An Avid Imitator

We present a case of disseminated cryptococcal disease, coexisting with and mimicking lymphoma. Determination of serum cryptococcal antigen should be considered for lymphopenic patients with hematologic malignancies, presenting with unexplained fever, and/or lymphadenopathy and/or pulmonary findings. Patients with hematologic malignancies treated with chemotherapy regimens are susceptible to diverse opportunistic infections. Therefore, in this patient population, it is often necessary to obtain a definitive pathologic diagnosis, to diagnose uncommon syndromes and guide management

Malignancy risk for solitary and multiple nodules in Hürthle cell–predominant thyroid fine‐needle aspirations: A multi‐institutional study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153015/1/cncy22213.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153015/2/cncy22213_am.pd

The Role of Tyrosine Kinase Growth Factor Receptors in Psoriatic Epidermal Hyperplasia: Analysis of Growth Factor Synergy in Cultured Human Keratinocytes and Receptor Expression in Psoriatic Skin

Psoriasis is a hyperproliferative disease of the skin characterized histologically by epidermal and dermal hyperplasia and inflammatory cell infiltrates. While the pathogenesis of psoriasis is unknown, altered expression of cytokine pathways is likely to produce many of the phenotypic changes in the disease. The epidermal growth factor (EGF) receptor pathway is an important mediator of keratinocyte growth and both ligand and receptorcomponents of this pathway are abnormally expressed in hyperproliferative epidermis. In contrast, little is known about the function of other growth factor pathways in regulating keratinocyte growth. The purpose of this thesis was to characterize the function of three other major tyrosine kinase growth factor receptor pathways -- insulin-like growth factor I (IGF-I), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF), in the regulation of keratinocyte growth in vitro and to characterize the expression of these receptors in normal and psoriatic skin. Growth of normal human keratinocytes in a chemically defined medium demonstrated that IGF-I, EGF, or basic FGF (bFGF) alone did not support significant keratinocyte spreading or proliferation. Considerable proliferation was observed when IGF-I was added in combination with either EGF or bFGF. In contrast, the combination of EGF with bFGF did not stimulate growth more than the addition of these factors alone. Growth synergy between IGF-I and EGF may be due in part to an IGF-I receptor mediated increase in keratinocyte EGF receptor expression. Treatment of cultured normal human keratinocytes with IGF-I increased EGF receptor binding an average of 1.8-fold in a dose and time dependent manner without altering EGF binding affinity. To analyze potential growth factor pathway interactions in vivo, sections of normal and psoriatic human epidermis were stained with IGF-I receptor, EGF receptor, and FGF receptor specific antibodies. In normal skin, plasma membrane IGF-I receptor staining localized exclusively to the proliferative basal cell compartment of the epidermis. IGF-I receptor staining was seen in both basal and suprabasal keratinocytes of lesional psoriatic skin correlating with the increased size of the proliferative cell compartment in psoriatic epidermis. In contrast, both EGF and FGF receptor expression was detected throughout the viable cell layers of the epidermis. Colocalization ofIGF-I receptors with EGF and FGF receptors in proliferating epidermal keratinocytes suggests that interactions among growth factor pathways may be necessary for keratinocyte growth activation. Since bFGF may regulate keratinocyte proliferation in skin, identification of a FGF receptor in keratinocytes was undertaken. Chemical crosslinking and immunoblotting experiments identified a single major FGF receptor protein with a molecular size of approximately 160 kd. Taken together with growth studies and immunohistochemical analysis, these data suggest that the FGF receptor protein identified may be involved in keratinocyte growth regulation. PDGF is a potent mitogenic and chemotactic factor for fibroblasts and other cell types. Analysis of PDGF receptor metabolism and immunohistochemical staining indicated that keratinocytes do not express PDGF receptors and are thus not directly responsive to this hormone. However, expression of PDGF receptors was greatly elevated in dermal fibroblasts and blood vessels of growth-activated skin and could contribute to dermal hyperproliferative changes seen in psoriasis. To begin analyzing the mechanism of action of anti-psoriatic drugs, the effects of anthralin and cyclosporin A (CSA) on keratinocyte proliferation and the EGF receptor pathway were examined. In contrast to CSA, anthralin-treated keratinocytes were more sensitive than lymphocytes to growth inhibition. CSA produced a cell cycle specific block at G1 in keratinocytes, while anthralin did not specifically block the cell cycle at any stage. While CSA did not significantly decrease expression of the EGF receptor or its ligand, transforming growth factor-alpha (TGF- α), anthralin decreased both TGF- α mRNA levels and EGF receptor binding in cultured keratinocytes. TGF- α expression remained at high levels in CSA-treated psoriasis patients suggesting that CSA does not act via direct modification of the EGF receptor pathway in vivo. These results may help explain differing response patterns to treatment with these two drugs. The findings of this thesis suggest possible mechanisms of interaction among the pathways studied that might contribute to the psoriatic phenotype. In particular, IGF-I receptor expression may define keratinocyte proliferative potential, and may, therefore, be a promising target for the development of new anti-psoriatic therapies

Role of Growth Factors, Cytokines, and Their Receptors in the Pathogenesis of Psoriasis

Psoriasis is characterized by epidermal hyperplasia, altered epidermal maturation, and local accumulation of acute and chronic inflammatory cells. Keratinocyte hyperplasia in psoriasis may be explained in part by overproduction of growth factors or cytokines which stimulate epidermal proliferation and by altered metabolism of growth-factor receptors in affected skin. Psoriatic epidermis displays overproduction of TGF-alpha and interleukin-6 (IL-6), factors produced by keratinocytes and other cell types in psoriatic skin. TGF-alpha and IL-6 are mitogens for normal human keratinocytes and act via specific receptors. The TGF-alpha receptor (EGF receptor) is overexpressed in psoriatic epithelium and its altered expression could be caused in part by gamma interferon which prevents normal receptor down-regulation in response to EGF binding. Several phenotypic features of the psoriatic keratinocyte, including growth activation and expression of HLA-DR, gamma-IP-10, ICAM-1, and other molecules, are best explained as resulting from the combined effects of TGF-alpha, IL-6, and gamma interferon (and possibly other cytokines) on epidermal keratinocytes. The multiple histologic features of psoriasis, including epidermal hyperplasia and accumulation of acute and chronic inflammatory cells, may be mediated by defined growth factors and cytokines that are produced in psoriatic skin and affect the function of diverse cell types

FNAB of benign thyroid nodules with papillary hyperplasia: A cytological and histological evaluation

Benign thyroid nodules with papillary hyperplasia (BTN-PH) are sometimes misinterpreted cytologically as papillary thyroid carcinoma (PTC). We evaluated a fine-needle aspiration biopsy (FNAB) series of BTN-PH to identify the causes of diagnostic error and to better define its cytologic criteria

Cytomorphologic features of poorly differentiated thyroid carcinoma: a multi-institutional analysis of 40 cases

BACKGROUND: Poorly differentiated thyroid carcinoma (PDTC) is an uncommon and aggressive malignancy. Despite the significant clinical implications of a diagnosis of PDTC, its cytomorphologic features have not been well defined. Statistical analysis was applied to a series of 40 PDTCs to identify a specific set of cytomorphologic features that characterized these tumors on fine-needle aspiration biopsy (FNAB). METHODS: In total, 40 thyroid FNABs that were highly diagnosed histologically as PDTC (19 insular carcinomas and 21 noninsular carcinomas) comprised the study group. A control group of 40 well differentiated thyroid neoplasms were selected for comparison. All FNABs were reviewed and scored for a series of 32 cytomorphologic features. The results were evaluated using univariate and stepwise logistic regression (SLR) analyses. RESULTS: In univariate analysis, 17 cytomorphologic features were identified that characterized the 40 PDTCs: insular, solid, or trabecular cytoarchitecture (P < .001); high cellularity (P = .007); necrosis (P = .025) or background debris (P = .025); plasmacytoid appearance (P = .0007); single cells (P < .0001); high nuclear/cytoplasmic ratio (P < .0001); scant cytoplasm (P = .03); nuclear atypia (P < .0001), including nuclear pleomorphism (P = .0052) and anisokaryosis (P < .0001); granular/coarse chromatin (P = .026); naked nuclei (P = .01); mitotic activity (P = .0001) and apoptosis (P < .0001); endothelial wrapping (P = .0053); and severe crowding (P < .0001). In logistic regression analysis, severe crowding (P = .0008) and cytoarchitecture (P < .0001) were identified as the most significant cytomorphologic features of PDTCs, and the combination of cytoarchitecture, severe crowding, single cells, and high nuclear/cytoplasmic ratio was the most predictive of PDTC. CONCLUSIONS: PDTCs have characteristic cytomorphologic features. By using logistic regression analysis, the features that were identified as the most predictive of PDTC were severe crowding, insular/solid/trabecular morphology, single cells, and high nuclear/cytoplasmic ratio