A Case of Sarcoidosis With Pulmonary and Extrapulmonary Manifestations

AUTHORS:
Hiliary Weill, MD; Joy Ishii Zarandy, DO; and Rajiv Joglekar, MD

CITATION:
Weill H, Zarandy JI, Joglekar R. A case of sarcoidosis with pulmonary and extrapulmonary manifestations Consultant. 2016;56(11):1030-1035.

A 40-year-old African American man presented with a peculiar rash involving the majority of his body. Over the past several months, he had developed night sweats, vision changes, cough, and lower-extremity pain. The rash had progressed over the past 5 years. He denied significant past medical history. His family history was negative for rheumatologic disease or cancers. In the past, he had tried over-the-counter topical corticosteroids for the rash with minimal relief.

Figure 1. Pink to violaceous scaling plaques of varying sizes on the patient’s back.

Figure 2. Pink scaling plaque on the patient’s lower back. Punch biopsies were taken at the 12 o’clock and 2 o’clock locations.

Figure 3. Scaling plaque on the patient’s posterior neck. This area was negative for dermatophytes on potassium hydroxide preparation testing.

PHYSICAL EXAMINATION

The patient was afebrile, with normal vital signs. A few pink and violaceous scaling plaques of varying sizes, ranging from 0.5 to 6.0 cm, were present on the patient’s upper extremities, back, and neck (Figures 1-3). Erythematous plaques were present on the eyelids, central face, and hairline (Figure 4). Scarring alopecia was noted on the frontal scalp (Figure 5). Irregularly shaped atrophic plaques were associated with tattoos on the patient’s forearms (Figure 6). Multiple tender, erythematous, subcutaneous plaques and nodules were located on the anterior shins bilaterally (Figure 7). The rash spared the mucous membranes, palms, and soles (Figure 8).

Figure 4. Erythematous plaques on the patient’s eyelids, central face, and hairline.

Figure 5. Scarring alopecia on the frontal scalp.

Figure 6. Firm, irregularly shaped, atrophic plaques associated with tattoos on the patient’s forearms.

Figure 7. Multiple tender, erythematous, subcutaneous plaques and nodules on the anterior shins.

Figure 8. The rash spared the patient’s palms and soles.

DIAGNOSTIC TEST RESULTS

Initial laboratory test results included the following values: alkaline phosphatase (ALP), 2190 U/L; aspartate aminotransferase, 73 U/L; alanine aminotransferase, 45 U/L; white blood cell count, 2300/µL; and hemoglobin, 10.5 g/dL. Otherwise, basic metabolic panel results, platelet count, mean corpuscular volume, ferritin level, total iron-binding capacity, and iron saturation were normal.

Upon further workup, levels of thyrotropin, α-fetoprotein, and test results were negative for HIV, syphilis, hepatitis, autoimmune disease, and tuberculosis. Results of antinuclear antibody and rheumatoid factor tests were negative. Results of blood culture, urine culture, and potassium hydroxide preparation were negative for pathogens. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level were elevated.

Chest radiographs showed fibrosis and reticulonodular infiltrate (Figure 9). Skin biopsy results of the lower back and posterior neck revealed granulomatous dermatitis with scattered multinucleated giant cells (Figure 10). Fungal and acid-fast bacilli stains were negative. Differential diagnoses based on skin biopsy results included infection, granuloma annulare, sarcoidosis, and rheumatoid-related granulomas.

Figure 9. Chest radiograph demonstrating bilateral fibrosis and reticulonodular infiltrate.

Figure 10. Results of skin biopsy of the lower back revealing a microscopic view of granulomatous dermatitis with scattered multinucleated giant cells.

At this point, an angiotensin-converting enzyme (ACE) test was obtained, revealing a level of 226 U/L, more than 3 times the normal range. A computed tomography (CT) scan of the chest was also performed, the results of which showed cervical and mediastinal adenopathy with bronchiectasis and tree-in-bud nodularity, all of which can be findings seen in sarcoidosis. Incidental multiple spleen lesions were noted, a finding that also could be related to sarcoidosis.

OUTCOME OF THE CASE

The patient received a diagnosis of sarcoidosis, presenting initially with cutaneous manifestations. A pulmonologist was consulted, and a bronchoscopy was performed with lymph node sampling and left upper-lobe biopsies in order to confirm the diagnosis.

The patient was started on prednisone 40 mg daily. Outpatient follow-up with rheumatology and ophthalmology specialists was arranged. On further outpatient workup, the patient was found to have ocular involvement, manifesting as uveitis and eyelid granulomas. His rash had improved after 1 month of treatment with systemic prednisone (Figure 11).

Figure 11. Sarcoidosis cutaneous manifestations after 1 month of treatment with systemic prednisone 40 mg/d. Images demonstrate improvement of facial lesions, lower-extremity erythema nodosum, and tattoo sarcoidosis of the left and right upper extremities.

DISCUSSION

Sarcoidosis is a granulomatous disorder that can affect many organ systems, most notably the pulmonary system. The etiology of sarcoidosis is unknown. Approximately 30% of patients initially present with extrapulmonary disease, including the skin, eyes, heart, kidneys, musculoskeletal system, central nervous system, and reticuloendothelial system.¹ Skin and ocular involvement is more frequent in the female population, while cardiac findings are more common in the male population.²

EPIDEMIOLOGY

The worldwide prevalence of sarcoidosis is estimated at 10 to 20 cases per 100,000 population.³ The incidence in African Americans is up to 4 times higher than in other populations. The lifetime risk in African Americans is estimated to be 2.4% vs 0.85% in the white population.⁴ Disease onset is typically up to 10 years earlier in African Americans than in whites, with presentation between 20 and 60 years of age.²

CLINICAL FEATURES

Pulmonary features. More than 90% of patients with sarcoidosis have pulmonary involvement.⁵ Common presenting symptoms are cough, dyspnea and chest pain with weight loss, fatigue, fever, and night sweats.

Staging of a patient’s chest radiograph can assist in determining the severity of sarcoidosis and the rate of spontaneous remission in patients with similar disease severity (Table).⁶ Not all patients will develop each stage of sarcoidosis on chest radiographs. Some will develop hilar adenopathy as in stage I disease, which then resolves spontaneously. The chest radiograph of the patient in our case showed stage IV sarcoidosis with reticular opacities and evidence of fibrosis of the lung fields (Figure 9).

Extrapulmonary features. Cutaneous involvement occurs in approximately 25% of patients with sarcoidosis.⁷ In a study involving 8 sarcoid patients presenting only with cutaneous manifestations, all 8 progressed to systemic involvement within 3 years.⁸ Sarcoid lesions classically appear as asymptomatic nodules or papules, although several variants have been described. Variations noted in our patient’s case included scar or tattoo sarcoidosis (Figure 6), sarcoidal alopecia (Figure 5), atrophic sarcoidosis, plaque and psoriasiform sarcoidosis (Figures 1-3).⁹ Our patient also had the presence of erythema nodosum, which is another cutaneous finding commonly associated with sarcoidosis (Figure 7).¹⁰

Ocular involvement occurs in up to 25% of sarcoid patients.¹¹ Ocular involvement can include the orbit, anterior and posterior segments of the eye, conjunctivas, lacrimal glands, and extraocular muscles.¹² In a study of 81 patients with sarcoidosis, 40% had uveitis, 30% had keratoconjuctivitis sicca, and 15% had eyelid or conjunctival granulomas causing symptoms such as dry eye, blurry vision, photophobia, redness, and pain.¹³ Potential late complications include secondary glaucoma, cataracts, and blindness.

Cardiovascular involvement in sarcoidosis is unclear. Some studies suggest cardiac findings in 5% of patients, while autopsy studies demonstrate subclinical cardiac involvement in as many as 70%. However, clinically significant cardiac involvement is rare in asymptomatic patients with normal electrocardiography findings.¹³

Hepatic sarcoidosis is relatively common, with histologic evidence of liver granulomas in 50% to 65% of patients. Hepatic involvement is twice as prevalent in the African American population as in the white population. Most patients are asymptomatic with hepatic enlargement and biochemical abnormalities, most notably an elevated alkaline phosphatase¹⁴ as seen in our patient’s case.

The reported prevalence of splenomegaly varies. One study demonstrated splenomegaly in 6% of patients based on physical examination findings,¹⁵ and another found that more than 30% showed splenomegaly as an imaging finding.¹⁶ Splenic involvement can lead to anemia, leukopenia, and thrombocytopenia.¹⁷ Our patient had evidence of splenomegaly on imaging and had laboratory test findings of leukopenia and anemia.

Other extrapulmonary symptoms include kidney and electrolyte abnormalities. Calcium metabolism defects can be seen as a result of the extrarenal production of calcitriol by activated macrophages.¹⁸ This defect can lead to hypercalcemia, and if untreated, renal calcium deposits can lead to chronic renal failure.

Diagnosis

The diagnosis of sarcoidosis is confirmed by excluding other diseases, with histopathologic evidence of noncaseating granulomas, and with clinical and radiographic evidence of manifestations of sarcoidosis. 

Noncaseating granulomas are commonly found in the alveolar septal walls of bronchi and along pulmonary vasculature. The granulomas are focal and are a result of a chronic inflammatory reaction formed by accumulating monocytes, lymphocytes, macrophages, and fibroblasts.¹⁹ Most granulomas resolve without scar formation or residual effects.

Laboratory findings may include leukopenia, elevated ESR and CRP level, elevation of the serum ALP level, and an increase in the ACE level. Elevated ACE levels are not necessarily diagnostic given that they have low sensitivity and specificity, with a nearly 10% false-positive rate.²⁰ Anemia is not common but can be due to anemia of chronic disease or splenic involvement.²¹

High-resolution CT (HRCT) is generally preferred for follow-up testing. Typically, HRCT demonstrates mid- to upper-lobe parenchymal changes, including thickening of bronchovascular bundles; nodules along bronchi, vessels, and subpleural regions; bronchial wall thickening; parenchymal bands; fibrosis; and cysts.^22,23 

Further imaging, including fluorine-18 fluorodeoxyglucose positron emission tomography and other radiotracer scanning, can be performed to detect occult lesions or sites of inflammation. Additionally, pulmonary function tests (PFTs) can be helpful in determining the effect of sarcoidosis on lung parenchyma. Most patients with sarcoidosis have abnormal PFT results, usually demonstrating a restrictive pattern and reduction in diffusing capacity of the lungs for carbon monoxide. However, normal PFT results are not unusual. Endobronchial lesions can also lead to an obstructive pattern.²⁴

Differential Diagnosis

The differential diagnosis for granulomatous lung disease is broad and includes infectious etiologies, hypersensitivities, foreign body reaction, pneumoconiosis, and immunodeficiency. Infectious causes include mycobacteria and fungi. Staining for mycobacteria and fungal elements should be performed on biopsy specimens. A detailed history should be taken for occupational exposures to rule out hypersensitivity pneumonitis, pneumoconiosis, or potential drug-induced hypersensitivity pneumonitis.

Other granulomatous lung diseases include pulmonary histiocytic disorders, vasculitis, and bronchocentric granulomatosis. Biopsy staining for specific histiocyte markers can differentiate sarcoidosis from pulmonary histiocytic disorders. A serum antineutrophil cytoplasmic antibody test can help identify systemic vasculitis. Granulomas due to bronchocentric granulomatosis are a result of necrotizing granulomatous inflammation.

Management

Newly diagnosed sarcoid patients should be evaluated for extrapulmonary disease, including electrocardiography and possibly echocardiography, PFTs, liver function tests, vitamin D level, spot urine creatinine and calcium to evaluate for hypercalciuria, HRCT scan, and ophthalmic evaluation. Ophthalmologists generally perform visual acuity testing, tonometry, slit-lamp examination, and fundoscopic examination.

Oral glucocorticoids are the mainstay for symptomatic treatment of pulmonary symptoms but do not cure the disease.²⁵ Not all patients with pulmonary sarcoidosis require treatment with oral glucocorticoids given that spontaneous remission is possible and occurs in the majority of asymptomatic patients. Indications for therapy include symptoms such as cough, shortness of breath, chest pain or discomfort, hemoptysis, decline in lung function, or worsening of radiographic changes.

Patients often may have extrapulmonary indications for therapy. Any degree of ocular, neurologic, myocardial, or kidney involvement, or hypercalcemia are indications for treatment in order to prevent complications such as vision loss, fatal arrhythmias, and kidney damage.²⁶

Follow-up is determined based on the severity of the disease. Patients with mild disease or stage I, without the need for corticosteroids, should be followed up every 6 months, then annually when they are stable. Symptomatic patients, usually stages II through IV, who are undergoing treatment should be followed up every 3 to 6 months with indefinite monitoring. Once treatment is discontinued, patients should be followed up for 3 years for potential relapse. No further follow-up is necessary after 3 years if the patient is stable. Follow-up should include a review of the patient’s symptoms, physical examination, chest radiography, spirometry, and other tests depending on organ involvement.²⁷

Hiliary Weill, MD, is a second-year postgraduate resident in the AnMed Health Family Medicine Residency in Anderson, South Carolina.

Joy Ishii Zarandy, DO, is in private practice with North Chattahoochee Family Physicians in Johns Creek, Georgia.

Rajiv Joglekar, MD, is on faculty at the AnMed Health Family Medicine Residency and is a physician with Hospital Medicine Consultants of Anderson in Anderson, South Carolina.

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