Helen M. Haupt

The lung in systemic lupus erythematosus. Analysis of the pathologic changes in 120 patients.

The nature and frequency of pulmonary involvement in systemic lupus erythematosus (SLE) is controversial. We reviewed the clinical and pathologic features of 120 patients with SLE described in autopsy records at The Johns Hopkins Hospital to determine the pulmonary parenchymal changes that could be attributed directly to SLE. Each case was reviewed to determine the extent of extrapulmonic SLE and possible alternative explanations for the observed lung pathology. Moderate or severe pulmonary parenchymal alterations that were attributed to SLE were found in 22 patients (18 percent). Five patients with interstitial fibrosis, two with pulmonary vasculitis, and one with pulmonary hematoxylin bodies were attributable only to SLE, as were 11 of 15 (73 percent) patients with interstitial pneumonitis. Alternative explanations for findings previously attributed to SLE included congestive heart failure, renal failure, infection, aspiration, oxygen toxicity and increased intracranial pressure. Alveolar hemorrhage, thought to be a feature of acute lupus pneumonitis, was unexplained in only two of 29 (7 percent) patients, alveolar wall necrosis was unexplained in one of seven (14 percent) and edema was unexplained in three of 70 (4 percent). Hyaline membranes, present in four patients, were always explained. Pleuritis and pleural effusions were attributed to SLE in 22 of 36 (61 percent) and three of 28 (11 percent) patients, respectively. The findings suggest that many nonspecific pulmonary lesions previously attributed to SLE, such as alveolar hemorrhage, alveolar wall necrosis, edema and hyaline membranes, are probably secondary to intercurrent infection, congestive heart failure, renal failure or oxygen toxicity.

The heart and cardiac conduction system in polymyositis-dermatomyositis: A clinicopathologic study of 16 autopsied patients

We reviewed the clinical records of 16 patients with polymyositis-dermatomyositis syndromes autopsied at The Johns Hopkins Hospital to determine the nature and extent of cardiac involvement and its correlation with the severity of disease as a whole. The adult patients ranged in age from 32 to 84 years (average 56); the 2 children were aged 2 and 10 years. The duration of disease ranged from 1 to 72 months (average 21). Seven patients had dermatomyositis, 5 had dermatomyositis with malignancy, 2 had childhood dermatomyositis, and 2 had an overlap syndrome. Seven patients had clinical evidence of congestive heart failure, 4 of whom had microscopic evidence of myocarditis. Two patients had bundle branch block; in 1 there was direct involvement of the conduction system by myositis and contraction band necrosis. Evidence of active myocarditis was present in 4 patients (25%); all had congestive failure. Focal myocardial fibrosis was present in 4 patients. Vascular alterations were present in the coronary arteries in 5 patients (31%). Three had active vasculitis, 1 had intimal proliferation, and 1 had medical sclerosis with calcification. All patients with active myocarditis had skeletal muscle involvement. Nine patients had myositis without myocarditis. There was no correlation of overall severity of the disease with the presence or absence of active myocarditis. The present study shows that cardiac involvement may be common in polymyositis; congestive failure or conduction abnormalities arising in this setting may be indicative of myocarditis.

Ara-C lung: noncardiogenic pulmonary edema complicating cytosine arabinoside therapy of leukemia.

Unexplained fatal pulmonary edema observed at autopsy in leukemic patients treated with cytosine arabinoside (Ara-C) suggested a possible role of the drug in causing increased alveolar capillary permeability. We reviewed clinical and pathologic features of the 181 patients with leukemia who were examined at autopsy at The Johns Hopkins Hospital in the past 12 years, 93 (51 percent) of whom had received intravenous Ara-C in doses of 7.5 to 30 mg/kg/day (average dose, 16 mg/kg/day). Fifty-one patients had received their last treatment within 30 days, and 42 patients between 31 and 894 days, prior to death. Among the 181 patients examined at autopsy 43 (24 percent) had massive edema, 59 (33 percent) had moderate edema, and 79 (44 percent) had either slight edema or no pulmonary edema. The 51 patients who had received Ara-C within 30 days of their death, compared to the other 130, had a highly significant increase in the frequency of pulmonary edema (p less than 0.001), which was massive in 24 and moderate in 18. In these 42 patients, causative or contributing factors that explained the edema were present in 14 (33 percent) of them, but in 28 (67 percent) there was no apparent explanation. In contrast, 60 of the 130 patients who had no or remote Ara-C therapy had massive (19 patients) or moderate (41 patients) pulmonary edema, which was explained in 55 (92 percent) and unexplained in only five (8 percent) (p less than 0.001). The unexplained pulmonary edema, a highly proteinaceous interstitial and intra-alveolar infiltrate, correlated with gastrointestinal lesions typical of Ara-C toxicity (p less than 0.001). Multivariate regression analysis showed that unexplained pulmonary edema was predicted by the recent administration of Ara-C, but by no other chemotherapeutic agent, including daunomycin, a potential cardiotoxin frequently given in conjunction with Ara-C. The study suggests that increased alveolar capillary permeability may result from the intravenous administration of cytosine arabinoside and that this complication should be considered when pulmonary edema develops in leukemic patients treated with Ara-C.

Metastatic carcinoma involving the testis. Clinical and pathologic distinction from primary testicular neoplasms.

Metastatic carcinoma to the testis is unusual. There are only seven previously reported cases in which a testicular mass was the first clinical manifestation of an underlying malignancy. The authors review 127 cases in which the testis was involved by metastatic carcinoma, and describe an additional two patients in whom a malignant testicular mass was the presenting sign of an underlying nontesticular carcinoma. The tumors most commonly reported to metastasize to the testis are: prostate (45 cases), lung (25 cases), melanoma (12 cases), colon (11 cases), kidney (10 cases), stomach (6 cases), and pancreas (5 cases). Neuroblastoma, retinoblastoma, carcinoid tumor, and cancers of the bile duct, ureter, bladder, salivary gland, and thyroid have also involved the testis secondarily. Nineteen patients (15%) had bilateral testicular metastases. Patients with secondary testicular neoplasms were older in general than those with germ cell tumors (mean, 55 years; median, 57 years). Histologically, the presence of extensive lymphatic and vascular invasion and an interstitial pattern, in which the seminiferous tubules are spared, is suggestive of a metastasis. In four of the nine cases (44%) in which testicular enlargement was the first manifestation of an underlying carcinoma the correct pathologic diagnosis was initially missed. Serum alpha‐fetoprotein (AFP) and human chorionic gonadotropin (HCG) are occasionally elevated in patients with nontesticular primary tumors, but markedly elevated levels in young patients suggest a nonseminomatous germ cell tumor, as does positive immunoperoxidase staining for AFP and HCG.

Right ventricular infarction: role of the moderator band artery in determining infarct size.

We studied 19 patients with proximal right coronary artery occlusions associated with acute myocardial infarcts less than 30 days old. Right ventricular infarct size, determined as a percentage of right ventricular surface area, ranged from 0% to 29%. Correlation of 24 variables measuring infarct size, chamber size and coronary artery disease failed to demonstrate a significant correlation with the extent of right ventricular infarction. However, estimates of the degree of obstruction to potential collateral flow into the right coronary arterial system from the left anterior descending coronary artery, especially through the moderator band artery, showed a significant positive correlation with infarct size (p < 0.02). Among the five patients with massive (>25%) right ventricular infarction, four had significant (>75%) obstruction of the left anterior descending system, resulting in potentially impaired collateral blood flow; the other patient had normal coronary arteries and embolic occlusion of the proximal right coronary artery with contraction band necrosis. The study suggests that collateral flow to the right ventricular myocardium, especially through the moderator band artery, protects against massive infarction in the presence of proximal right coronary artery occlusion.

Gonadal morphology in patients receiving chemotherapy for leukemia: Evidence for reproductive potential and against a testicular tumor sanctuary

To evaluate the possible reproductive potential in patients who receive chemotherapy for leukemia, we reviewed the gonadal histologic findings at autopsy in 183 treated leukemic patients and in 183 age- and sex-matched control subjects. The 103 male leukemic patients had significantly reduced spermatogenic activity and tubular fertility index and increased interstitial fibrosis as compared with control subjects (p less than 0.001). The 80 females had marked reduction of secondary follicles (p less than 0.001). These lesions showed no predilection for grouping by sexual maturity or by leukemia diagnosis. There was no correlation with the type of chemotherapy or time since last dose of any antileukemic agent. Despite these extensive pathologic changes, there was histologic evidence of residual reproductive potential--a tubular fertility index greater than zero in 65 percent of males and intact primary follicles in 81 percent of premenopausal females. Testicular leukemia was present in 25 percent of males; all of the patients with testicular leukemia had additional foci of leukemia in other organs. The study shows histologic evidence of possible reproductive potential in treated leukemic patients of both sexes and does not support the concept of the testis as a tumor sanctuary in leukemia.

Asplenia and Polysplenia Malformation Complexes Explained by Abnormal Embryonic Body Curvature

Asplenia and polysplenia malformation complexes characteristically have severe cardiovascular defects and visceral heterotaxy. We examined the hypothesis that the conditions may arise from an altered timing of development of embryonic body curvature: delayed in asplenia, accelerated in polysplenia. The morphologic features of the 25 patients with asplenia and 15 with polysplenia autopsied at The Johns Hopkins Hospital were determined. The time of appearance of various morphologic features and the evolution of body curvature was studied in 351 staged serially sectioned human embryos of The Carnegie Embryological Collection. All asplenia patients had severe atrioventricular canal malformations. Bilateral trilobed lungs were found in 12 patients. The polysplenia patients had severe interatrial septal defects in 10 patients; but ventricular septal defects in only six. Bilateral bilobed lungs were seen in five patients. Comparison of the time of appearance of anatomic structures in normal embryos with the observed malformations suggest that asplenia and polysplenia complexes originate in stages 13 to 15. The observations are consistent with the concept that the malformations in asplenia and polysplenia can be explained by minor alterations in the sequence of development of embryonic body curvature relative to organ maturation.

Adenocarcinoma of the hepatic duct junction. A reappraisal of the histologic criteria of malignancy

The morphologic distinction between benign and malignant sclerotic processes involving the hepatic duct junction may be difficult. To determine reliable histologic criteria of malignancy, the authors reviewed 18 cases of clinically suspected adenocarcinoma of the hepatic duct junction (Klatskin tumor) retrieved from our autopsy and surgical pathology files over the last decade. The lesions were compared histologically to a variety of benign sclerotic biliary duct lesions, including four cases of primary sclerosing cholangitis (PSC) treated surgically over the same time period. A diagnosis of malignancy was confirmed histologically in 16 suspected Klatskin tumors, based on the presence of severe cytologic atypia (13) and/or perineural invasion (15). The tumor patients averaged 59 years of age with a male to female ratio of 2:1. Patients with segmental tumor resection and postoperative radiotherapy have survived as a group 6 months longer (average, 15.7 months) than those treated with drainage procedures alone (average, 9.5 months) (P < 0.005), but have had extensive postoperative morbidity. In all the surgical specimens, tumor was present at one or more margins of resection. Primary sclerosing cholangitis patients were younger (average, 31 years of age) with a similar male predominance, but with a strong history of inflammatory bowel disease. All are alive up to 6.5 years since disease onset, with comparatively little postoperative morbidity. Two clinically diagnosed Klatskin tumors were not confirmed on histologic review. Both patients are alive at 1 and 3.5 years following onset of disease, having experienced little postoperative morbidity. Data indicate that Klatskin tumors are relatively aggressive malignancies, distinct from more indolent benign sclerotic disease, but occasionally mimicked by it clinically. Malignancy can be diagnosed histologically with adequate tissue sampling, thereby facilitating clinical decisions regarding radiotherapy or other palliative surgical procedures.

Hypothesis test for causal explanations in human pathology: evaluation of pulmonary edema in 181 autopsied patients with leukemia

Abstract Symbolic logic, as used in the formal theory of scientific explanation proposed by Hempel and Oppenheim, has been suggested as the basis for automated medical diagnosis. In human autopsy pathology the determination of cause-and-effect relationships is a major area subject to logical analysis. We propose a modification of the Hempel-Oppenheim schema in which the logical relationships must only be satisfied “much” of the time, as determined by binomial significance tests. The analysis employs “certainty levels” logic with a more limited consistency requirement than classical logic. The analysis is applied to a series of 181 autopsied patients with leukemia in an attempt to determine a possible role of chemotherapeutic agents in the etiology of pulmonary edema. Among 51 patients who had received cytosine arabinoside (Ara-C) within 30 days of death, there was significantly more unexplained moderate or massive pulmonary edema than among patients with no or remote therapy (p