COVID 19- How to tackle community spread?

 

COVID 19- How to tackle community spread?

Corona virus infection of 2019 (COVID 19) which started first in China is now showing all features of a pandemic with more than 100 countries affected. It appears to be a fast spreading viral infection and needs community participation to contain it. Disease is mild with mortality risk of about 3.4%. However it has created panic all over the world. The main concern is international travel and the ability of the virus to spread through contacts. This can be attributed to the high reproductive number (R0 value) of 2.28 the virus boasts coupled with the fact that the virus chose the most populous country in the world to wreak havoc. This high R0 value stresses the need for strict infection control and management to contain this illness.

As per preliminary reports death rate is not very high, but may differ from one country to other due to climate, geographical, ethnic and genetic factors. Most important factor in containing this epidemic is through community participation. Govt. should issue directions regarding the measures to be undertaken for controlling the spread. These directions are binding to all citizens across the region. Restricting international travel is one important measure, especially travel in and out of most affected countries is to be strictly restricted. Avoidable travel, travel for tourism purpose etc. can be cancelled or postponed to a later date.

Next important measure is surveillance in international airports; where in all international passengers are screened by a team of health care providers. Symptomatic should be isolated in health care facilities and treated and asymptomatic contacts can be quarantined in their homes so that mixing with other public is strictly restricted for at least 14 days. All contacts and suspects should be tested for presence of viral antigen.

Since the initial symptoms of the disease are like any other flu illness, even a minor running nose has created an undue fear amongst the people. Seeking early professional advice puts these patients at a higher risk of acquiring Covid 19 from the hospitals. Hence, self-quarantine is of paramount importance and needs to be stressed. Patients need to initially isolate themselves from their immediate kin, wear a surgical mask and follow strict hygiene measures to restrict transmission. Initially, symptomatic measures such as anti pyretics, adequate hydration and nasal decongestants may be taken. Professional help need only be sought if the symptoms persist.

A monitoring cell under the district health authority is to be formed and that is responsible for treating symptomatic, tracking contacts, allaying fear among public and to give directions to the public. There will be state cell to coordinate district activities and to provide money and materials to the district units. Health centers designated for quarantine of suspects should have chambers with negative pressure to contain the spread of the virus. Health workers should also be equipped with adequate supplies of gloves, N95 masks, respirators, goggles, face shields, gowns and aprons. It cannot be emphasized enough that these workers, being at the forefront of combating this illness, need to be protected at all costs. All details about each individual case so far reported should be traced with special details regarding mode of acquisition, age, travel and contact history, symptoms and signs, investigation reports, severity of disease, co morbidities, course of the disease and outcomes.

Contact tracing of a case suspect is of paramount importance to prevent spread in the community, especially in a highly populous country like India. Both primary and secondary contacts should be tracked and put on strict home quarantine. Meticulous planning and sincere effort done by the Govt. of Kerala in this direction is a model being appreciated by all.

There should be directions to avoid mass gatherings especially, festivals, meetings, marriage celebrations where large number of people are exposed.  It will be better to close all educational institutions for a period till containment is achieved. News bulletins, public awareness programmes through social media are essential to give updated information to the public. At the same time care should be taken not to create panic among citizens. Awareness about cough hygiene, hand hygiene and other general measure with special emphasis on early reporting and reassurance are the need of the hour.

WHO has declared Covid 19 as a pandemic and wanted all the countries to take urgent measures to contain the disease. The report from China is hopeful that number of new cases reported is coming down drastically. Hope that, with the concerted efforts of all we will be able stop the onslaught of 2019-nCoV.

Dr Ravindran Chetambath & Dr Jesin Kumar C

The fatal association!!

 

Obesity, obstructive sleep apnoea and metabolic syndrome

The fatal association!!

Ravindran Chetambath 

Abstract:

Obesity is the most common health risk for individuals of all age groups across the globe. Obstructive sleep apnoea (OSA) is now recognized as a major health problem in developed countries. Prevalence of OSA is undoubtedly rising given the epidemic of obesity. Recent data also suggest that OSA is associated with the metabolic syndrome.  Pathophysiological triggers of intermittent hypoxia and sleep fragmentation in OSA is responsible for cardiometabolic dysfunction. The potential mechanisms of OSA-obesity-metabolic syndrome interaction involve sympathetic activation, oxidative stress, inflammation and neurohumoral changes. In spite of support for an independent role of OSA in the contribution towards metabolic dysfunction, obesity plays a determinant role in initiating both these conditions.

Keywords: obesity, cardiometabolic dysfunction, metabolic syndrome.

Introduction:

The obesity epidemic and its impact on the prevalence of both metabolic syndrome and OSA are well recognized. OSA is widely prevalent in patients with obesity, diabetes, and hypertension. Clustering of cardiovascular risk factors (metabolic syndrome or Syndrome X) was recognized as early as 1920s and is currently thought to be linked to obesity and OSA. Given the obesity epidemic at hand, the prevalence of both metabolic syndrome and OSA are rising. In patients with established coronary artery disease, treatment of OSA may confer long term cardiovascular benefits. Our understanding of the relative importance and interactions of these cardiovascular disease mechanisms and risk factors in patients with OSA may have direct implications for the development of targeted preventive and therapeutic strategies¹. The results of various studies have undisputedly shown that appropriate treatment of OSA with Continuous Positive Airway Pressure (CPAP) therapy significantly reduces blood pressure² and other cardiovascular complications like CAD, arrhythmias and stroke. Treatment of OSA also improves the altered metabolic physiology in patients with syndrome X. Further a new syndrome, syndrome-Z was recognized to highlight the dreadful combination of syndrome-X and OSA as a risk factor for coronary artery disease (CAD).

Obesity

Obesity is a complex disease involving an excessive amount of body fat. Obesity is a risk factor for diabetes, hypertension, obstructive sleep apnoea and cardiovascular events³ and increases mortality, especially in middle-aged adults. In adults obesity is diagnosed when the body mass index (BMI) is 30 Kg/M² or more. Obesity rates are also increasing in children⁴. Since obese children tend to become obese adults, the cardio-metabolic disease associated with obesity could begin in childhood⁵.

Individuals with high body mass index (BMI) are classified as overweight when BMI is between 25-29.9, class-1 obesity when BMI is between 30-34.9, class-II Obesity when BMI is between 35-40 and class-III obesity when BMI is more than 40.

Obesity is characterized by the expansion of white adipose tissue, as a result of increased size (hypertrophy), and, additionally, by an increased number of adipocytes (hyperplasia). Adipose tissue is a central player in metabolic regulation through the production and release of multiple adipokines⁶. Moreover, adipocytes and inflammatory cells, such as macrophages, show a high degree of interaction in obesity⁷.

The localization of excess white adipose tissue in the body carries relevant metabolic consequences. Increased visceral fat mass is associated with more severe health effects compared to peripheral obesity, which is characterized by predominant accumulation of subcutaneous fat. The expansion of visceral fat increases the risk of developing insulin resistance (IR), type-II diabetes, atherosclerosis, OSA, steatohepatitis, and cardio- and cerebrovascular disease. Changes in body weight are known to affect OSA severity. Most adult patients with OSA have central obesity and increased visceral fat⁸, the latter being associated with neck adiposity, increased upper airway fat and metabolic abnormalities⁹.

The adverse consequences of obesity may be attributed in part to comorbidities, but results from several observational studies detailed by the Expert Panel on the Identification, Evaluation, and Treatment of Overweight Adults, show that obesity on its own is associated with increased cardiovascular morbidity and mortality and greater all-cause mortality¹⁰. For a person with a BMI of 25-28.9 kg/m², the relative risk for coronary heart disease is 1.72. The risk progressively increases with an increasing BMI; with BMIs greater than 33 kg/m², the relative risk is 3.44. Similar trends have been demonstrated in the relationship between obesity and stroke or chronic heart failure. For persons with severe obesity (BMI ≥40), life expectancy is reduced by as much as 20 years in men and by about 5 years in women.

Many clinical and biochemical factors associated with increased cardiovascular risk (i.e. dyslipidaemia, arterial hypertension, hyperglycaemia, hyperuricaemia and microalbuminuria) are often present in visceral (or central) obesity. The term “adiposopathy” has been proposed to indicate the strong link between visceral fat and obesity-associated metabolic abnormalities¹¹.

Treatment of obesity starts with comprehensive lifestyle management which includes diet, physical activity and behavior modification. In addition, several surgical options are also available for morbid obesity.

Obstructive Sleep Apnoea

The spectrum of breathing disorder ranges from intermittent, partial obstruction of the airway without sleep disturbance (snoring) to frequent arousals associated with hypoxemia leading to sleep fragmentation and daytime sleepiness. There will be recurrent episodes of cessation of respiration (apneas), decrements in airflow (hypopneas), or respiratory event related arousals (RERAS). This spectrum ranges from snoring, upper airway resistance syndrome (UARS), sleep hypopnea syndrome, to obstructive sleep apnea syndrome (OSAS) of which OSAS is the most severe form having considerable impact on the individual’s health.

Obstructive sleep apnea affects approximately 10% of middle aged men and 5% of women and is therefore a common condition. The prevalence of clinically significant obstructive sleep apnea (OSA) in middle-aged adults is estimated to be 2–5% in males and 2% in females. However 82% of men and 93% of women suffering from moderate to severe sleep apnea have not been clinically detected or treated. There are many serious consequences for undiagnosed and untreated OSA. The quality of life of these patients is seriously impaired mainly due to their excessive daytime sleepiness. These patients also suffer from psychological impairment such as cognitive dysfunction, decreased vigilance, disturbed concentration and memory, increased mental stress, fatigue, general mood disorders, and male sexual dysfunction¹². There is an estimated three- to seven fold greater prevalence of motor vehicle accidents involving drivers with OSA¹³. Most of these accidents are attributed to poor vigilance and falling asleep while driving.

The cardiovascular consequences of untreated OSA are coronary artery disease, congestive heart failure, myocardial infarction, stroke, systemic hypertension, and pulmonary hypertension¹⁴. The association between hypertension and OSA is well established. It is shown that hypertension associated with untreated OSA is often refractory and that a high prevalence of OSA has been observed in men with therapy-resistant hypertension¹⁵.  Patients with OSA have many features in common with those with syndrome X, including systemic hypertension which is commonly reported. Obstructive sleep apnea (OSA) has been linked to increased cardiovascular morbidity and mortality¹⁶ and can be considered an independent risk factor for CAD. Pathophysiologic mechanisms that are present in patients with OSA, including sympathetic activation, endothelial dysfunction, oxidative stress, systemic inflammation, hypercoagulability, hyperleptinemia, and insulin resistance, may influence the development and progression of cardiac and vascular pathology. These mechanisms are found to be common for both metabolic syndrome and OSA.

Metabolic Syndrome (Syndrome-X)

Metabolic Syndrome” or “Syndrome X” constitutes one of the most important risk factors for CAD. The diagnosis of metabolic syndrome is made when an individual has three of the following five characteristics: increased waist circumference, high blood pressure, elevated fasting glucose, elevated triglycerides, and decreased high-density lipoprotein (HDL) cholesterol. The criteria proposed by the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) are the most current and widely used. According to the ATP III criteria, the metabolic syndrome is identified by the presence of three or more of these components:

• Central obesity as measured by waist circumference: In men greater than 40 inches and in women greater than 35 inches

• Fasting blood triglycerides greater than or equal to 150 mg/dL

• Blood HDL cholesterol: In men less than 40 mg/dL and in women less than 50 mg/dL

• Blood pressure greater than or equal to 130/85 mmHg

• Fasting blood glucose greater than or equal to 110 mg/dL

Other important features of the metabolic syndrome include microalbuminuria, hypercoagulability, increased inflammation, endothelial dysfunction, poor cardiorespiratory function and sympathetic activation. Cardiovascular metabolic syndrome X is becoming very common in India.

Coughlin and colleagues¹⁷ performed a cross-sectional study of 61 otherwise healthy subjects with OSA and 29 subjects without OSA. To mitigate confounding due to obesity, they also matched 34 of the OSA patients by body-mass index (BMI) to the 29 controls. Their results suggest that the prevalence of metabolic syndrome is about 40% greater in patients with OSA. Also, proper management of syndrome X reduces the apnea hypopnea index in patients with co-existent OSA thus underlying the importance of simultaneous management of both the conditions

Syndrome-Z

It has even been suggested that the metabolic syndrome (Syndrome X) may co-exist with OSA (Syndrome Z)¹⁸. Syndrome Z was introduced in medical practice by Ian Wilcox in 1996¹⁸. Wilcox attached the respiratory partner for CAD risk, OSA, to syndrome X (Table-1). The importance lies in the fact that the medical fraternity is now challenging CAD by risk factor modification, but one of the major culprits, OSA, remains largely unnoticed and under treated.

Components of syndrome Z
1 2 3 4 5 6	Hypertension Glucose intolerance Low serum high-density lipoprotein (HDL)-cholesterol Elevated serum triglyceride Abdominal obesity OSA

Table-1: Components of syndrome Z

 

Interaction

It is conceivable that OSA and obesity may interact and potentiate their detrimental consequences. OSA-associated metabolic abnormalities have been reproduced in animal models exposed to a pattern of intermittent hypoxia similar to that found in humans with sleep disordered breathing¹⁹. However, hypoxia of adipocytes could play an important role in the metabolic disturbances associated with obesity²⁰. In addition, OSA and obesity share common mechanisms. Nocturnal ischemia in these patients is probably a result of simultaneous oxygen desaturation, increased sympathetic activity, tachycardia and increased systemic vascular resistance, a prothrombotic state, and any underlying subclinical coronary artery disease. Experimental studies support the theory that there might be a cause-and-effect relationship between OSA and atherosclerosis. OSA and metabolic syndrome share the common pathophysiologic mechanism increasing CAD risk.

Human obesity is usually associated with high plasma leptin and attenuated leptin signalling (leptin resistance)²¹. Leptin might be involved in the pathogenesis of hypoventilation disorders and its transcription is activated by exposure to continuous severe hypoxia in vitro²². In recent years, the role of leptin in immune function and inflammation has been increasingly studied, and some data indicate that leptin could contribute to the pathogenesis of atherosclerotic lesions by promoting inflammation²³. Adiponectin exerts an insulin-sensitizing action, and its levels are decreased in obesity²⁴. Adiponectin has anti-atherogenic and anti-inflammatory properties, and its circulating levels are lower than normal in patients with type-II diabetes, metabolic syndrome (MetS), hypertension and coronary artery disease²⁵. The protective role of adiponectin and its modulation by hypoxia suggest that it may be a useful marker of metabolic dysfunction in obesity and OSA.

Although inflammation contributes to the development of IR and MetS²⁶, the sequence of events leading to the inflammatory response in the adipose tissue is incompletely defined. An increased adipocyte size may be an important signal, through dys-regulation of insulin signaling at the level of insulin receptor substrates (IRS). Phosphorylation of IRS-1, an early event in insulin signaling, is decreased in large adipocytes²⁷.

Independent association between OSA and metabolic syndrome were assessed in two case-controlled studies on Caucasian men and reported a 6-9 fold cardiovascular risk in these subjects²⁸. In a community-based study among Chinese subjects²⁹, a positive correlation was demonstrated between AHI and the number of metabolic components. There are other studies also demonstrating association between sleep-disordered breathing and metabolic factors within the metabolic syndrome, independent of obesity.

OSA and Obesity

Obesity is considered as an important risk factor for the development of OSA³⁰. It also plays an important role in the pathogenesis of the metabolic syndrome³¹. Positive correlations between the severity of OSA and the degree of obesity in various ethnic populations have been established through epidemiologic studies³². Waist-to-hip ratio, waist circumference, and neck circumference are found to be better predictors of OSA severity than BMI³³. How adiposity and its distribution predispose to development of OSA is not clearly described. Greater mechanical load imposed by central obesity on the upper and lower-respiratory tracts and obesity-related inflammation may predispose to pharyngeal collapse³⁰. On the other hand OSA itself may modulate the secretion of hormones and other biological mediators which in turn lead to obesity.

It is proved through longitudinal cohort study that a 10% weight loss was associated with a 26% decrease in AHI³⁴. It is also proved that weight loss could result in complete resolution of OSA in the mild-to-moderate AHI range³⁵. Weight reduction is best achieved by reducing energy intake through dietary modifications and enhancing energy expenditure through physical activity. Bariatric surgery has been used and shown to improve the metabolic profile as well as sleep-disordered breathing in morbid obese individuals.

 

OSA and Insulin Resistance

Insulin resistance and glucose intolerance are two essential components of metabolic syndrome. There are evidences of positive and independent association between OSA and insulin resistance or glucose intolerance³⁶. Subjects with OSA may have multiple factors leading to insulin resistance and glucose intolerance. Central obesity itself leads to insulin resistance through increased lipolysis and fatty acid availability³⁷. Insulin resistance was observed not only in obese, but also in the non-obese patients suffering from OSA³⁸.

In the Wisconsin Sleep Cohort study conducted on 1300 subjects, an independent relationship between OSA and diabetes was not established even after 4-year follow-up, despite a higher prevalence of diabetes in OSA subjects³⁹. Intravenous glucose-tolerance test did not show impaired insulin sensitivity or impaired insulin secretion in diabetic with OSA.

OSA and Dyslipidemia

Obesity is associated with increased plasma lipids, and adipose tissue distribution⁴⁰. The American Sleep Heart Health Study reported that HDL-cholesterol levels were inversely related to AHI levels, independent of obesity. Similarly triglycerides levels were positively correlated with AHI in younger men and women, but not in elderly⁴¹. Many patients attending the sleep clinic show a higher prevalence of dyslipidemia compared with those without OSA, after adjustment for BMI. Significant association between high AHI and presence of CAD and dyslipidemia was shown by case-controlled studies. Even though few observational studies reported that treatment with nasal CPAP improved lipid parameters; it was not validated through randomized, controlled studies. It is proved that low-density lipoprotein is more injurious to endothelial cells and underlying smooth muscle cells, and is thus more atherogenic.

Pathogenesis of cardio-metabolic dysfunction in OSA

Intermittent hypoxemia with re-oxygenation and sleep fragmentation, may lead to multiple events altering cellular metabolism.  Obstructive sleep apnea is considered to be a chronic stress state with activation of neuro-humoral pathways that participate in metabolic regulation. Obese subjects have increased sympathetic activity, and in subjects with OSA there is further elevation of sympathetic activity more than what is attributed to obesity⁴². Surges of sympathetic over activity, causes transient increases in systemic blood pressure. Sympatho-adrenal activation persists in the day, as evidenced by sympathetic nerve activity and catecholamine output⁴³. This sympathetic activation may modulate many other mechanisms or mediators, including the angiotensin-renin system, insulin and adiponectin, which may all contribute to cardio-metabolic dysfunction in OSA⁴³. Sympathetic over activity in OSA, is an important factor in the pathogenesis of hypertension⁴⁴. At the same time its role in glucose and lipid metabolism is less clear. Changes in the duration or quality of sleep may affect neuroendocrine and metabolic function⁴⁵. OSA subjects have been reported to have altered pattern of cortisol secretion⁴⁶. Obstructive sleep apnea may also modulate hormones that regulate energy metabolism. These patients have lower leptin levels, in proportion to weight gain⁴⁷.

The recurrent intermittent hypoxia with reoxygenation, may result in generation of oxidative stress, which itself lead to cardio-metabolic dysfunction⁴⁸. Obesity and the metabolic syndrome have been associated with this enhanced oxidative stress⁴⁸. It is proved in animal models that intermittent hypoxia induces various metabolic alterations, such as insulin resistance and dyslipidemia⁴⁹. These patients have increased levels of various oxidative stress markers, such as nitric oxide, 8-isoprostane, reactive oxygen species, and lipid peroxidation.

It is believed that inflammation plays a pivotal role in the pathogenesis of endothelial dysfunction, insulin resistance and lipid peroxidation. Inflammation is a key component in OSA. Inflammation in OSA, independent of obesity, is evidenced by activation of neutrophils, lymphocytes, monocytes, and platelets; activation of NF-κB and increased circulating levels of pro-inflammatory cytokines⁵⁰. Expression of adipocytokines in obesity state is associated with inflammation. In obesity, inflammation occurs in adipose tissue and has an impact on glucose, lipid and energy metabolism. It is possible that OSA-induced intermittent hypoxia may interact with adiposity to promote metabolic dysfunction.

Intervention

Nowadays, the focus is on primary prevention of coronary artery disease (CAD), which means risk factor modification. Early recognition of risk factors and primary prevention have significantly decreased the morbidity and mortality associated with CAD. The risk assessment and preventive therapy is a combined decision taken by the patient and their physician. Modifiable risk factors for coronary artery disease include:

·         Type 2 diabetes mellitus

·         Hypertension

·         Smoking

·         Dyslipidemia

·         Obesity

·         Metabolic syndrome

Lifestyle modification with diet, exercise, and smoking cessation is crucial to reduce cardiovascular risk factors. Further control of hypertension, diabetes, and hyperlipidemia is essential to reduce the risk of CAD. Replacing saturated fats with dietary mono-saturated and polyunsaturated fats are found to be beneficial to reduce cardiovascular risks. Besides, dietary sodium reduction is found to have reduced blood pressure and decreased risk for cardiovascular events.

Physical activity is also equally beneficial for CAD risk reduction. Moderate activities like brisk walking, cycling, active yoga, and swimming or vigorous activities like jogging/running, biking playing tennis, etc. may help in reducing the risks. Weight loss has consistently shown to improve the cardiovascular risk profile. Strong recommendations include high levels of physical activities, low-calorie diet, and if possible, weight-loss maintenance programs.

Control of hypertension by pharmacological management along with non-pharmacological measures is recommended to reduce cardiovascular morbidity. Weight loss also has a positive impact on lowering blood pressure.

Diabetes mellitus is another important cardiovascular disease risk. Dietary modifications using a heart-healthy diet and physical activities are encouraged. Additionally, weight loss is recommended if the individual is overweight or obese. Metformin can also be considered as first-line therapy for type 2 DM to improve the glycemic index and reduce cardiovascular risk.

Most of the above measures have a positive impact on obesity and OSA. These measures also help to control the two important health risk of metabolic syndrome such as diabetes and hypertension. OSA symptoms are well controlled on weight reduction and many of the pathophysiological changes associated with OSA can be controlled with weight reduction and CPAP therapy.

Conclusion

Obesity is a primary determinant of OSA and metabolic syndrome. OSA can modify the components of metabolic syndrome and vice versa. Early diagnosis and treatment of OSA is the cornerstone in the management of metabolic syndrome and hence CAD. The important measures include weight reduction, regular exercises, control of hypertension and diabetes, along with treatment of OSA. Thus clinicians should keep high index of suspicion for obesity, OSA and MetS while dealing patients with cardiovascular morbidity.

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Malignant Transformation of Thymoma After 26 Years

 

Recurrence and Malignant Transformation of Thymoma After 26 Years – A Rare Presentation

Ramseena Ibrahim¹, Sanjeev Shivashankaran², Jesin Kumar³, Ravindran Chetambath⁴

 

Abstract

Thymoma is a mediastinal tumour with malignant potential, which has a recurrence rate after complete resection ranging from 5 to 50%. It is an epithelial neoplasm of the thymus, which commonly lies in the anterior mediastinum. Here we present an interesting case of a 58 year old female patient on treatment for Myasthenia Gravis for the past 26 years. She had undergone   thymectomy with dissection of pericardium and adjacent pleura 26 years back. Now she had presented with worsening myasthenia symptoms, underwent treatment comprising of steroid pulse therapy and plasmapheresis along with regular medications. She was evaluated for left lung collapse, which revealed a thymoma involving left lung and a solitary deposit on the right side probably metastasis. Though the recurrence rate of thymoma is high, this case is unique as it recurred as malignant thymoma after 26 years.

Keywords: Thymoma, thymic carcinoma, myasthenis gravis, recurrence

Introduction

The thymus is a lymphoepithelial organ that is derived embryologically from the third and fourth pharyngeal pouches, which descend to the anterior mediastinum in the sixth week of human gestation. ^[1] Thymoma is the most common neoplasm of the anterior mediastinum, accounting for 20-25% of all mediastinal tumors and 50% of anterior mediastinal masses. Thymoma accounts for <1% of all adult malignancies. Thymic carcinoma is a rare carcinoma of the thymus representing less than 1% of thymic malignancies. Arising from the thymic epithelium, it exhibits an overt propensity for capsular invasion and metastasis. Patients with mediastinal thymomas are often clinically asymptomatic (50%-60%) or present with local symptoms (30% -40%) or with associated systemic parathymic disease syndromes (30%-40%). Myasthenia gravis (MG) is the most common systemic parathymic syndromes. About 30-40% of patients who have a thymoma experience symptoms suggestive of MG and 20% of patients suffering from MG is associated with thymoma. The prognosis is worse for patients with symptomatic thymomas because these patients are more likely to have malignant thymomas. The single most important factor predicting the outcome of patients with thymomas is evidence of invasion. All thymomas have to be resected due to their malignant potential.  Malignant thymomas are often fatal with metastasis to regional lymph nodes, bone, liver and lung. ^[2] Patients presenting with advanced disease have a 5-year survival rate of 30-50%.

 

Case Report

A 58-year-old female, a known case of myasthenia gravis since 26 years and diabetes mellitus since 10 years on regular medications with pyridostigmine and metformin, reported with complaints of gradually worsening breathlessness since three months and intermittent episodes of fever since 10 days. Her past history suggested that she had ocular myasthenia with thymic shadow on x-ray 26 years back. CT thorax showed an anterior mediastinal mass suggestive of thymic mass. Median sternotomy was done followed by dissection of thymus with removal of pericardium and its adjacent pleura as the tumour extended to the pericardium and mediastinal pleura. There was adherence to pericardium. Histopathology report of the dissected specimen was benign thymoma with residual persistent thymus and features of thymic hyperplasia. There was no evidence of malignancy.

 

On examination at presentation in the outpatient, she had tachycardia, tachypnea and an oxygen saturation of 88% on room air. There were features of oculo-pharyngeal myasthenia and respiratory system showed features of left lung collapse. Chest x-ray showed complete left lung collapse with ipsilateral tracheomediastinal shift (Figure 1). Arterial blood gas analysis showed hypoxemia with respiratory alkalosis. Contrast enhanced CT thorax revealed a left lung mass with intraluminal extension into left main bronchus and complete collapse of left lung (Figure 2). It also showed a well-defined lobular mass on right lower lobe (Figure 3). Fibreoptic bronchoscopy was performed which showed a lobulated mass with smooth margins obstructing left main bronchus (Figure 4). Bronchoscopic biopsy from mass showed undifferentiated carcinoma and immune-histochemical analysis (IHC) analysis revealed B3 Thymoma. Histopathology showed lobulated architecture with cellular lobules, intersecting fibrous bands, epithelial cells and lymphocytes (Figure 5). Focal cystic changes were also seen. 

  

 Figure 1: X-ray chest PA (incomplete film) showing left lung collapse. There is a small ill-defined opacity in the right midzone. Sternal wires due to previous thoracotomy are visible.

 

 

Figure 2A: shows a mass with necrosis and intraluminal extension to left main bronchus; 2B: shows complete collapse of left lung with ipsilateral mediastinal shift.

 

Figure 3 A: shows collapse of left lung; 3 B shows an irregular lobulated nodular density in the right lower lobe.

 

Figure 4A & B: showing highly vascular intraluminal lesion occluding the left main bronchus

 

 

Figure 5: Low magnification (A) showing lobulated architecture with cellular lobules and intersecting fibrous bands, High magnification (B) showing neoplastic epithelial cells, various lymphocytes associated with focal cystic changes

 

Discussion

This case report refers to a rare presentation of benign thymoma associated myasthenia gravis recurring after 26 years with malignant transformation. The thymus is a lympho-epithelial organ that is derived embryologically from the third and fourth pharyngeal pouches, which descend to the anterior mediastinum in the sixth week of human gestation.^[1^] Thymomas are an uncommon heterogeneous group of anterior mediastinal tumors that are generally considered benign. But it is a potentially malignant tumour. Usually complete resection is advised to prevent malignant transformation. When presenting with myasthenia gravis, thymus is resected even if there is no thymic enlargement.  Thymic carcinoma on the other hand is a rare carcinoma of the thymus representing less than 1% of thymic malignancies. Arising from the thymic epithelium, it exhibits an overt propensity for capsular invasion and metastasis. The presence of cytological features of overt malignancy differentiates it from thymoma.^[3^]  

Thymomas occur in all ages, but there is a broad peak between 40 to 60 years of age. The gender distribution of thymoma is approximately equal, although it is slightly more common in women in older age groups.^[4^] 

               Patients with mediastinal thymomas are often clinically asymptomatic (50-60%) or present with local symptoms (30- 40%) or associated systemic parathymic disease syndromes (30-40%). Vague chest pain, dyspnea, and cough are the common symptoms of thymomas. Myasthenia gravis is the most common systemic parathymic disease syndrome. Other paraneoplastic/autoimmune syndromes include neuromuscular syndromes such as Lambert-Eaton myasthenic syndrome and myotonic dystrophy, autoimmune diseases such as systemic lupus erythematosus, polymyositis, Sjögren syndrome and ulcerative colitis, endocrine disorders like Addison disease and hyperthyroidism, hematologic diseases such as hypogamaglobulinemia, red cell aplasia, pancytopenia and aplastic anemia. Malignant thymomas are often fatal with metastasis to regional lymph nodes, bone, liver and lung.^[2^]

According to the latest classification of histologic criteria for thymic epithelial tumors by the World Health Organization (WHO) Consensus Committee, published in 2004, thymic epithelial tumors are classified into two major categories:  thymoma (types A, AB, B1, B2, and B3) and thymic carcinomas.^[5] Reported lymphogenous and hematogenous metastases are uncommon.

Earlier literatures reported very few cases of retroperitoneal invasive thymomas.^[6] Treatment of thymoma is thymectomy with or without resection of adjacent structures depending on extent of tumor, whenever possible. Neoadjuvant chemotherapy or radiation or postoperative chemotherapy or radiation depending on stage and involvement of margins may be required. Relapse after primary therapy for a thymoma may occur after 10-20 years. Therefore, long-term follow-up probably should continue to be performed throughout the patient's life.

                      The International Thymic Malignancy Interest Group (ITMIG) has recently defined a standard set of definitions for recurrence.^[7^] The term ‘recurrence’ is appropriate if all disease has been potentially eradicated (R0 resection); recurrences are classified as local (anterior mediastinum), regional (intrathoracic not contiguous with the thymus), and distant (intrapulmonary and extrathoracic).

The recurrence rate of thymoma ranges according to different reports. In the study by Japanese Association for Research on Thymus (JART), among all the 2835 thymoma patients operated during 1991–2010, 420 (14.8 %) experienced recurrence.^[8^] The average disease-free time till recurrence was 5 years, and recurrence after 32 years of initial surgery was also reported.^[9^] The time to relapse was 10 years for patient of clinical stage I, and 3 years for patient of stage II, III and IV. Most recurrence are local and regional.^[10,11] About 46–80 % of recurrent cases are found in the thoracic cavity,^[12,13] and then in the mediastinum and lungs,^[14^] distant metastases occur in less than 5 % of the cases.^[15^] In the report of Detterbeck et al, among patients with recurrences, the pleural space or the lung was involved in 58% (most often as a nodule under the parietal pleura), the pericardium or mediastinum in 41%, bone in 10%, and liver in 8%. According to the study of The Japanese Association for Chest Surgery,^[16^] of 862 patients whose information is available, 67 (7.8 %) developed recurrence. The recurrence rates in stages I, II, III, and IV were 0.9, 4.1, 28.4, and 34.3%, respectively. Recurrence rate in thymic carcinoma is reported as 51%.

 

Conclusion

Thymoma with local extension to pericardium or pleura is often considered malignant. Even if the histopathology report is benign thymoma, it should be treated with radical surgery followed by radiotherapy. In such patients recurrence rate is high. These patients require lifelong monitoring. The case reported here had a histopathologically proven benign thymoma which was resected 26 years back. Peroperative findings suggested extension to pericardium and mediatinal pleura. Now the patient presented with intratoracic mass with lung collapse and histopathology showing evidence of B3 thymoma. Even though late recurrence is reported in thymoma, recurrence after 26 years with malignant transformation is rare.

 

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