FINAL DIAGNOSIS: GRANULOMATOUS PNEUMONITIS SECONDARY TO SARCOIDOSIS.
Sarcoidosis is an inflammatory, multisystemic disease characterized by the formation of non-necrotizing granulomas. Although its incidence is only 11 per 100,000 in Caucasians and 34 per 100,000 in patients of African descent (Schorr 2004), it is the second most common type of interstitial lung disease (ILD) necessitating lung transplantation, with idiopathic pulmonary fibrosis being the first (Sulica et al., 2001).
Clinically, the disease manifests itself in the third to fourth decades of life. Vague symptoms like fever, anorexia, and arthralgias suggest an inflammatory condition, while dyspnea on exertion, nonproductive cough, and chest pain target the clinician toward the pulmonary system. The diagnosis of sarcoidosis is difficult, in part because it can involve many organs such as the skin, eye, liver, heart, and brain. Nevertheless, the primary morbidity and mortality from sarcoidosis is via pulmonary involvement (Schorr et al., 2004). Crackles on auscultation are sometimes detected, and a restrictive pattern of disease is seen with pulmonary function tests in more advanced cases of sarcoidosis.
Radiology is an essential part of the workup. Chest x-rays first show bilateral hilar lymphadenopathy, with intraparenchymal infiltrates appearing in more advanced stages of sarcoidosis. The final stage of sarcoidosis is reached when diffuse fibrosis has rendered the lungs virtually nonfunctional (Schorr, 2004). High resolution CT scans typically demonstrate central bronchial distortion, peripheral honeycombing, and diffuse linear opacities. Nearly 100% of sarcoidosis patients demonstrate air trapping, the extent of which correlates with the severity of the pulmonary function test results (Chung et al., 2001; Nagai et al., 2001). Constitutional symptoms like weight loss and fever, combined with the appearance of hilar masses, mandate that a neoplastic process such as lymphoma be ruled out (Shadid and ter Maaten, 2002). Also, 5% of sarcoidosis cases manifest themselves by the coalescence of granulomas into solitary or multiple nodules 1-7 cm in diameter. This variant, called nodular sarcoidosis, can easily be mistaken for metastatic carcinoma on radiographic studies (Gal and Koss, 2002; McCullough and McCullough, 2002).
Once the differential diagnosis has been established clinically, the pathologist becomes involved. Both transbronchial and endobronchial biopsies are useful because the granulomas frequently involve the airways, and when performed simultaneously, they have a combined diagnostic yield between 60-80% (Halme et al., 2001; Schorr et al., 2001). In the biopsy, non-necrotizing granulomas are a prerequisite for the diagnosis of sarcoidosis.
Granuloma formation begins when helper T-cells recognize as-of-yet-unknown antigens on class II histocompatibility molecules, which are located on antigen-presenting cells. The resulting cascade of interleukins, interferons, and tumor necrosis factor from the T-cells trigger monocyte chemotaxis and giant cell formation. This, in turn, destroys functional tissue and replaces it with hyalinized fibrotic material (James 2001; Nagai et al., 2001; Gal and Koss, 2002). This means that when the pathologist examines the biopsy, there should be macrophages that have merged into multinucleated giant cells and have assumed an epithelioid shape as they encircle hyalinized, fibrotic nodules. Surrounding the macrophages are lymphocytes, monocytes, and fibroblasts (Gal and Koss, 2002).
On larger specimens like wedge resections and pneumonectomies, the full pathology of sarcoidosis becomes more apparent. Grossly, numerous small white granular nodules in a lymphangitic pattern are seen, especially in the pleural/subpleural and bronchovascular areas [Images 2 & 3]. Corresponding with CT scans, honeycombing, particularly in the upper lobes, is seen. Microscopically, the granulomas are present around blood vessels [Images 8 & 9], bronchi, bronchioles, interlobular septa, and beneath the pleura [Image 6]. Only rarely are they actually located in the alveoli. In advanced cases like this one, the once-discrete granulomas merge into large, fibrotic aggregates [Image 6]. Some central necrosis can be seen without necessarily being of infectious origin when the disease is severe enough [Image 11]. Cytoplasmic inclusions are often present, including basophilic calcifications (Schauman's bodies) and lucent, birefringent calcium oxalate crystals. Asteroid bodies in the giant cells are a nonspecific finding [Image 12, arrow].
It is important to remember the differential diagnosis for granulomas. Over half of all granulomas seen in lung tissue have a mycobacterial (especially M. tuberculosis) or fungal etiology; thus, acid fast and silver stains are obligatory on initial specimens and correlation with microbial tissue cultures is strongly recommended. Suspicion for an infectious process is even higher if only solitary granulomas are encountered, if they have a necrotic core, and if neutrophils and eosinophils are present in or around the granulomas. Unfortunately, even if only non-necrotizing granulomas are seen, it does not definitively rule out M. avium intracellulare, hypersensitivity pneumonia, or berylliosis (Schorr 2001; Gal and Koss, 2002). The diagnosis of sarcoidosis is thus a complicated one of exclusion, requiring the integration of clinical, radiologic, and pathologic data.
In an effort to both enhance diagnostic power and understand the etiology of sarcoidosis, clinical pathology and cytology are playing a larger role. Wolff et al. (2003) demonstrated a specific pattern of cytokines in the bronchoalveolar lavage fluid (BALF) of sarcoidosis patients. There is a marked increase in fibronectin, a mild increase in tumor necrosis factor-alpha, a slight decrease in interferon-gamma, and a sharp decrease in platelet-derived growth factor-BB. This profile is distinctive from healthy controls as well as from other ILDs, and may prove to be useful in diagnosis. Granulomas may even be isolated from BALF, but only rarely (Hendricks et al., 1999). Induced sputum has been shown to be effective in isolating CD4+ T-cells and in detecting the elevated CD4/CD8 ratio that distinguishes sarcoidosis from nongranulomatous ILDs (Olivieri et al., 2000). Particularly compelling is the recent report by Psathakis et al. (2004) demonstrating the ability to detect and monitor the degree of sarcoidosis by measuring the levels of 8-isoprostane in the exhaled breath of patients. This volatile prostaglandin-like compound is a product of the reactive oxygen cascade that accompanies inflammation, and thus is a noninvasive marker for oxidative stress and active disease.
Despite the severe course that the disease sometimes takes (as in this case), the vast majority of patients with sarcoidosis do not require lung transplantation. Indeed, many are completely asymptomatic, with hilar masses and lung nodules detected incidentally on chest x-rays. Of those that exhibit symptoms, approximately 75% will require only treatment with NSAIDs, the remainder requiring various lengths of corticosteroid therapy (Schorr 2004). In a case study of intractable multisystemic sarcoidosis, TNF-alpha blockade with infliximab dramatically reduced the severity of disease (Ulbricht et al., 2003).
Although no specific causative factor has been identified in the pathogenesis of sarcoidosis, occupational exposure to insecticides, mold, and mildew are associated with an increased likelihood of developing the disease. Oddly enough, smoking is actually associated with a decreased risk of sarcoidosis (Newman et al., 2004)-a fact few clinicians are eager to share with their patients who smoke! In large part, the development and outcome of sarcoidosis appears related to polymorphisms in genes encoding components of the inflammatory cascade, including class II histocompatibility molecules and the inhibitor kappa B-alpha promoter (Sato et al., 2002; Abdallah et al., 2003). Those who tend to have an unfavorable genotype, like Africans, are more likely to develop the disease and are more likely to advance to end-stage diffuse fibrosis and require lung transplantation. Interestingly, almost 50% of sarcoidosis transplant recipients will have a recurrence of granulomas in the new lung, but rarely exhibit symptoms. Sarcoidosis patients have rates of rejection and survival comparable to other indications for lung transplant (Padilla et al., 1997; Walker et al., 1998; Collins et al., 2001; Sulica et al., 2001; Schorr et al., 2004).
Not only do Africans require transplantation for sarcoidosis more frequently, but they also have higher rates of rejection and poorer outcomes following transplantation. This pattern has been noticed in other organ transplants involving Africans, and it has been attributed to the increased variations in major histocompatibility genes between Africans compared to the variations between Caucasians (Schorr et al., 2004). Parenthetically, this is consistent with the finding that there are more genetic variations overall between Africans than between Caucasians or Asians, attributable to a postulated "bottleneck" effect from colonization of Eurasia by a single clan of Africans roughly 35-40,000 years ago (Ingman et al., 2000). [For an equally fascinating paper on human adaptation and disease, read the report by Ruiz-Pesini et al. (2004).]
Thus, the study of sarcoidosis encompasses clinical and anatomic pathology, radiology, surgery, immunology, pharmacology, physiology, molecular biology, and even anthropology. However, the fact that this disease is neither fully understood nor entirely curable underscores how much more we have to learn.
This is a 30 year-old woman who developed progressive cough and shortness of breath that was diagnosed as sarcoidosis. Anti-inflammatory medications failed to prevent the progression of the disease, and the patient underwent a double lung transplant years after the original diagnosis. Pathological examination of the native lungs demonstrated the full extent of the disease.
Since the transplant, the patient developed recurrent sarcoidosis and bilateral lower lobe infiltrates in the allograft lungs. She also had to fight off a fungal infection at the anastomosis site. However, only minimal acute cellular rejection was observed on transbronchial biopsy, and overall she feels much better post-transplant. December 2004 PFTs are as follows:
|FVC||% predicted||FEV1||% predicted||FEV1/FVC|
Contributed by Craig Horbinski, MD, PhD, and Sanja Dacic, MD, PhD