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Circulating anti-neutrophil cytoplasmic antibodies (ANCA) have been described in most patients with "pauci-immune" necrotizing and crescentic glomerulonephritis. A 29-kDa serine protease (p29 or proteinase 3) and myeloperoxidase are the two best characterized antigens recognized by ANCA. The study presented here was conducted to define the diagnostic value of assays for antibodies against these two antigens in rapidly progressive glomerulonephritis. Radioimmunoassays were developed for anti-p29 and anti-myeloperoxidase antibodies, with purified antigens, and the results of the radioimmunoassays were compared with those obtained by immunofluorescence tests for ANCA. We performed assays on serum samples from 123 patients with the syndrome of rapidly progressive glomerulonephritis, as well as from 200 blood bank donors and from 717 additional control patients. Without knowledge of the results of ANCA tests, the renal pathologic findings in the 123 patients with rapidly progressive glomerulonephritis were analyzed, and 42 were classified as pauci-immune necrotizing and crescentic glomerulonephritis, 18 were classified as anti-glomerular basement membrane nephritis and 63 were classified as other forms of renal disease. We found radioimmunoassays to be more reliable in the diagnosis of pauci-immune necrotizing and crescentic glomerulonephritis than immunofluorescence testing. By radioimmunoassay, ANCA were found in 40 of 42 patients (95% sensitivity) with pauci-immune necrotizing and crescentic glomerulonephritis (14 with anti-p29 and 26 with anti-myeloperoxidase antibodies). The tests for antibodies to p29 and myeloperoxidase were 99.9 and 99.5% specific for pauci-immune necrotizing and crescentic glomerulonephritis, respectively. In the setting of rapidly progressive glomerulonephritis, a positive radioimmunoassay for anti-p29 or anti-myeloperoxidase antibodies (together with a negative test for anti-GBM antibodies) gives a probability of pauci-immune necrotizing and crescentic glomerulonephritis of over 99%.

We studied the histologic findings from extrarenal biopsies (especially of the lung or upper respiratory tract) or autopsies of 68 patients who were tested for serum antineutrophil cytoplasmic antibodies (ANCAs). We used antigen-specific assays to detect antibodies against proteinase 3 (PR3) and myeloperoxidase (MPO), the two types of ANCAs of proven diagnostic value for the spectrum of diseases that includes Wegener's (pathergic) granulomatosis, microscopic polyarteritis (microscopic polyangiitis), Churg-Strauss syndrome, idiopathic necrotizing and crescentic glomerulonephritis, and their variants. Twenty-eight patients had antibodies to PR3 and 16 had antibodies to MPO; no patient had antibodies to both. All 44 patients with ANCAs had histologic evidence of this spectrum of diseases. Thirteen patients without histologic evidence of this spectrum of diseases had negative tests for ANCAs. There were no pathologic features that reliably identified patients with one or the other type of ANCA. Eighteen of 31 patients with lesions of Wegener's granulomatosis had antibodies to PR3, seven had antibodies to MPO, and six had neither. Three of four patients with necrotizing arteries without granulomas had anti-MPO antibodies, but similar lesions were seen, together with extravascular granulomas, in three patients with anti-PR3 antibodies. Of 16 patients with alveolar hemorrhage, nine had anti-PR3 and five had anti-MPO antibodies. Two patients diagnosed clinically as having Churg-Strauss syndrome had anti-MPO antibodies. In 16 of the 25 patients with ANCAs and a histologic diagnosis of Wegener's granulomatosis the diagnosis was made on the basis of extravascular granulomatous lesions alone, which argues against the requirement for vasculitis. Of six patients with negative tests for ANCAs and histologically diagnosed Wegener's granulomatosis, none had evidence of renal involvement. We conclude that in the appropriate clinical setting the presence of anti-PR3 or anti-MPO antibodies provides reliable evidence of the above spectrum of diseases, but that subclassification (to the extent this is possible) depends on the presence of distinctive clinical or pathologic features. In patients with negative tests for ANCAs, interpretation of clinical and histologic findings remains the only definitive method of diagnosis.

Problems with the classification and diagnosis of vasculitides are discussed. The evidence related to the pathogenetic importance of immune complexes in vasculitis, both in experimental models and human disease, is reviewed. The finding, by immunofluorescence, of immunoglobulins and complement components in vessel walls has provided indirect evidence of a role of immune complexes in certain forms of human vasculitis. However, specific antigens have been demonstrated in very few instances, notably in some patients with hepatitis B infection. In most forms of human vasculitis there is no information about causative factors. The widely held belief that therapeutic drugs cause an appreciable proportion of cases of human vasculitis appears unfounded.

Presentation of Case A 31-year-old woman was admitted to the hospital because of asthma and neurologic deficits. There was a four-year history of occasional episodes of asthma, with intermittent treatment by corticosteroids during the five months before entry. The patient was otherwise well until about 10 weeks before admission, when hyposensitization therapy was begun with dust and mite antigens. After the second dose of antigen therapy fever, urticaria, purpura, and arthritis developed. She was admitted to another hospital, where laboratory studies revealed eosinophilia and an erythrocyte sedimentation rate of 45 mm per hour. An x-ray film of the chest disclosed . . .

Presentation of Case A 64-year-old woman was admitted to the hospital because of Clostridium perfringens sepsis, a gallbladder mass, dysproteinemia, and progressive neuropathy. She was well until t...

Presentation of Case A 37-year-old man was admitted to the hospital because of a pulmonary mass. There was a long history of paranoid schizophrenia, with repeated admissions to psychiatric hospitals. Six months before admission a chronic cough developed and was intermittently productive of blood. Three weeks before entry the patient began to complain of pain in the knees, shins, and heels. An x-ray film of the chest showed a pulmonary mass. He was admitted to the hospital. The patient smoked two to three packs of cigarettes daily for 20 years. He lost 9 kg in weight during the year before . . .

In view of the apparent conflict between the recent finding of the Arias-Stella reaction in early pregnancy and our opinion of the regressive and involutional nature of this reaction based on a study of ectopic pregnancies and spontaneous abortions, we investigated 75 cases of therapeutic abortion in the first trimester. The Arias-Stella reaction was seen in 26, but features of degeneration were found in Arias-Stella reaction nuclei as well as focal decidual necrosis. Studies of hormonal levels obtained from the endocrinologic literature demonstrated declines during early pregnancy at the time of the ovary-placenta change-over. This association of the cytologic and histologic features of degeneration with declining hormone levels supports our opinion that the Arias-Stella reaction is a regressive phenomenon in early pregnancy as well as in ectopic pregnancy and spontaneous abortion.

Presentation of Case A 70-year-old woman was admitted to the hospital because of fever of unknown origin. She was in a stable state of health until eight weeks earlier, when she began to experience increasing fatigue. During the next two weeks a nonproductive cough developed, with rise of the temperature as high as 38.4°C, chilliness, sweats, malaise, and a severe headache over the right ear and the occiput. A physician prescribed erythromycin, without improvement, and she was admitted to another hospital. Urinalysis was normal. The hematocrit was 31.5 percent; the white-cell count was 7500, with 86 percent neutrophils. The erythrocyte . . .

In 6 women of 60 years of age or over with vaginal bleeding, 2 cases of thecoma, 3 cases of mixed granulosa- and theca-cell tumor, and one case of estrogenic thecomatosis were found. Except for one woman with a postmenopausal period of amenorrhea of 2 years, the others had postmenopausal periods of 10 years or longer. No palpable adnexal masses were felt in 4 of these 6 women but all had hyperplasia of the endometrium with mitotic figures. The importance of mitotic figures as an indicator of estrogenic activity in the endometrium is stressed. It is recommended that any colporrhagic woman with a postmenopausal amenorrhea of more than 3 years and hyperplasia of the endometrium with mitotic figures should have an exploratory laparotomy whether or not a palpable adnexal mass is present, provided no estrogen has been administered. The use of the terms estrogenic thecomatosis and androgenic hyperthecosis is suggested to lessen the confusion due to morphologically similar cells producing different hormones.

We reviewed open lung biopsies from 35 patiens with Wegener's (pathergic) granulomatosis in order to study the histogenesis of the pulmonary lesions and to identify the early lesions. The process of pathergic necrosis is fundamental in the production of extravascular and vascular lesions and was divided into micronecrotic and macronecrotic types. Micronecrosis, usually with neutrophils (microabscesses), constitutes the early phase in the development of the pathognomonic organized palisading granuloma. The palisading granuloma differs from the compact granuloma of tuberculoid type, which occurs in infections and sarcoidosis but not in Wegener's (pathergic) granulomatosis. There is a progression of disease from micronecrosis to macronecrosis (widespread necrosis) and then to fibrosis. Macronecrosis surrounded by palisading histiocytes or diffuse granulomatous tissue in dicates active disease, whereas necrosis surrounded by fibrous tissue indicates previously active disease. Most cases have a combination of micronecrosis, macronecrosis, and fibrosis. We established the relative diagnostic value of various histologic features. Arteritis and phlebitis as classically described in Wegener's granulomatosis were present in most but not all cases. We believe that Wegener's granulomatosis primarily affects both vascular and extravascular collagen and reticulum and that vasculitis represents a primary necrosis of walls of blood vessels. We believe that the concept of Wegener's granulomatosis as a vasculitis is too restrictive and does not include many cases with only extravascular histologic changes.

Twelve cases of pathergic (Wegener's) granulomatosis are described, with special attention focused on the long duration of mucosal and skin lesions in untreated cases, designated as the protracted superficial phenomenon, and on the histologic features that may be helpful in making the diagnosis. The long duration, often the result of a lack of proper interpretation of histologic details, was associated in some of the cases studied with the development of intractable renal failure or mutilation of the face. Since cytotoxic therapy offers the opportunity to prevent these complications, the desirability of an early diagnosis is obvious. Biopsy is the principal means of diagnosis, and therefore interpretation of histologic details is of paramount importance. Helpful histologic features found in the extravascular and vascular tissues of the specimens studied were focal necrosis, fibrinoid degeneration, palisading granulomas, giant cells, and vasculitis. Nonpalisading foci of granular necrosis or fibrinoid degeneration appeared to precede the development of the typical palisading granuloma. Both focal necrosis and focal fibrinoid degeneration occurred independently of intrinsic vascular involvement and in themselves are distinctive features of pathergic (Wegener's) granulomatosis. There was predominance of the extravascular components in the cases studied with occasional absence of vasculitis. Both the extravascular and vascular components are important in making a definitive diagnosis, but the extravascular component is characteristic, even in the absence of vasculitis. The extravascular tissues and the vessels are parallel contemporaneous target tissues.

THE importance of mucormycosis as a clinical entity is becoming more and more evident as indicated by the increasing number of cases in the literature. The case reported below is submitted because of the uniqueness of the localization, no similar localization having been found in the literature. Furthermore, the progress in vascular surgery that has led to increased use of thrombendarterectomy and segmental aortic resection, with prosthetic replacement, suggests the need of focusing attention on this type of mycotic infection, with its ominous prognosis. Case Report A 45-year-old housewife was admitted to the Beverly Hospital 2 weeks after the onset . . .

IDIOPATHIC pulmonary hemosiderosis is a rare disease in a young adult and until recently was diagnosed only at post-mortem examination. Browning and Houghton1 have reviewed the English literature, finding only 3 adult cases, and added 3 adult cases in their report. Recently, Soergel2 surveyed the entire literature, reporting only 12 documented cases in adults. Only 1 case3 has been reported in an adult over the age of thirty at onset of symptoms. The following case is reported because it is unusual for the disease to have a rapidly fatal outcome without recurrent manifestations and also because its occurrence in a . . .

THE RHEUMATOID nodule is considered by many to be the most characteristic histologic lesion associated with rheumatoid arthritis. Usually subcutaneous in location and occurring during the course of the disease in 25 to 30 per cent of all patients, 1 nodules have been found in the pleura, pericardium, aortic valve, 2 mitral valve, sheath of the rectus abdominis, kidney 3 and eye. Scleral localization has been designated as scleromalacia perforans, 4 scleritis necroticans, 5 necroscleritis nodosa excavans 6 or nodular episcleritis, 7 depending on the observer's concept of the lesion. The presence of a scleral lesion in a patient with enlargement of the phalangeal joints was noted by Holthouse in 1893. 8 In 1938 Verhoeff and King 6 reviewed 14 previously reported cases and described a carefully observed one of their own. Since then several additional cases have been reported. 9 The majority of these patients were over the age of 50, and the sex

I N A P R E v I 0 u s study of the stromal theta cell1 a peculiar accumulation of lipid was noted in the stromal spindle cells (the ovarian “fibroblasts”) forming a band just below the surface of the ovary. The distribution and location were different from those of the polygonal stromal theta cells, called luteinized stromal cells by Scully,” and there was no connection with the follicular apparatus. In the same study,l evidence was presented that a spindle form of the stromal theta cell was an early stage in the development of the polygonal form. Since the presence of lipid in the ovary appeared to be intimately connected with the synthesis of the steroid hormones, it was thought appropriate to compare the stromal spindle cells forming the lipid band with the stromal theta cells and the theta interna cells which are also derived from morphologically similar stromal spindle cells. Methods ap