Mohammed Akhtar

Hashimoto thyroiditis: a century later.

More than a century has passed since the first description of Hashimoto thyroiditis (HT) as a clinicopathologic entity. HT is an autoimmune disease in which a breakdown of immune tolerance is caused by interplay of a variety of immunologic, genetic, and environmental factors. Thyrocyte injury resulting from environmental factors results in expression of new or hidden epitopes that leads to proliferation of autoreactive T and B cells. Infiltration of thyroid by these cells results in HT. In addition to the usual type of HT, several variants such as the fibrous type and Riedal thyroiditis are also recognized. The most recently recognized variant is immunoglobulin G4+ HT, which may occur as isolated thyroid limited disease or as part of a generalized Ig4-related sclerosing disease. The relationship between HT and Riedel thyroiditis remains unclear; however, recent evidence seems to suggest that it may also be part of the spectrum of Ig4-related sclerosing disease. HT is frequently associated with papillary thyroid carcinoma and may indeed be a risk factor for developing this type of cancer. The relationship between thyroid lymphoma and HT on the other hand appears well established.

Survivin: role in diagnosis, prognosis, and treatment of bladder cancer.

Survivin belongs to a family of proteins, which serve as inhibitors of apoptosis. Survivin inhibits apoptosis by blocking activation of effector caspases in both extrinsic and intrinsic pathways of apoptosis. Expression of survivin has been demonstrated in several malignant neoplasms and is generally associated with adverse prognosis. In the case of bladder cancer, survivin is expressed in the neoplastic epithelium but not in the uninvolved mucosa. Several studies on bladder cancer have indicated that there may be a relationship between survivin expression and ultimate behavior of the carcinoma, although the exact nature of this relationship is still not fully understood, because the results of some of these studies seem to be contradictory. As survivin is differentially expressed in bladder cancer and not in the normal urothelium, several studies have demonstrated efficacy of urine testing of survivin as a diagnostic tool for an early detection of bladder cancer. Survivin has also been suggested as a suitable target for developing specific therapy for local treatment of bladder cancer with encouraging initial results. Thus, survivin is a potentially significant protein with a crucial role in the diagnosis, prognosis, and treatment of bladder cancer.

Molecular basis of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a serious, life-threatening genetic disease in which extensive epithelial-lined cysts develop in the kidneys and, to a lesser extent, in other organs such as liver, pancreas, and ovaries. In a majority of cases (80-85%), the gene involved is PKD1, which is located on chromosome 16 (16q13.3) and encodes polycystin-1, a large receptor-like integral membrane protein that contains several extracellular motifs indicative of cell-cell and cell-matrix interaction. In the remaining (10-15%) cases, the disease is milder and is caused by mutational changes in another gene (PKD2), which is located at chromosome 4 (4q21-23) and encodes polcystin-2, a transmembrane protein, which acts as a nonspecific calcium-permeable channel. Both polycystins function together in a nonredundant fashion, through a common pathway, and produce cellular responses that regulate proliferation, migration, differentiation, and kidney morphogenesis. Through combined function of polycystins, normal tubular cells are maintained in a state of terminal differentiation, and their proliferation is strictly controlled. Loss of function of either protein due to gene mutations results in the tubular cells reverting to a less differentiated state, which is more prone to proliferation. Patients with ADPKD carry a germ-line mutation in PKD1 or PKD2. A second somatic mutation in some of the tubular cells results in loss of both normal alleles, leading to loss of polycystin function. The affected cells lose the normal terminally differentiated state, revert to less differentiated phenotype, and undergo proliferation, which leads to cyst formation. As the cysts enlarge over many decades, the normal renal parenchyma is progressively destroyed, leading to renal failure. Recently, the crucial role of primary cilia in modulating proliferation, migration, and differentiation of tubular epithelium has been recognized. Most of the tubular cells have one or two primary cilia projecting from the apical surface into the luminal space. The cilia act as mechanoreceptors as they bend with the urinary flow within the tubules. Both polycystins are strategically located within the cilia and act as important mediators of ciliary mechanosensation. Loss of this important function due to mutational changes in PKD1 or PKD2 leads to loss of normal control over cellular proliferation, resulting in cyst formation. Several other ciliary proteins have recently been found to contribute directly to a wide spectrum of human kidney diseases with cystic phenotype, thus underscoring the pivotal role the primary cilia play in maintaining the normal structure and function of the tubular cells and probably other cells in the body.

Wilms tumor: an update.

Wilms tumor (WT) is the most common neoplasm of the kidney in children. It is an embryologic tumor that histologically mimics renal embryogenesis and is composed of a variable mixture of stromal, blastemal, and epithelial elements. Nephrogenic rests, generally considered to be precursor lesions of the WT, are foci of the embryonic metanephric tissue that persist after the completion of renal embryogenesis. These are classified as perilobar and intralobar based on their location and maybe present as single or multiple foci. Intralobar and perilobar rests and the tumors arising from these rests differ morphologically and are characterized by 2 different sets of genetic abnormalities involving 2 adjacent foci, WT1 and WT2, on the short arm of chromosome 11. WTs arising in the intralobar rests tend to be stromal predominant and have a mutation or deletion of WT1. Germline mutation in WT1 may be associated with syndromic conditions such as WAGR and Denys-Drash syndromes. Perilobar rests and their corresponding tumors usually have loss of imprinting/loss of heterozygosity involving WT2, which contains several parentally imprinted genes. Loss of function of these genes, if present constitutionally, may be associated with Beckwith-Wiedemann syndrome or may result in isolated hypertrophy. Abnormalities in several other genes may also be seen in WT. These include WTX, (on chromosome X), CTNNB1 (chromosome 3), and TP53 (chromosome 17) among others. WT with loss of heterozygosity at 1p and 16q may have poor prognosis, requiring aggressive therapy. Treatment modalities for WT have evolved over many decades, primarily through the efforts of Dr J Bruce Beckwith at National WT study. This work is now being carried out by Children Oncology Group in North America and International Society of Pediatric Oncology in Europe. Although their therapeutic approaches are somewhat different, both have reported excellent results with equally high cure rates.

Intratubular germ cell neoplasia of the testis: a brief review.

Germ cell tumors of the testis may be divided into 3 broad categories according to age at presentation. The tumors in the pediatric age group include teratoma and yolk sac tumor. These tumors are generally not associated with convincing intratubular neoplasia. The second group consists of tumors presenting in third and fourth decade of life and include seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma as well as mixed germ cell tumors. The precursor cell for these tumors is an abnormal gonocyte that fails to differentiate completely into spermatogonia. These abnormal cells stay dormant in the gonad during intrauterine life as well as infancy and childhood, but undergo proliferation during puberty and can be identified as intratubular germ cell neoplasia unclassified (IGCNU). These tumor cells continue to manifest protein expression pattern that resembles primitive germ cells (PLAP, c-KIT, OCT3/4). After a variable interval following puberty, IGCNU cells may acquire ability to penetrate the seminiferous tubules and present as an overt germ cell tumor. Acquisition of isochrome 12 and other genetic abnormalities are usually associated with this transition. The level of DNA methylation generally determines the phenotype of the germ cell tumor. The third type of germ cell tumors is spermatocytic seminoma, which is a rare tumor encountered later in life usually in fifth and sixth decade. The cell of origin of this tumor is probably postpubertal mature spermatogonia which acquire abnormal proliferative capability probably due to gain of chromosome 9 resulting in activation and amplification of genes such as DMRT1. The tumor cells manifest many of the proteins normally expressed by mature sperms such as VASA, SSX2, and occasionally OCT2. Although spermatocytic seminoma may also have an intratubular growth phase, it completely lacks features of IGCNU.