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Objective To attempt to determine whether a relationship exists between carcinoid tumors and sarcoidosis. Material and Methods We present a series of seven case reports and discuss hypotheses about possible disease associations. Results Certain malignant lesions have tended to occur in patients with sarcoidosis. Seven patients who were encountered at Mayo Clinic Rochester between 1950 and 1994 had both sarcoidosis and carcinoid tumors. These patients ranged in age from 31 to 66 years, and three of the patients had a history of benign thyroid disorders. Malignant tumors have been thought to be related to sarcoidosis in one of two ways: (1) immunologic abnormalities in sarcoidosis may promote the development of neoplasms or (2) malignant disease may promote the onset of sarcoidosis either by causing local sarcoid reactions that progress or by directly initiating the manifestations of systemic sarcoidosis. Because the chronology of events differed in our seven cases, various mechanisms of action may have a role in the manifestations of these two disease entities. Our cases emphasize the importance of avoiding the diagnosis of disseminated malignant disease in patients with cancer and associated hilar and mediastinal lymphadenopathy without biopsy confirmation of metastatic disease. Conclusion Application of the knowledge gained about the mechanisms of disease in sarcoidosis will perhaps facilitate identification of the pathogenesis of carcinoid tumors and other neuroendocrine tumors.

Objective To determine the frequency and the types of neurologic involvement in a series of patients with Churg-Strauss syndrome (CSS). Design We reviewed the medical records of 47 consecutive patients with CSS who were examined at the Mayo Clinic between January 1974 and June 1992. Material and Methods The study patients were classified into two groups: (1) those with a histopathologically confirmed diagnosis of CSS who had evidence of either vasculitis or Churg-Strauss granuloma, the presence of asthma, and peripheral eosinophilia (more than 10% eosinophils) on at least one differential leukocyte count (N = 33) and (2) those with a clinical diagnosis of CSS who had evidence of vasculitis based on either multiple mononeuropathy or necrotizing cutaneous lesions, the presence of asthma, and peripheral eosinophilia (more than 10% eosinophils) on at least one differential leukocyte count (N = 14). Results Of the 47 patients, 29 (62%) had neurologic involvement. Peripheral neuropathy was detected in 25 patients: 17 had multiple mononeuropathy, 7 had distal symmetric polyneuropathy, and 1 had an asymmetric polyneuropathy. Three patients had cerebral infarctions. Less commonly identified problems included radiculopathies, ischemic optic neuropathy, and bilateral trigeminal neuropathy. Asthma preceded the onset of neurologic involvement in all cases (mean duration, 6.7 years). Follow-up data, when available, showed that corticosteroid therapy usually yielded improvement or stabilization. Conclusion Neurologic involvement is common in CSS, usually manifesting as peripheral neuropathy. In this series of patients, asthma preceded the neurologic manifestations.

Objective To characterize the clinicopathologic spectrum of respiratory tract involvement in patients with positive results of immunofluorescence microscopy for anti-neutrophil cytoplasmic autoantibodies with a perinuclear staining pattern (p-ANCA) and to assess the clinical value of p-ANCA testing. Design We retrospectively reviewed the medical records of all patients at Mayo Clinic Rochester in whom p-ANCA were detected by indirect immunofluorescence microscopy during 1992. Material and Methods Additional target antigen identification was performed with use of enzyme-linked immunosorbent assays for antibodies against myeloperoxidase (MPO) and proteinase 3. We summarized the clinical findings in MPO-positive and MPO-negative patients. Results Sera were positive for p-ANCA in 42 of 2,381 patients (1.8%). In 13 of these 42 patients (31%), the respiratory tract was involved. Twelve patients had chest roentgenographic abnormalities, including a diffuse alveolar filling pattern (N = 8), a diffuse interstitial pattern (N = 2), and a combined interstitial and alveolar pattern (N = 2); three others had nasal inflammation. Ten of 16 sera tested were positive for MPO, and proteinase 3 antibodies were detected in 1 specimen. All patients with alveolar hemorrhage were positive for MPO antibodies. Conclusion Testing for p-ANCA by immunofluorescence microscopy discloses a wide range of clinical disorders distinct from the main cytoplasmic-staining ANCA-associated disease—namely, Wegener's granulomatosis. In particular, the respiratory tract is affected much less frequently. Further evaluation of positive p-ANCA immunofluorescence test results by enzyme-linked immunosorbent assay to determine whether MPO is the target antigen is necessary to obtain clinically useful information from this test.

Progressive dyspnea that developed in a 52-year-old woman with a lifelong history of asthma did not respond to high-dose orally administered glucocorticoids. Initially, a diagnosis of allergic broncho-pulmonary aspergillosis or hypersensitivity pneumonia was suggested as the cause of the worsening dyspnea. Pulmonary function tests demonstrated severe airway obstruction; substantial improvement was noted after bronchodilator therapy. Maximal inspiratory pressure was decreased, and the diffusing capacity of the lungs was abnormal. Computed tomography of the chest showed no parenchymal or mediastinal abnormalities. During a sniff test, fluoroscopy of her diaphragm disclosed paradoxical motion of both hemidiaphragms during inspiration, consistent with bilateral hemidiaphragmatic paralysis. Parsonage-Turner syndrome was diagnosed. The dose of glucocorticoids was tapered. Follow-up of the patient by telephone contact in March 1994 (9 months after her initial examination at our clinic) revealed that the dyspnea was still severe.

Between January 1973 and October 1991 at the Mayo Clinic, 5 of 345 patients with Wegener's granulomatosis initially had features suggestive of giant cell arteritis and subsequently were found to have biopsy-proven vasculitis of the temporal artery. All five patients were older than 60 years of age and had jaw claudication, sudden loss of vision, severe headache with or without diplopia, or polymyalgia rheumatica at the time of initial examination. The erythrocyte sedimentation rate was high at the time of onset of symptoms in four patients (and unavailable in one patient). A temporal artery biopsy specimen revealed giant cell arteritis in one patient and non-giant cell arteritis in four patients. All five patients subsequently had pulmonary and renal lesions characteristic of Wegener's granulomatosis, with typical histopathologic features on biopsy or positive cytoplasmic staining antineutrophil cytoplasmic antibodies. Thus, overlapping features of giant cell arteritis and Wegener's granulomatosis do occur in some patients.

The development of the antineutrophil cytoplasmic autoantibody (ANCA) test has lent support to the concept of Wegener's granulomatosis as a spectrum that may affect one or more of the major anatomic sites: upper respiratory tract (E), lung (L), or kidney (K). It is C-ANCA that has high specificity for Wegener's granulomatosis (WG). The sensitivity is highest in the fully expressed Wegener's triad, or ELK, and less in local regional disease. It is possible that isolated manifestations such as episcleritis, subglottic stricture, or diffuse alveolar hemorrhage associated with C-ANCA may be considered in the Wegener's spectrum, although traditional histopathologic criteria are lacking. Until specific etiologic agents are uncovered for the various ANCA-associated entities, classification schemes should continue to employ previously established clinicopathologic syndromes such as WG using the ANCA test to better define their clinical spectrums.

Wegener's granulomatosis is a multisystem disease often with protean manifestations. Eye signs and symptoms can be prominent and may be the patient's initial complaint. For a definitive diagnosis of Wegener's granulomatosis, a tissue biopsy specimen must show vasculitis and necrotizing granuloma. The presence of anticytoplasmic autoantibodies in the serum of patients has been found to be highly specific for Wegener's granulomatosis and can considerably facilitate early diagnosis and be used to monitor disease activity. In two illustrative cases, the utility of this laboratory test in the differential diagnosis of scleritis and orbital pseudotumor is demonstrated.

Wegener's granulomatosis and the Churg-Strauss syndrome are both syndromes that appear to begin with a phase of regionally limited symptomatology before they progress at unpredictable rate to a generalized phase characterized by symptoms of systemic vasculitis. The clinical features of atopy, peripheral blood eosinophilia, and tissue eosinophilia distinguish CSS from WG, with its typical necrotizing granulomatous respiratory tract lesions. Whereas in generalized WG with renal involvement the use of cyclophosphamide usually cannot be avoided, the generalized systemic vasculitis phase of CSS appears to respond well to glucocorticoids alone. For the more limited forms of WG, adapted therapy regimens including trimethoprim-sulfamethoxazole have been reported to be successful. Anticytoplasmic autoantibodies (c-ANCA = ACPA) are a new diagnostic serum test with high specificity for WG. Serial determinations of c-ANCA are a promising tool to monitor disease activity.

Since its first description by Wegener in 1936, Wegener's granulomatosis has undergone significant changes in terms of clinical scope, diagnosis, and treatment. It is no longer tenable to insist on the fulfillment of the Wegener's triad to make the diagnosis. The wide range of clinical presentations is encompassed by the ELK (ear, nose, and throat; lung; kidney) classification in which any combination or singular involvement of the major sites can be considered within the Wegener's spectrum if supported by the appropriate pathologic findings or the presence of a cytoplasmic antineutrophil cytoplasmic antibody pattern. Treatment is based on the extent of involvement and clinical tempo. Trimethoprim-sulfamethoxazole may be used for patients with localized disease. Systemic disease, including involvement of the kidney, mononeuritis multiplex, and skin vasculitis, is treated with systemic glucocorticoids and cyclophosphamide. Research into the antineutrophil cytoplasmic antibody phenomenon is yielding new insights into possible pathogenic mechanisms.

For over 25 years, glucocorticoids have been the chief agents used in the treatment of pulmonary sarcoidosis. Most authorities agree that such treatment is effective, but much controversy exists about the indications for administration. Presented herein is a method of treatment using an alternate-day regimen of administration of prednisone; this approach is based on a synthesis of personal experience and findings in the literature.

We describe two patients with diffuse non-Hodgkin's lymphoma, hypercalcemia, and increased activity of serum angiotensin-converting enzyme. A mechanism similar to that operative in sarcoidosis is speculated to have caused the hypercalcemia. A lymphokine elaborated by the malignant lymphoma may cause activated macrophages to produce 1,25-dihydroxyvitamin D3.

Twelve patients with Wegener's granulomatosis were treated with antimicrobial agents, chiefly trimethoprim-sulfamethoxazole. The clinical course improved in 11 of the 12 patients who received this treatment. The success of antimicrobial treatment suggests the possibility of a microbial infection as the inciting cause of Wegener's granulomatosis in some patients. Alternatively, these agents--in particular, trimethoprim-sulfamethoxazole--may possess immunosuppressant activity.

A population-based study was conducted among residents of Rochester, Minnesota from 1935-1984 to examine the influence of diagnostic access bias on the incidence and mode of presentation of clinically recognized sarcoidosis. Immigrants had an elevated risk of sarcoidosis and were more likely to present with asymptomatic sarcoidosis diagnosed on routine screening chest radiographs. Similar patterns were observed for health professionals, a group with markedly greater access to the diagnostic procedures which label them as having sarcoidosis. Sarcoidosis exhibits a spectrum of manifestations, ranging from a totally asymptomatic process discernible only by specific diagnostic scrutiny to a clinically obvious presentation with significant morbidity. For disease entities such as this, apparent patterns of occurrence may depend on differential access in the study population to the maneuvers necessary for diagnosis. Diagnostic access bias, in addition to other diagnostic biases, deserves more careful scrutiny in epidemiologic research.

Serum angiotensin-converting enzyme (SACE) levels were measured in 44 subjects six weeks after acute pulmonary histoplasmosis. All patients were infected in a common-source outbreak of histoplasmosis which occurred on one day. All patients had both strictly defined clinical and serologic evidence of infection. The SACE activity was elevated at six weeks compared to normal controls, and seven of the 44 had levels more than 2 SD above the normal mean. SACE levels were also measured at three and 24 weeks after acute infection in a smaller number of the same subjects. Serial observations demonstrated that all subjects (including those with normal and elevated SACE at six weeks) had a rise and fall in SACE activity following symptomatic acute pulmonary histoplasmosis. Our findings suggest that elevated SACE does not reliably separate sarcoidosis from histoplasmosis, although elevations in histoplasmosis are much less common and may occur only briefly following acute pulmonary histoplasmosis. More important, it seems that SACE activity rises acutely in all patients with symptomatic acute histoplasmosis and then falls gradually toward baseline over several months, coinciding temporally with the granulomatous response.

The awareness that sarcoidosis can involve intrathoracic lymph nodes and lung parenchyma in sequential fashion evolved during the first half of this century. This awareness resulted in a roentgenographic staging system that has relevance to the course and prognosis, pulmonary function changes, and the symptom of dyspnea. The following definition or roentgenographic staging is proposed as the simplest, most reproducible system based solely on the roentgenographic appearance, avoiding histopathologic and pathophysiologic inferences. Stage I: bilateral hilar lymphadenopathy; stage II: bilateral hilar lymphadenopathy plus parenchymal infiltration; and stage IQ: parenchymal infiltration without bilateral hilar lymphadenopathy. The early data concerning bronchoalveolar lavage, determination of serum angiotensin-converting enzyme, and gallium 67 citrate scanning appear to have no clear relationships to staging, suggesting that staging continues to have unique value to the clinician in the classification of sarcoidosis and in the delineation of its clinical course and prognosis.

Twenty-four patients with sarcoidosis had normal serum angiotensin converting enzyme (SACE) values at time of diagnosis. Sixteen patients were in stage I and eight of these underwent complete remission and four followed a stable course. Seven of eight patients in stages II and III experienced improvement while receiving glucocorticoid treatment. In six, serial SACE measurements fell significantly, paralleling the clinical improvement. The data suggest that a normal SACE in stage I indicates a good prognosis. Patients in stages II and III with normal SACE levels may still have active disease potentially responsive to glucocorticoid treatment. The reduction of SACE while receiving treatment may be viewed as the "suppressible" SACE compartment, representing that portion of the enzyme elaborated by the granuloma or its cellular precursors. The level remaining after suppression by glucocorticoids may be considered "basal" SACE, probably related to normal turnover of SACE producing cells in vascular endothelium.

Allergic granulomatosis is a distinct clinical syndrome occurring in adults with asthma, eosinophilia, and multisystem vasculitis. Atopy and drug sensitivity are other important features. The skin reactions are most commonly nodular and inflammatory lesions. A unique feature is the deep papulonodules, which may occur singly on the scalp or symmetrically on the extremities. Cutaneous findings may range from purpura to urticaria and ulceration. The most common histologic finding is the extravascular granuloma; however, necrotizing vasculitis of small vessels is seen, as well as periarteritis nodosa involving larger vessels of the skin. This varied histologic and clinical spectrum seen in patients with systemic allergic granulomatosis is a reflection of a unique host response to multiple antigens. The cutaneous findings imply that allergic granulomatosis probably represents a unique host response to the same causative and pathogenetic factors as are usually found in periarteritis nodosa and necrotizing vasculitis.

140 patients with biopsy-proven Wegener's granulomatosis were examined during a 16-year period at the Mayo Clinic. Forty patients had diverse and explosive ophthalmic involvement, including conjunctivitis, episcleritis, scleritis, corneal ulceration, uveitis, retinal vasculitis, optic neuropathy, orbital mass, orbital cellulitis, and obstruction of the nasolacrimal duct. The multiple ophthalmic and systemic complications in these 40 patients and the importance of establishing the pathologic diagnosis are discussed. Treatment with corticosteroids and immunosuppressive agents has dramatically improved the prognosis, although substantial mortality (four patients died of Wegener's granulomatosis) and ocular morbidity (three eyes were enucleated) are still associated with this disease.

The records of 81 patients with a roentgenologic pattern of diffuse reticulonodular pulmonary disease and a pathologic diagnosis of chronic interstitial pneumonitis and fibrosis were reviewed. All had restrictive patterns on pulmonary function testing with impairment of CO diffusing capacity. The most common features were characteristic dry rales, digital clubbing, and evidence of altered immune activity. Twenty patients manifested evidence of other disease thought to be of an autoimmune or hypersensitivity nature, with the pulmonary lesion dominating the clinical picture. The concept of “classic interstitial pneumonitis-fibrosis (CIP-F)” as a clinicopathologic syndrome has been proposed with the following categories: (1) definite-complete syndrome with rales, clubbing, and evidence of altered immune activity; (2) probable- rales and clubbing without evidence of altered immune activity; and (3) possible -histopathologic finding with or without evidence of altered immune activity but no rales or clubbing. Some patients progress from possible CIP-F to definite CIP-F; the latter category implies chronicity and commensurately worse prognosis.