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Hepatocellular Carcinoma and Recurrence Rate: Comparison of Living and Deceased Liver Donor Transplantation by Michele Finotti in Open Access Journal of Biogeneric Science and Research

Introduction

Hepatocellular carcinoma (HCC) represents the 75-85% of primary liver tumors. Chronic liver disease, in particular cirrhosis, is the leading risk factor for HCC [1]. Liver Transplantation (LT) is an effective therapy for HCC, allowing an oncological resection of the tumor and a resolution of the underlying liver dysfunction. However, due to the shortage of liver grafts and a concomitant increase of candidates for LT, a longer waiting time for LT is occurring [2]. In patients affected by HCC, a longer waitlist is associated with a higher risk of drop out, especially due to tumor progression. In the last years, Living Donor Liver Transplantation (LDLT) has been evaluated as a viable option to Deceased Donor Liver Transplantation (DDLT) to reduce waitlist mortality and/or the risk of patient drop out.

With the increased experience in LDLT for patients with HCC, concerns have been raised about the outcome in terms of HCC recurrence and Overall Survival (OS) compared to DDLT. The aim of this paper is to summarize the available studies comparing DDLT versus LDLT in patients affected by HCC, especially in terms of HCC recurrence rate.

HCC Recurrence after LDLT

The correct patient selection and prioritization for LT are ongoing matters of debate in DDLT. Variables such as number, dimension and bio markers of HCC, especially AFP, have been proposed to select the patients with lower risk of HCC recurrence and the best OS after LT. The Milan criteria (a single tumor size of ≤5 cm or up to 3 tumors with sizes ≤3 cm in diameter with no macrovascular invasion) are widely apply to select HCC patients for LT [3-6]. However, different selection criteria have been proposed, such as utility models (based on radiologic morphology) biology models, or a combination of the two [7]. HCC recurrence is an essential variable also in the LDLT, and a debate has been raised about the HCC recurrence after LDLT compared to DDLT.

Some studies showed that LDLT was associated with a higher HCC recurrence rate, compared to DDLT [8-11]. Some features related to the LDLT procedure have been proposed as possible explanations.

In the LDLT the graft used is different compared to DDLT. The whole organ is usually used in the DDLT, while the right liver graft is mainly used in adult LDLT. Some studies suggested that the consequent liver regeneration after LDLT, with a rapid increase in growth factors and cytokines, might stimulate HCC recurrence. Furthermore, the small-for-size grafts have been associated with higher endothelial growth-factor expression and angiogenesis [12-16].

However, the implication of these factors in HCC recurrence is questioned [17]. A technical aspect has been suggested as possible further explanation of higher HCC recurrence in LDLT showed in some studies. In particular, in the recipient, the preservation of the native inferior vena cava, the longer hepatic artery and bile duct might be associated with insufficient tumor removal and HCC residue and dissemination.

Another variable introduced with the LDLT compared to DDLT is the waiting time list. In the LDLT the waiting time list is drastically reduced, with the potential to overcome the organ shortage, reducing the waitlist mortality and the risk of drop out due to HCC progression. For example, Bhangui et al. reported the waiting time for LDLT patients (2.8±2.4 months) was significantly shorter than DDLT (7.9±9 months; P<0.001), and some center reported a median of 44 days [18,19].

However, time in the waiting list is another important indirect selection criterion that can influence the HCC recurrence. During the waiting time, the patient is usually observed and, in some cases, treated with loco regional treatments, such as TACE or ablative techniques (MWA or RFA). The waitlist and the response to the loco regional treatments could show the patient with a more aggressive HCC pattern. In the LDLT this “test of time” is significantly reduced compared to DDLT, and the results of the higher HCC recurrence can be the consequence of the inclusion of patient with aggressive tumor [8, 10, 11, 20-24].

Last but not least, patients who underwent LDLT often exceeded the most common HCC inclusion criteria (Milan criteria, UCSF) and the criteria used for DDLT are not the same for LLDT. Most studies report an LDLT offered to a patient affected with a more advanced HCC, raising concern about the ethical aspect [25]. All these factors would predispose the LDLT to have a worse outcome in terms of OS, RFS and HCC recurrence. However, as previously reported, the data are inconsistent.

To date, few meta analysis comparing the HCC outcome after LDLT or DDLT are available. In 2012, Lian et al. evaluated 1310 patient affected by HCC underwent to LDLT or DDLT in seven studies. Six were retrospective cohort studies, one was a prospective study, none was randomized trial [20]. To note, the tumor-related baseline variables, such as the TNM stage, size, and number of tumors, tumor differentiation, microvascular invasion, MELD score, Child-Pugh class, percentage of patients beyond the Milan or UCSF criteria, and treatment before LT were comparable between groups in all studies. In the LDLT groups, a significantly shorter waiting period and cold ischemia time have been showed. At 1, 3 and 5 years the LDLT and DDLT recipients had similar OS rate with no significant heterogeneity among the studies, except for the 5-year survival rates (4 studies showed a statistically significant heterogeneity; P . 0.13, I2 . 47%). Similarly, the RFS at 1,3 and 5 years was similar between LDLT and DDLT with no significant heterogeneity among the studies. The HCC recurrence rate at 1,3 and 5 years showed a similar pattern, but varying degrees of heterogeneity were found in the studies comparisons at 1,3 and 5 years20.

An additional analysis was performed comparing LDLT and DDLT in patients with HCC Milan criteria in or out. At 1,3 and 5 year the OS and RFS were similar between the two groups within the Milan criteria, while the LDLT recipients had a greater 1-year recurrence rate than DDLT recipients (insufficient data were available to perform a 3- and 5-years comparison). In the patients beyond Milan criteria, the OR, RFS and recurrence rate were similar between DDLT and LDLT20.

In 2019, Zhang et al. published a meta-analysis selecting, with strict inclusion criteria, seven studies, reporting a significantly increased risk of HCC recurrence in the LDLT group compared to DDLT group (P = 0.01) [26]. Zhu et al. performed a meta-analysis comparing LDLT and DDLT in twenty-nine studies with 5376 HCC patients with an Intention to Treat analysis (ITT). At 1,3 and 5 year the OS, DFS and HCC recurrence were similar between the LDLT and DDLT groups. Furthermore, LDLT was associated with better 5-year intention-to-treat patient survival than DDLT (RR = 1.11, 95% CI = 1.01–1.22, P = 0.04) [27].

The inconsistent data reported by the previous meta-analyses can be explained by some bias associated with the studies. These meta analyses compared multiple studies that often have an extremely heterogeneous transplanted population. HCC staging system, selection criteria, pre-LT treatment, waitlist time, donor preservation, surgical technique, and post LT management are some of the most variables that contribute to increase the complexity of LDLT evaluation. Furthermore, the evaluation of the outcome starting not at the time of the LT but at the waitlist (ITT analyses) is another factor leading to different results among the studies.

Conclusion

Deeping in the studies that reported a higher HCC recurrence rate in LDLT compared to DDLT, most of them reported patients with higher levels of AFP, more tumors beyond Milan and/or UCSF criteria and micro vascular invasion. Furthermore, less pre-LT ablation therapy is used in patients treated with LDLT due to the shorter waiting time compared to DDLT. Thereby, the main reasons for a different outcome reported by some studies and higher HCC recurrence in LDLT compared to DDLT could not be related to the type of technique per se (LDLT or DDLT), but probably to the different patient’s selection.

Transplant benefit might be the correct way to evaluate the real outcome of LDLT compared to DDLT. Most of the studies evaluated only the post LT outcomes, without including the results for patients on the waitlist. In particular, a percentage of patients listed for DDLT will drop out from the waitlist due to tumor progression, while in the LDLT group with a shorter waiting time allows these patients with more aggressive HCC pattern to be transplanted, affecting the final outcome. With this consideration, probably the transplant survival benefit in the LDLT is not correctly evaluated compared to DDLT [20]. In the last years, studies with an ITT analysis (evaluating the outcome from the time of listing, and not from the time of LT), showed comparable results in terms of OS and HCC recurrence among LDLT and DDLT groups [28]. In particular, Goldaracena et al. showed a transplant benefit of LDLT compared to DDLT in an ITT analysis associated with a reduction in the drop out rate in the LDLT groups. Similar results were obtained by Wong et al. that performed a ITT and propensity score matching analysis of 375 patients with 5-year OS of 81.4% for LDLT versus 40.8% for DDLT.

In conclusion, LDLT was firstly associated with a higher HCC recurrence. In the last years, most studies showed similar results comparing LDLT to DDLT in terms of HCC recurrence and OS, especially at ITT analysis. To date, no randomized studies are available comparing LDLT to DDLT. The different outcome between LDLT and DDLT might be related more to the variables associate with the procedure (patient selection, HCC staging, waitlist, pre- and post-LT treatment) than the procedure itself.

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Handgrip Strength and Vertical Jump and their Relationship with Body Fat in Hong Kong Chinese Children and Adolescents by Clare Chung-Wah Yu* in Open Access Journal of Biogeneric Science and Research

Abstract

Aim: To examine the associations of handgrip strength and vertical jump with gender, pubertal status and body composition, and establish normal reference values of handgrip strength and vertical jump of Hong Kong Chinese children and adolescents. Methods: This study included 1154 children and adolescents aged between 8 and 17 years, who participated in a territory-wide cohort study. Data of anthropometry, pubertal status handgrip strength and vertical jump were collected. Percentile curves of handgrip strength and vertical jump were constructed using the LMS method. General linear model was used to evaluate the effects of age, sex, pubertal stage, body size, body fat and the possible 2-way interactions on handgrip strength and vertical jump. Results: According to the international BMI cutoffs, the prevalence rate of overweight or obesity (20.7%) in our cohort of children was similar to that obtained from previous local report. General linear model revealed that handgrip strength and vertical jump increased with increasing age, and boys were significantly stronger than girls after aged 12 year or older. Among overweight/ obese children, those with high body fat had significantly lower handgrip strength than those with low body fat. A full model including age, sex, BMI z score, body fat z score and age*sex interaction explained 67.8% and 60.1% of the variance of handgrip strength and vertical jump respectively. Handgrip strength and vertical jump was positively associated with age, male sex and BMI z score, but was negatively associated with body fat z score. Conclusions: Classifying children’s weight status by BMI cutoffs, additional information on children’s body composition should also be considered. Reference values for handgrip strength and vertical jump are established for Hong Kong Chinese children and adolescents aged 8 to 17 years.

Keywords: Bioelectrical impedance; normative fitness values; body fatness, muscular strength.

Introduction

Childhood obesity is the most serious global public health challenges of the 21st century [1]. It is reaching alarming proportions in many countries, in just 40 years the number of schoolchildren with obesity has risen more than 10-fold, from 11 million to 124 million [2]. Hong Kong, as one of the most urbanized cities in China, cannot escape from this global epidemic and the overweight prevalence in Hong Kong children was 20.4% [3]. Childhood obesity undermines the physical, social and psychological well-being of children [4,5]. One of the most possible explanations for this global epidemic consists in the decline of fitness, produced primarily by decreases in physical fitness [6]. Obesity and physical fitness are two interrelated factors and changes in one may cause changes in the other [7]. A recent longitudinal study confirmed a strong reciprocal relationship between physical fitness and obesity in Hong Kong children [8].

Muscular strength, as an important component of physical fitness, has been increasingly recognized in the pathogenesis and prevention of disease [9,10]. Some evidence suggests that muscular strength is inversely and independently associated with cardiovascular and all-cause mortality events in both healthy adults and clinical populations [9,11]. Muscular strength is also inversely associated with age-related weight gain, risk of hypertension and prevalence of metabolic syndrome [9,12,13]. Similar associations have also been reported in children [14-16]. This phenomenon may be partly explained by the fact that muscle tissue is an important organ influencing metabolism and can directly affect risk of metabolic diseases [17]. However, muscular strength changes with growth, and therefore, age-specific values obtained in healthy children should serve as a reference for with acute and chronic conditions using muscle strength for diagnostic purposes, follow-up, or to assess the efficacy of therapy [18]. For population-based studies, it is essential that the techniques involved should be simple and quick, so that such studies do not have follow laboratory conditions strictly. Two tests which satisfy these conditions are the handgrip and the vertical jump.

The vertical jump, a measure of lower body power, and handgrip strength, a measure of upper-limbs muscular strength, have both been acknowledged as being strong measures of one’s health, and recommended for potential use in school fitness testing which in line with recent recommendations [19]. Moreover, handgrip strength can be used as a tool to have a rapid indication of someone’s general muscle strength [20]. Meanwhile, the vertical jump is a simple method to calculate peak leg power which is a component of test batteries used to assess physical ability [21]. Both measurements are inexpensive, easy and reliable method of muscular strength assessment [16,22,23].

In recent studies, handgrip strength is reported to be differed significantly across ethnic groups, with lower handgrip strength associated with higher prevalence of type 2 diabetes mellitus [24,25]. This highlights the importance of ethnic-specific reference standards for screening and monitoring purposes. Normative data for handgrip strength and/or vertical jump have been developed for children in different countries [22,26-31]. Only one recent publication from China mainland reported the reference data of the muscular strength [32]. However, the association between muscular strength and the Anthropometric measurements was note addressed in this report. Among the published reports, few explored this association [22,26,33]. Furthermore, muscular strength is correlated with BMI and, particularly, muscle mass [34]. However, this could simply reflect the gender difference because of the effect of sex steroid hormones [35,36]. In fact, scientific evidence suggests that Asians have different associations between weight status, body composition and health risks than do European populations. For example, in some Asian populations a specific BMI reflects a higher percentage of body fat than in white or European populations [37]. The association of muscular strength, weight status, and body composition in Hong Kong Chinese children and adolescents is not known. In this study, we aimed to examine the associations of handgrip strength and vertical jump with gender, anthropometric variables and body composition. We also establish normal reference values for handgrip strength and vertical jump for Hong Kong Chinese children.

Materials & Methods

Design

This cross-sectional study measured grip strength in a cohort of healthy children and adolescents. The data were used to generate normative values for handgrip strength and vertical jump.

Subjects

This was a part of a territory-wide cohort study on 24-h ambulatory blood pressure of Chinese children and adolescents conducted in 2011 to 2012 [37]. A two-stage cluster sampling method was used. Data from the Education Bureau, the government of the Hong Kong Special Administrative Region, were used to compile a sampling frame of all schools in Hong Kong. In the first stage, one primary school and one secondary school were randomly selected from each of the 18 Districts in Hong Kong. In the second stage, students were selected randomly by computer generated numbers and were invited to join the study. Details were mentioned in our previous publication [37]. An information sheet explaining the purpose and procedure of the study was given to each child and his/her parents. All children completed a validated self-reported Pubertal Development Scale [38]. Informed assent was obtained from the children and consent from their parents before the measurements. This study was approved by the Joint Chinese University of Hong Kong and New Territories East Cluster Clinical Research Ethics Committee. (CRE-2009.540)

Procedures

Anthropometric Measurements

A team of three trained research staff visited each selected school on a pre-arranged date for data collection. Standing height without shoes was measured using a stadiometer (seca 217, UK) to the nearest 0.1 cm. Body weight and percentage body fat were measured with light clothing using foot-to-foot bio-electrical impedance by a validated electronic body composition analyzer (Model BF-522, Tanita, Japan) [39,40]. Children emptied their bladder before the measurement. They were asked to stand barefoot on the metal sole plates of the machine, and gender and height details were entered manually into the system. Body weight and percentage body fat, estimated using the standard built in prediction equations for children, were displayed on the machine and printed out. Body mass index was converted to z score using local normal reference [41]. Children were classified into underweight, normal weight, overweight or obese based on their body mass index (BMI) using the International Obesity Task Force cut-offs [42]. Percentage body fat was also converted to z score using local normal reference [40]. Children were categorized into high and low body fat groups using the 85th percentile of the local reference as the cutoff [40].

Handgrip Strength

Handgrip strength was done by an assessor with background of Sports Science and Physical Education. Each subject was given a brief demonstration and verbal instructions for the handgrip strength test using the Takei T.K.K.5001 GRIP-A handgrip dynamometer (Takei Scientific Instruments Co. Ltd, Tokyo, Japan). The dynamometer was adjusted according to the child’s hand size. The test was done in the standing position, with the wrist in the neutral position and the elbow extended. Subjects were given verbal encouragement to ‘squeeze as hard as possible’ and apply maximal effort for at least 2 seconds. Two trials were allowed in the dominant arm and the highest score recorded as peak grip strength (kg) [43]. Limb dominance was determined by asking the children whether they are left-handed or right-handed.

Vertical Jump

Vertical jump skill was assessed by means of the process-oriented method proposed in the Western Australian Teachers Resources [Department of Education Western Australia (EDWA), 2013] done by two trained assessors. A demonstration of how to jump was provided to each subject and he/she was allowed to practice the jump until meeting the jump criteria, which usually takes two jumps. The jump was a countermovement jump with the use of arms. The jump began from a standing position, keeping the feet flat on the ground, with the preferred shoulder adjacent to a wall. Standing reach height was obtained by asking the subject to reach up with his/her hand as high as possible to touch the wall. After that, the child bent knees to about a 90 degree angle while moving their arms back in a winged position; then thrusted forward and upward and touched the wall at the highest point of the jump. The results of the jump was measured and recorded on a centimeter scale (cm).Vertical jump score was calculated as the difference in distance between the standing reach height and the jumping height. Two jumps using the correct technique were allowed for each subject and the best score was retained for analysis [30].

Statistical Analysis

Statistical analyses were performed using PASW Statistics 21.0 (IBM SPSS Inc., New York, USA). Percentile curves were constructed using LMS method [44]. The LMS method estimates the measurement centiles in terms of three age-sex-specific cubic spline curves: the L curve (Box-Cox power to transform the data that follow a Normal distribution), M curve (median) and S curve (coefficient of variation). In brief, if Y(t) denotes an independent positive data (e.g. handgrip) at age t, the distribution of Y(t) can be summarized by a normally distributed SD score (Z) as follows:

Once the L(t), M(t), and S(t) have been estimated for each parameter at age t, the 100α th centile at t age could be derived from

C100α(t) = M(t) [1 + L(t)S(t)Zα]1/L(t)

where Zα is the α centile of the Normal distribution (for example for the 95th centile, α = 0.95 and Zα = 1.65). The LMS program (version 12.43, Institute of Child Health, London, UK) was employed to fit the data.

The Q-Q test was used to assess the normality of the anthropometric, handgrip and vertical jump variables (p > 0.05). Estimated marginal means for handgrip strength and vertical jump were generated and age and gender interactions were determined using two-way analysis of covariance (ANCOVA) with mass and stature as covariates. General linear model was used to evaluate the effects of age, sex, pubertal stage, body size, body fat and the possible 2-way interactions on handgrip strength and vertical jump. Significance level was set at p <0.05.

Sample Size Calculation

Assuming both handgrip strength and vertical jump are normally distributed among each age and gender, sample size was calculated in terms of the standard deviation of the 100th centile (SDc100) and the age- and gender-specific SD described by Healy.

To find out the age and gender-specific means and SDs for sample size calculation, pilot data were collected from 200 healthy children aged 8-17 years. The required sample sizes for each gender and age group to obtain an extreme centile, i.e. the 97th centile, with an error of 4% were listed in supplementary table. The estimated total number of subjects required for handgrip strength and vertical jump are 944 and 794, respectively (S1 Table).

Results

Subject Characteristics

A total of 1175 subjects aged 8-17 years from 32 schools (14 primary and 18 secondary schools) participated in the study. Twenty-one students were excluded due to incomplete data. The remaining 1154 subjects (49.3%, 569 boys) were included in the final analysis. Sex- and age-specific characteristics are shown in (Table 1). No subjects had any previous history of metabolic disease, and no participants were taking any type of medication. The mean ± SD age for boys and girls were 12.6y ± 2.7 (range: 8.2–17.9y) and 12.7y ± 2.8 (range: 8.1–17.9y) respectively.

According to the BMI cutoffs from the International Obesity Task Force (IOTF) [42], 13.9% (160/1154), 65.4% (755/1154), 15.1% (174/1154) and 5.6% (65/1154) of subjects were classified as underweight, normal weight, overweight and obese, respectively. The prevalence rate of overweight or obesity (20.7%) in our cohort of children was similar to that (20.4%) obtained from the previous Hong Kong Student Health Service Survey in 2008/2009 [3]. A total of 235 (20.4%) subjects were classified as having high percentage body fat, of whom 184 were overweight/obese and 51 were normal weight by IOTF definitions.

Handgrip Strength

The smoothed age-specific centile curves for boys and girls are shown in (Figure 1). General linear model revealed that handgrip strength was positively associated with age (F=1763, p <0.001), male sex (F=96.8, p <0.001) and the age*sex interaction (F=159, p <0.001). The age- and sex-specific error bar chart demonstrated that the sex difference was significant for subjects aged 13 years or older. (Figure 2) The pubertal stage*sex interaction was also significant (F=22.5, p <0.001). Significant sex differences were observed in subjects of pubertal stage III or later. (Figure 3)

BMI z score was positively associated with handgrip strength (F=12.9, p <0.001). The interaction between BMI z score and body fat z score was also significant (F=12.9, p <0.001). Further analysis revealed that among overweight/obese children, those with high body fat had significantly lower handgrip strength than those with low body fat [estimated marginal mean (SE): 18.0kg (0.5) c.f. 20.3kg (1.0), p = 0.039].

A full model including age, sex, BMI z score, body fat z score and age*sex interaction explained 67.8% of the variance of handgrip strength. The model demonstrated that handgrip strength was positively associated with age, male sex and BMI z score, but was negatively associated with body fat z score. (Table 2) The BMI z score*body fat z score interaction became insignificant (p = 0.83) in the fully adjusted model.

Figure 4: Smoothed centiles curves of vertical jump for Hong Kong Chinese Children aged 8 to 17 years.

Figure 5: Error bar charts of vertical jump by age and sex *indicates significant sex difference, p <0.05.

Figure 6: Error bar charts of vertical jump by pubertal stage and sex *indicates significant sex difference, p <0.05.

Table 2: Significant correlates of handgrip strength and vertical jump

Vertical Jump

The smoothed age-specific centile curves for boys and girls are shown in (Figure 4). General linear model revealed that vertical jump was positively associated with age (F=800, p <0.001), male sex (F=116, p <0.001) and the age*sex interaction (F=229, p <0.001). The age- and sex-specific error bar chart demonstrated that the sex difference was significant for subjects aged 12 years or older. (Figure 5) The pubertal stage*sex interaction was also significant (F=36.0, p <0.001). Significant sex differences were observed in subjects of pubertal stage II or later. (Figure 6) Vertical jump was positively associated with BMI z score (F=9.5, p = 0.002) but negatively associated with body fat z score (F=16.7, p <0.001). The interaction between BMI z score and body fat z score was not significant (F=2.1, p = 0.15).

A full model that included the same list of factors as those correlated with handgrip strength, i.e. age, sex, BMI z score, body fat z score and age*sex interaction, explained 60.1% of the variance of vertical jump. (Table 2) The model demonstrated that vertical jump was positively associated with age, male sex and BMI z score, but was negatively associated with body fat z score. (Table 2)

Discussion

We established age and gender specific normative values of handgrip strength and vertical jump in Hong Kong Chinese children. Although another report has provided normative data previously [32], the subgroups according to age and gender only mean and standard deviation were shown in most studies [46]. Handgrip strength and vertical jump increase with age in both genders, with boys stronger than girls particularly after the age of 12 years.

Similar to previous investigations, maximal handgrip strength was measured in ACFIES [43], EUROFIT [47] and CHMS [48], while the maximal jump height was reported in a sample of English school children [30]. Our results are close to the Britain children in both handgrip strength [43] and vertical jump [30]. As expected, our result was very different from those of CHMS, performed in Canadian children with handgrip strength between 24 and 89 kg in boys and between 21 and 56 kg in girls aged 8–19 years old [48]. Our finding indicates the importance of having a reference value for different populations.

In regard of the gender difference, body composition is largely due to the action of sex steroid hormones [35], probably leading to a difference in muscular strength. Nevertheless in boys, growth hormone and testosterone have more effects on muscular strength than in girls [49]. In our study, age, gender, BMI, and body fat were important predictors of handgrip strength and vertical jump, which were in line with previous findings from other countries [22,26-31]. There were only a few reports on the associations between handgrip strength and weight status [22,26]. Our finding was similar to these studies [22,26] that handgrip strength increased with weight status, as reflected by BMI. Importantly, our further analysis showed that overweight and obese children with high body fat had significantly lower handgrip strength compared to their overweight and obese peers with low body fat. Our study also found that vertical jump was positively associated with BMI but negatively associated with body fat. Children who were heavier, or being classified into overweight and obese categories, may have increased or no increased lean muscle mass in addition to fat [50], that the increased lean muscle mass may contributes to the better performance of handgrip strength and vertical jump.

BMI, as a measure of weight adjusted for height, correlates with body fat and with cardiovascular risk factors in children and adolescents, and a high value also predicts future adiposity, morbidity and death [51], Although BMI is the most widely used surrogate measure for screening for obesity, it cannot distinguish between fat mass and lean muscle mass. Thus, individuals with increased muscle mass may have increased BMI and although classifying as overweight their body fat level may still within normal range and they have low risk for cardiovascular risk factors. In our sample, about 20% of the children we tested fell into this category. It highlights the importance that when classifying children’s weight status by BMI cutoffs, additional information on children’s body composition such as percentage body fat, or fat-free mass should also be considered.

This study has some limitations. Our findings should be interpreted with caution as it is a cross-sectional study, it cannot demonstrate cause-and-effect. A longitudinal study is required to assess the longer-term health outcomes which may be associated with handgrip strength and vertical jump. Second, we utilized bioelectrical impedance as a measure of percentage of body fat and this technique is not without its limitations in children. Poor validity and measurement error have been reported [52], although, previous work in the same population has shown it is an adequate surrogate for percentage of body fat when compared to dual x-ray absorptiometry [53].

Advantages of this study include – huge sample size and pretty representative of the territory. It is noteworthy considering handgrip strength and vertical jump as a physical fitness test battery for the schoolchildren because it is more likely to be implemented in normal physical education settings.

Conclusion

The reported data enables health professionals to identify children and adolescents with poor strength according to age, gender and body composition, and to evaluate the effects of therapeutic interventions. Reference values for handgrip strength and vertical jump are provided for Hong Kong Chinese children and adolescents aged 8 to 17 years.

Acknowledgments

We would like to express our gratuities to Mr. Tsang Fan Pong for his help on data collection. We thank the school principals, teachers, parents and students for their support and help for this study. The project is supported by the Health and Health Service Research Fund (they now renamed Health and Medical Research Fund since December 2011) [Ref no: 08090141], Food and Health Bureau, Hong Kong SAR Government, Peoples’ Republic of China.

Authors’ Contributions

CCWY led the study conception and designed the study, participated in the coordination and execution of the study, and drafting, writing, and revising of the manuscript; HKS participated in coordination and execution of the study and drafting, and revising of the manuscript; CTA contributed to the acquisition of data analysis and interpretation of data; AMM, AML and RYTS participated in conceptualizing and designing the study, and revising of the manuscript. All authors have read and approved the final version of the manuscript, and agree with the order of presentation of the authors.

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Plant pathology Articles in JBGSR

Citrus Melanose and Quality Degradation of Fruit by this Disease: A Review by Fazal ur Rehman* in Open Access Journal of Biogeneric Science and Research (JBGSR)

Abstract

Citrus melanose, caused by Diaporthe citri Wolf, is a worldwide fungal disease that is prevalent in many citrus growing areas of Pakistan as well as in the world. Out of two stages of Diaporthe citri Wolf i.e. perfect stage and imperfect stage, the perfect stage causes the citrus melanose disease in many citrus species. Extended rainfall with warm environmental conditions favours the disease initiation and development. This disease result in degradation of fruit quality that results in reduction of marketing and export values of fruit. Proper pruning and use of copper based fungicides are advisable for the treatment of citrus melanose. Plantation of susceptible varieties should be avoided in high rainfall areas. In this article, history of citrus melanose, symptoms of disease, pathogen, epidemiology of disease, quality degradation of fruit and integrated management practices has been discused.

Keywords: Diaporthe citri Wolf; Mud cake Melanose: Teleomorph; Anamorph; Copper-based fungicides

History of Citrus Melanose

The perfect and imperfect stages of Diaporthe citri Wolf cause two different citrus diseases with perfect stage causing citrus Melanose and imperfect stage causing Phomopsis stem-end rot Swingle and Webber firstly described citrus melanose disease near Citra, Floridain 1892 [1]. In 1912, Floyd and Stevens published with evidences that stem-end rot and melanose were caused by the same fungus. At that time they were unable to produce the isolates of fungus from the infected leaves showing the symptoms of citrus melanose on inoculation. The comparison of P.citri and D.citri was made by Fawcetin1932 [2].

In 1940, Ruchle and Kuntz demonstrated that the spores of both P.citri and D.citri had anability to cause the symptoms of citrus melanose [3].Initialy, D.citri was given the name of D.melusaea. But on later, D.citri was given the priority over D.melusaea by Fisher in1972 [3].P.cytosporela was also used for P.citri and it was also proposed that P.cytosporella should be used in place of P.citri. But this proposal was never adopted. The genus Diaporthe/ Phemopsis was place dinphylum Ascomycota with class and order as Sordariomycetes and Diaporthales respectively [4][5]. Four species were found to be different from F.valgure based on their molecular, morphological and cultural data [6]. According to the studies of Gome they have a wide range of host and have ability to form colony on the host that may be diseased plant or dead plant [7]. It was recognized as them most actively transmitting pathogen of citrus.

Symptoms of the Disease

The citrus melanose disease, which is superficial and has no effects on internal quality of fruit but cause the external quality degradation, produces its symptoms on fruits, leaves and small twigs. In case of foliage, the symptoms appear with the formation of small water-soaked speaks that on later become centrally depressed and surrounded by undepressed translucent yellow arcas [8]. After a week, the exudation of gummy substances occurs due to the rapture of leaf cuticle that on later become brown in colour and hardened. These areas have sandpaper- like texture. In case of severe infection, the leaves become pale green to yelow.

The infections may occur on the green twigs .In case of severe infection, the defoliation Occurs that induces the twigs dieback [9].On fruit, scattered speaks are formed in case of high infestation. The infection on young fruits may causet the premature abscission of fruit. In case of late infection, flater pustules are produced. In severe cases, firstly the formation of solid patches of blemish and then cracking of fruit surface occurs, this condition is called mud cake melanose [10]. On the fruit surface, there is also formation of tear-streaks and water droplets patern. The formation of star melanose occurs by the late application of copper based fungicides on the diseased portion of plant because of formation of dark and corky lesions, more prominent then normal and are in star shape [11].

Pathogen

The Teleomorph of fungal pathogen is Diaporthe citri Wolf and anamorph is Phomopsis citri Fawc. Mostly leaves and fruits are infected by Diaporthe citri Wolfand Phemopsis citri attacks on stem and causes the stem-end rot [11]. In citrus, fungal pathogen also acts as saprophyte for the infestation on dead twigs. The hyline ascospores of Diaporthe citri produced in each cell are slightly constructed at septum and are in the form of oil droplets. Ascospores are produced in flask shape perithecium. The average size of ascospores is 12.85 microns by 3.85 microns with the perithecium size on average is 500 microns by 50 microns at beak and the base is of diameter125to160microns[12].

The perithecium are projected outward from the stem. The ascospores are ejected from the perithecium forcefully and then they become air borne and spread out over the large distance [1]. On culture media, fan-shaped, white colored mycelia are produced [13]. When spores get substrates, they produce septate hyphae [12]. In disease cycle, the most important state of fungal pathogen is its conidial state. Two types of conidia i.e. alpha conidia and beta conidia are produced by the pathogen. The primary source of spread of fungal pathogen and with the size range from 5-9 microns by 2.5-4 microns are alpha conidia tha are hyaline and single celled. The beta conidia that are slender-rod shaped and hook-like at the end, are spread with great efficiency during rainy condition over nearby substrate and from mycelium [12].

Epidemiology of Disease

The attack of fungal pathogen causing citrus melanose is during the immature stage of foliage, fruits and twigs. Because when the tissues are matured, they mostly become more resistant to the attack of pathogen. Therefore, the susceptibility period for the attack of pathogen over the plant is the period of first 8 to9 weeks after their formation. The formation of symptoms of melanose can vary according to the level and the time of infection. The flyspeck melanose symptoms are produced at the end stage of susceptibility period [14].

As the discharge of ascospores is forcefully and they can be dispersed over the long distance, therefore, the inoculums of fungal pathogen can be spread over the large distance. That's why, there is an increase in the cases of infection be cause of wide spread of large number of ascospores [15]. The disease wil be initiated when the ascospores or conidia of Diaporthe stage or Phemopsis stage land on the surface of plant tisue. The favourable environmental conditions for the infection include dry conditions and the temperature ranging between 17 to 35°C. Above or below this temperature the spores mostly die and the chances of infection reduced [16].

About 10 to 24 hours of moisture are required for the germination of spores but approximately 36 to 48 hours are required for the germination as well as the formation of germ tube that directly penetrates into the tissue of cuticle layer [16]. Then the infection of citrus Melanose pathogen starts.

Quality Degradation of Fruit

Melanose is a serious disease of citrus plant which results in small spots on the surface of citrus fruit. These spots increase in number as the disease reaches its serious stage. These spots cover the entire surface of fruit and reduce the aesthetic quality of fruit. When the disease affects the young fruit, they remain small in size and fall of before reaching maturation stage. In this way, it also results in quality reduction. Atadvanced stage of disease, the spots produced are more solid and the surface of fruit becomes cracked. The fruit affected by melanose disease is not preferable for marketing and export purpose due to quality degradation and thus the market value and export of citrus reduced because the quality of citrus fruit is reduced. However, the disease does not affect the pulp so the fruit for processing purpose is not generally affected but the marketing and export of the diseased fruit is reduced due to the quality degradation and this may cause serious economic losses.

Melanose is a severe disease of citrus in most citrus producing countries and mostly the grape fruit and lemon are affected by this disease [17]. The quality and value of disease afected fruit is reduced and it is not accepted by consumers as a fresh fruit and marketing value is also reduced. The diseased fruit is used as low grade fruit for processing purposes. Farmers and exporters are economically affected due to value loss of citrus fruit by melanose disease.

Integrated management practices

Although, there is no any impact of disease over the yield, so the juice and processing also Remains unaffected But the quality of the fruit for marketing and export purpose is adversely afected. So following integrated management practices should be done for the control of quality losses and fruit degradation by citrus melanose. a. Dead branches should be prune out periodicaly. The pruning will help to increase the circulation of air through canopy of plant to keep it dry and the sites for the survival of saprophytic pathogen will also be reduced. It will also enhance the effective penetration of fungicides through for foliage [18]. b. The fungicides should also be applied for the the disease control. Mostly the application of Copper-based fungicides is done worldwide. The symptoms of star melanose can also be produced over the application of Copper-based fungicides that are not the actual symptoms of this disease [19]. c. The plantation of susceptible varieties including sweet orange, grape fruit and pomelo should be avoided in high rainfall areas [20]. d. Other management practices should be done including plantation of citrus in low rainfall and sunny areas, proper sanitation should be done, and intercropping should be avoided.

Conclusion

The symptoms, signs, signals of fever are only seen at the presence of fever. During cancer, the symptom, signs, and signals of cancer are shown every time. A patient having cancer and fever at the same time, symptoms, signs, and signals of both cancer and fever are shown every time. A symptom of cancer never becomes a symptom of fever or a symptom of fever can never become a symptom of cancer.

If fever is a symptom, one symptom has no ability to make other symptoms

Fever makes numerous symptoms, signals, and actions, etc.

If fever is a symptom we cannot call a person as a fever patient

If fever is a symptom no treatment is required to reduce fever. Treatment is required only for disease and its cause. Our immune system never increase elevated the symptom in the hypothalamus.

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Predicting Abnormal Medical Tests, on a Symptom-by-Symptom Basis, Using the Large Analytic Bayesian System (Labs): A Bayesian Solution Applied to Diagnostic Test Management by Nelson Hendler* in Open Access Journal of Biogeneric Science and Research

Abstract

Earlier research described the development of a Large Analytic Bayesian System (LABS) which uses Bayesian analytics to list, on a symptom-by-symptom basis, the likelihood of having abnormal medical testing from a list of possible medical tests associated with a symptom, or cluster of symptoms. LABS produces a rank ordered list of medical tests, comparing the symptom(s) with the frequency and severity of abnormal medical tests. Seventy-eight medical charts with evaluations including all pertinent medical tests, and a completed Diagnostic Paradigm with 2008 possible symptoms were reviewed. On a symptom-by-symptom basis, medical test results in the chart were compiled using the Large Analytic Bayesian System (LABS) and created a rank ordered list of abnormal medical tests from a list of possible 107 medical tests. This resulted in a 2008 by 107 matrix, which was analyzed by the use of a program called the Diagnostic Test Manager. The results clearly demonstrated that physiological testing, such as root blocks, facet blocks and provocative discograms had nearly double the frequency of abnormalities compared to anatomical tests, such as X-ray, CT scans and MRIs in the same patient. This evidence-based approach will help physicians reduce the use of unnecessary tests, improve patient care, and reduces medical costs.

Introduction

The medical literature abounds with articles which report a misdiagnosis rate ranging from 35% to 67% for a variety of disorders, including pneumonia, and heart disease, low back and neck pain, and headache (25, 4, 5, 15). Primary care physicians missed 68 out of 190 diagnoses (35%) according to a 2013 study, with pneumonia and congestive heart failure the most commonly missed (1). The two leading causes for misdiagnosis were ordering the wrong diagnostic tests (57%), and faulty history taking (56%) [1].

Diagnostic errors lead to permanent damage or death for as many as 160,000 patients each year, according to researchers at Johns Hopkins University [1]. Not only are diagnostic problems more common than other medical mistakes-and more likely to harm patients-but they're also the leading cause of malpractice claims, accounting for 35% of nearly $39 billion in payouts in the U.S. from 1986 to 2010, measured in 2011 dollars, according to Johns Hopkins [1].

Misdiagnoses of some diseases range from 71% to 97% (RSD, electrical injuries, and fibromyalgia) [2-5]. This high rate of misdiagnosis is costly to insurance companies and other payers, as well as to employers of chronic pain patients, where 13% of the workforce loose productive time, estimated to cost industry $61 billion a year [6]. Furthermore, misdiagnosis creates protracted treatment and psychological problems for the patients themselves. Of all the misdiagnosed disorders, the most prevalent problem is chronic pain, which, according to the Academy of Pain Medicine, accounts for 100,000,000 patients in the United States alone [7]. The annual cost of health care for pain ranges from $560 billion to $635 billion (in 2010 dollars) in the United States, which includes the medical costs of pain care and the economic costs, related to disability, lost wages and productivity [7].

Insurance companies and physicians could improve patient care if they had a mechanism which would address the two-leading cause of misdiagnosis: faulty history taking and ordering the wrong medical tests. [1]. Therefore, a valuable tool for any health care system would be a questionnaire which could provide accurate diagnoses, and, based on the accurate diagnoses, predict the outcome of an expensive medical laboratory tests, to allow physicians to determine, using “evidence-based medicine,” which tests would be diagnostic and which test would be of no value. This concept is best exemplified by the Ottawa Ankle Rules, and Ottawa Knee Rules, developed in Canadian emergency rooms. They developed a questionnaire, using “predictive analytic techniques,” which could predict which patient would or would not have abnormal ankle or knee X-rays. When the use of the Ottawa Ankle and Knee Rules was applied in emergency rooms, for the selection or denial of patients for ankle or knee X-rays, it decreased ankle and knee radiography up to 26 percent, with cost savings of up to $50,000,000 per year [8-11]. This significant savings was just in the city of Ottawa, and just for ankle and knee pain. If these techniques were applied to other cities and other conditions, the extrapolated savings would be billions of dollars a year.

Later research by the group from Ottawa focuses demonstrated that expert system evaluations, based on predictive analytic research, which were more accurate in predicting the results of cervical spine X-rays, and CT, than unstructured physician judgment [12-14]. These same “predictive analytic” techniques allowed physicians from Mensana Clinic and Johns Hopkins Hospital to develop a Pain Validity Test which could predict with 95% accuracy which patient would have moderate or severe abnormalities on medical testing, and predict, with 85% to 100% accuracy, who would have no abnormalities, or only mild ones [15-18].

Past research reports from Mensana Clinic indicate that 40% to 67% of chronic pain patients involved in litigation are misdiagnosed [19,20]. When evaluating complex regional pain syndrome, (CRPS), formerly called reflex sympathetic dystrophy (RSD), Hendler found that 71% of the patients, and Dellon found that 80% of the patients, who were told they had only CRPS I, actually had nerve entrapment syndromes (2,3). These errors in diagnoses are costly to the patient and the insurance industry alike, since they prolong or result in inappropriate treatment.

Most physicians use an MRI, which is test used to detect anatomical abnormalities, to determine disc damage in the spine. However, the medical literature shows that the MRI has a 28% false positive rate, and a 78% false negative rate for detecting spinal disc damage, compared to a provocative discogram. [21,22]. Therefore, the physicians from Mensana Clinic and Johns Hopkins Hospital supplemented the anatomical MRI findings with physiological testing, such as provocative discograms, facet blocks, and root blocks, which are typically not used by most physicians. Donlin Long, MD, PhD, former chairman of neurosurgery at Johns Hopkins Hospital, used these physiological tests in a group of 70 patients who previously had normal MRI, CT, and X-ray (anatomical tests), and were told by their treating doctors that nothing more could be done to help these patients. When properly diagnosed, 95% of the patients required physiological testing, and 63% required surgery [23]. Using these techniques, 93% of the patients receiving good to excellent relief after proper diagnosis and correct surgery [23]. Additionally, Johns Hopkins Hospital saved 54% a year on its workers’ compensation expenses, with the simple expedient of having all of Johns Hopkins Hospital employees injured on the job seeing only Johns Hopkins Hospital doctors [24], instead of physicians in the local community, where the misdiagnosis rate was 40-71% [2, 19,20].

The Maryland Clinical Diagnostics (MCD) Diagnostic Paradigm is a questionnaire, containing 72 multi-part questions, with 2 to 74 possible responses to a question, for a total of 2008 possible answers. These questions duplicate the questions asked during an evaluation process for a patient with chronic pain, by former faculty members from Johns Hopkins University School of Medicine. Asking these questions and recording answers to these questions can take a physician 50 to 60 minutes to complete. The test is then computer scored and interpreted. The MCD Diagnostic Paradigm questionnaire is administered over the Internet (www.MarylandClinicalDiagnostics.com).

Each answer is scored on a spread sheet. The Maryland Clinical Diagnostic Paradigm was designed to detect 60 diagnoses and 44 differential diagnoses most commonly seen after workers’ compensation and auto accident (post-traumatic) injuries. In a published research report, the MCD Diagnostic Paradigm accurately replicated the diagnoses made by staff members of Johns Hopkins Hospital staff members 96.2 % of the time [25]. The validity of this test is borne out by outcome studies which report that the diagnoses from the Diagnostic Paradigm and Treatment Algorithm can predict intra-operative findings with 100% accuracy [26].

Historically, physicians take a careful history, derive a diagnosis and differential diagnosis, and use medical testing to confirm or reject the various diagnoses. However, a shift in the medical evaluation paradigm has occurred. Physicians are now relying more on medical testing rather than a careful history. In fact, the time a physician spends with patients averaged 11 minutes, with the patient speaking for about 4 minutes of the 11 minutes [27] Therefore, this increasingly prevalent process, which we deplore, follows the format of first getting a list of the symptoms, then getting medical testing pertinent to the symptoms to establish or eliminate diagnoses, and finally reaching a diagnosis, i.e., using medical testing to make a diagnosis. Unfortunately, with an inadequate history, the chance of an erroneous diagnosis increases, leading to the selection of incorrect medical testing. The technique we describe augments the latter paradigm of truncated history taking, and provides evidence-based medicine for selecting the correct medical test, to supplement inadequate history taking.

Methods

For decades, traditional database application design approaches were attempted to classify and organize large amounts of available medical data. Our Bayesian approach offers a solution to a dilemma faced when the authors attempted to categorize and rank this statistically congruent data group of 660,000,000 data points presented for analysis. This data group is simply too large and complex for a standard database application. To manage that amount of data would require terabytes of dynamic storage, thus making a Bayesian type solution for even the largest of computing platforms impractical. A new application, titled Diagnostic Test Manager, is the result of recent developments in science and machine intelligence, which involve computer aided process optimization. This new approach allows Diagnostic Test Manager or DRM, to be hosted on a typical PC desktop computer with rapid, almost instant, response and analysis.

For this evidentiary predictive application, the authors randomly selected 78 completed Mensana Clinic medical charts as a starting point during the software application development and functional demonstration phase. The completed medical charts included a patient symptom questionnaire (Diagnostic Paradigm) with 72 questions, and a total of 2008 possible multiple-choice answers which rate the type, frequency, and location of the patient’s pain. As a result of the diagnoses reached by evaluating these symptoms, there were 107 medical tests which could be administered. The medical test results were ranked from Within Normal Limits (WNL), Mild, Moderate, or Severe/Abnormal indications. It should be noted that doubling the number of charts of the initial group, which represented 147,000,000 data points, increased the predictive accuracy of DRM by only ~2%. Mensana Clinic (which Business Week listed as one of the top 8 best pain centers in the United States, along with Mayo Clinic, Cleveland Clinic and Johns Hopkins Hospital) [28], was operated by Johns Hopkins Hospital staff members, who ordered sophisticated laboratory tests not commonly ordered by other physicians. This resulted in a collection of medical data that is not typically available at almost any other medical center or from treating physicians. It is highly unlikely that the data obtained from these charts can be duplicated. Thus, the results of the process are unique, exhaustive, and proprietary.

DRM accumulated all the answers to the Diagnostic Paradigm for all 78 patients. The range of affirmative answers was 18 to 1,237 of the 2008 possible answers, depending on the type of injury the patient sustained. If the patient only had a nerve entrapment in the wrist, the patient had very few positive answers to the questions. On the other hand, if the patient has been in a severe automobile accident and had pain in the neck, both arms, and both legs, the patient would have many more answers to the questions. DRM listed all the positive answers to the Diagnostic Paradigm which had been marked by all patients. Obviously, for the most common type of injury there would be more data points for certain answers, since there would be more patients with those symptoms.

Fifty-two of the patient charts represented patients with a complete evaluation with all recommended testing completed, while the remaining charts represented patients with at least 50%-95% of all recommended tests completed. Charts with less than 50% of the tests completed were not included in this research. Also, excluded from the research sample were patients who had only an evaluation, but no medical tests, patients who had less than 50% of the recommended testing performed, patients who had a chronic pain problem which was not covered by the diagnostic assessment of the Diagnostic Paradigm, such as genital pain, facial pain after a face lift, rectal pain, or nipple pain after breast augmentation.

The DRM showed the specific medical test results, of the 107 possible medical tests, which were administered to each patient. DRM associated these medical test results to the answers for each of the patients. The basic logic is that patients who responded to symptom questions are going to have a similar spectrum of test responses. This forms evidence-based data for optimal test performance decisions. These data can be displayed using histograms, for visual recognition, and a simple Excel spread sheet, for a numerical representation. DRM automates the assessment of a benchmark instrument which compiles a matrix comparing the answers on the MCD Diagnostic Paradigm to the results of the medical testing, in much the same manner the Ottawa Ankle and Knee rules did for ankle and knee X-rays, and the Pain Validity Test did for objective medical testing in chronic pain patients. However, DRM provides a broadly expanded clinical set of data.

Based on this analysis, a data base is created which rank orders the likelihood of a test being positive for a given set of symptoms. The data organization for this reporting process is straight forward and simply the recordation of a specific question’s choice. The data storage action accumulates all of the patients’ medical test results for each of the specific answers. This resulting evaluation is a numerical count of the medical test abnormalities found for each answer. The number of abnormal medical tests associated with each of the possible answers can be displayed as a graph or refined into a MS Word/Excel compatible report.

Results

The DRM results revealed the rank ordered tests, from most frequently abnormal, to least frequently abnormal for each symptom a patient had for all 75 patients. Clusters of symptoms typically seen for the most common diagnoses also were evaluated. Some of the most common diagnoses symptoms and the abnormal medical test rank order are shown below in (Table 1). The percentage represents the number of abnormal tests obtained for a patient with a specific symptom as a percentage of all tests of that type performed on a patient with that symptom. There are various reasons that not all of the patients with certain symptoms received all of the appropriate testing:

Insurance would not pay for the procedure,

The patient was afraid of the interventional testing,

The test could not be scheduled before the patient departed,

There were anatomical abnormalities which prevented the insertion of a needle into a disc space,

There was no clinical indication to order a provocative discogram, for example because just neck pain is not associated with discogenic neck pathology . Therefore, only the actual number of patients receiving the test is recorded and is represented by the N which follows the type of test.

There are two ways to represent the results of this comparison. The first is a frequency histogram, and the second is an Excel spread sheet. (Figure 1) below represents the frequency histogram for all medical test results for the single symptom, “My neck pain is constant.” There are many etiologies to this single symptom, such as a herniated disc, thoracic outlet syndrome, radial nerve entrapment, cervical radiculopathy, and cervical facet syndrome, to name a few. This accounts for the variety of abnormal medical tests for just a single symptom. Additionally, a patient may have more than one symptom, and symptoms related to other areas of the body. A patient injured in an auto accident may have neck and back pain but the frequency histogram reports all abnormal test a patient has, even though just one symptom is being examined.

(Table 1) below shows these data in an Excel format of abnormal tests for a single symptom, eliminating abnormal tests for the lower body, for the sake of clarity. Auto accident cases frequently have hyperextension injuries, which produce thoracic outlet syndrome, and accounts for the high level of abnormal vascular flow studies in the arms, when in Roos position. This position detects post-traumatic vascular compression [29,30]. In addition to damaged discs, other disorders, such as radial nerve entrapment, radiculopathy, and cervical facet syndrome produce neck pain.

When symptoms are aggregated, such as “pain and numbness into the thumb and index finger,” the dynamic changes. This may represent a subset of patients with just neck pain, i.e., of all patients with neck pain, not all have “pain and numbness, and pins and needles into the thumb and index finger.” This can be seen in radial nerve entrapment, thoracic outlet syndrome, C5-6 radiculopathy, C5-6 herniated disc, etc.

Symptoms of thumb and index pain and numbness:

In right thumb - Numb

In right thumb - Pins and Needles

In right thumb - Constant Pain

In right index finger - Numb

In right index finger- Pins and Needles

In right index finger - Constant Pain

These symptoms are compatible with a radial nerve entrapment, C5-6, and or C4-5 damage disc and associated radiculopathy, and elements of thoracic outlet syndrome, and overlaps with median nerve entrapment. Refer to the small example presented in (Figure 2) and (Table 2), in which the example patient had constant pain in the thumb and index finger which also was also numb and had pins and needles. DRM shows that 24 patients with some or all of these symptoms, when aggregated, had an abnormal provocative discogram at C3-C4 58.3% of the time, an abnormal provocative discogram at C4-C5 62.9% of the time, and an abnormal provocative discogram at C5-C6 51.8 % of the time. However, in 32 patients who had an MRI of the neck for these same set of symptoms, only 28.1% had a moderately or severely abnormal MRI, only 14.1% had an abnormal X-ray, and 33.3% had an abnormal 3D-CT. Additionally, 100% of the 12 patients with symptoms of radial nerve entrapment had an abnormal radial nerve block, and the root blocks from C4-C7 had positive results which ranged from 73-88%. From these data, a physician can determine which test will be most productive in confirming his or her diagnosis and will quickly recognize the rank order of positive testing as an aid in establishing a diagnosis.

Discussion

The DRM serves as the benchmark against which symptoms of an individual patient can be compared. DRM is a stable and statistically valid tool that can evaluate any new patients’ Diagnostic Paradigm questionnaire and the specific answers they have compared to the large data base of medical test results. This resulting individual test evaluation can offer a numerical count of the patient’s potential test results and select the medical test most likely to be abnormal based on the highest frequency of this test. The rank ordering of medical test results declines based on frequency of abnormal results. This can be used to predict which test is most likely to be abnormal for which symptom.

In a practical clinical application, symptoms of an individual patient can be compared to the DRM’s data point system. Then, abnormal medical tests results can be predicted by comparing individual symptoms against the specified symptoms for DRM analysis. Individuals from a clinical setting can have their medical symptoms compared against the expected outcome of abnormal medical testing based on the data analysis by DRM. The results of the analysis will show that a predicted medical test will be abnormal for a certain symptom or grouping of symptoms. DRM has the ability to accumulate various symptoms, typically found in most disorders, to give overall expected medical test results for that constellation of symptoms. From this research, the percentage chance of a test being abnormal in any given patient can be predicted from the Bayesian Medical Accumulator. As an example, a typical report would say:

“In a compilation of 634 patients, from the Large Ordered Bayesian State Application (LOBSA), who had the same symptoms as the patient, 79% of them had abnormal finding on the provocative discogram, 54% had positive root blocks at C4-5, 51% had positive facet blocks at C4-7, 4 % had abnormal EMG/Nerve conduction velocity testing, 31% had abnormal CT, 28% had abnormal MRI, and 2% had abnormal X-rays.” This list of expected results will allow a physician or insurance carrier to determine, in a rank ordered fashion, the most productive test results which would be anticipated, through the least likely. More importantly, any test not listed on the expected testing list could be assumed to not have ever been ordered for a patient with the same symptoms as the example patient and, therefore, be totally unproductive.

What was immediately evident from these data is the value of physiological testing compared to anatomical tests when evaluating a patient with chronic pain. Anatomical tests, such as MRI, CT, and static X-rays, had a low percentage of abnormalities, because they merely take pictures. Physiological tests, such as stellate ganglion blocks, lumbar sympathetic blocks, provocative discogram, root blocks, peripheral nerve blocks, and facet blocks, had much higher positive findings, because they physiologically do something to the body, and the response is recorded [31]. Since pain is a physiological condition, a physician cannot take a picture of pain. Physiological testing is designed to administer a test, to see if it modifies, increases, or reduces, the pain for a patient. Anatomical tests do not do that.

The importance of obtaining abnormal test results rests with the ability to provide care for a patient. Clearly, abnormal testing produces an “actionable” event, i.e., something which a physician can address and correct if possible. By providing a physician with a list of what would be expected to be the most abnormal tests, rank ordered down to the least likely to be abnormal gives a physician a check list of tests to order, which would be the most likely to provide an opportunity for intervention, and treatment. Unnecessary testing or non-productive testing would be reduced or eliminated. Moreover, it helps a physician recognize a diagnosis which may have been overlooked and consider it in the differential diagnosis. The net results will be improved patient care, reduced treatment time and greatly reduced medical costs.

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Head and Neck Paragangliomas: a Narrative Review by Diego Duminy-Luppi in Open Access Journal of Biogeneric Science and Research

Abstract

Head and neck neoplasms arising in the paraganglion tissue, comprising carotid body, vagal and temporal bone paragangliomas, account for a small part of extraadrenal paragangliomas. They represent, however, a challenging diagnosis that is often made quite late, appearing in some of the most complex anatomical areas with regards to surgery. Morbidity is also high, with often permanent cranial nerves damage or audio-vestibular injury, both by the tumours themselves or as a consequence of late surgery. Therefore, it is important for physicians to be informed as much as possible on this subject. Throughout a vast and thorough assessment of the state-of-the-art advances, as well as some previously published remarkable takes on the matter, this narrative review aims to cover what is needed to know about the epidemiology, pathophysiology, clinical manifestations, diagnosis and treatment of this otorhinolaryngological condition.

Keywords: Head and neck paraganglioma; Paraganglioma; Carotid body tumour; Vagal paraganglioma; Temporal bone paraganglioma; Jugulotympanic paraganglioma; Tympanomastoid paraganglioma; Otorhinolaryngology; Head and neck surgery; Narrative review.

Introduction

Paragangliomas are traditionally poorly defined in literature, as the definition varies depending on the sources. Some more specific designations have recently been revised, such as non-chromaffin (parasympathetic) and metameric (sympathetic), and the term chemodectoma is no longer used [1]. The 2017 WHO classification of tumours of the endocrine organs defines ‘extra-adrenal paraganglioma’ as both functional (catecholamine secreting) and non-functional, sympathetic or parasympathetic-derived neoplasms arising in extra-adrenal paraganglion tissue. Tumours with the same characteristics originated inside the adrenal glands would be referred to as pheochromocytomas [2], although in clinical practice the term ‘paraganglioma’ generally refers to head and neck tumours with these characteristics [3].

In this review, we will focus on the epidemiology, pathophysiology and clinical manifestations, as well as the diagnosis and treatment of three specific and most frequent types of head and neck paragangliomas (HN-PGLs), consisting of carotid body paragangliomas (CBPs), vagal paragangliomas (VPs) and temporal bone paraganglioma (TBPs), which includes both tympanomastoid (TMPs) and tympanojugular paragangliomas (TJPs). All of them are parasympathetic-derived paragangliomas, with CBP arising from the carotid body at the carotid bifurcation, VP arising mainly (but not only) from the nodose ganglion or inferior ganglion of the vagus nerve. TBPs arise from Jacobson’s nerve (i.e. the tympanic branch of CN IX), Arnold’s nerve (the auricular branch of CN X) and intravagal paraganglia inferior to foramen jugulare [4]. The apparition near the jugular bulb describes TJPs whereas the apparition in the tympanic or mastoid canaliculi describe TMPs [5]. They are indolent slow-growing tumours, mostly non-secreting, in a complex anatomical area [6].

The description of temporal bone paragangliomas has been highly inconsistent, coming from the lack of consensus terminology. The distinction between tympanomastoid and tympanojugular paraganglioma is often unavailable, mentioning ‘jugulotympanic paraganglioma’ as a sole entity, leaving unclear to the reader if the first is simply dismissed or included in the latter. Others have adopted the terminology ‘middle ear paraganglioma’, without specifying up to which extent nearby paragangliomas outside of the middle ear are considered. It is however consistent that glomus tympanicum and glomus jugulare are now both included and referred to as jugulotympanic paraganglioma. We will therefore mention as temporal bone paraganglioma all tympanomastoid paragangliomas, tympanojugular or jugulotympanic paragangliomas, temporal paragangliomas and jugular foramen paragangliomas, specifying the subtype only when the information refers to that specific subtype exclusively. Finally, ‘Head and neck’ is commonly defined as the anatomical area delimitated inferiorly by the clavicle and superiorly by the cranial vertex, and so does this review [7].

Methods

Resource publications for this narrative review were identified and selected through searches of PubMed and MEDLINE, using ‘cervical paraganglioma’, ‘paraganglioma’, ‘head and neck paraganglioma’, ‘vagal paraganglioma’, ‘carotid body paraganglioma’, ‘carotid body tumor’, ‘glomus jugulare’, ‘temporal bone paraganglioma’, ‘jugular foramen paraganglioma’, ‘middle ear paraganglioma’, ‘glomus tympanicum’ and ‘jugulotympanic paraganglioma’ as search terms. Studies selected for this review include the most recent advances in research until November 2019, they were published in high-impact, peer-reviewed journals, and showed results based on satisfactory numbers of study participants, covering a relevant population.

Epidemiology

The incidence of head and neck paragangliomas in the general population ranges from 1/30.000 to 1/100.000 per year. CBPs account for approximately 60% and TBPs account for 30% of them, leaving approximately 10% to VPs. Laryngeal paragangliomas are extremely rare, with less than 100 cases reported in literature. The remaining ones (non-head and neck) are mostly found in the abdomen region [8-11]. Only 10% of paragangliomas do not occur in the adrenal paraganglia and are thus not pheochromocytomas. Of these, 97% arise in non-head and neck locations [12].

60% of HN-PGLs are sporadic, although the remaining 40% are familial inherited cases associated with succinate dehydrogenase subunits mutations [10]. These familial cases are more likely to be bilateral and multiple (10-25% for CBPs and 20-40% for VPs, 30% for TBPs). Only 5% of cervical paragangliomas are catecholamines producers. Malignant behaviour isn’t predictable by clinical manifestations nor histology, although familial cases are associated with higher rates of malignancy than sporadic ones [8-10] The pathologies most associated with paragangliomas are type 2B Multiple Endocrine Neoplasia (MEN), type 1 neurofibromatosis and Von Hippel-Lindau syndrome [8,9].

CBPs appear between the 5th and 6th decade of life, show approximately 2:1 (female:male) gender predilection and are rarely bilateral if sporadic (5%) [10] VPs usually appear during the 5th decade of life, also show 2:1 (female:male) gender predilection and have higher chances of being bilateral/multifocal or metastatic than CBPs [10].

TBPs also usually appear between the 5th and 6th decades of life and exhibit female gender predilection with a female:male ratio of 3:1 [10,12] Jugular paragangliomas have their peak incidence in the 6th decade, and some authors point at a higher female to male ratio, as high as 4:1 or 6:1 [10,13,14]. Bimodal distribution of cases in tympanic paraganglioma has been mentioned, with a first smaller peak around the 4th decade [15] Malignant TBP cases are lower than in other HN-PGLs, and often associated to SDHB mutations. These range from 2-5% and come from the presence of metastases, as proliferative index Ki67 is almost always very low, around 1-2% [5,13,16] Interestingly, the incidence of cervical paragangliomas is higher in people living above 1.000m over the sea level, as encountered in a single cohort study, postulating a potential role of chronic hypoxia as a risk factor for CP [17].

Pathophysiology

Cervical paragangliomas are a rare group of tumours, originated from the chromaffin cells of the extra-adrenal paraganglionic system (derived originally from the crista neuralis), following the autonomous system chain over the head and neck. They are slowly growing and invasive to nearby structures, and consist of highly vascularized structures, getting its blood supply mainly from external carotid artery branches [18].

To elucidate the aetiology, it’s mandatory to separate between the familial and the sporadic cases. As mentioned before, the familial cases are related to succinate dehydrogenase (SDH) mutations in 4 locus: 11q23 (SDHD gene causing PGL1), 11q13 (PGL2), 1q21 (SDHC gene causing PGL3) and 1p36.1p35 (SDHB gene causing PGL4 [19] The inheritance pattern is autosomal dominant, with incomplete penetrance [20] SDH plays a role in the tricarboxylic acid cycle and oxidative phosphorylation located in the mitochondrial complex II. The mutation in SDH produces similar effects as chronic hypoxia in paraganglionic cells [21]. Mutations in SDHD and SDHB increase intracellular concentrations of hypoxia molecular mediators (HIF) and stimulate angiogenic genes (VEGF) that translate into an increased hyperplasic proliferation, causing the neoplasia [19]. SDHD mutations are more common in multifocal paragangliomas, including non-functional ones, whereas SDHB mutations are more associated with malignant behaviours [22]. Finally, the SDHA subunit mutation hasn’t been related with paragangliomas nor other tumours, but with the autosomal recessive young encephalopathy [23].

Macroscopic pathology of paragangliomas appears as well-circumscribed reddish-brown masses usually ranging from 2 to 6 centimetres at resection [6]. Rarely, the tumour can be pigmented [14] Jugular paragangliomas had an average size of 3.5 centimetres in a large retrospective study, whereas tympanic paragangliomas had considerably a smaller size with a mean of 0.7 centimetres [11].

Microscopic pathology shows a characteristic ‘Zellballen’ pattern composed by nests of neuroendocrine chief cells and peripheral glial-like sustentacular cells, surrounded by delicate vascular septae. Both types of cells are positive to immunochemistry staining with chromogranin, synaptophysin, neuron-specific enolase, CD56 and CD57 (chief cells) and S-100 (sustentacular cells). Antibodies against proteins encoded by recognised susceptibility genes (as previously mentioned) may also be used to establish an increased risk of germline mutations of these genes [24].

Clinical Manifestations

Clinical manifestations of head and neck paragangliomas are not so obvious, and whereas functional tumours are often suspected with the presentation of otherwise unexplained fluctuating or persistent specific symptoms such as headache, profuse sweating, palpitations, tachycardia, hypertension or anxiety, these only represent 1% of HN-PGLs, as even catecholamine secreting tumours often don’t reach high enough levels to produce symptoms [25,26] Most CBPs and VPs are thus non secreting at a clinically-significant level and grow on average at a rate of 0.83mm/year. Clinical manifestations mostly come from the compression or invasion of nearby structures, depending on the direction of the growth [6] TBPs also exhibit a similar slow growth, but often present in a symptomatic fashion. However, diagnosis is usually made after a considerable time, with patients waiting on average around 30 months before consultation [12,27].

The most common presentation of CBPs is that of an asymptomatic, pulsatile cervical mass, with a limited mobility in the cephalocaudal axis and good mobility in the lateral axis (classically referred to as Fontaine’s sign). In some cases, headache and syncope have also been reported as main complaints [28] Early detection through physical examination or self-detection may be challenging especially in obese patients. Bulging of the oropharyngeal wall is present in approximately 10% of tumours, originating hoarseness, dysphagia or foreign body sensation. Larger CBPs may cause vagal and hypoglossal palsy, and the compression of arteries may result in a noticeable bruit. Differential diagnosis of these masses includes carotid aneurysms and neurilemmomas [14].

VPs also present as painless cervical masses, and occasionally patients will show dysphagia and hoarseness. Oropharynx may be deviated following the occupation of parapharyngeal space. Cranial nerve (CN) dysfunction occurs more frequently than with CBPs, with preoperative weakness of CN X occurring in one third of patients [14,29]. In some cases, other CNs may be involved, such as CN IX, and although rare, the involvement of the sympathetic chain can cause Horner’s Syndrome. Also rare but of major importance, VPs may reach the skull base and extend intracranially (dumbbell-shaped tumour), or involve the jugular foramen and the atlas [6] Polymyalgia rheumatica is a described paraneoplastic syndrome associated with benign VP [30].

TBPs usually present as symptomatic tumours. Depending on their location and extension, symptoms may vary, as these appear based on the structure they alter by compression or erosion. Jugular paragangliomas will have higher rate of CN dysfunction, whereas tympanic paragangliomas will have significantly higher hearing symptoms. Both can however extend into the other’s anatomical area, ultimately behaving in a similar manner [11]. Most commonly reported symptoms are pulsatile tinnitus ranging from 60 to 80% of patients, and hearing loss, in 55 to 80% of patients [5,13-15,27] Conductive hearing loss is predominant, whereas neurosensorial hearing loss is less frequent and shows itself in extended tumours with vestibular involvement [13,27]. Aural fulness is also frequently reported, in up to 70% of patients [10,15] CN abnormalities are often present, in up to 40% of patients [5,16] These will show up in a clinical examination, or through a wide variety of symptoms such as dysphonia, dysphagia, dysarthria, tongue weakness, hoarseness and shoulder pain or weakness [12-15,31] Specifically, CN VII is affected in up to 39% of patients, CN IX and X in up to 40% of patients, and CN XI and XII in up to 30% of patients [5] Both Vernet syndrome (CN IX, X, XI abnormality) as well as Collet-Sicard syndrome (CN IX, X, XI, XII abnormality) have been described associated to TBPs, with the latter in up to 10% of jugular paragangliomas [13].

Some authors have considered the presence of a red, vascular middle-ear mass as pathognomonic of TBP, whereas others simply describe it as very common finding [5,14]. This mass can also be pulsatile [5,14,15] Other characteristic sings are Brown’s sign, described as a blanching of the lesion when pneumatic pressure is applied, revealing the vascular nature of the tumour, and the rising sun sign, presenting as an inferior semi-circular red-blue lesion behind the tympanic membrane [5,15] Rarer presentations may be vertigo (in up to 20%), otalgia (3%), otorrhagia (1.5-9.6%) and epistaxis (uncommon) [15,27]. Horner’s syndrome can also be seen [16].

CBPs’ malignancy rate is estimated between 5-10%. Pain, young age and rapid enlargement are the most predictive features. Although a retrospective cohort study reported a CBP with aggressive soft tissue invasion which affected the brachial plexus and cervical nerve roots, this is generally not accepted as a malignant CBP; malignancy requires the presence of regional or distant metastasis [11,29].

Metastatic CBP and VPs are rare but represent a challenging medical management. VPs are more like to become malignant and metastasize than CBPs [32] Described locations of metastatic CBP include peripheral lymph nodes or distant organs such as liver, bone, kidney, lungs, breast, pancreas, brain and thyroid gland [28,33]. Wang et al. mentioned what they believe to be the first case of CBP brain metastasis, with the particularity of having an endocrine activity [33]. The symptoms described were right limb weakness, dizziness, vomiting, hypertension and hyperglycaemia, resolving after the tumour extirpation. Needless to say, these are not the common rule. TBPs have even lower metastatic rates than CBPs, although some cases have been reported, especially in bone, lungs, lymph nodes and liver [5].

Differential diagnosis of CBPs include lymph nodes, which may or may not contain metastatic disease, mainly from other neuroendocrine tumours such as neuroendocrine carcinomas, Merkel cell carcinoma and medullary thyroid carcinoma. For VPs, differential diagnosis can be established with schwannomas, vascular tumours and parotid gland salivary tumours. When investigating a possible TBP, clinicians should keep in mind that meningioma, middle ear adenoma and haemangioma can present in a similar manner and share part of neuroendocrine markers [10]. Also, an inflammatory polyp, an aberrant internal carotid artery, an anatomic variation of the jugular bulb, a CN VII neuroma, an osteoma, a cholesteatoma or a cholesterol granuloma can be misdiagnosed as a TBP [27].

HN-PGLs may be hard to distinguish from atypical carcinoids, although some characteristics may help differentiate both: atypical carcinoids usually appear during the 6th-7th decade, metastasize frequently and primarily affect male patients (3:1 M:F), although they have the same clinical manifestations and ultimately require histologic analysis [10].

Diagnosis

As mentioned before, although clinically non-secreting, HN-PGLs may secrete catecholamines, which justifies why biochemical tests such as plasma free metanephrines or urinary fractionated metanephrines are recommended as initial investigation for paragangliomas [34]. Imaging studies should be performed once a positive biochemical test occurs, and include both contrast enhanced CT or Magnetic Resonance Imaging [34]. MRI is preferred in HN-PGLs, with a sensitivity of 90-95% (higher than CT), and it helps differentiate HN-PGLs from other tumours (such as Schwannoma, neurofibroma, carotid artery aneurism), and provides excellent details on extension and vascularization [4,34,35]. CBPs and TBPs show a characteristic salt-and-pepper image in contrast in T1 MRI, distinguishing areas with subacute haemorrhage and slow blood flow (‘salt’) from serpent-shaped flow voids (‘pepper’). Gadolinium intensively enhances these lesions, and T2 shows mildly and heterogeneously hyperintense, well defined mass [4-6,15,35].

If the invasion of the skull base is suspected, contrast enhanced CT provides excellent spatial resolution. MRI can be, and usually is, complementary to CT [6]. CBPs appear as a hypervascular mass that spreads between the internal and the external carotid arteries. However, it is usually located at the same level or below the carotid bifurcation, not above. Digital subtraction angiography may be performed to evaluate internal carotid infiltration or preoperatively if embolization is considered. The image is classically described as a ‘lyre sign’, and CBPs show a slow and prolonged blush. VPs can also appear as CBPs but they usually present behind the internal carotid artery and push the vessels in an anteromedial direction [4,6,29,35] Another characteristic is that they may separate the jugular vein from the carotid sheath [29].

In TBPs, radiologic studies are also paramount in order to further classify the tumour and determine the most appropriate approach to treatment. High-resolution CT scan with contrast is both sensitive and specific, usually showing localized irregular bone destruction at the jugular foramen, with sometimes enlargement of the latter. This pattern is traditionally described as ‘moth-eaten’ [4,5]. TBPs are a soft tissue mass, enhanced by contrast [35]. The erosion of the jugular plate suggests that the tumour is a jugular paraganglioma [36]. MRI is preferred and complementary to CT in order to precisely determine intracranial involvement, especially in those tumours reaching outside of the middle-ear [5,15,35]. Furthermore, MRI differentiates more accurately tympanic paragangliomas from jugular paragangliomas [5,12]. Angiography is not always performed, but can be considered in case of suspected invasion of the internal carotid artery, or the anterior vertebral artery [5]. Tympanic paragangliomas may grow inside the tympanic cavity without destroying the ossicles, but being attached to them [4,15].

Ultrasound, if performed, shows solid hypoechoic lesions [35]. Biopsy of suspected PGLs is contraindicated because of the high risk of bleeding [37]. For metastatic cases, 18FDG PET-CT is preferred because of its higher sensitivity when compared to other techniques, especially in SDHB-related PPGLs [34].

Treatment

There is widespread consensus in the literature with regards to surgery as the only available option for treatment. There is no effective medical therapy.

Shamblin et al [38]. suggested a classification in 1971 based on CBP tumour size and carotid artery invasion to assess resection possibilities:

Shamblin 1: Less frequent group, containing small size (<4cm) and well localized tumours, without invasion of major vessels and easily resectable.

Shamblin 2: Nearly 50% of the cases, containing of mid-size (>4cm) tumours, adhered to or partially surrounding major vessels. They compress the internal and external carotid artery but can be removed through a cautious subadventitial dissection.

Shamblin 3: More than 25% of the cases, containing big size tumours, invading carotids and nearby structures. In order to be completely removed, partial or total resection of these structures is needed.

The reasons to resect a cervical paraganglioma include the following: [39]

Some HN-PGLs could eventually become malignant, although it’s not possible to know before or after the surgery.

There is no true consensus on an optimal follow-up strategy.

No cases of spontaneous regression, even correcting hypoxemia, have been published.

The risk of vascular injury in experienced surgical teams intervening a Shamblin 1 tumour is minimal.

All tumours can become symptomatic.

The basic surgical technique consists of an incision over the anterior edge of sternocleidomastoid muscle. The deep anterior fascia is dissected in order to expose the common carotid artery, which is important for an early vascular control. The dissection plane then extends anteriorly until the carotid bifurcation. This way the subadventitial plane or ‘white line’ as described by Gordon-Taylor can be identified, which allows a fine separation of the tumour and the artery due to a relatively avascular plane [39,40].

The risk of an arterial injury during the resection increases with tumour size, but without a significative increase of brain ischaemic events. Adjacent CN lesions are one of the major risks during surgery, mainly accessory spinal nerve (XI), vagus nerve (X) and hypoglossal nerve (XII). Again, the risk increases with tumour size, but locating, isolating and carefully dissecting these structures prior to tumour resection decreases the risk. In vast tumours, where surgical resection could entail bigger morbidity, or in suboptimal basal patients, either because of age or because of concomitant pathologies, radiotherapy is indicated, with 45Gy in 25 fractions showing good results in/at stopping tumour progression at 5 and 10 years of follow-up (only 4 to 6% recurrence at 5 and 10 years respectively), but sometimes leaving an asymptomatic residual mass [39,41,42]. Regarding potential complications of radiotherapy, histologic examination has shown that chief cells are minimally affected by irradiation, although the distinctive vascular structure of the tumour is replaced by fibrous connective tissue, raising awareness over the appearance of malignant tumours such as fibrosarcoma [43-45]. 15% of patients who underwent radiotherapy suffered at least one complication, which include inflammation of the external auditory canal and middle ear, skin loss with bone exposure, osteoradionecrosis, cranial nerve neuropathies (specially hearing and taste loss, in <3%) and direct injury to brain tissue, among others. Additionally, it is worth mentioning that if radiotherapy fails, surgery will be more difficult [40,42,45-47] For CBPs, 14% of <5cm tumours extirpation entail CN disfunction as compared to 67% of >5cm tumours [12].

Another alternative worth mentioning is embolization, a technique consisting in introducing a catheter (generally through a percutaneous approach to the femoral vessels with Seldinger technique) to deploy coils in tumour’s vascularisation that will form a clot and interrupt blood flow, reducing blood loss and facilitating tumour resection. The procedure is usually undergone 48h before surgery to avoid intraoperatory inflammatory phenomena. There have been some controversial discussions regarding its efficacy, since it also entails some risks (distal embolization, necrosis, cerebral or ocular infarcts, etc.), so there is no real general consensus over the existing evidence [48].

For VPs, the same management options are generally considered. However, surgery isn’t supported by high levels of evidence, especially when compared to small CBPs, because an intervention almost always (93%) implies complete resection of the vague nerve which causes serious side effects such as unilateral vocal fold paralysis, pharyngeal plexus deficit, pharynx numbness and soft palate dysfunction, resulting in dysphagia and dysphonia among others, often worse than the tumour itself would cause. The typical approach is lateral, transcervical and preauricular, sometimes superiorly extended. Damage to other CNs is also possible, with numbers ranging from 21% to 39%. When compared to Radiotherapy (RT) and Stereotactic Radiosurgery (SRS), results are similar to surgery but with less damage to CN, postulating the option of an observation ± RT ± SRS as a reasonable alternative to surgery in selected patients [12]. A recent study has shown that immediate selective laryngeal reinnervation using the phrenic nerve and the ansa cervicalis as donor nerves after VP excision improves both dysphagia and dysphonia. [49] However, further evidence is needed to define management algorithms for VPs.

Regarding TBPs, the modified Fisch and Mattox classification is used to divide them based on their extension, which at the same time determines the optimal surgical approach (presented between brackets). Tympanomastoid paragangliomas, on the one hand, can be classified as class A, if they are confined to middle ear, and then further subdivided into A1 if the tumour margins are clearly visible on otoscopic examination (transcanal approach) or into A2 if margins are not visible on otoscopy (retroauricular-transcanal approach, glove finger flap technique). An emerging new technique, consisting of transcanal endoscopic minimally invasive surgery, has demonstrated feasibility and promising results among this class [50-52]. They can also be classified as class B if they are confined to the tympanomastoid cavity without bone destruction in the temporal infralabyrinthine compartment, and then further subdivided into B1 if they extend to the hypotympanum alone (canal wall up mastoidectomy with posterior tympanotomy), into B2 if they extend to the hypotympanum and the mastoid (canal wall up mastoidectomy with posterior tympanotomy and subfacial recess tympanotomy) or into B3 if they erode the carotid canal (subtotal petrosectomy with middle ear obliteration).(27) Major postoperative complications such as CN deficits are usually not expected, but minor complications such as postoperative conductive hearing loss may occur [53].

Tympanojugular paragangliomas, on the other hand, can be classified as class C if they extend beyond the tympanomastoid cavity, destroying bone of the infralabyrinthine and apical compartment of the temporal bone and involving the carotid canal, with further subdivisions C1-C4 depending on the degree of invasion (C1, tumours with limited involvement of the vertical portion of the carotid canal; C2, tumours invading the vertical portion of the carotid canal; C3, tumours with invasion of the horizontal portion of the carotid canal; C4, tumours reaching the anterior foramen lacerum). They can also be classified as class D if they extend intracranially (De1, tumours up to 2 cm dural displacement; De2, tumours with more than 2 cm dural displacement; Di1, tumours up to 2 cm intradural extension; Di2, tumours with more than 2 cm intradural extension; Di3, tumours with inoperable intradural extension) or as class V if they involve the vertebral artery (Ve, tumours involving its extradural portion; Vi, tumours involving its intradural portion) [5]. They are usually resected via an infratemporal approach, but C1, C2, De1, De2, Di1 and Di2 may demand a variant of the juxtacondylar approach [54] Because these tumours are adherent and occasionally CN IX-XII are involved, higher rates of CN deficits are anticipated for the postoperative outcome, and thus possibly requiring further surgical procedures attempting to correct them.(55,56) Di1 and Di2 tumours should be generally resected in a two-stage multidisciplinary procedure involving neurosurgeons, whereas in Di3 tumours palliative radiotherapy is advocated. Although some inconsistencies regarding Fisch classification and follow-up intervals among different studies must be taken into account, long-term success rate following surgical therapy of tympanojugular paragangliomas is 72-95% [54].

Conclusion

Paragangliomas are functional or non-functional, sympathetic or parasympathetic-derived neoplasms arising in extra-adrenal paraganglion tissue. Amongst these, HN-PGLs are mainly composed by CBPs, VPs, and TBPs. Some genetic associations have been described. Clinical manifestations are diverse although some signs and symptoms strongly suggest the diagnosis. Biochemical screening is the first complementary step when investigating a possible HN-PGL, followed, if positive, by the best available imaging technique, which usually narrows down the differential diagnosis. Surgical intervention, with or without previous embolization, is the best and only approved therapeutic option for CBPs and TBPs, whereas for VPs further evidence is needed to determine whether surgery with reinnervation or a combination of RT and SRS is the best therapeutic management strategy. For some tympanomastoid paragangliomas, endoscopic surgery is emerging with promising results.

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