—  SHORT COURSE #26  —

Lung Biopsy Interpretation

Case 5 - Sarcoidosis

Anna-Luise A. Katzenstein & Jeffrey L. Myers


Clinical History
This 28 year old man presented with a several month history of dry cough and was found to have a collapsed left upper lobe and enlarged hilar and mediastinal lymph nodes. The patient underwent thoracotomy. At surgery firm tumor-like tissue was found in the hilar area and also in nodules studding the pleural surface. A left upper lobectomy was performed.

Microscopic Description:


Case 5 - Figure 1 - Non-necrotizing granuloma located along an interlobular septum. The granuloma is well-demarcated from the surrounding tissue, and the adjacent alveolar septa are normal without evidence of interstitial inflammation.
Case 5 - Figure 2 - Higher magnification view of the non-necrotizing granuloma in Figure 1 showing focal hyalinization and a surrounding thin rim of lymphocytes.
Case 5 - Figure 3 - Granulomatous vasculitis involving a medium sized artery.

This biopsy shows extensive non-necrotizing granulomatous inflammation in the lung interstitium. The granulomas are well-demarcated, mature, and "sarcoid-like", and they are present around bronchioles and arteries as well as in alveolar septa and in the pleura. Extensive hyalinization is present in the center of some confluent areas of granuloma formation, and there are small foci of necrosis. The interstitium adjacent to the granulomatous areas is normal with no significant inflammation. A prominent granulomatous vasculitis is present in most arteries and is characterized by the infiltration of the media and intima by non-necrotizing granulomas. The vascular elastic layer is often distorted by the process, and there is intimal thickening by fibrosis and chronic inflammation with luminal narrowing.

Discussion
Non-necrotizing granulomas are the histologic hallmark of sarcoidosis, and although granulomas can have numerous etiologies, sarcoid granulomas have several features that should suggest the diagnosis. First, the granulomas are located exclusively in the interstitium where they follow a lymphangitic distribution along bronchovascular bundles, interlobular septa and the pleura. Second, they appear sharply demarcated, composed of central tightly organized epithelioid histiocytes surrounded by a peripheral rim of fibroblasts and variable numbers of lymphocytes. Third, areas of hyalinized fibrosis frequently replace portions of the cellular components of the granulomas, and they may be prominent as in this case. Common but entirely non-specific associated findings include multinucleated giant cells and various intracytoplasmic structures such as asteroid bodies, Schaumann or conchoid bodies and crystalloid inclusions.

A variety of atypical histological features may be encountered in well documented examples of sarcoidosis:

Atypical Histologic Features in Sarcoidosis

Prominent granulomatous vasculitis
Necrosis in granulomas
Loosely formed granulomas
Large, polarizable crystals

Sometimes, as in this particular case, granulomatous vasculitis is prominent, and the possibility of necrotizing sarcoid granulomatosis or other primary vasculitis enters the differential diagnosis. Granulomatous vasculitis is common in ordinary sarcoidosis, however, occurring in about 60% of cases where it is found in and around the parenchymal granulomatous inflammation. In some reported cases the granulomatous vasculitis was so severe and extensive that pulmonary hypertension developed due to occlusion of arteries and veins by the vascular granulomas. Necrotizing sarcoid granulomatosis differs from ordinary sarcoidosis in that the granulomatous vasculitis is found in areas of lung not containing parenchymal granulomas, and there is prominent parenchymal necrosis. Wegener's granulomatosis is not a serious consideration in the differential diagnosis since it does not have non-necrotizing granulomas. Another unusual feature is the presence of small foci of necrosis within the granulomas. Although necrosis should stimulate careful search of special stains for organisms, it does not preclude the diagnosis of sarcoidosis, and unless it is extensive, necrotizing sarcoid granulomatosis should not be considered in the differential diagnosis. Sometimes the granulomas in sarcoid are loose rather than well-formed. In such cases other causes of granulomatous inflammation need to be carefully excluded, especially infection, and the diagnosis will ultimately rest on the clinical assessment. Occasionally the granulomas contain large, polarizable crystals that are so numerous as to suggest the possibility of inhaled or injected exogenous substances in the etiology. These crystals have been shown to be calcium oxalate and calcium carbonate and are thought to represent metabolic breakdown products of cellular metabolism. They can be found in any chronic granulomatous process and are not unique to sarcoidosis.

The diagnosis of sarcoidosis requires careful correlation of the clinical with the pathologic findings as well as exclusion of other known causes of granulomatous inflammation, especially infections. Interestingly, sarcoidosis has been described in patients with HIV infection, usually in association with highly active anti-retroviral treatment (HAART), and rare cases have also been described in patients receiving interferon therapy for hepatitis C. Because of the need for clinical correlation, the pathologist usually can only make a descriptive diagnosis of "non-necrotizing granulomas", although in histologically typical cases the phrase, "consistent with sarcoidosis", can be added and is often helpful clinically.

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