8 Pericardium and mediastinum V

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VIRNAZAMPA, GIULIAGRANAI, PAOLAVAGLI

8.1 Pericardium

8.1.1 Introduction

Indications for a Magnetic Resonance Imaging (MRI) study of pericardial disease usually follow the findings of echocardiographic screening. Indeed, Computed Tomography (CT) and MRI are employed when the clinical symptoms are not in agreement with the echocardiographic findings, or when Echocardiography is inadequate because of technical limitations, or whenever a more specific characterization of the findings has been requested. In the specific case of expanding lesions involving the pericardium, MRI is always the best choice for diagnostic investigation: in fact transthoracic Echocardiography, just as Transesophageal Echocardiography (TEE), is con- strained by a limited Field Of View (FOV); CT is penalized by inevitable artifacts (especially when it is not synchronized with ECG) and, except for detection and measurement of calcifications, it seems to be inferior to MRI in characterizing the injury; furthermore, it scarcely differentiates effusions from epicardial thickenings. Therefore, MRI is generally preferred although it may give sub optimal results when pericardial disease is accompanied by arrhythmia.

8.1.2 Normal anatomy

The pericardium is formed of two layers that fold over the heart chambers, enveloping them all the way to the base of the great vessels. Its anchoring points to the sternum, spine and diaphragm limit excursion of this sac during movement of the body.

The visceral pericardium, formed by a single layer of mesothelial cells, is closely adherent to the cardiac surface, except in those areas where fatty tissue is interposing (in variable amounts from one individual to another). The fatty tissue is more abundant at the level of sulci and surrounds the vessels that run across the myocardium. The parietal layer often has a thick fibrous

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component and is separated from the visceral layer by a small quantity of serous liquid (15-50 ml).

The folds of the pericardium over the cardiac structures create recesses, which are: the oblique sinus, located behind the left atrium and separated from the pericardial cavity; the anterior-superior recess, which surrounds the aorta and the pulmonary a. (the distension of this structure allows to confirm the presence of pericardial effusion in the cases where it is difficultly identi- fied); the transverse sinus, located dorsally to the ascending aorta, which can erroneously be misinterpreted for aortic dissection. In fact in order to avoid such errors, it is important for the operator to have extensive knowledge on the anatomy of these structures.

The best images of the pericardium are acquired by cardiac gating. In absence of abundant pericardial fluid, the two pericardial layers are visual- ized in SE images as a thin single line with no signal, interposed between the high intensity of the mediastinal and subepicardial adipose tissue, and the intermediate signal of the myocardium. The best visualization of the pericardium is obtained in systole, about 200 msec after the R wave. In the regions near the lungs, such as in the postero-lateral region of the left ventricle, the sac is difficultly distinguishable from the pulmonary parenchyma.

The normal pericardium has a thickness of 2 mm [1]; measurements should be made on an image, on axial plane, that simultaneously represents the right atrium and the left and right ventricles. In more caudal images, pericardial thickness may be overestimated: either due to the ligamentous inser- tion of the diaphragm into the pericardium or to the images in axial view with tangential position to the inferior border of the heart and the relative pericardium.

8.1.3 Congenital disease

Congenital abnormalities of the pericardium are rare; they are classified in:

congenital absence or defects of the pericardium such as pericardial cysts, diverticoli, and theratomas.

The total absence of the pericardium is rare. The disease most frequently affects the left ventriculum (70%); in half of the cases the entire left portion is missing and there are partial defects in the remaining portions. In one third of cases, pericardial defects accompany other congenital defects (tetralogy of Fallot, defect of the atrial septum, patency of arterial ductus, bicuspid aortic valve, hiatus hernia, or bronchogenic cysts). Partial defects can lead to hernia of the heart or to compression on the coronary. Usually, the total absence of the pericardium remains asymptomatic. It can be sup- posed from the standard radiographic exam of the chest, which evidences the unusual contour of the heart that reveals the more defined borders of its segments. The absence of the pericardium, which generally folds between

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the aorta and pulmonary artery makes the edges of pulmonary artery more visible. Often the partial lack of the pericardium is accompanied by a shift of the heart to the left, sometimes with a blurred profile of the left ventricle.

MRI directly visualizes the altered pericardial anatomy and accurately demonstrates the extension of the defect, therefore providing a definite diagnosis.

Pericardial cysts have a congenital origin and develop separated isles of pericardial tissue during the embryonic stage; they are enveloped and do not have any connection to the pericardial space. Seventy percent of cysts are located on the right side and 90% of them are found within cardio-phrenic sulci; those located at other sites cannot be distinguished from bronchogenic or thymic cysts.

At MRI, pericardial cysts appear as para-cardiac masses with low signal intensity in the T1-weighted images and with high signal intensity in T2- weighted images. They show no internal septation, are homogeneous and with no changes after contrast agent administration, and are surrounded by a thin line of low intensity signal from the pericardial tissue. On rare occur- rences, they may contain protein-rich fluid, which gives an elevated intensity on T1-weighted images.

The pericardial diverticulum (congenital, or in consequence of a hernia through a defect of the parietal pericardium) contains a layer of pericardium and communicates with the pericardial cavity, with the result that its volume changes with the volume of the pericardial fluid. The signal characteristics are similar to those given by cysts and sometimes indistinguishable due to the impossibility of seeing an extremely small-sized passage (Fig. 8.1).

Theratomas and intra-pericardic bronchogenic cysts represent the most frequent benign tumoral lesions of the pericardium. MRI can be useful in demonstrating the relationship of the mass with contiguous anatomical structures and in characterizing the nature of the lesions.

Fig. 8.1 a, b. Pericardial diverticulus on the anterior-right border of the heart (postsurgery diagno- sis). The lesion gives an intermediate signal in “black blood” images (a), and hyperintensity in T2 (b) as typical for liquid lesions. In this case, the communication with the pericardial is not visible, which makes differential diagnosis with pericardial cyst impossible

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8.1.4 Pericardial effusion

Pericardial effusion derives from the obstruction of venous or lymphatic drainage of the heart, or from an altered capillary permeability that occurs in consequence to one of a range of causes (heart or kidney failure, infections, neoplasia, trauma, etc.).

MRI is very sensitive in detecting localized pericardial effusions, even of small dimensions; these deposits usually have an elliptic shape and are rec- ognizable in a posterior-lateral position to the right atrium and the left ventricle. Non-complicated effusions present the typical MRI signal emitted from liquids, while effusions rich of protein matter or of haematic nature show an increase in signal intensity in T1-weighted images (Figs. 8.2, 8.3). In particular, blood deposits usually yield a hyperintense signal in T1-weighted images and a low signal in cine-GRE images [1].

The shift of fluid in systole and diastole can be detected by cine-MRI, thus differentiating small effusions from limited pericardial thickenings [2].

8.1.5 Constrictive pericarditis

MRI represents the technique of choice in the evaluation of a patient with suspected constrictive pericarditis. If not idiopathic, the most common causes of this condition are heart surgery, radiotherapy, infections, connective disease, uremia, and neoplasia. In constrictive pericarditis the thickness of the pericardium, which can be measured directly by MRI, should be equal to 4 mm or thicker [2]; pericardial thickening can eventually be limited to the heart’s right section alone, or even to a less extended region. Such evaluation may become difficult in the presence of a concomitant effusion. The presence of calcium, typical of this pathology cannot be directly proved by MRI

Fig. 8.2 a, b.Haematic pericardial effusion due to heart rupture, complicating Acute Myocardial Infarction. In the T1-weighted (a) and triple IR (b), the effusion appears in-homogeneous due to the presence of partially organized haematic matter with medium intensity. Bilateral pleural effusion

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because the absence of signal from calcium is the same as that created by a thickening of the pericardium. A CT investigation is therefore mandatory.

The diagnosis of constrictive pericarditis is based on coexisting anamnes- tic, clinical and anatomical criteria (tubular left ventricle, dilatation of the right atrium and of the superior vena cava) and evidence of a thickening of the pericardium (Fig. 8.4).

It must be underlined that the detection of thickenings and calcifications of the pericardium are not indicative of constrictive pericarditis if there are no coexisting symptoms and clinical signs.

8.1.6 Hematoma

MRI is particularly useful in the diagnosis of pericardial hematoma due to the peculiar signal characteristics emitted from the catabolites of hemoglo- bin, which can lead the operator to the nature and the date of the bleeding.

Hematomas in a sub-acute phase show a heterogeneous signal with high intensity areas in T1 and T2 images. The organized chronic hematomas present areas of low signal intensity which are seen better in GRE images in relation to calcifications and hemosiderin.

Fig. 8.3 a-c.Patient with previous cardio-surgical intervention complicated by purulent pleu- ro-pericarditis. In the axial “black blood” images (a), triple IR (b), and cine-FIESTA (c) under- score the pleural and pericardial deposit, the latter partially organized and hypointense in cine images. In addition there is purulent material in the left paracardial region with small gaseous bubbles

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Fig. 8.5 a, b.Pericardial mesothelioma. The broad thickening of the pericardium in T1-weighted images (a, b) and the neoplastic involvement of the pleura

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Fig. 8.4 a-c.Constrictive pericarditis. In the T1- weighted image (a) a thickening of the peri- cardium >4 mm can be detected in correspon- dence to the right atrio-ventricular groove; the intermediate signal intensity from the inside the right atrium can also be seen as a consequence of the slowed blood-flow. The cine-FIESTA images on the axial (b) and sagittal (c) plane put into evidence the dilatation of the left atrium, the tubular aspect of the right ventricle, and the dilatation of the inferior vena cava

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The absence of flow and the detection of the contrast agent are the elements that differentiate the hematoma from pseudoaneurysms and masses of other nature.

Pericardial tumors are treated in detail ahead in the chapter on cardiac tumors. Here, special mention should be given, however, to the malignant primary mesotheliome of the pericardium that can manifest itself as an isolated effusion, and only on occasions is associated to nodules with a specific signal characteristics (Fig. 8.5). In the case of pleural mesotheliome it is not rare to incur in a case of a direct invasion.

8.2 Mediastinum

8.2.1 Introduction

This part of the chapter deals with indications and limits of applying MRI to non-vascular pathology of the mediastinum and in particular to tumors. MRI represents a useful complement to CT whenever it becomes necessary to establish through multiplanar vision the exact spatial relation between masses and surrounding structures. Despite the fact that continuous methodological and technological developments have lead to a marked improvement of image quality, MRI is not a routine procedure in the study of the mediastinum, where instead CT is the technique of choice. Yet, in the evaluation of mediastinal masses, MRI can provide information on the tissue components of a lesion that, together with shape, dimension, and geographic location represents the base for differential diagnostics of the tumoral pathology of this district.

The most frequent cases in which MRI is suggested are: tumors of nerv- ous origin, pre-operatory evaluation of mediastinal tumors, and patients with contraindications to iodinated contrast.

8.2.2 Technological and methodological aspects

The mediastinum is an anatomical district located between the two pleural cavities, the diaphragm and the superior thoracic outlet, and includes sever- al anatomical structures, among which the heart and the great vessels. The artifacts caused in these regions by breathing and flow can be reduced by syn- chronizing the acquisition with cardiac and respiratory cycles, or by making the acquisition during breath-holds.

Synchronization with heart beat is performed with the application of elec- trocardiographic triggering: to obtain an adequate R wave, specific MRI elec- trodes are positioned on the rib cage or on the patient’s back as in the study of the heart.

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According to the clinical aim, the technique employs either a body coil, a surface coil, or a phased array – whichever is the most suitable for increasing the Signal-to-Noise Ratio (SNR).

To study the mediastinum, it is advisable to begin by acquiring a first series of T1-weighted coronal images with a large thickness for a first impres- sion on the conditions of the mediastinum and of the chest; this will help position the subsequent axial acquisitions. The integration of the two planes allows the analysis of those regions of the mediastinum that are difficult to evaluate with other techniques, such as the aorto-pulmonary window or the sottocarenal region.

T1 and T2 axial images, with a thickness ranging according to the diagnostic query, are synchronized with the cardiac and/or respiratory cycle; the flow signal is saturated to minimize the artifacts. The fast sequences or the Turbo T2-weighted sequences, that have substituted conventional T2 SE thanks to their much shorter acquisition times, are acquired with prospective respiratory gating. This allows the acquisition of data during the expiratory phase, eliminating the artifacts caused in most part by the subcutaneous adipose tissue. In conventional T1-weighted acquisitions, respiratory compensa- tion is used instead; this procedure retrospectively reorganizes the encoding lines of K-space in a manner that eliminates the artifacts.

The study of flow is performed with GRE sequences. Thanks to the use of a very short TR, the images can be acquired in breath holding or, if the patient is not compliant, in free breathing by using an ECG trigger approach (cine-MRI).

At present, ultrafast sequences such as SSFP are available and are preva- lently used for kinetic studies that allow to perform acquisitions in breath hold (See Chapter 7).

Finally, for the study of the sovraclavear o retrosternal region, the use of a sagittal scanning plane is recommended.

8.2.3 Clinical applications

The main application of MRI for the study of the mediastinum is in cases of tumoral pathologies, with the aim of obtaining a more accurate characterization of the mediastinal masses of various nature.

Primitive tumors of the mediastinum are represented by a heterogeneous group of neoplastic, congenital, and inflammatory alterations; approximately 2/3 of the lesions are of benign nature. The lesions, sub-grouped according to their location, are:

– Anterior mediastinum (posterior to the sternum and anterior to the heart and vessels)

Thymic pathologies, mediastinal goiter, parathyroid adenoma, lymphan- gioma, dysontogenetic tumors.

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– Medium mediastinum (includes heart and vessels, trachea and bronchi) Cysts (bronchogenic, henterogenic, pericardial), carcinoma of the esopha- gus.

– Posterior mediastimun (delimited frontally by the heart and extending to the thoracic vertebrae) Neurogenic tumors, lymphomas which are ubiqui- tous in this district.

Tumors of the thymus are the most frequent tumors of the anterior mediastinum. There are no characteristic MRI signal features that aid in differentiating these lesions from other mediastinal expansive lesions. In T1-weighted images thymomas have a signal similar to that of muscle and a high signal in T2-weighted images, sometimes inhomogeneous due to the presence of cystic, necrotic, or hemorrhagic components (Fig. 8.6). The spreading of the tumor beyond the capsula and infiltration of neighboring structures are indicative criteria of malignancy of the lesion (invasive thymoma, Fig. 8.7); a multinodular aspect of the lesion in T2 is more frequently described with invasive thymomas.

MRI is sometimes used in the pre-surgical phase and in the posttherapy follow-up of the tumoral pathology of the thymus, to get a better contrast resolution than that provided by CT, especially in the evaluation of the invasion of surrounding structures.

Carcinomas of the thymus are a heterogeneous group of malignant epithelial neoplasias that have a local invasiveness and metastasic potential.

They are masses with scarcely defined limits, infiltrating, often associated to pleural and pericardial effusion. The differential diagnosis with invasive thymoma in absence of metastasis and enlarged lymph nodes is difficult.

Fig. 8.6 a, b.Thymoma. The lesion presents a hemorrhagic component that can be recognized in the T1-weighted image (a) for its hyperintensity and the presence of a cystic component, which is well defined in the T2-weighted image (b)

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The thymic carcinoid is a rare neoplasia with characteristics similar to those of carcinoids of other districts; endocrine alterations are found in 50%

of cases (often the Cushing syndrome), while the classical form has low inci- dence. It manifests itself as a lobulate mass with cystic and necrotic areas, sometimes with pointy dystrophic calcifications, and often tends to local invasiveness. Metastases of lymph nodes are reported in 73% of cases [3].

The thymolipoma is a rare benign tumor with slow growth, mostly in young adults. It manifests itself as an encapsulated mass formed by adipose and thymus tissue that often extends to the antero-inferior mediastinum and is characterized by the fact it changes shape with movement of the body. MRI reveals the classical combination of parenchymal and fatty tissue; if the latter is prevailing, this structure may not be distinguishable from a lipoma.

The use of MRI for the study of thyroidal masses is rare; sometimes the study of large goiters plunged into the mediastinum is requested to get a better picture (than that provided by CT images) of the altered anatomy and on the relationship between the goiter and the neighboring structures.

A true utility of MRI is found instead in the evaluation of parathyroid adenomas located within the mediastinum, which is a district of difficult explo- ration by means of echo-Doppler; also CT, which is limited to axial scanning, provides a less elegant and clear representation of the cervical-thoracic outlet. The examination of the neck is performed with a surface coil, a small FOV (16-36 cm), and a thin scanning thickness (3-5 mm) because of the small size that the ademomas usually have. The study of the mediastinal region implies the use of larger FOV (28-36 cm) and of coils suitable for this district.

Fig. 8.7.Invasive thymoma. Voluminous thymic neoformation that has invaded the mediastinal fat and extends to the anterior chest wall

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The “typical” parathyroid adenoma is characterized by a low and high signal, respectively in the T1- and T2-weighted images (Fig. 8.8a, b), and has a marked enhancement after administration of the contrast agent. There have also been cases of adenomas with low signal in T2 [4] or hyperintense in the T1-weighted images (Fig. 8.8c, d).

The diagnostic accuracy of MRI reaches high values especially if the anatomical findings correlate to the functional findings of scintigraphy [5].

Dysontogenic tumors represent 10-15% of the primitive masses in the mediastinum and are usually found in young adults. They occur more frequently in the anterior mediastinum (only 5% in the posterior); in 80% of the cases they are benign.

A theratoma is a capsuled tumor characterized by the coexistence of solid areas and cystic areas; it contains elements of various origin: ecto-(teeth and

Fig. 8.8 a-d.Typical parathyroid adenoma. Typical signal features by the retrosternal lesion: low intensity in T1 sagittal image (a), and a high intensity in the T2-weighted axial image (b). A differ- ent case with atypical signal features: high signal intensity in T1 (c) and STIR (d) sequences a

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hairs), meso-(bone), and endodermic (intestinal and pancreatic tissue). The presence of solid tissue is described in almost all theratomas; the presence of liquid component in 76%, and calcium in 54%; these elements together are present in 36% of cases, while 15% are purely cystic [6]. A liquid/fat level is considered highly indicative of these lesions, yet quite rare [7]; in these pathologies it is important to adopt techniques for fat suppression to dis- criminate the adipose component from a macro-hemorrhagic area, which are both hyperintense in T1.

In MRI images the aspect varies according to the composition of the tumor: cystic areas, fat, liquid/fat levels, focal and linear calcifications, and ossifications are peculiar to these lesions; the pleiomorphic aspects of such tumors allow a differential analysis with lesions of the thymus or lymphomas.

However, MRI is less reliable in recognizing calcification compared to CT.

Immature tumoral forms (seminomas: malignant tumors of germinal cells) do not have specific characteristics and their malignancy is hypothe- sized based on their tendency to infiltrate other surrounding structures and the presence of metastases. Tumoral masses can be scarcely delimited; calcifications are rarer and a capsule enhanced by contrast medium is usually observed. In these cases it is important that serologic results (such as values of AFP,β-HCG) and imaging features correlate. Indeed, the values of AFP and β-HCG are positive in case of malignant tumor of the germinal cells, and only 10% of subjects with seminoma have high values ofβ-HCG, while AFP values are always in normal range.

Congenital cystic lesions (bronchogenic, esophageal duplication, neuro- henteric, pericardial and thymic) represent 15-20% of the mediastinal masses: they are spherical lesions, well delimited by a capsule, with liquid contents, and delimited by epithelium. In MR images they appear characterized by the typical signal emitted by liquids (low T1 and high T2). Cysts with non-serous liquid contents given by the presence of proteins, hemorrhage, calcium, or mucous can yield higher attenuation values with CT (>20 HU), and perhaps do not appear in T1-weighted MR images with the typical signal of liquid.

Such lesions preserve however a high intensity in T2-weighted images, which is extremely useful, together with the feeble wall enhancement by the contrast medium, for a differential diagnosis with solid masses [8] (Fig. 8.9).

The mediastinal lympho-angioma represents 0.7-4.5% of tumors in the mediastinum and is typical of the newborn and infants. It is formed by mul- tiple cyst-like formations, sometimes snake-like, typically located in the region of the neck or axilla. Approximately 10% later extend to the mediastinum [9]. These tumors are grouped according to the size of the lymphatic vessels into: simple (capillaries), cavernous, or with cysts. The latter are the most common.

In MR images the lympho-angioma is characterized by signal heterogene- ity in T1 images, the high intensity signal in T2 (indicative of liquid contents), and by marked enhancement of septa after administration of the contrast

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agent. The recognition of the septa inside the lesion is more immediate with MRI than with other techniques.

MRI represents the technique of choice in the study of neurogenic tumors (10% of the mediastinum masses in adults, 30% in children) that are typically located in the posterior mediastinum, owing to the more sophisticated and reliable demonstration it offers on the relations of the tumor with the conju- gation foramens, the spinal canal, spinal chord, and bone [10]. The age of the patient and the growth pattern are the pivotal elements for establishing the benign or malignant nature of the lesion. The tumors originating from the peripheral nerves and from myelin coating are more common in the adult (schwannoma, neurofibroma and neurogenic sarcoma); those originating from the sympathetic ganglia are more common in children (ganglioneuroma, ganglioneuroblastoma, neuroblastoma).

The schwannoma or neurinoma grows eccentrically from the nerve of origin, compressing the fibers of the nerve; it has a pseudo-capsule, and MRI generally shows a high central signal intensity in relation to the cystic degeneration and an outer component with lower signal intensity, in T2-dependant images; usually the enhancement following the administration of a contrast medium is marked (Fig. 8.10).

Contrarily to the neurinoma, the neurofibroma grows centrally to the nerve which remains trapped in the mass; it is non-capsulated and usually presents a high signal in T2, at times with a ‘salt and pepper’ or ‘target’ aspect;

Fig. 8.9 a-c.Bronchogenic cysts. The lesion has an intermediate signal in the T1-weighted image (a); the hyperintensity of the signal in T2 (b) and the missing caption of contrast agent (c) are sug- gestive on the cystic nature of the lesion

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it has a central fibrous area of low signal intensity enhanced after contrast administration, and a distal area of high signal and a mixed contents that does not show enhancement after administration of the contrast. This aspect is not found in all cases and can resemble a neurinoma, but is however a sign of benignancy. The cystic degeneration is more rare than in the case of neurinoma. Both tumors can grow inside the conjunction foramens and extend into the spinal canal.

Radiological imaging offers a scarce aid in diagnosing the malignant form of peripheral nerves; criteria suggesting malignancy (dimensions, surrounding oedema, hemorrhage-related lack of homogeneity and necrosis, invasion of the adipose planes, involvement of lymph nodes and bones, pleural effusion) are non-specific and with no absolute value.

The ganglioneuroma is a benign tumor that affects teenagers and young adults; they are undistinguishable from other neurogenetic tumors even if a

Fig. 8.10 a-c.Mediastinal neurinoma. In the T2- weighted image (a) the lesion presents charac- teristic in-homogeneous signal with central hyperintensity in relation to cystic degeneration, and a peripheral component of lower signal intensity that clearly presents the captation of contrast agent (c). Coronal T1-weighted pre-con- trast image (b)

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spiraloid aspect has been described as typical in T1-weighted images, which corresponds to layers of Schwann cells and collagen fibers, and heterogeneous hyperintensity of the signal in T2-weighted images.

The high intensity of the signal in T2 is related to the abundant mixoid component, and scarce cellular and fiber component; on the other hand an intermediate signal indicates hypercellularity, an abundant fibrous component and a scarce mixoid component (Fig. 8.11). In dynamic studies, enhancement is not homogenous, but rather delayed and gradually increases over time [11].

The ganglioneuroblastoma affects children of older age groups in respect to the neuroblastoma and is less common. It can appear as a large round mass or small and elongated. The larger masses show minimal or no signal change after administration of the contrast medium. Most neuroblastomas occur in children below 5 years of age and origin in the suprarenal glands, 15-30% in the mediastinum. The extradural invasion of the spinal canal is frequent, sometimes asymptomatic and can be accurately demonstrated by MRI.

Lymphomas (especially that of Hodgkin), represent one of the most frequent neoplasias of the mediastinum both as an isolated manifestation and as a disease associated to a systemic involvement. CT continues to be the technique of choice in the staging of this pathology as it can also evaluate an eventual involvement of the pulmonary parenchyma. The use of MRI for

Fig. 8.11 a, b.Ganglioneuroma. The lesion appears markedly in-homogeneous; there is a recogniz- able mixoid component at the center, and a peripheral portion of fibrous nature, rich of cells with intermediate intensity. The relationship of the mass with the intervertebral foramen is well visible in the coronal (a) and the sagittal (b) images

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evaluating the activity of the disease of the lymphomatose residues treated with chemo- and radiotherapy is still argued and non-reliable.

A study [12] that analyzed the changes of the signal from the masses sub- jected to treatment after the introduction of a contrast agent demonstrates that in cases of total remission, enhancement of the residual mass decreases until reaching the enhancement of muscular tissue; a marked enhancement and a growth in size represent fundamental points in the diagnosis of per- sistence or reactivation of the disease.

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