Radiation diagnostics of sarcoidosis in modern conditions is CT, supplemented by radionuclide studies (SPECT, PET), ultrasound, MRI. The paper describes the classic signs of pulmonary sarcoidosis (according to the Statement on Sarcoidosis, 1999), which have changed their characteristics due to the widespread use of CT: variants of lymphadenopathy, dissemination, interstitial involvement. New unfavorable forms of thoracic sarcoidosis are discussed: fibrous sarcoidosis (with a description of the variants of sarcoid fibrosis and their differences from other progressive pulmonary fibrosis) and progressive sarcoidosis (possible causes and patterns). Radiation semiotics of extrapulmonary and comorbid manifestations is touched upon.
- pulmonary sarcoidosis
- systemic sarcoidosis
- comorbidity in sarcoidosis
- radiation diagnostics
- computed tomography
Sarcoidosis is a polysystemic inflammatory disease of unknown etiology, related by its morphological characteristics to the group of lymphotropic granulomatosis with the formation of noncaseating granuloma, most often the disease reveals, itself as pulmonary sarcoisosis (PS) manifestations [1, 2]. The clinical and radiation symptoms of PS are well studied and defined by the American Thoracic Society (ATS), the World Association for Sarcoidosis and Other Granulomatous Diseases (WASOG), the European Respiratory Society (ERS) and the Russian Respiratory Society [2, 3, 4]. On the basis of the traditional X-ray picture of the process, Scaddıng J.G. , identified 5 stages of PS, which are used to this day, in a modified version of the assessment by computed tomography (CT). In recent decades, due to the widespread use of CT in patients with РS, there have been revealed changes in the lungs that are not characteristic of this disease and go beyond the stages of its generally accepted radiological classification. According to various authors, the frequency of atypical forms of РS varies from 2–25% or more of all detected cases [6, 7]. In recent decades, there has been an increase in the number of cases of atypical and progressive variants of the course of sarcoidosis, including the formation of fibrosing sarcoidosis of the lungs, damage to vital organs (kidneys, heart, central nervous system) requiring transplantation, and an increase in mortality from sarcoidosis [8, 9]. The ineffectiveness of the treatment has led to the identification of a separate form - refractory sarcoidosis . Most often, sarcoidosis is treated by pulmonologists (since the main manifestation of the disease is РS), a thoracic radiologist who is well aware of the radiation semiotics of disseminated lung processes works with them. However, sarcoidosis is systematic, which requires a pulmonologist to know about possible variants of damage to other organs and systems, and from a radiologist about the radial signs of their damage, the ability to analyze multimodal studies and draw up an optimal radiation algorithm to identify all systemic changes . The incidence of organ damage in sarcoidosis varies across studies, which makes these figures not very reliable (this is probably due to the use of hospital design in most studies, which includes patients with sarcoidosis observed in certain clinics; studies using population design, based on national or regional registers are considered to be the best). It is clear that the likelihood of extrathoracic lesions is very high and underestimated, since they are mostly favorable, asymptomatic (like most of the РS). Isolated extrathoracic lesions in sarcoidosis are very difficult. They mimic various diseases, are poorly recognized without the support of a pulmonologist, are confirmed only morphologically, are often the reason for multiple revisions of morphological data (they will not be considered in this study). The multisystem nature of the lesion can lead to a significant decrease in the patient’s quality of life . Extrathoracic lesions in sarcoidosis require additional examination under the supervision of a physician of the relevant specialty. Now, the criteria for cardiosarcoidosis and neurosacoidosis have been published; there are no clear recommendations on the volume and methods of radiation studies in other localizations. Thus, in general clinical practice in the absence of symptoms, a basic eye examination is proposed for screening ocular sarcoidosis, a basic serum creatinine test for screening renal sarcoidosis, a serum alkaline phosphatase test for screening liver sarcoidosis, an ECG for detecting possible heart damage . In determining the typical radiation semiotics of damage to various organs in sarcoidosis, the structured Delphi methodology is used, when the agreement of more than 70% of experts allows a consensus to be reached. This is necessary because a radiologist should be a member of a multidisciplinary team dealing with a patient with sarcoidosis, know the clinical manifestations, possible variants of systemic damage and the optimal radiation algorithm for examining patients with different risks.
While proceeding clinically favorably, sarcoidosis does not really bother the patient, however, comorbid lesions (neoplasms, infectious processes, PE) change both the clinical picture of the disease and its radiation signs [12, 13]. The different types of dissemination seen on CT scan suggest a comorbidity is present. To simplify the assessment of systemic damage in sarcoidosis, attempts have been made to create diagrams that simplify the diagnosis. So, in the work of Schupp J.C., et al. , five clinical clusters of sarcoidosis were proposed: (1) damage to the abdominal organs, (2) damage to the eyes, heart, skin and central nervous system, (3) damage to the skeletal muscle and skin tissue, (4) involvement of the pulmonary and intrathoracic lymph nodes, and (5) extrapulmonary involvement. In 2014, the World Association for Sarcoidosis and Other Granulomatous Diseases (WASOG), according to the Delphi study, proposed a probability scale : certain: the likelihood of sarcoidosis causing this manifestation is at least 90% (e.g.: uveitis, bilateral hilar lymphadenopathy, perilymphatic foci on chest CT); probable: the probability of sarcoidosis is 50–90% (for example: paralysis of the seventh cranial nerve, edema of the lacrimal gland, localization of the process in the upper lobes or diffuse peribronchovascular infiltrates); possible: the probability of sarcoidosis is less than 50% (for example: arthralgias, localized infiltration on radiographs). However, in practice, the use of these criteria is not always convenient. Studies in systemic and comorbid sarcoidosis suggest radiation multimodality (MRI, PET, SPECT, 67 Ga scintigraphy), however, CT with its various techniques (HRCT, functional tests, CT angiography) remains the main and at the same time expert method for its diagnosis, which allows and qualitatively answer the questions of the pulmonologist. The article discusses the changes detected during routine CT examination of patients with sarcoidosis, to which a radiologist should draw the attention of the pulmonologist. These findings can change the tactics of patient management and require additional radiation studies.
2. Radiation patterns of modern sarcoidosis (alphabet)
We analyzed the data of radiological studies of 873 patients observed with a diagnosis of sarcoidosis from 2006 to 2021 at the St. acad. I.P. Pavlova. The observation period ranged from 6 months to 22 years. The average age of the patients was 47.2 ± 10.2 years (f / m - 500/373). All patients underwent CT, a pulmonary function tests (PFTs), and echocardiography, in some patients, if necessary, additional radiation studies (MRI, PET, SPECT) were performed. CT data revealed a number of radiation signs of typical (determined by WASOG) and not contradicting (probable and possible by WASOG) РS, which a radiologist needs to know to interpret radiation data correctly. The typical nature of the lesion suggests the possibility of making a diagnosis without biopsy (since even the most benign biopsy options are not desirable due to the development of scars at the site of the surgical injury and the likelihood of a decrease in FVC and DLСО). Radiation signs that do not contradict the manifestations of sarcoidosis require the convening of a multidisciplinary council and a decision to conduct histological verification, atypical radiation manifestations need to be supplemented with morphology. An analysis of the results of radiation research revealed the following radiation features of modern РS:
The transition of РS in stages III and IV is accompanied by fibrosis processes (which, in a number of patients, requires the inclusion of the disease in the category of progressive pulmonary fibrosis). Typical are
Not contradicting the diagnosis of sarcoidosis is the identification of a “honeycombing lung”, which is rarely observed (1.9%), has a short length and can be localized both in the subpleural and in the basal regions. Preservation of lymphadenopathy and perilymphatic foci is possible at III and IV stages of the disease These forms belong to the unfavorable variants of the clinical course - fibrosing and progressive sarcoidosis. According to Xu L. et al. , in contrast to the “honeycombing” in the case of usual interstitial pneumonia (UIP), the “honeycomb” in РS is located centrally and is accompanied by traction expansion of large bronchi (bronchiectasis). It was noted that fibrous and active granulomatous patterns are present in the final stage of РS. Abehsera M. et al.  believe that two main models of fibrosing sarcoidosis of the lungs have characteristic radial and functional features: in peribronchovascular fibrosis, obstructive disorders in PFTs with a decrease in FEV1, an increase in OOL, with the formation of a “honeycombing lung” - restrictive disorders with PFTs with a decrease in FVC, DLCO. They also noted that progressive pulmonary sarcoidosis was characterized by the presence of chronic Aspergillus or bacterial infection. D. Valeyrea et al.  highlighted the same two main CT patterns of progressive pulmonary sarcoidosis with different functional profiles, noting that they may be with or without signs of activity, concluding that an algorithm based on pulmonary function and CT, allows predicting survival in progressive sarcoidosis. According to our data, 8.9% of patients had a severe course of the disease with dyspnea and radiation signs of fibrosis, which were not typical for the classical version of the course, the traditional radiation pattern and the existing X-ray classification of PS. Our analysis allowed us to identify several models of atypical pulmonary sarcoidosis.
According to M.H. Jeon, et al. , interstitial lung disease with pulmonary fibrosis and pulmonary hypertension was associated with increased mortality, with pulmonary fibrosis accounting for 9.0% of deaths in sarcoidosis. According to Sève P., et al.  fibrotic changes on CT in sarcoidosis correlate with PFTs, 6-minute walk test data (6MWT) and the results of the St. George respiratory questionnaire. Thus, a decrease in the ratio of the forced expiratory volume in one second (FEV1)/FVC may be associated with significant deformation of the bronchi, their stenosis due to fibrosis, due to diffuse bronchial granulomatosis, compression of the bronchi with a significant increase in the lymph nodes of the mediastinum, and as a result granulomatous bronchiolitis or bronchial hyperreactivity. Low DLCO values may result from diffuse parenchymal lesions or sarcoid alveolitis.
Calandriello L., et al.  write about new trends in the assessment of SP, pointing to new directions: attempts to assess the state of the lung tissue in sarcoidosis using artificial intelligence (radiomics), the wider use of low-dose CT and MRI programs of the chest.
The algorithm of radiation examination for sarcoidosis suggests performing CT to assess intrathoracic changes with the analysis of signs of damage to the organs of the upper abdomen included in the scan area (liver, spleen, lymph nodes, kidneys), supplemented by ultrasound of the abdomen, if necessary, CT examination of the chest and abdomen in the conditions of intravenous bolus contrast enhancement and the use of MRI, PET, SPECT with gallium as reserve methods for assessing the systematicity of the lesion and comorbidity. The decision to appoint additional radiation studies is made by a multidisciplinary council. According to Kobak S. , the prevalence of extrapulmonary sarcoidosis is up to 80%. However, it is not known how to assess the systemic nature of the lesion, because almost all patients have minimal extrathoracic radiation and clinical manifestations. It is believed that the skin, eyes, heart and musculoskeletal system are the most commonly affected organs after the lungs. There were reported rare lesions of the gastrointestinal tract and isolated cases of sarcoidosis of the prostate, bladder, bone marrow and thyroid gland. Multiple organ damage is always chronic and more severe, and can lead to a serious disability or potentially fatal consequences. At the same time, according to Jeon M.H., et al. , there is no data on a significant difference in PFTs indicators in patients with and without systemic manifestations. According to C.-W. Li, et al. , patients with PS and extrapulmonary lesions had more pronounced changes in CT examination in patients with stage II of PS. It is not known which of the combinations of PS and systemic manifestations are the most dangerous. According to our data, systemic lesion in PS is accompanied by changing the favorable course of the disease to a more severe one, symptoms of damage to other organs come to the fore, but the pulmonological multidisciplinary council continues to play a decisive role in the diagnosis. Thoracic changes are the most specific and make it possible to make a diagnosis, while extrathoracic changes may be similar to other processes. Most of the extrathoracic changes are clinically as favorable as classical PS and are detected by chance during additional studies (ultrasound, CT, MRI of the abdomen and pelvis). Others have a vivid clinical picture (neurosarcoidosis, sarcoid cirrhosis of the liver, sarcoid sialoadenitis, sarcoid uveitis), and some may manifest as sudden death (cardiac sarcoidosis). In all cases, the X-ray archive is very important, since at the time of extrathoracic symptoms, PS as a rule has already been delitescent for some time and can be identified retrospectively, even if it was overlooked in the initial analysis. Numerous attempts have been made to combine the symptoms of damage to different organs in sarcoidosis [9, 11, 14, 22, 23]. According to our data, the most frequent X-ray findings during chest CT were extrathoracic lymphadenopathy and damage to the parenchymal organs of the abdomen.
The lesion of the parenchymal organs of the abdomen in sarcoidosis is a frequent accidental finding during CT of the chest organs, because the liver, spleen and kidneys are partially covered by the scanned area.
E.D. Crouser, et al.  showed that
Polysystemicity presupposes the lesion of other organs, so, according to Lee J.K.T., et al. , an autopsy found sarcoidosis of the pancreas, intestines and testicles in 5% of patients. In our study, pancreatic sarcoidosis was suspected in 1 patient with increased metabolism of 18-FDG on PET, intestinal sarcoidosis was not detected, testicular sarcoidosis was an accidental finding during PET in 2 patients (0.2%) (increased metabolism 18 -FDG) and not manifesting clinically. Patient I., 46 years old. Systemic sarcoidosis. Lymphadenopathy of the peritracheobronchial groups, perilymphatic dissemination in the lung tissue are typical manifestations of SP II st. (Figure 5m), the absence of anatomical changes in the testes on CT (Figure 5n), high metabolism of 18-FDG in them on PET (Figure 5o).
The relationship between the radiation signs of
The combination of
For sarcoidosis, combinations with pulmonary inflammatory processes, both nonspecific and specific, are rare. The most common were the combination of sarcoidosis with COVID-19 lung damage (5.1%) and the formation of mycetomas in the sarcoid cavities (1.6%). The presence of
There is no increased risk of viral infection in sarcoidosis, however, during the COVID-19 pandemic, some patients with sarcoidosis have suffered this comorbid pathology. An analysis by Robert P. Baughman, et al. of five surveys of US and European survivors of sarcoidosis with COVID-19  provided evidence that the incidence of COVID-19 infection in patients with sarcoidosis was higher than in the general population. They also noted that of the spectrum of immunosuppressive therapies taken by sarcoidosis patients, only rituximab was associated with an increased risk of COVID-19 infection. There was no association between prednisone intake and the development of COVID-19, regardless of the prescribed dose (≥ 10 and < 10 mg / day). We have identified three main options for the combination of
Patient L., 43, histologically verified sarcoidosis. CT from 2014 (Figure 6s) - typical manifestations of PS with the presence of hilar lymphadenopathy and sarcoid alveolitis. CT scan from 2018 (Figure 6s) shows regression of the disease. On CT from 06.06.2020 (PCR on RNA SARS-CoV-2 (+) (Figure 6u) - bilateral edema of the peripheral and central pulmonary interstitium - CT picture of “ground glass” opacity - manifestations of sarcoid alveolitis overlapping small focal perilymphatic dissemination, lymphadenopathy of peritracheobronchial groups (significant, symmetrical, without violating the integrity of the capsule and the structure of the nodes) - exacerbation of sarcoidosis against the background of COVID-19.
Patient V., 68 years old, histologically verified sarcoidosis. CT scan from 2020 (Figure 6v) - typical manifestations of SP III st. with the presence of peribronchovascular fibrotic changes with the formation of traction bronchiectasis, moderate hilar lymphadenopathy, perilymphatic dissemination. Areas of interstitial infiltration in the subpleural regions on both sides - manifestations of COVID-19 lesions (PCR on RNA SARS-CoV-2 (+) (Figure 6w). On CT from 2019 (Figure 6x) changes characteristic of COVID- 19 were not identified.
Patient A., 62 years old, histologically verified sarcoidosis. CT scan from 2019 (Figure 6y) - manifestations of SP II st. with the presence of perilymphatic small focal dissemination, hilar lymphadenopathy, PH. CT from 2020 (Figure 6z) - areas of interstitial and alveolar infiltration in the subpleural and nuclear regions on both sides - manifestations of COVID-19 lesion (PCR on SARS-CoV-2 (+) RNA. On CT from 2021 (Figure 6
The sarcoid alphabet is an attempt to fully represent the radiation patterns of modern sarcoidosis in images from a to z with an explanation of their features and mechanisms of occurrence. Radiation diagnostics of pulmonary sarcoidosis is now a multimodal study with CT leading (as an expert technique) and supplementing, if necessary, radionuclide studies (SPECT, PET), ultrasound, MRI. Modern classical signs of SP (according to the Statement on Sarcoidosis, 1999) have changed their characteristics due to the widespread use of CT: variants of lymphadenopathy (features of the structure, localization of the affected lymph nodes), perilymphatic dissemination (manifestations of sarcoid alveolitis, types of foci), lesions pulmonary interstitium. Radiation patterns of unfavorable forms of SP were revealed: fibrosing sarcoidosis (with a description of the variants of sarcoid fibrosis and their difference from other progressive pulmonary fibrosis) and progressive sarcoidosis (with the identification of possible causes of its occurrence and radiation patterns). For the convenience of interpreting changes in SP detected by CT, we proposed models of unfavorable forms of SP: interstitial edema (IO), idiopathic pulmonary fibrosis (IPF), hypersensitive pneumonitis (PP), their combination, pneumoconiosis and progressive SP. It was noted that the model of interstitial edema in SP is often combined with multisystem lesions (eyes, kidneys), and has a high risk of developing interstitial fibrosis (transition to the IPF model). The main points to which a radiologist should draw a pulmonologist’s attention when performing a CT scan of the chest of a patient with sarcoidosis: describe all unfavorable models of sarcoidosis with the formation of fibrosis, expansion of cardiac cavities (indirect signs of cardiac sarcoidosis, especially in young patients, which requires MRI, or PET of the heart), signs of pulmonary hypertension (the causes of which may be vascular lesions in sarcoidosis and PE, which requires CT angiography, or SPECT), enlargement of the spleen (always within the scan area, may indicate additional hematological problems, both associated with sarcoidosis or not), identification of non-lymphotropic disseminations in sarcoidosis (a sign of comorbidity, requires CT in the whole body mode with multiphase contrast). Patients with sarcoidosis are seen by a pulmonologist and a thoracic radiologist, but the polysystemic nature of the lesion requires these specialists to know the signs of extrapulmonary manifestations of sarcoidosis (both clinical and radiation). If you suspect primary extrathoracic sarcoidosis (neurosarcoidosis, sarcoidosis of the kidneys, skin, eyes) in patients observed by doctors of other specialties, it is necessary to include not only a pulmonologist, but also a radiologist in the multidisciplinary consultation. Detection of radiation signs of comorbidity in sarcoidosis is especially important because it leads to a change in the tactics of patient management. The complexity of the layering of different types of pulmonary dissemination and lymphadenopathy and the multisystem nature of the lesion can be fully determined during a multidisciplinary consultation comprised of a pulmonologist and a radiologist with the involvement of an oncologist, neurologist, infectious disease specialist. The accumulation of experience in clinical and radiation examination of patients with sarcoidosis makes it possible to identify unfavorable clinical and radiological forms: fibrosing, progressive SP, as well as to assess its systemic manifestations and comorbidity, which is important for treatment tactics.
Deep gratitude to Baranova O.P. – PhD, Senior Scientific Researcher and Scientific Institute of Interstitial and Orphan Diseases of Federal State Educational Institution of Higher Education “First St.-Petersburg State Medical University n.a. academician I.P. Pavlov of Ministry of Health of Russian Federation (Roszdrav)”, Deep gratitude to prof. Ilkovich M.M. chef of Scientific Researcher and Scientific Institute of Interstitial and Orphan Diseases of Federal State Educational Institution of Higher Education “First St.-Petersburg State Medical University n.a. academician I.P. Pavlov of Ministry of Health of Russian Federation (Roszdrav)” and his staff.
Conflict of interest
The authors declare no conflict of interest.