Nuclear Localization of Immunoreactive β-Catenin Is Specific to Familial Adenomatous Polyposis in Papillary Thyroid Carcinoma

Thyroid carcinoma is the first symptom in some patients with familial adenomatous polyposis (FAP). We evaluated the cellular localization of β-catenin in thyroid carcinomas associated (n=4) or not associated (n=173) with FAP, since loss of functional protein of the adenomatous polyposis coli (APC) gene leads to nuclear accumulation of β-catenin in adenomas and carcinomas of the FAP colon. Immunoreactive β-catenin was demonstrated at the cell membrane of glandular cells of the non-neoplastic thyroid and non-FAP carcinomas. On the other hand, cytoplasmic and nuclear accumulation of β-catenin is specific to FAP-associated papillary carcinomas. The abnormality in the APC/β-catenin pathway is thus also important in FAP-associated thyroid carcinoma, and β-catenin immunohistochemistry is a feasible screening method to identify occult FAP in young patients with thyroid tumors.     

Polymerase chain reaction screening of immunoglobulin heavy chain and T cell receptor γ gene rearrangements: A practical approach to molecular DNA analysis of non-Hodgkin's lymphoma in a surgical pathology laboratory

Characterization of the clonality of non-Hodgkin's lymphoma (NHL) by the rearranged segments of immunoglobulin heavy chain (Ig(H)) or T cell receptor (TCR) genes is not only useful in the confirmation of the diagnosis but also for the future assessment of how a secondary lymphoma, such as a recurrence or another primary lymphoma, occurs. As a practical approach to obtaining and registering this information in a surgical pathology laboratory, FR3 and FR1 regions of Ig(H) gene and TCRgamma gene were concurrently amplified by polymerase chain reaction (PCR) using each pair of consensus primers and the same PCR protocol. Examined samples consisted of 134 primary NHL (phenotypically, 108 B cell and 26 T cell NHL), 19 reactive lymphadenopathies, as well as five secondary lymphomas whose primary lesions were included in this study. Among the primary NHL, the combined PCR analysis disclosed the clonality in 103 of 134 NHL (77%), by FR3 PCR in 77 B cell and two T cell NHL, by FR1 PCR in 59 B cell and one T cell NHL, and by TCRgamma PCR in 11 B cell and 17 of 26 T cell NHL, but in none of the reactive lymphadenopathies. Among the secondary lymphomas, the same pattern of PCR analysis was obtained in two cases (the durations between first and second lymphomas; 6 and 10 months), which suggested recurrence. In contrast, different results were obtained in three cases (17-37 months), which indicated another primary or emergence of the subclones. The results of Southern blot analysis were concordant with the PCR results of the first and the secondary lymphomas. Although the combined PCR analysis cannot replace Southern blot hybridization because of its lower detection rate, it can select those cases suitable for further Southern blot analysis thus reducing the number of unnecessary examinations by nearly 75%. This approach may also be useful in the comparative evaluation of primary and secondary lymphomas.     

Somatic mutations of LKB1 and beta-catenin genes in gastrointestinal polyps from patients with Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is characterized by multiple gastrointestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer, mainly in the gastrointestinal tract. We examined mutations of the LKB1, beta-catenin, APC, K-ras, and p53 genes in 27 gastrointestinal hamartomatous polyps from 10 patients in nine PJS families. Of these hamartomatous polyps, one intestinal polyp had an adenomatous lesion, and one gastric polyp contained adenomatous and carcinomatous lesions. Germ-line mutations of the LKB1 gene were detected in six PJS families. Somatic mutations of the LKB1 gene were found in 5 polyps, whereas loss of heterozygosity (LOH) at the LKB1 locus at 19p was seen in 14 other polyps. In adenomatous lesions microdissected from hamartomatous polyps, both beta-catenin mutation and 19p LOH were detected. Furthermore, a carcinomatous lesion in a gastric hamartomatous polyp was found to contain a mutation of the p53 gene and LOH at the p53 locus in addition to LOH at the LKB1 locus and a beta-catenin mutation. K-ras mutations were detected in a few polyps, whereas no APC mutation or 5q LOH was detected in hamartomatous polyps. These results suggest that gastrointestinal hamartomatous polyps in PJS patients develop through inactivation of the LKB1 gene by germ-line mutation plus somatic mutation or LOH of the unaffected LKB1 allele, and that additional mutations of the beta-catenin gene and p53 gene convert hamartomatous polyps into adenomatous and carcinomatous lesions.     

MEN1 gene mutations in sporadic neuroendocrine tumors of foregut derivation

Foregut-derived neuroendocrine (NE) tumors occur sporadically or in association with multiple endocrine neoplasia type 1 (MEN1) syndrome. Thirty-nine sporadic NE tumors of foregut derivation (six thymic, 21 bronchial, three gastric, and nine pancreatic tumors) as well as two hindgut-derived rectal carcinoids for somatic MEN1 gene mutation were analyzed by direct sequencing analysis. Five tumors showed mutations: nonsense mutations (Q393X and R98X) in thymic and pancreatic NE tumors, respectively, a 4 b.p. deletion (357del4) in a gastric NE carcinoma, and missense mutations (D172Y and S178Y) in pancreatic NE tumors. No mutation was identified in pulmonary or rectal NE tumors. In a patient with a pancreatic NE tumor (D172Y), the corresponding germline DNA showed the same mutation, suggesting that sporadic MEN1 syndrome was masked in this case. Somatic MEN1 gene mutations and deletions may play a crucial role in the tumorigenesis of a subset of foregut-derived NE tumors. Sporadic MEN1 syndrome may occur as a sporadic NE tumor of the pancreas.     

A family with pseudodeficiency of acid α-glucosidase

A unique family is presented which consists of a patient with the juvenile muscular dystrophy form of glycogenosis type II and four healthy individuals, both parents and sisters, with low acid alpha-glucosidase activity. It was almost impossible to distinguish the homozygote from the heterozygous members by lymphocyte assay alone. In cultured skin fibroblasts, acid alpha-glucosidase activity measured with a synthetic substrate was less than 1% of the normal mean value in the patient and about 15% in the parents. The activity toward glycogen was not detectable in the patient and was about 30% of the normal mean value in the parents. These values are also lower than expected in heterozygotes. To explain these results properly, a new mutant allele of acid alpha-glucosidase is proposed. Both parents could be compound heterozygotes for the pseudodeficiency allele and the juvenile form of glycogenosis type II allele.     

Usual interstitial pneumonia following resolution of cavitated pulmonary masses in a patient with ANCA‐associated vasculitis

A 72‐year‐old woman with slight pulmonary interstitial reticular markings was initially diagnosed with microscopic polyangiitis (MPA). Two years later, cavitated pulmonary masses appeared, and a biopsy specimen revealed granulomas. Granulomatosis with polyangiitis (GPA) was diagnosed. The masses resolved with treatment. Ten years later, the usual interstitial pneumonia (UIP) pattern appeared on chest computed tomography (CT). The diagnosis of lung toxicity from methotrexate (MTX) or cyclophosphamide (CYC) was precluded by the clinical course. Despite treatment with prednisolone (PSL), the UIP progressed. The change of pulmonary pathology from masses to UIP is rare in patients with GPA.     

Two cases of methotrexate induced lymphomas in rheumatoid arthritis: an association with increased serum IgE.

We describe 2 patients with rheumatoid arthritis (RA) in whom non-Hodgkin's lymphomas developed during low dose pulsed methotrexate (MTX) treatment. The tumors regressed after discontinuation of MTX with no additional treatment. Serum levels of IgE increased concomitantly with the development of lymphoma, and decreased along with the regression of the lymphoma in both patients. These 2 cases and a review of the literature suggest that measuring serum IgE may have a predictive value for monitoring lymphoma in patients with RA treated with MTX.