in detail. In addition, we report on a 79-yr-old man with partial hypopituitarism and empty sella. Screening of a human pituitary cDNA library with his serum revealed autoantibodies against secretogranin II. This is a protein commonly present in human gonadotrophs, thyreotrophs and corticotrophs. Since the patient selectively showed the corresponding pituitary insufficiencies, we speculate on an autoimmune background. Further studies may ascertain the importance of secretogranin II autoantibodies as markers for LyH.

Loss of parafibromin expression in a subset of parathyroid adenomas.

Inactivation of the hyperparathyroidism-jaw tumour syndrome (HPT- JT) gene, HRPT2, was recently established as a genetic mechanism in the development of parathyroid tumours. Its encoded protein parafibromin has tumour-suppressor properties that play an important role in tumour development in the parathyroids, jaws and kidneys. Inactivating HRPT2 mutations are common in HPT- JT and parathyroid carcinomas, and have been described in a few cases of parathyroid adenomas with cystic features. In this study, 46 cases of cystic parathyroid adenomas previously investigated for HRPT2 mutations were characterized with regard to MEN1 gene mutations, cyclin D1 expression and parafibromin expression. In normal tissues and cell lines, parafibromin was ubiquitously expressed. Furthermore, parafibromin was detected as a dominating nuclear and a weaker cytoplasmic signal in transfected cell lines. In the three parathyroid tumours with inactivating HRPT2 mutations parafibromin expression was not detectable, and in one of two cases with aberrantly sized parafibromin the protein was delocalized. Both high and low cyclin D1 levels were found among HRPT2-mutated and -unmutated tumours, suggesting that these events are not mutually exclusive in parathyroid tumour development. The presented data suggest that in the majority of benign parathyroid tumours the expression of parafibromin remains unaltered, while the loss of parafibromin expression is strongly indicative of gene inactivation through mutation of the HRPT2 gene.

Lack of mutations in the TSHr and Gsalpha genes in TSHr antibody negative Graves' disease.

The aim of this study was to investigate whether TSHr antibody negative Graves' disease is associated with somatic mutations in the TSHr or Gsalpha genes and whether histopathologically defined thyroid lesions, i.e., hyperfunctioning adenoma, non-functioning follicular adenomas, or nodules in toxic and non-toxic multinodular goiters are associated with such mutations. No mutations but three germ-line polymorphisms were found in patients with TSHr antibody negative Graves' disease. The three polymorphisms are expected to have no or only minor effects on the signaling properties, and is not associated with altered antigenecity imposed by such mutations. Two heterozygous somatic TSHr mutations were found in two hyperfunctioning adenomas and in two toxic multinodular goiters. The lack of TSHr and Gsalpha mutations in TSHr antibody negative Graves' disease patients indicates that such mutations are neither primary nor secondary events in this disease. The results also confirm that somatic gain-of-function TSHr mutations are present in hyperfunctioning follicular adenomas and goiters, but not in non-functioning thyroid lesions.

Intraductal serrated adenoma of the pancreas. A case report.

CASE REPORT: A 48-year-old male with known hypothyreosis consulted his physician for symptoms compatible with TIA (transient ischemic attacks). Computer tomography (CT) in December 2001 revealed an irregular, lobulated mass in the processus uncinatus of the pancreas head. A CT examination 14 months later revealed status quo. In July 2004, a new CT showed an increase in size of the expansive pancreatic mass. The patient was operated on in August 2004 with a preliminary diagnosis of incidentaloma of the pancreas. The pathological examination showed a 4 x 3.5 x 2.5 cm large tumour. Histology revealed an intraductal serrated adenoma. The epithelial fronds had sawtooth-like configurations. An area with early invasive carcinoma was found. The tumour had progressed slowly during the 2.7 years of surveillance. Serrated neoplasia in the duodenum may result in similar cases in the future.

KI-67 AND hTERT expression can aid in the distinction between malignant and benign pheochromocytoma and paraganglioma.

The clinical and histopathological distinction between benign and malignant pheochromocytomas and paragangliomas is difficult, and reliable diagnostic markers are lacking. Here we have evaluated the prognostic value of human telomerase reverse transcriptase (hTERT) gene expression detected by reverse transcription PCR (RT-PCR); telomerase activity (TA) measured by TRAP (telomeric repeat amplification protocol) assay; immunohistochemical staining for Ki-67/MIB-1; and the mRNA expression of matrix metalloproteinase (MMP)-2 and EMMPRIN (extracellular matrix metalloproteinase inducer) analyzed by in situ hybridization in 32 primary pheochromocytomas or abdominal paragangliomas. hTERT was expressed in 7/11 malignant tumors (defined as presence of metastasis and/or extensive local invasion) as compared with in 2/21 benign tumors. All of the benign tumors showed <1% proliferative activity, as measured by Ki-67/MIB-1 staining. In all three patients with malignant tumors who developed metastases and/or invasive local recurrence during follow-up, the tumors were positive for either hTERT expression or Ki-67/MIB-1 immunoreactivity. TA was not a significant discriminator between benign and malignant tumors, and the value of EMMPRIN and MMP-2 as predictive markers was limited. In conclusion, the findings imply that the combined use of Ki-67/MIB-1 and hTERT, in addition to histopathology, provides a highly specific tool to identify benign pheochromocytoma and abdominal paraganglioma cases that are not at risk of developing recurrent or metastatic disease.

The management of benign and malignant pheochromocytoma and abdominal paraganglioma.

AIMS: To report treatment and outcome in patients with malignant and benign pheochromocytoma and abdominal paraganglioma. METHODS: Review of clinical and therapeutic features in 85 patients with pheochromocytoma or abdominal paraganglioma between 1976 and 1999. RESULTS: Thirty-nine of 85 patients presented with symptoms other than classical paroxysmal attacks. Paragangliomas were more often malignant (7/15) than pheochromocytomas (7/70). No recurrences have occurred in 71 patients with tumours initially classified as benign after a median follow-up time of 144 months (range 7-287). Nine of 14 patients with tumours classified as malignant have developed metastasis and/or local recurrence. Treatment of malignant tumours with cyclophosphamide, vincristine and dacarbazine (CVD) improved or stabilised the disease in three of four patients. CONCLUSION: Life long follow-up of patients with benign pheochromocytoma is not necessary. Combination chemotherapy (CVD) is a valid option in the treatment of malignant pheochromocytomas and abdominal paragangliomas.