Diagnoses: Sarcoidosis, active stage II disease, with airway stenosis and arterial, venous, and lymphatic granulomatous angiitis. Cor pulmonale. Acute pulmonary hemorrhage, right lower lung (enlarged bronchial arteries). Mediastinal and bilateral hilar granulomatous lymphadenopathy (autopsy limited to the chest)


Pulmonary Sarcoidosis

Introduction: Sarcoidosis is a systemic disease that is characterized histologically by non-necrotizing granulomas. It mainly affects young adults and usually involves the lung, among other organs. The diagnosis is based on the presence of consistent clinical and radiographic features, as well as the presence of granulomas. Other diseases with granuloma formation must be excluded. The cause of sarcoidosis is not known. It may be self-limited, or chronic and relapsing. The different clinical patterns and the varied organ involvement suggest that the disease may have more than one cause, or that clinical differences may be related to genetic factors in the host [1,2].

Clinical features of pulmonary disease and initial patient evaluation: Patients with pulmonary disease may be asymptomatic with an abnormal chest radiograph or have cough, dyspnea, chest pain, or wheeze. Typically, there are rales, restricted lung volumes, and gas exchange abnormalities, but airway obstruction is also frequently present [3]. Additionally, because sarcoidosis is a systemic disease, evaluation at the onset should include a history of occupational and environmental exposures and medications (to exclude other diseases), a physical examination that emphasizes the organs mainly involved (lung, skin, eye, liver, heart), biopsy showing non-necrotizing granulomas that yield no organisms, chest radiography, PFTs and measurement of gas exchange, electrocardiography, ophthalmologic evaluation, liver and renal function tests, and a determination of the serum calcium level [1]. The course is characterized by spontaneous remission in 2/3 of patients and chronicity in 1/3. The disease causes death in 1-6%, usually due to pulmonary or cardiac disease [4].

Unusual aspects of the current case: The remarkable features of this case of severe, untreated, subacute disease are outlined and then discussed further below.

Parenchymal disease

Non-necrotizing granuloma: The basic lesion of sarcoidosis is a non-necrotizing granuloma composed of epithelioid (activated) macrophages, which appear as polygonal or spindled cells with abundant pink cytoplasm and resemble squamous epithelium. Non-phagocytic, these cells are believed to have a secretory function. Multinucleated giant cells result from fusion of the macrophages. Nuclei of giant cells may form a ring at the periphery of the cell (Langhans' giant cell) or have nuclei scattered throughout (foreign body giant cell). Schaumann bodies, birefringent calcium oxalate crystals, and asteroid bodies, although not specific for sarcoidosis, are frequent findings in the giant cells [5]. T lymphocytes mingle with the macrophages. Spindled fibroblasts are found at the periphery [5]. Although typically non-necrotizing, the granulomas occasionally have central necrosis with or without PMNs [6]. Because of the small size of the granuloma, radiographic shadows are always caused by collections of granulomas. Thus, radiographic lesions are absent in stage I disease, in which granulomas tend to be solitary.

Miliary disease: The "miliary" pattern in this case was caused by a combination of confluent granulomas around the bronchovascular bundle, extending to the centrilobular region, as well as perivenous and subpleural collections of granulomas. This distribution has been referred to as following lymphatic pathways, a descriptive shorthand term, as there is no known pathophysiologic connection between the granulomas and lymphatics. Further, the pattern was not caused by random, hematogenously disseminated nodules as the term miliary implies: CT showed some spared areas.

Nodular sarcoidosis: Spread of granulomas into the alveolar parenchyma is uncommon in sarcoidosis. However, occasionally, confluent granulomas occur in nodules or masses several centimeters in extent, with central necrosis. The nodules may cavitate. Although the term "necrotizing sarcoid granulomatosis" was introduced by Liebow for this condition, there appears to be no good reason to separate this nodular form from other types of sarcoidosis [7,8].

Lymphocytic alveolitis: The term lymphocytic alveolitis is used for the increased numbers of lymphocytes found in bronchoalveolar lavage fluid in sarcoidosis. Histologically, an interstitial infiltrate has been described in alveolar walls in early stages of disease, preceding the formation of granulomas in some cases [9]. In the present case, however, there was no interstitial pneumonia, but lymphocytes, which could produce a lymphocytosis on BAL, were present around the granulomas.

Evolution of parenchymal disease: Granulomas may resolve or scar. In some cases, progressive interstitial fibrosis accompanies the scarred granulomas. The end result may be architectural distortion, thin-walled cysts, honeycombing, upper lobe cavities, or perihilar conglomerates. Similarly, granulomas in hilar lymph nodes may resolve and adenopathy disappear, or the nodes may remain enlarged and become scarred with or without calcification. Histologically, the residue of the granuloma may be a few giant cells, scattered lymphocytes, and occasional Schaumann bodies embedded in scar tissue [10].

Airway disease

Our patient had airflow obstruction, which was caused by confluent granulomas that thickened airway walls and replaced normal mucosa, glands, smooth muscle, and cartilage. The resulting nodules and plaques narrowed the lumens of many bronchi and bronchioles. The trachea had only focal mucosal hyperemia and no narrowing. The blood supply to the actively proliferating granulomas was an expanded network of bronchial arteries, which formed thin-walled channels very close to the surface. It is likely that the terminal bleed was from these enlarged vessels. Further, the destruction of supporting mural structures predisposes to bronchiectasis if the granulomas resolve or to stricture or stenosis if scarring of granulomas prevails.

Vascular disease

Angiitis: Our patient had extensive stenosing and obliterative angiitis involving small and medium-sized arteries and veins, as well as lymphatics, producing cor pulmonale. Sarcoidosis is characterized by a granulomatous angiitis that in one series was detected in 88/128 (69%) of patients who had an open biopsy [11]. In an autopsy study, granulomatous angiitis was found in all of 40 cases [12]. All sizes and types of vessels were involved including elastic arteries, muscular arteries, arterioles, venules, veins, bronchial vessels, and lymphatics [11,12]. Granulomas produced destruction of mural structures and narrowed or obliterated the lumen. Veins were involved more frequently (92%) than arteries (39%) [11]. The frequency of angiitis increased as the overall number of granulomas increased [11,12]. Granulomatous angiitis is not specific for sarcoidosis, as similar angiitis may be found in mycobacterial or fungal infections, but much less frequently. Granulomatous angiitis also occurs in Wegener's granulomatosis, in schistosomiasis, and in intravenous drug abusers, who develop granulomas in small pulmonary arteries containing injected foreign particles [11].

Pulmonary hypertension: Pulmonary hypertension in sarcoidosis is usually related to end stage scarring. Both lymph node compression of arteries and narrowing of large, as well as small, vessels by fibrosing granulomas have been described [13]. In our patient there was no diffuse scar: vessels were compressed or stenosed by active granulomas. Another case report described a patient similar to ours, who died of cor pulmonale with active granulomas narrowing medium and small-sized vessels. In that case, as well as in ours, the pulmonary hypertension was thought to be potentially reversible [14]. Also, there is a report of a case of sarcoidosis with pulmonary hypertension (pulmonary artery pressure 82/52) caused by veno-occlusive disease with granulomatous involvement of veins but not arteries [15].

Pleural disease

Pleural involvement in sarcoidosis: Nodules composed of granulomas were frequent in the visceral and parietal pleura of our patient. Adhesions, which probably antedated the biopsy because they were fibrous, were present around the right lower lobe. Their marked vascularity from systemic arteries (bronchial and intercostal) probably accounts for the pleural hemorrhage that occurred following the transbronchial biopsy that yielded skeletal muscle. A review of 227 patients with sarcoidosis (87% of whom were African-American) found effusions in 15 (7%), all with stage 2 or greater disease, and pleural fibrosis in 8 with stage 3 or 4 disease. The effusions were transudates in 8/15 and resolved in 1-2 mos [16]. A review of 3,146 reported cases of sarcoidosis that mentioned pleural involvement found only 76 (2.4%) with pleural effusions, which were unilateral or bilateral, but rarely loculated. Effusions were usually serous (occasionally serosanguineous) and small, but massive effusions have been described [17]. Effusions are either exudates or transudates. Lymphocytes are the predominant cell type [16-18]. The pleural granulomas and surrounding fibrosis account for the later development of fibrous pleural thickening, which is a common finding of little clinical significance [17].

Diagnosis of pulmonary disease

Transbronchial biopsy is the usual procedure used to diagnose pulmonary disease, but complications of bleeding or pneumothorax occasionally occur [4]. In a recent retrospective study of bronchoscopic findings in 150 patients with sarcoidosis, it was found that 55% had abnormalities of the bronchial mucosa: erythema, plaques, nodules, or cobblestoning. Therefore, endobronchial biopsies were performed in many of the patients. It was found that these biopsies were more likely to contain non-necrotizing granulomas in African-Americans than in whites (85% vs 38%, p <0.0008), whereas transbronchial biopsies were positive in 74% of African-Americans and 50% of whites (p < 0.0038). The findings suggest that African-American patients should undergo endobronchial biopsy, which is a safer procedure than transbronchial biopsy [19]. A similar frequency of mucosal abnormalities was found in another study of 101 patients. The overall yield of a positive bronchial biopsy was 57%, but when mucosal abnormalities were present, the yield was 91% [20].

Radiographic patterns in lymph nodes and parenchyma

Nodal involvement: Commonly, enlargement of hilar nodes on both sides, right paratracheal nodes, and middle mediastinal nodes is present. Anterior and posterior mediastinal nodes are seldom involved alone, but may accompany middle mediastinal node involvement. With chronicity, upward retraction of the hila occurs if there is upper lobe fibrosis. An eggshell type of peripheral calcification resembling that seen in silicosis is a rare occurrence, first occurring 5 to 7 y after diagnosis [21]. More common are amorphous, punctate, or popcorn-like calcifications that were described in 20% of 111 patients with stage II or III sarcoidosis who were followed for 10 y or more [22]. The calcification is a dystrophic type that occurs in fibrotic tissue in patients with normal serum calcium levels.

Parenchymal changes: Interstitial disease as in our case, occurs along bronchovascular bundles, the pleura, and interlobular septa. As a result of interstitial inflammation, there may be honeycombing in the late fibrotic stage. Occasionally, acinar nodules greater than 5 mm in diameter occur (nodular sarcoidosis). These nodules have poorly-defined margins, may represent active or scarred granulomas, may show air bronchograms, or may form cavities with thick walls. Although typically multiple and bilateral, they may be unilateral or solitary [17].

Airway changes: Bronchial stenosis and lobar atelectasis may occur even in otherwise normal lungs as a result of extrinsic nodal compression or intrinsic endobronchial disease. Middle lobe atelectasis is most common. In the fibrotic stage, bronchiectasis and cystic spaces may occur. Bronchiectasis may be a result of compression by lymph nodes, from granulomatous destruction of wall structures, or some combination. Cystic emphysematous spaces may result from destruction of alveolar walls around collections of scarred granulomas. Fungal colonization is a complication [17].

Correlation of CT with radiographs and function: In a study of 27 patients, the extent of disease on CT correlated well with overall profusion of opacities on radiographs (r = 0.85). Correlation of CT or radiographic changes with dyspnea, diffusing capacity, or vital capacity showed similar findings, but neither the CT nor the radiograph was a good predictor of functional impairment [23]. The CT changes in stage IV disease [24] are described on another page.

Differential diagnosis of pulmonary sarcoidosis

Clinically, the differential diagnosis includes infectious granulomas, beryllium disease, lymphangitic carcinoma, other interstitial pneumonias, lymphoma, and eosinophilic granuloma. The histologic differential diagnosis includes infectious granulomas, hypersensitivity pneumonia, lymphocytic interstitial pneumonia, foreign body reactions (including aspiration pneumonia and occupational exposure to certain dusts (aluminum, titanium [25]), beryllium disease, reaction to cancer [26] (granulomatous reaction is believed to confer a better prognosis in Hodgkin's disease [27]), chronic granulomatous disease [28], and BCG vaccination or treatment. As a histologic differential feature, it has been noted that the granulomas of sarcoidosis and mycobacterial infection contain no stainable B cells, whereas granulomas reactive to tumor have B cells [29].

Natural history and treatment

Patients with pulmonary sarcoidosis have a variable course. Young patients who present with Lofgren's syndrome (bilateral hilar adenopathy, erythema nodosum, and polyarthritis) have a favorable course even without therapy. Others require therapy for symptoms from the onset or during the course. African-American patients tend to have a worse prognosis than white patients. It is not surprising then that long term studies of the effects of corticosteroid therapy on the natural history of the disease have been inconclusive. A recent British study discusses some of the problems encountered in such studies. For their study, they selected a group of patients with stage 2 or 3 disease, who did not require steroid therapy for symptoms and did not show radiographic improvement by 6 months after diagnosis, for randomization into long-term therapy or selective treatment for symptoms or deteriorating lung function. Of the 149 patients, only nine were non-white. At 5 years, those in the long-term therapy group had a vital capacity that was 9% greater than those in the symptomatic treatment group. A more important discriminating factor was the overall clinical score based on lung function, breathlessness, and chest radiographs, where the long term steroid group had significantly more improvement than those in the group receiving symptomatic therapy [30]. In another study of 337 patients seen over a 4 year period, 64% were African-American. Those who had spontaneous remissions without therapy had a relapse rate requiring therapy of 8%, whereas those who achieved a complete remission for at least one month following discontinuation of steroids had a clinical relapse rate of 74%. About 1/3 of patients required continued steroid therapy. African-American patients required therapy twice as frequently as whites [31].

Possible transmission of sarcoidosis

A transmissible agent is believed by many to be the cause of sarcoidosis, but as yet none has been found. Thus, two reports of possible transmission of disease are intriguing. A patient with lymphoma received a bone marrow transplant from his brother who was in clinical remission from pulmonary sarcoidosis. Three months after the transplant, he developed sarcoidosis, which resolved after 10 weeks of treatment with steroids [32]. Granulomas consistent with sarcoidosis were also reported transiently in a surveillance transbronchial biopsy after heart transplantation from a patient with sarcoidosis [33].

Recurrence of sarcoidosis after lung transplantation

Lung transplantation has been performed in a few patients with end stage lung disease, and disease tends to recur in the transplant. Four of five patients with sarcoidosis, who underwent lung transplantation, developed transient granulomas (seen only up to 83 days) on surveillance biopsies after transplantation. These patients did not differ from controls in their development of bronchiolitis obliterans, in their survival, or by pulmonary function, but tended to have more acute rejection [34].

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Clinical summary

Comments: mw6825@itsa.ucsf.edu

Last revised 3/26/00

Copyright 2000 by Martha L. Warnock. All rights reserved.

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