2. HISTORY
• In 1887, Sir Jonathan
Hutchinson was the first to
describe a case of cutaneous
sarcoidosis. He named it
“Mortimer’s Malady” after the
patient.
• In 1899, Caesar Boeck called
this condition ‘Sarcoid’ as he
thought it resembles a sarcoma.
It was called “Boeck’s Sarcoid”
in his honour.
3. INTRODUCTION
• Sarcoidosis is a systemic granulomatous
disease of unknown cause that may involve
many different tissues and organs
• Lung is most commonly affected
• Variable clinical outcome
4. EPIDEMIOLOGY
• Occurs worldwide; Nordic population
• Female > Male
• Usually occurs in adults < 40 years
• Prevalence: 20-60 per 1,00,000 population
• African Americans to Whites – 3:1 to 17:1
• Familial form
5. ETIOLOGY
• Unknown
• Propionibacter acnes
• Mycobacterial protein
• Environmental exposure to insecticides and molds
• Healthcare workers
• Multiple agents
• Genetic susceptibility
6. PATHOGENESIS
• HLA Association
– HLA-B8 – 67% of Pts.(normal popn 24%)
– HLA-DR3 – 90% (normal popn 26%)
(seen in Pts.with hilar lymphadenopathy,
arthropathy and erythema nodosum)
– HLA-DRW52 and DR5 more common in Japan
– HLA-DR3/B8/CW7 – associated with good
prognosis
7. PATHOGENESIS
• Disease of disordered immune regulation
• The T cell is a necessary part of initial inflammatory
response
• Intra-alveolar and interstitial accumulation of CD4+ T
cells
• Increased levels of IL-2 and IFN-γ
• TNF as a disease markers
8. PATHOGENESIS
• Impaired dendritic cell function
• Anergy to common skin test antigens such as Candida
or tuberculosis purified protein derivative (PPD)
• Polyclonal hypergammaglobulinemia
• Chronic form – 20%
9. CLINICAL MANIFESTATIONS
• Asymptomatic to those with organ failure
• Respiratory complaints including cough and dyspnea
are the most common presenting symptoms
• Symptoms related to cutaneous and ocular disease are
the next two most common complaints.
• Nonspecific constitutional symptoms include fatigue,
fever, night sweats, and weight loss
• frequency of specific organ involvement appears to
be affected by age, race, and gender
11. Lungs
• Involved in >90% of sarcoidosis patients
• The most commonly used method for detecting
lung disease is still the chest roentgenogram.
• Scadding scoring system for chest
roentgenograms
– Stage1 - hilar adenopathy alone
– Stage 2 - adenopathy plus infiltrates
– Stage 3 - infiltrates alone.
– Stage 4 - fibrosis.
13. Lungs
• Reduced lung volumes.
• Approximately one-half present with obstructive
disease
• Airway hyperreactivity
• Pulmonary arterial hypertension in at least 5% of
sarcoidosis patients.
14. Skin
• Identified in over a third of patients with sarcoidosis.
• Erythema nodosum, maculopapular lesions, hyper-
and hypopigmentation, keloid formation, and
subcutaneous nodules.
• Lupus pernio
• Löfgren’s syndrome
17. Eye
• The frequency of ocular manifestations varies
depending on race.
• Most common manifestation - anterior uveitis
• Retinitis and pars planitis.
• Photophobia, blurred vision, and increased tearing
• Ocular sarcoidosis can eventually develop into
blindness
• Mikulicz syndrome
• Heerfordt syndrome
18. Liver
• Liver involvement can be identified in over one-half
of sarcoidosis patients
• Elevation of the alkaline phosphatase level
• Elevated transaminase levels
• Ascites and esophageal varices
• Liver transplants are rare
19. Bone marrow and spleen
• Most commonly – lymphopenia
• Anemia occurs in 20% of patients
• Bone marrow examination reveals granulomas
• Splenic biopsy reveals granulomas in 60% of
patients.
• More common in African Americans than whites
• Splenectomy
20. Calcium metabolism
• Hypercalcemia and/or hypercalciuria occur in about
10% of sarcoidosis patients
• More common in whites than African Americans
21. Renal
• Direct kidney involvement <5% of sarcoidosis
patients.
• Most likely cause of sarcoidosis associated renal
disease – Hypercalcemia
• Acute renal failure in 1-2%
22. Nervous system
• 5–10% of sarcoidosis patients
• CSF findings – lymphocytic meningitis
• Commonly affected areas - cranial nerve
involvement, basilar meningitis, myelopathy, and
anterior hypothalamic disease
• Seizures and cognitive changes
• Bell’s palsy
• Optic neuritis
• Multiple sclerosis
23. Cardiac
• Influenced by race.
• Congestive heart failure and cardiac arrhythmias
• Heart block
• Recurrent arrhythmias
26. MORPHOLOGY
• Well-formed nonnecrotizing granulomas
•
• Schaumann bodies and Asteroid bodies
• Hamazaki-Wesenberg bodies
• In lungs lesions are distributed primarily along the
lymphatics around bronchi and blood vessels
27. MORPHOLOGY
• Lymph nodes - hilar and mediastinal nodes
• Liver contains scattered granulomas, more in portal
triads than in the lobular parenchyma.
• Bone lesions - widening of the bony shafts or new
bone formation on the outer surfaces.
28.
29. • Photomicrograph from patient lung wedge resection showing a nonnecrotizing,
sarcoid-like granuloma with epithelioid histiocytes and a Langhans-type giant cell
(black arrow). Magnification: 400, H & E.
31. An epithelioid cell granuloma located in the peripheral airway. Another granuloma
is embedded in the interstitium in the right lower quadrant . 100x.
33. Noncaseating granuloma in parietal lobe showing the granuloma surrounded by
epithelioid cells and nodular inflammatory infiltrates (hematoxylin and eosin, 100x
42. ….contd
• The PET scan has increasingly replaced gallium-67
scanning to identify areas of granulomatous disease
43. ….contd
• Functional:
– Reduced lung volumes
– Reduced FEV1/FVC
– Reduced DLCO.
• Tuberculin test:
– Depressed or absent in most cases due to depressed
cell mediated immunity
– Positive tuberculin test virtually rules out
sarcoidosis
44. ….contd
• Serum angiotensin-converting enzyme
– Serum ACE levels increased in 60% of pts. with
active disease
– Increased in CSF/ BAL fluid of pts with
sarcoidosis
– Levels fall following steroid therapy and is
associated with clinical improvement
– Neither sensitive nor specific
45. ….contd
• Other markers – SAA, sIL-2R, lysozyme,
glycoprotein KL-6
• Anemia, lymphopenia, leucopenia
• Hypercalcemia and hypercalciuria
• Elevated ALP and transaminases
• Hyperglobulinemia
• ECG: arrhythmias and heart block
• Echocardiography
• Eye examination
46. ….contd
• The Kveim Siltzbach test
– Considered a diagnostic test
– Sensitive and specific
– Largely replaced by TBLB
– May have a role in Neurosarcoidosis
48. PROGNOSIS
• The risk of death or loss of organ function
remains low in sarcoidosis
• Poor outcomes in patients who present with
advanced disease
• Many patients resolve their disease within 2–5
years
• Chronic patients
49. REFERENCES
• Harrison’s Principles of Internal Medicine (20th
edition).
• Robbins and Cotran Pathologic Basis of Disease,
Ninth Edition
• Miyoshi S, Hamada H, Kadowaki T, Hamaguchi N,
Ito R, Irifune K, et al. Comparative evaluation of
serum markers in pulmonary sarcoidosis. Chest. 2010
Jun. 137(6):1391-7
DIFFERENTIATED from other granulomatous diseases like TB, syphilis, leprosy, cat-scratch disease, fungal infections, crohn.
Other organs commonly affected are skin, eyes and liver.
The clinical outcome of sarcoidosis varies, with remission occurring in over one-half of patients within a few years of diagnosis; however, the remaining patients may develop a chronic disease that lasts for decades.
Highest prevalence noted in Nordic countries denmark, finland, iceland, norway and sweden. .
At least 5% of patients with sarcoidosis will have a family member with sarcoidosis. Sarcoidosis patients who are Irish or African American seem to have a two to three times higher rate of familial disease.
An agent that triggers an inf response in a genetically susceptible host
Studies show much higher incidence of P. acnes in lymph nodes of sarcoidosis patients. P. acnes can produce a granulomatous response in mice similar to sarcoidosis.
Some studies demo presence of myco protein in granulomas of some sarcoidosis patients. This protein is resisitant to degradation and may be the persistent antigen. Thus a mycobacterium similar to M. tb could be responsible.
The antigen-presenting cell and helper T cell complex leads to the release of multiple cytokines. This forms a granuloma. Over time, the granuloma may resolve or lead to chronic disease, including fibrosis.
These include interleukin (IL)-2 released from the T cell and interferon γ and tumor necrosis factor (TNF) released by the macrophage
Sarcoidosis in HIV patients
T cell derived cytokines – IL2 and IFNy
TNF released by activated macrophages and conc in BAL as disease marker
Increased levels of cytokines like IL8, TNF, macrophage inf protein 1a in the local environment
Polyclonal hyper…..mia is again a manisfestation of helper T cell dysregulation.
Chronic – increased levels in bld and/or BAL of IL8, IL17 and CXCL9. Excessive amts of TNF is also released in areas of inflamm in such patients.
Literature suggest that as many as one-third of sarcoidosis patients are asymptomatic.
In many cases, the patient presents with a 2- to 4-week history of these symptoms. Unfortunately, due to the nonspecific nature of pulmonary symptoms, the patient may see physicians for up to a year before a diagnosis is confirmed. For these patients, the diagnosis of sarcoidosis is usually only suggested when a chest roentgenogram is performed.
However, because skin lesions are readily observed, the patient and treating physician are often led to a diagnosis. In contrast to patients with pulmonary disease, patients with cutaneous lesions are more likely to be diagnosed within 6 months of symptoms.
Fatigue is perhaps the most common constitutional symptom that affects these patients. Given its insidious nature, patients are usually not aware of the association with their sarcoidosis until their disease resolves
Over time, skin, eye, and neurologic involvement seem more apparent.
eye disease is more common among African Americans. Under the age of 40, it occurs more frequently in women. However, in those diagnosed over the age of 40, eye disease is more common in men.
1. Usually the infiltrates in sarcoidosis are predominantly an upper lobe process. Only in a few noninfectious diseases is an upper lobe predominance noted. In addition to sarcoidosis, the differential diagnosis of upper lobe disease includes hypersensitivity pneumonitis, silicosis, and Langerhans cell histiocytosis. For infectious diseases, tuberculosis and Pneumocystis pneumonia can often present as upper lobe diseases.
Posterior-anterior chest roentgenogram demonstrating bilateral hilar adenopathy, stage 1 disease.
CT scan is not usually considered a monitoring tool for patients with sarcoidosis
characteristic CT features, including peribronchial thickening and reticular nodular changes, which are predominantly subpleural
Although the CT scan is more sensitive, the standard scoring system described by Scadding in 1961 for chest roentgenograms remains the preferred method of characterizing the chest involvement.
diffusion of carbon monoxide (DLCO) is the most sensitive test for an interstitial lung disease. Reduced lung volumes are a reflection of the restrictive lung disease seen in sarcoidosis. However, a third of the patients presenting with sarcoidosis still have lung volumes within the normal range, despite abnormal chest roentgenograms and dyspnea.
Obstructive disease reflected by reduced FEV1/FVC with cough being a very common symptom.
Airway hyperreactivity, as determined by methacholine challenge, will be positive in some of these patients
direct vascular involvement or the consequence of fibrotic changes in the lung can lead to pulmonary arterial hypertension.
In sarcoidosis patients with end-stage fibrosis awaiting lung transplant, 70% will have pulmonary arterial hypertension.
Erythema nodosum is more common in women and in certain selfdescribed demographic groups including whites and Puerto Ricans.
Lupus pernio is more common in African Americans than whites. A specific complex of involvement of the bridge of the nose, the area beneath the eyes, and the cheeks is referred to as lupus pernio (Fig. 360-4) and is diagnostic for a chronic form of sarcoidosis.
In contrast, erythema nodosum is a transient rash that can be seen in association with hilar adenopathy and uveitis (Löfgren’s syndrome)
A specific complex of involvement of the bridge of the nose, the area beneath the eyes, and the cheeks is referred to as lupus pernio.
Maculopapular lesions on the trunk of a sarcoidosis patient.
The frequency of ocular manifestations for sarcoidosis varies depending on race. In Japan, >70% of sarcoidosis patients develop oculardisease, whereas in the United States only 30% have eye disease, with problems more common in African Americans than whites
Although the most common manifestation is an anterior uveitis, over a quarter of patients will have inflammation at the posterior of the eye, including retinitis and pars planitis.
Although symptoms such as photophobia, blurred vision, and increased tearing can occur, some asymptomatic patients still have active inflammation
Bilateral sarcoidosis of the parotid, submaxillary, and sublingual glands constitutes the combined uveoparotid involvement designated as Mikulicz syndrome
Heerfordt – b/l hilar lymphadenopathy, fever, facial palsy, parotid elnargement and uveitis
Using biopsies to detect granulomatous disease, liver involvement can be identified in over one-half of sarcoidosis patients
However, using liver function studies, only 20–30% of patients will have evidence of liver involvement
The most common abnormality of liver function is an elevation of the alkaline phosphatase level, consistent with an obstructive pattern
only 5% of sarcoidosis patients have sufficient symptoms from their liver disease to require specific therapy
Although symptoms can be due to hepatomegaly, more frequently symptoms result from extensive intrahepatic cholestasis leading to portal hypertension.
most common hematologic problem is lymphopenia, which is a reflection of sequestration of the lymphocytes into the areas of inflammation
Anemia occurs in 20% of patients, and leukopenia is less common.
Bone marrow examination will reveal granulomas in about a third of patients.
Although splenomegaly can be detected in 5–10% of patients, splenic biopsy reveals granulomas in 60% of patients.
splenectomy may be indicated for massive symptomatic splenomegaly or profound pancytopenia.
The mechanism of abnormal calcium metabolism is increased production of 1,25-dihydroxyvitamin D by the granuloma itself. The 1,25-dihydroxyvitamin D causes increased intestinal absorption of calcium, leading to hypercalcemia with a suppressed parathyroid hormone (PTH) level.
Serum calcium should be determined as part of the initial evaluation of all sarcoidosis patients, and a repeat determination may be useful during the summer months with increased sun exposure.
Direct kidney involvement occurs in <5% of sarcoidosis patients. It is associated with granulomas in the kidney itself and can lead to nephritis.
In 1–2% of sarcoidosis patients, acute renal failure may develop as a result of hypercalcemia.
The presence of granulomatous inflammation is often visible on magnetic resonance imaging (MRI) studies. The MRI with gadolinium enhancement may demonstrate space-occupying lesions, but the MRI can be negative due to small lesions or the effect of systemic therapy in reducing the inflammation.
The cerebral spinal fluid (CSF) findings include lymphocytic meningitis with a mild increase in protein. The CSF glucose is usually normal but can be low.
Of the cranial nerves, seventh nerve paralysis can be transient and mistaken for Bell’s palsy
In such cases, the presence of meningeal enhancement or hypothalamic involvement suggests neurosarcoidosis, as does evidence of extraneurologic disease such as pulmonary or skin involvement, which also suggests sarcoidosis
Because the response of neurosarcoidosis to glucocorticoids and cytotoxic therapy is different from that of multiple sclerosis, differentiating between these disease entities is important.
The presence of cardiac involvement is influenced by race. Although over a quarter of Japanese sarcoidosis patients develop cardiac disease, only 5% of sarcoidosis patients in the United States and Europe develop symptomatic cardiac disease. However, there is no apparent racial predilection between whites and African Americans
Cardiac disease, which usually presents as either congestive heart failure or cardiac arrhythmias, results from infiltration of the heart muscle by granulomas
Arrhythmias can also occur with diffuse infiltration or with more patchy cardiac involvement. If the atrioventricular (AV) node is infiltrated, heart block can occur, which can be detected by routine electrocardiography. Ventricular arrhythmias and sudden death due to ventricular tachycardia are common causes of death.
The confirmation of cardiac sarcoidosis is usually performed with either MRI or positron emission tomography (PET) scanning.
Although systemic therapy can be useful in treating the arrhythmias, patients may still have malignant arrhythmias up to 6 months after starting successful treatment, and the risk for recurrent arrhythmias occurs whenever medications are tapered.
Direct granulomatous involvement of bone and muscle can be documented by radiography (x-ray, MRI, PET scan [Fig. 360-7], or gallium scan) or confirmed by biopsy in about 10% of sarcoidosis patients.
However, a larger percentage of sarcoidosis patients complain of myalgias and arthralgias.
Recent studies have demonstrated a link between fatigue and small peripheral nerve fiber disease in sarcoidosis.
Death from sarcoidosis occurs in about 5% of patients seen in sarcoidosis referral clinics. The usual causes of death related to sarcoidosis are from lung, cardiac, neurologic, or liver involvement.
Lung complications can also include infections such as mycetoma, which can subsequently lead to massive bleeding.
In addition, the use of immunosuppressive agents can increase the incidence of serious infections.
well-formed nonnecrotizing granulomas composed of aggregates of tightly clustered epithelioid macrophages, often with giant cells. Central necrosis is unusual. With chronicity the granulomas may become enclosed within fibrous rims or may eventually be replaced by hyaline fibrous scars.
Laminated concretions composed of calcium and proteins known as Schaumann bodies (88%) and stellate inclusions known as asteroid bodies (2-9%) are found within giant cells in approximately 60% of the granulomas. Asteroid bodies represent functionally obsolescent cell organelles.
Though characteristic, these microscopic features are not pathognomonic of sarcoidosis, because asteroid and Schaumann bodies may be encountered in other granulomatous diseases (e.g., tuberculosis).
HW bodies- yellow brown bodies, seen in lymph nodes, similar appearance to yeast, PAS+ve, probably lysosomes.
The lesions are distributed primarily along the lymphatics around bronchi and blood vessels, although alveolar lesions and pleural involvement are also seen. The relatively high frequency of granulomas in the bronchial submucosa accounts for the high diagnostic yield of bronchoscopic biopsies.
There seems to be a strong tendency for lesions to heal in the lungs, so varying stages of fibrosis and hyalinization are often found.
Lymph nodes are involved in almost all cases, particularly the hilar and mediastinal nodes, but any other node in the body may be involved. Nodes are characteristically enlarged, discrete, and sometimes calcified.
The liver is affected slightly less often than the spleen. It may be moderately enlarged and typically contains scattered granulomas, more in portal triads than in the lobular parenchyma.
Radiologically visible bone lesions have a particular tendency to involve phalangeal bones of the hands and feet, creating small circumscribed areas of bone resorption within the marrow cavity and a diffuse reticulated pattern throughout the cavity, with widening of the bony shafts or new bone formation on the outer surfaces.
1.
1.
1.
1. HRCT may identify active alveolitis or fibrosis and correlates with yield of biopsy.
1. Lambda pattern of uptake in the parahilar, infrahilar bronchopulmonary, and mediastinal lymph nodes & Symmetric uptake in the parotid and lacrimal glands leads to panda appearance.
Pretreatment and posttreatment PET findings of a patient with sarcoidosis. (a) Coronal PET image showing pathologically increased FDG uptake in the pulmonary parenchyma and paraoesophageal lymph nodes. (b) Coronal PET image after therapy with infliximab showing resolution of the pathologically increased FDG uptake in the pulmonary parenchyma and paraoesophageal lymph nodes. FDG, fluorodeoxyglucose
PET appears especially helpful in those persistently symptomatic patients without serological signs of inflammatory activity, in patients with radiologic signs of fibrosis and in the detection of active cardiac sarcoidosis. The use of PET to assess the extent of disease can uncover a suitable location for biopsy to obtain histological evidence for the diagnosis or to explain the (mainly extrathoracic) symptoms. Furthermore, the detection of unexpected organ involvement may offer prognostic value.
Both restrictive and obstructive pattern.
Decrease in DLCO is the most common abnormality.
SACE is a membrane bound glycoprotein found in activated macrophages and at surface of epitheloid cells
Most widely used in follow-up.
SACE increased in berylliosis, asbestosis, gauchers, hypersensitivity pneumonitis, miliary TB, coccidiodomycosis, silicosis and primary biliary cirrhosis, DM, Leprosy, Crohns, hyperthyroidism.
Dr. Morten Kveim, norway, 1941 and later studied by Dr. Louis Siltzbach in New York.
Intradermal injection of a suspension of granuloma containing spleen or lymph node from a pt of sarcoidosis.
Positive test – formation of papule at injection site within 4-6 wks, biopsy shows nonnecrotizing granuloma
Presence of one or more of these features supports the diagnosis of sarcoidosis: uveitis, optic neuritis, hypercalcemia, hypercalciuria, seventh cranial nerve paralysis, diabetes insipidus.
1.
Poor outcomes usually occur in patients who present with advanced disease in whom treatment seems to have little impact. In these cases, irreversible fibrotic changes have frequently occurred.
chronic patients can be identified at presentation by certain risk factors at presentation such as fibrosis on chest roentgenogram, presence of lupus pernio, bone cysts, cardiac or neurologic disease (except isolated seventh nerve paralysis), and presence of renal calculi due to hypercalciuria
Poor outcomes usually occur in patients who present with advanced disease in whom treatment seems to have little impact. In these cases, irreversible fibrotic changes have frequently occurred.
chronic patients can be identified at presentation by certain risk factors at presentation such as fibrosis on chest roentgenogram, presence of lupus pernio, bone cysts, cardiac or neurologic disease (except isolated seventh nerve paralysis), and presence of renal calculi due to hypercalciuria
