Angiomyomatous hamartoma of lymph nodes, revisited: clinicopathologic study of 21 cases, emphasizing its distinction from lymphangioleiomyomatosis of lymph nodes.

Angiomyomatous hamartoma of lymph nodes (AMH-LN) is an uncommon benign proliferation of smooth muscle, blood vessels, collagenous stroma, and adipocytes, most commonly affecting inguinal LN. A similar constellation of cell types constitutes various members of the perivascular epithelioid cell tumor (PEComa) family, including lymphangioleiomyomatosis (LAM), which can involve LN in women. Because some LN-LAM patients have tuberous sclerosis complex and/or other PEComa family lesions, it is clinically relevant to distinguish LN-LAM from AMH-LN. Given their similar features, however, the possibility that AMH-LN is a morphologic variant of LN-LAM merits inquiry. The dual melanocytic and myoid immunophenotype distinguishes the PEComa family from its mimics. Cathepsin K has recently emerged as a more sensitive marker for the PEComa family than HMB-45, which can be weak and focal, but cathepsin K has not been studied in AMH-LN. This study evaluated 21 AMH-LNs for clinical, morphologic, and immunophenotypic features of LN-LAM. None (0/21) had tuberous sclerosis complex or PEComas. Thirteen (62%) were male, unlike LN-LAM, which is restricted to women. All cases exhibited intraparenchymal proliferation of variable-sized, thick-walled blood vessels within collagenous stroma containing a sparse to focally cellular population of haphazardly distributed smooth muscle cells. Admixed adipocytes were commonly present. None exhibited classical features of LN-LAM such as subcapsular localization, extranodal extension, intralymphatic growth, compact nests, branching lymphatic channels, plump cell shape, or foamy/clear cytoplasm. None exhibited any staining for cathepsin K, HMB-45, or microphthalmia transcription factor. There is no clinical, morphologic, or immunohistochemical evidence to suggest that AMH-LN is a variant of LN-LAM.

Respiratory epithelial adenomatoid hamartoma: a poorly recognized entity with mast cell recruitment and frequently associated with nasal polyposis.

Respiratory epithelial adenomatoid hamartoma (REAH) is regarded as a rare tumor of the nasal cavity. The mechanisms driving the development of REAH are unknown, and its nature as a benign tumor, hamartoma, or reactive inflammatory process is still open to discussion. A total of 150 consecutive patients operated on for nasal polyposis (NP) were extensively checked for the diagnosis of REAH. The profile of REAH occurring in association with NP was compared with solitary REAH in a series of 19 cases. The possible role of tryptase-producing mast cells (MC) and of metalloproteinases MMP2 and MMP9 in REAH development was investigated by immunohistochemistry. REAH lesions were identified in 35% of patients who had surgery for NP (53/150). The distribution of the lesions suggested that REAH originated in the olfactory cleft. Solitary REAH occurred about 20 times less frequently than those observed in an NP context but shared the same microscopic characteristics. Tryptase-producing MCs were recruited at high density in REAH (135/10 hpf), compared with inflammatory polyps (45/10 hpf; P<0.00005) and hypertrophied turbinates (51/10 hpf; P<0.0005). REAH also showed constant MMP9 expression and to a lesser degree MMP2 expression in epithelial cells. If solitary REAH is a relatively rare lesion, we demonstrated that an exhaustive sampling allows the detection of a high proportion of NP-associated REAH, sharing the same clinical and histologic characteristics with solitary REAH. Tryptase-producing MCs, possibly in association with MMP expression, may play a central role in REAH formation.

Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases.

Mammalian target of rapamycin (mTOR) is the core component of two complexes, mTORC1 and mTORC2. mTORC1 is inhibited by rapamycin and analogues. mTORC2 is impeded only in some cell types by prolonged exposure to these compounds. mTOR activation is linked to tubular cell proliferation in animal models and human autosomal dominant polycystic kidney disease (ADPKD). mTOR inhibitors impede cell proliferation and cyst growth in polycystic kidney disease (PKD) models. After renal transplantation, two small retrospective studies suggested that mTOR was more effective than calcineurin inhibitor-based immunosuppression in limiting kidney and/or liver enlargement. By inhibiting vascular remodeling, angiogenesis, and fibrogenesis, mTOR inhibitors may attenuate nephroangiosclerosis, cyst growth, and interstitial fibrosis. Thus, they may benefit ADPKD at multiple levels. However, mTOR inhibition is not without risks and side effects, mostly dose-dependent. Under certain conditions, mTOR inhibition interferes with adaptive increases in renal proliferation necessary for recovery from injury. They restrict Akt activation, nitric oxide synthesis, and endothelial cell survival (downstream from mTORC2) and potentially increase the risk for glomerular and peritubular capillary loss, vasospasm, and hypertension. They impair podocyte integrity pathways and may predispose to glomerular injury. Administration of mTOR inhibitors is discontinued because of side effects in up to 40% of transplant recipients. Currently, treatment with mTOR inhibitors should not be recommended to treat ADPKD. Results of ongoing studies must be awaited and patients informed accordingly. If effective, lower dosages than those used to prevent rejection would minimize side effects. Combination therapy with other effective drugs could improve tolerability and results.

Dysregulation of the TSC-mTOR pathway in human disease.

The mammalian target of rapamycin (mTOR) has a central role in the regulation of cell growth. mTOR receives input from multiple signaling pathways, including growth factors and nutrients, to stimulate protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase and eukaryote initiation factor 4E binding protein 1. High levels of dysregulated mTOR activity are associated with several hamartoma syndromes, including tuberous sclerosis complex, the PTEN-related hamartoma syndromes and Peutz-Jeghers syndrome. These disorders are all caused by mutations in tumor-suppressor genes that negatively regulate mTOR. Here we discuss the emerging evidence for a functional relationship between the mTOR signaling pathway and several genetic diseases, and we present evidence supporting a model in which dysregulation of mTOR may be a common molecular basis, not only for hamartoma syndromes, but also for other cellular hypertrophic disorders.

Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults.

Lhermitte-Duclos disease (LDD), or dysplastic gangliocytoma of the cerebellum, is an unusual hamartomatous overgrowth disorder. LDD can be familial or, more commonly, sporadic. It has been only recently recognized that LDD may be associated with Cowden syndrome (CS). Over 80% of patients with CS carry germline mutations in PTEN. It remains unclear whether all cases of LDD, even without features of CS, are caused by germline PTEN mutation and whether somatic PTEN mutation occurs in sporadic LDD. We obtained paraffin-embedded LDD lesions from 18 unselected, unrelated patients and performed mutational analysis of PTEN. Overall, 15 (83%) of 18 samples were found to carry a PTEN mutation. All individuals with mutations were adult-onset patients, but the three without mutations were diagnosed at the ages of 1, 3, and 11 years. Germline DNA was available from six adult-onset cases, and all had germline PTEN mutations. Of these six, two had CS features, one did not have CS features, and three were of unknown CS status. Immunohistochemistry revealed that 75% of the LDD samples had complete or partial loss of PTEN expression accompanied by elevated phosphorylated Akt, specifically in the dysplastic gangliocytoma cells. These data suggest that the loss of PTEN function is sufficient to cause LDD. The high frequency and spectrum of germline PTEN mutations in patients ascertaining by LDD alone confirm that LDD is an important defining feature of CS. Individuals with LDD, even without apparent CS features, should be counseled as in CS.

Overexpression of cyclooxygenase 2 in hamartomatous polyps of Peutz-Jeghers syndrome.

OBJECTIVE: Peutz-Jeghers syndrome (PJS) is an autosomal-dominant hamartomatous polyposis syndrome. Affected individuals are at risk for intestinal and extraintestinal malignancies. Prostaglandins and polyamines are small molecules believed to be important in tumor formation and growth. Cyclooxygenase (COX) and ornithine decarboxylase (ODC) are key enzymes in the prostaglandin and polyamine biosynthetic pathways, respectively. The aim of this study was to measure and compare COX-1 and COX-2 expression in normal and hamartomatous tissue of PJS patients. METHODS: We measured COX-1 and COX-2 protein expression in normal and hamartomatous GI tissues from affected PJS individuals and compared it with that in normal controls. COX-2 RNA in these tissues was also measured and compared by reverse transcription polymerase chain reaction (PCR). In addition, COX-2 expression was detected in tissue slides by immunostaining. ODC activity was measured between normal and hamartomatous tissues of PJS compared with control tissues. RESULTS: COX-1 expression was similar in normal and control GI tissues. In contrast, COX-2 overexpression was noted in hamartomatous polyp tissue from PJS patients compared with normal control and PJS tissue. COX-2 expression by reverse transcription PCR was 10-fold greater in a hamartoma compared with other tissues. COX-2 expression was noted in the epithelial cells of hamartomatous polyps, and also coursing throughout the stromal tissue of the lamina propria, including muscle cells. ODC activity was similar in the tissues studied. CONCLUSIONS: Selective COX-2 overexpression was noted in hamartomatous polyp tissue from PJS individuals. The results of the study provide an avenue for possible effective chemoprevention of polyp formation and growth in PJS.

Glutathione-S-transferase M1, M3, T1 and P1 polymorphisms and susceptibility to non-small-cell lung cancer subtypes and hamartomas.

Polymorphic glutathione-S-transferase (GST) genes causing variations in enzyme activity may influence individual susceptibility to lung cancer. In this case-control study (consisting of 389 Caucasian lung cancer patients, including 151 adenocarcinomas (ACs) and 172 squamous cell carcinomas (SCCs), and 353 hospital control subjects without malignant disease, genotype frequencies for GSTM1, GSTM3, GSTP1 and GSTT1 were determined by polymerase chain reaction (PCR)/ restriction fragment length polymorphism (RFLP)-based methods. While adjusted odds ratios (ORs) indicated no significantly increased risk for lung cancer overall due to any single GST genotype, the risk alleles for GSTM1, GSTM3 and GSTP1 conferring reduced enzyme activity were present at higher frequency in SCC than in AC patients. This is consistent with a reduced detoxification of carcinogenic polycyclic aromatic hydrocarbons (PAHs) from cigarette smoke that are more important for the development of SCC than for AC. An explorative data analysis also identified statistically significantly increased ORs for the combinations GSTT1 non-null and GSTP1 GG or AG for lung cancer overall (OR 2.23, CI 1.11-4.45), and for SCC (OR 2.69, CI 1.03-6.99). For lung cancer overall, and especially among SCC patients, the GSTT1 null genotype was underrepresented (SCC 11.2% v. control subjects 19%, P = 0.026, OR 0.57, CI 0.30-1.06). Additionally, in 28 patients with hamartomas, the GSTT1 null genotype was also protective (P = 0.013), while GSTP1 variant allele carriers were overrepresented (OR 2.48, CI 1.06-6.51). In conclusion, GST genotypes may act differently, either by detoxifying harmful tobacco carcinogens and/or by eliminating lung cancer chemopreventive agents. The latter role for GSTT1 would explain the observed lower risk of SCC and hamartoma associated with GSTT1 null. Further confirmatory studies are required.

In vitro effects of folic acid on gamma-glutamyltransferase and glutathione reductase activities in malignant lung and thymus tumors.

In vitro effects of folic acid (10(-5), 10(-4), and 10(-3)M) on activities of gamma-glutamyltransferase and glutathione reductase, the enzymes involved in glutathione metabolism, were studied in tissue samples obtained after surgical treatment of the lungs and thymus. Folic acid did not change gamma-glutamyltransferase activity in lung cancer tissue, but in thymoma tissue this substance in a concentration of 10(-3)M inhibited it by 16%. Folic acid had no effects on glutathione reductase activity in benign tumors and normal lung and thymus tissues, but increased this activity in thymoma and lung cancer tissues. Activation of glutathione reductase was probably related to binding of folic acid in the allosteric center of the enzyme, which probably induced conformational changes in the catalytic center, acceleration of electron transport from NADPH(2) to oxidized glutathione via flavin adenine nucleotide, and intense production of reduced glutathione.

Familial medial telangiectatic nevus: variant of nevus flammeus--port-wine stain.

Six families in which a few members, in three generations, were affected with medial telangiectatic nevus (salmon patch, stork bite, angel's kiss) on the forehead, glabella, upper eyelids, upper lip, nose, and nuchal and occipital areas are presented. This is a mild variant of lateral telangiectatic nevus (nevus flammeus, port-wine stain) that disappears in about 50 percent of patients during the first years of life. In one family, lateral telangiectatic nevus (nevus flammeus, port-wine stain) and superficial (strawberry) hemangioma coexisted with medial telangiectatic nevus. This paper discusses the familial incidence of medial telangiectatic nevus and a new modality of treatment. Moreover, the paper presents a classification of vascular malformations and proposes a new terminology.