J. Thomas Stocker

Congenital cystic adenomatoid malformation of the lung: Classification and morphologic spectrum

Thirty-eight cases of congenital cystic adenomatoid malformation of the lung are described, and a classification based on clinical, gross, and microscopic criteria is proposed. The type I lesion is composed of single or multiple large cysts (more than 2 cm. in diameter), frequently producing mediastinal herniation. The cysts are lined by ciliated psuedostratified columnar epithelium. The walls of the cysts contain prominent smooth muscle and elastic tissue. Mucus producing cells are present in approximatley one-third of the cases, and cartilage in the wall is rarely seen. Relatively normal alveoli may be seen between the cysts. The prognosis is good. Radiographic analysis of the type I lesion can preoperatively suggest the diagnosis, especially with the typical multicystic pattern. The gross appearance of the lesion corresponds closely to the radiographic image and adds another dimension to the pathologists evaluation of the disease. The type II lesion is composed of multiple small cysts (less than 1 cm. in diameter) lined by ciliated cuboidal to columnar epithelium. Structures resembling respiratory bronchioles and distended alveoli are present between the epithelium lined cysts. Mucous cells and cartilage are not present. Striated muscle fibers may be seen rarely. The type II lesion is associated with a high frequency of other congenital anomalies, and the prognosis is poor. The type III lesion is a large, bulky noncystic lesion producing mediastinal shift. Bronchiole-like structures are lined by ciliated cuboidal epithelium and separated by masses of alveolus-sized structures lined by nonciliated cuboidal epithelium. The prognosis is poor.

Undifferentiated (embryonal) sarcoma of the liver. Report of 31 cases

Thirty‐one cases of undifferentiated (embryonal) sarcoma of the liver are presented. The tumor is found predominantly in the pediatric age group, the majority of patients (51.6%) being between 6 and 10 years of age. An abdominal mass and pain are the usual presenting symptoms. Radiographic examination is nonspecific except to demonstrate a space‐occupying lesion of the liver. The tumors are large, single, usually globular and well demarcated, and have multiple cystic areas of hemorrhage, necrosis, and gelatinous degeneration. Histologic examination shows a pseudocapsule partially separating the normal liver from undifferentiated sarcomatous cells that, near the periphery of the tumor, surround entrapped hyperplastic or degenerating bile duct‐like structures. Eosinophilic globules that are PAS positive are usually found within and adjacent to tumor cells. Areas of necrosis and hemorrhage are prominent. The prognosis is poor, with a median survival of less than 1 year following diagnosis.

Extralobar Sequestration with Frequently Associated Congenital Cystic Adenomatoid Malformation, Type 2: Report of 50 Cases

ABSTRACTExtralobar pulmonary sequestration (ELS) represents a mass of pulmonary parenchyma separate from the normal lung. The coexistence of congenital cystic adenomatoid malformation (CCAM) in ELS has been reported. To define this association, the clinical, gross, and histologic features of 50 ELS cases were analyzed.The age at diagnosis varied from birth to 65 years with 24% of cases diagnosed prenatally and 61% (23/38) diagnosed within the first 3 months of life. Fifty-two percent of cases were in females and 48% in males. Forty-eight percent of ELS(s) were located in the left hemithorax, 20% in the right hemithorax, 8% in the anterior mediastinum, 6% in the posterior mediastinum, and 18% beneath the diaphragm. The blood supply to the sequestration in 77% of cases was directly from the aorta. Grossly, the lung, though hypoplastic in some cases, was otherwise unremarkable.Fifty percent (23/46) of ELS cases were associated with a coexistent CCAM. In contrast to the series as a whole, 92% (11/12) of the ELS/CCAM cases, excluding those prenatally diagnosed, were diagnosed within the first 3 months and 57% occurred in females. ELS/CCAM lesions, while randomly distributed, were more frequently seen on the left side. Gross features of the ELS/CCAM cases were similar to those cases with ELS alone. All CCAM cases had a type 2 pattern on histologic examination with 48% of those cases also displaying rhabdomyomatous dysgenesis.Our findings indicate that the occurrence of CCAM in ELS is more frequent than reported in the literature and differs in presentation from ELS cases not associated with CCAM.

Congenital and Developmental Diseases

The pathology of infectious diseases of the lung is, for the most part, similar in adults and children. However, a number of other disorders either are seen almost exclusively in the pediatric age group (e.g., congenital anomalies) or occur in circumstances peculiar to this age group (e.g., hyaline membrane disease and bronchopulmonary dysplasia). Congenital anomalies of the lung are usually noted within the first weeks to months of life but may not be discovered until later in childhood or, in some cases such as bronchogenic cysts, until adulthood. A knowledge of the development of the lung is important in the understanding of the morphologic features of these anomalies.

Breast Masses in Children and Adolescents: Radiologic-Pathologic Correlation

The spectrum of breast lesions in children and adolescents varies markedly from that for adults, with the former lesions being overwhelmingly benign. A breast mass in a young boy or girl may arise from normal and abnormal breast development. Other causes of masses include infection, trauma, and cyst formation. After onset of puberty, most cases of breast enlargement arise from benign fibroadenoma in girls and gynecomastia in boys. These conditions have specific imaging appearances, although juvenile (often giant) fibroadenoma cannot be distinguished from phyllodes tumor, which can be benign or malignant. In children, both conditions usually appear as well-circumscribed, hypoechoic masses at sonography and show diffuse enhancement except for nonenhancing septations at magnetic resonance imaging. A diagnosis of juvenile papillomatosis (a benign lesion) portends later development of breast cancer, and patients with this condition should be closely monitored. Malignant lesions of the breast in children are rare. The most common malignant lesions are metastases and are usually associated with widespread disease. The most common primary breast malignancy is malignant phyllodes tumor. Primary breast carcinoma is exceedingly rare in the pediatric age group, but its imaging appearance in children is the same as seen in adults and is different from that of almost all benign lesions. In girls, diagnostic interventions may injure the developing breast and cause subsequent disfigurement. Given this risk and the low prevalence of malignant disease in this population, a prudent course should be followed in the diagnosis of breast lesions. Imaging findings are very helpful for selecting patients for further diagnostic procedures. Although malignancy is rare, lesions with suspicious imaging findings or progressive growth should be subjected to cytologic or histologic examination.

Congenital disseminated malignant rhabdoid tumor: a distinct clinicopathologic entity demonstrating abnormalities of chromosome 22q11.

The clinical, pathologic, and immunohistochemical features of a widely disseminated tumor with rhabdoid phenotype are described in nine infants < or = 3 months of age. Five neonates had tumor evident at birth, two of which had placental metastases. The average survival following diagnosis was < 6 weeks. None of the infants had an apparent primary tumor in either the kidney or brain. In four cases, the dominant mass involved the head and neck region, and in two cases, the primary mass was paraspinal. The histologic features were those of a high-grade, round cell neoplasm with abundant cytoplasm and containing cells with cytoplasmic filamentous inclusions. Immunohistochemical studies revealed polyphenotypic antigen expression. Genetic information was available from eight of nine cases. Karyotype analysis revealed abnormalities of chromosome band 22q11-12 in three of six tumors. Fluorescence in situ hybridization studies or molecular studies demonstrated 22q11.2 deletions in all five cases with available frozen tissue, two of which had translocations involving 22q by karyotype analysis. The similar clinical and pathologic findings in these rapidly fatal tumors in infants and the demonstration of abnormalities of chromosome 22q11 in a majority of the cases supports their histogenetic and nosologic relationship to the family of malignant rhabdoid tumors that typically occur in young children in several anatomic sites, including kidney, soft tissues, liver, and brain. Like neuroblastoma and rhabdomyosarcoma, malignant rhabdoid tumor can appear as disseminated disease at birth or shortly thereafter.

Inhibition of type 1 diabetes in filaria-infected non-obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells

We sought to determine whether Litomosoides sigmodontis, a filarial infection of rodents, protects against type 1 diabetes in non‐obese diabetic (NOD) mice. Six‐week‐old NOD mice were sham‐infected or infected with either L3 larvae, adult male worms, or adult female worms. Whereas 82% of uninfected NOD mice developed diabetes by 25 weeks of age, no L. sigmodontis‐infected mice developed disease. Although all mice had evidence of ongoing islet cell inflammation by histology, L. sigmodontis‐infected mice had greater numbers of total islets and non‐infiltrated islets than control mice. Protection against diabetes was associated with a T helper type 2 (Th2) shift, as interleukin‐4 (IL‐4) and IL‐5 release from α‐CD3/α‐CD28‐stimulated splenocytes was greater in L. sigmodontis‐infected mice than in uninfected mice. Increased circulating levels of insulin‐specific immunoglobulin G1, showed that this Th2 shift occurs in response to one of the main autoantigens in diabetes. Multicolour flow cytometry studies demonstrated that protection against diabetes in L. sigmodontis‐infected NOD mice was associated with significantly increased numbers of splenic CD4+ CD25+ FoxP3+ regulatory T cells. Interestingly, injection of crude worm antigen into NOD mice also resulted in protection against type 1 diabetes, though to a lesser degree than infection with live L. sigmodontis worms. In conclusion, these studies demonstrate that filarial worms can protect against the onset of type 1 diabetes in NOD mice. This protection is associated with a Th2 shift, as demonstrated by cytokine and antibody production, and with an increase in CD4+ CD25+ FoxP3+ regulatory T cells.

Hepatoblastoma: the prognostic significance of histologic type.

The clinicopathologic features of 105 hepatoblastomas accessioned to the Armed Forces Institute of Pathology between 1967 and 1987 were reviewed. DNA content was analyzed by flow cytometry. A multivariate analysis using the Cox proportional hazards model was performed to evaluate the effect of stage, histologic type, and DNA content on the prognosis for survival. The relative risks of death for a given stage compared to the other stages combined were 0.1637, 0.5672, 2.8742, and 3.5148 for stages I-IV, respectively. The relative risk of death for a given histologic type adjusted for age, sex, and stage compared to the other types was 1.0739 (p = .8850) for the fetal pattern, 1.7409 (p = .1662) for the embryonal pattern, 0.5292 (p = .0754) for the mixed pattern, 1.1980 (p = .7729) for the macrotrabecular pattern, and 3.7096 (p = .1061) for the small-cell undifferentiated pattern. Of 19 hepatoblastomas analyzed for DNA content, 5 were DNA diploid and 11 were DNA aneuploid; 3 could not be classified. The stage of disease at presentation proved to be a significant prognostic factor, whereas histologic type and DNA content did not have a significant effect.

Helminth Protection against Autoimmune Diabetes in Nonobese Diabetic Mice Is Independent of a Type 2 Immune Shift and Requires TGF-β

Leading hypotheses to explain helminth-mediated protection against autoimmunity postulate that type 2 or regulatory immune responses induced by helminth infections in the host limit pathogenic Th1-driven autoimmune responses. We tested these hypotheses by investigating whether infection with the filarial nematode Litomosoides sigmodontis prevents diabetes onset in IL-4–deficient NOD mice and whether depletion or absence of regulatory T cells, IL-10, or TGF-β alters helminth-mediated protection. In contrast to IL-4–competent NOD mice, IL-4–deficient NOD mice failed to develop a type 2 shift in either cytokine or Ab production during L. sigmodontis infection. Despite the absence of a type 2 immune shift, infection of IL-4–deficient NOD mice with L. sigmodontis prevented diabetes onset in all mice studied. Infections in immunocompetent and IL-4–deficient NOD mice were accompanied by increases in CD4+CD25+Foxp3+ regulatory T cell frequencies and numbers, respectively, and helminth infection increased the proliferation of CD4+Foxp3+ cells. However, depletion of CD25+ cells in NOD mice or Foxp3+ T cells from splenocytes transferred into NOD.scid mice did not decrease helminth-mediated protection against diabetes onset. Continuous depletion of the anti-inflammatory cytokine TGF-β, but not blockade of IL-10 signaling, prevented the beneficial effect of helminth infection on diabetes. Changes in Th17 responses did not seem to play an important role in helminth-mediated protection against autoimmunity, because helminth infection was not associated with a decreased Th17 immune response. This study demonstrates that L. sigmodontis-mediated protection against diabetes in NOD mice is not dependent on the induction of a type 2 immune shift but does require TGF-β.

Angiosarcoma of the Liver in Childhood: A Clinocopathologic and Follow-up Study of 10 Cases

The clinical, morphologic, and follow-up findings in 10 cases of childhood hepatic angiosarcoma are reported. Six patients were female and four were male. The age range was 18 months to 7 years, with a mean of 3.7 years. The usual presenting feature was an abdominal mass, with or without associated symptoms. The histologic pattern of childhood hepatic angiosarcoma typically consists of large hypercellular whorls of spindled sarcoma cells intermingled with bile ducts, vessels, and collagen. Factor VIII staining of tumor cells is focal, cytoplasmic, and weak in character. Intracellular eosinophilic, PAS-positive globules are present in most cases and may be abundant. The prognosis is poor; follow-up available in seven cases showed only one to be alive 32 months after diagnosis. The remaining six patients had died 0-27 months (mean 10 months) after diagnosis.