Frank Gonzalez-Crussi

Neonatal Necrotizing Enterocolitis: Clinical Considerations and Pathogenetic Concepts

Necrotizing enterocolitis (NEC), a disease affecting predominantly premature infants, is a leading cause of morbidity and mortality in neonatal intensive care units. Although several predisposing factors have been identified, such as prematurity, enteral feeding, and infection, its pathogenesis remains elusive. In the past 20 years, we have established several animal models of NEC in rats and found several endogenous mediators, especially platelet-activating factor (PAF), which may play a pivotal role in NEC. Injection of PAF induces intestinal necrosis, and PAF antagonists prevent the bowel injury induced by bacterial endotoxin, hypoxia, or challenge with tumor necrosis factor-a (TNF) plus endotoxin in adult rats. The same is true for lesions induced by hypoxia and enteral feeding in neonatal animals. Human patients with NEC show high levels of PAF and decreased plasma PAF-acetylhydrolase, the enzyme degrading PAF. The initial event in our experimental models of NEC is probably polymorphonuclear leukocyte (PMN) activation and adhesion to venules in the intestine, which initiates a local inflammatory reaction involving proinflammatory mediators including TNF, complement, prostaglandins, and leukotriene C4. Subsequent norepinephrine release and mesenteric vasoconstriction result in splanchnic ischemia and reperfusion. Bacterial products (e.g., endotoxin) enter the intestinal tissue during local mucosal barrier breakdown, and endotoxin synergizes with PAF to amplify the inflammation. Reactive oxygen species produced by the activated leukocytes and by intestinal epithelial xanthine oxidase may be the final pathway for tissue injury. Protective mechanisms include nitric oxide produced by the constitutive (mainly neuronal) nitric oxide synthase, and indigenous probiotics such as Bifidobacteria infantis. The former maintains intestinal perfusion and the integrity of the mucosal barrier, and the latter keep virulent bacteria in check. The development of tissue injury depends on the balance between injurious and protective mechanisms.

Complete and incomplete forms of Beckwith-Wiedemann syndrome: Their oncogenic potential

The diagnosis of Beckwith-Wiedemann syndrome may be missed because of variable or incomplete clinical expression. Recognition of such patients is important, however, because they have the potential for development of neoplasia. It seems likely that BWS and the congenital asymmetry-abdominal malignancy syndrome are at either end of the same spectrum, and that intermediate forms are the connecting links.

Incomplete Kawasaki disease with coronary artery involvement

We report four patients with Kawasaki disease in whom characteristic coronary artery abnormalities developed after illnesses that did not meet diagnostic criteria. An additional patient lacked a history of acute manifestations of Kawasaki disease, but severe Kawasaki-like arterial changes were noted at autopsy. Fever was present in four of the five patients, in three lasting from 7 to 14 days. Despite manifestation of few classic acute clinical features of Kawasaki disease, three of four patients had desquamation of the fingers and toes 10 to 14 days after onset of illness, and the fifth had desquamation several months prior to death. These patients were seen over a 2-year period during which 22 other children were seen with Kawasaki disease with coronary artery abnormalities. Thus, strict adherence to currently accepted criteria for diagnosis of Kawasaki disease may lead to failure to recognize incomplete forms of this illness, with potential sequelae of myocardial infarction or sudden death. This finding suggests that children with prolonged unexplained febrile illnesses, especially those associated with subsequent peripheral desquamation, should undergo echocardiography 3 to 4 weeks after onset of the illness. This practice would help to identify those patients with illnesses characterized by incomplete diagnostic criteria but in whom significant coronary abnormalities develop.

Infantile sarcoma with intracytoplasmic filamentous inclusions : distinctive tumor of possible histiocytic origin

This report describes four malignant tumors originating in infants, (one present at birth), for which a common origin is proposed. The common nature of these tumors was suggested by a remarkable similarity of histologic and ultrastructural features, including the presence of intracellular filamentous aggregates, as well as a shared aggressive clinical course consistent with sarcomatous origin. Two of these neoplasms arose within the kidney and were classified as “rhabdoid” sarcomas, according to the NWTS nomenclature. However, cells from these neoplasms could not be identified as muscular in origin. In culture, these cells demonstrated adherence to substratum, ability to phagocytose particles, and cell surface complement receptors. In addition, the renal tumors contained definite tumor cells positive for muramidase; the liver primary tumor contained only a limited number of such cells, which could not be interpreted as neoplastic. These findings suggest that among the “round‐cell sarcomas” of infants and young children, a distinct, highly malignant form may be identified on clinical and morphologic grounds. The possibility that the tumor cells may be linked to the mononuclear phagocyte system was suggested, but not proved, and deserves further study.

Platelet-activating factor: an endogenous mediator for bowel necrosis in endotoxemia.

We have developed a model of isochemic bowel necrosis in the rat by injecting platelet‐activating factor (PAF) or PAF in combination with bacterial endotoxin. PAF causes profound hypotension, and it has been suggested that it is released during endotoxin shock. Because ischemic bowel necrosis is often associated with shock or infection, it is possible that PAF is the endogenous mediator that causes shock and bowel necrosis during sepsis. In this study, we have demonstrated that: 1) normal intestine contained a small amount of PAF; 2) necrotic lesions of the intestine could be induced by endotoxin injection; 3) PAF production in the bowel is markedly increased in animals treated with endotoxin; 4) pretreatment of the animal with PAF antagonists prevent endotoxin‐induced necrosis; 5) isolated, buffer‐perfused small intestine produced a small quantity of PAF in response to endotoxin injection. Therefore, we conclude that PAF is a likely endogenous mediator in endotoxemia, which causes bowel necrosis and shock.—Hsueh, W.; González‐Crussi, F.; Arroyave, J. L. Platelet‐activating factor: an endogenous mediator for bowel necrosis in endotoxemia. FASEB J. 1: 403‐405; 1987.

Intraabdominal desmoplastic small-cell tumors with divergent differentiation : observations on three cases of childhood

We studied three intraabdominal tumors that manifested in childhood and were attached to peritoneum, and in which the histologic pattern suggested metastatic tumor of epithelial nature but gave no evidence of a primary neoplasm in the major abdominal organs. Follow-up observation lasted from 1 to 6 years but never disclosed a primary site. Histologic, immunohistochemical, and electronmicroscopic observations indicated a primitive malignant neoplasm of uncertain histogenesis capable of simultaneously expressing epithelial, mesenchymal, and, less consistently, neural phenotypes. In childhood, the possibility of embryonic neoplasm, such as nephroblastoma occurring in atypical sites, is difficult to exclude. Despite the prevailing uncertainty about histogenesis, combined therapy achieved an apparent cure in one of our cases.

Histiocytosis X: A seven-year experience at a children's hospital

Thirty-two patients with histiocytosis X were evaluated and treated at Childrens Memorial Hospital, Chicago, during the years 1978 to 1984. Twelve patients (38%) had solitary or multifocal bone lesions, three (9%) had bone lesions and diabetes insipidus, and seventeen (53%) had cutaneous and/or multisystem involvement. Age at diagnosis ranged from 2 days to 15 years. Fifteen patients were 2 years of age or younger at the time of diagnosis. Sixteen patients (50%) had skin infiltrates, of whom,seven (43%) had cutaneous lesions documented at birth. Cutaneous lesions included vesicopustules, erythematous papules, nodules, eczematous dermatitis, granulomatous ulcerative lesions, petechiae, and hemorrhagic lesions. Xanthomas and nail dystrophy were not observed. The therapeutic regimen chosen was based on extent of involvement and location of infiltrates. Only two of the thirtytwo patients died; both had multisystem disease.Thirty-two patients with histiocytosis X were evaluated and treated at Childrens Memorial Hospital, Chicago, during the years 1978 to 1984. Twelve patients (38%) had solitary or multifocal bone lesions, three (9%) had bone lesions and diabetes insipidus, and seventeen (53%) had cutaneous and/or multisystem involvement. Age at diagnosis ranged from 2 days to 15 years. Fifteen patients were 2 years of age or younger at the time of diagnosis. Sixteen patients (50%) had skin infiltrates, of whom seven (43%) had cutaneous lesions documented at birth. Cutaneous lesions included vesicopustules, erythematous papules, nodules, eczematous dermatitis, granulomatous ulcerative lesions, petechiae, and hemorrhagic lesions. Xanthomas and nail dystrophy were not observed. The therapeutic regimen chosen was based on extent of involvement and location of infiltrates. Only two of the thirty-two patients died; both had multisystem disease.

Hepatoblastoma. Attempt at characterization of histologic subtypes

This is a clinicopathologic study summarizing the experience with hepatoblastomas at Childrens Memorial Hospital of Chicago between 1954 and 1981. Of 21 patients studied, 13 (61.9%) died. Three major histologic epithelial patterns were identified: fetal, embryonal, and macrotrabecular. The first two many represent different stages of cytodifferentiation of hepatoblastoma cells. The macrotrabecular type had features similar to hepatocellular carcinoma of adults, from which distinction was difficult; this type pursued an aggressive clinical course. The fetal type exhibited advanced differentiation, and two cases in this category survived after surgery only; local extrahepatic dissemination was present in other cases of the fetal type. Mixed epithelial and mesenchymal tumors constituted only 23% of this series, and none contained rhabdomyoblastic elements. Although modern chemotherapy may alter the course of this disease, the small size of this series precluded definite statements in this regard. Only patients in whom the tumor was completely excised as primary treatment became longterm survivors.

Calcifying fibrous pseudotumor versus inflammatory myofibroblastic tumor: A histological and immunohistochemical comparison

Calcifying fibrous pseudotumor (CFP), a recently described lesion, is characterized by a predominantly lymphoplasmacytic infiltrate with abundant hyalinized collagen and psammomatous or dystrophic calcifications. The cause and pathogenesis are unclear, but it has been postulated that CFP may represent a sclerosing end stage of inflammatory myofibroblastic tumor (IMT). We compared the histological and immunohistochemical profiles of seven cases diagnosed as CFP and seven as IMT. Histologically, the CFP demonstrated varying degrees of calcifications in addition to fibroblastic proliferation admixed with inflammatory cells composed of lymphocytes, eosinophils, and mast cells. The IMTs rarely contain calcifications and had a myofibroblastic proliferation varying from hyalinized acellular collagen to florid fibroblastic proliferations simulating sarcoma. The inflammatory component was composed primarily of plasma cells and lym-phocytes, sometimes arranged as lymphoid aggregates with germinal centers. All CFP cases were diffusely positive for factor XIIIa and negative for smooth muscle actin, muscle-specific actin, and CD34. All IMTs demonstrated diffuse positivity for actin, variable positivity for CD34, and focal positivity for Factor XIIIa. This study demonstrates certain distinct histologic, immunohistochemical, and electron microscopic features between IMTs and CFPs.

Peripheral neuroectodermal tumors of the chest wall in childhood.

A retrospective review of primary chest wall malignant tumors of childhood collected at the Childrens Memorial Hospital of Chicago was undertaken. Among twelve instances of poorly differentiated neoplasms whose uniform, montonous structure made accurate classification difficult or impossible by conventional histologic study, there were three tumors with features suggestive of neuroectodermal differentiation. Electron microscopic and immunohistologic findings further strengthened this interpretation, despite the fact that none of the patients had evidence of a primary neuroblastoma outside the chest wall. These results and a review of the pertinent literature support the conclusion that neuroectodermal neoplasms in childhood may present in peripheral somatic tissues with greater frequency than is commonly assumed. This importance of this distinction is discussed, particularly the need to distinguish these neoplasms from Ewings sarcoma.