Relative risk of high grade squamous intraepithelial lesion associated with prior abnormal Pap smears.

OBJECTIVE: Pap smear frequency remains controversial, especially for women with consecutive negative smears. We undertook the current study to ascertain the association of high grade squamous intraepithelial lesions (HSIL) and prior abnormal Paps. STUDY DESIGN: Women with biopsy-proven HSIL (cervical intraepithelial neoplasia 2 and 3) diagnosed between September 1996 and December 1997 and age-matched controls with a negative Pap obtained during the same time period were selected. RESULTS: Sixty-three cases (mean age = 32 years) of HSIL and 69 controls (mean age = 33 years) constituted the study population. Any prior abnormal diagnosis conferred a 15-fold increased risk of HSIL on the current Pap (50/63 vs. 14/69, P < .0001). When limited to the 60 women with at least three prior Paps, the odds ratio for HSIL on the current Pap with any prior abnormal was 18 (28/31 vs. 10/29, P < .0001). Three cases had at least three consecutive negative Paps prior to the diagnosis of HSIL. CONCLUSION: Women with one or more prior negative Pap smears had a significantly decreased risk of HSIL on the current Pap. Consecutive negative Paps did not appear to further decrease the risk; 10% of HSIL patients had had three or more consecutive prior negative Paps. To detect HSIL at its earliest stage, women should be advised to continue annual Pap screening in spite of consecutive negative results.

Endometrial endothelial cells express estrogen and progesterone receptors and exhibit a tissue specific response to angiogenic growth factors.

OBJECTIVE: To develop a reliable method for the isolation and longterm culture of microvessel endothelial cells from human endometrium and to evaluate their response to angiogenic growth factors and steroid hormones in comparison to endothelial cells derived from other organs. METHODS: Endometrial tissue from hysterectomy specimens were digested sequentially with collagenase and trypsin, cultured for 24 h, then selected by adhesion to anti-CD-34 coated magnetic beads. Alternatively, anti-CD-34-coated beads could also be substituted by Ulex europaeus agglutinin-1, anti-PECAM, or anti-E-selectin-coated beads. Characterization of the isolated cultures included expression of endothelial cell markers, regulation of E-selectin in response to TNF-alpha, proliferative response to angiogenic growth factors, and expression of progesterone and estrogen receptors. We also analyzed the relative binding affinity of VEGF on endometrial endothelial cells in comparison to other endothelial cell types. RESULTS: Selection on anti-CD-34-coated beads eliminated contaminating cells and resulted in a homogeneous population of human endometrial endothelial cells (HEEC), as assessed by expression of PECAM, von Willebrand's factor, and uptake of acetylated-LDL. HEEC also upregulated E-selectin in response to TNF-alpha in a manner similar to that seen for other endothelial cell types. Expression of progesterone and estrogen receptor was revealed by immunocytochemistry and RT-PCR consistently until passage 5. Endometrial endothelial cells were more responsive to growth stimulation by VEGF than were dermal endothelial cells isolated under similar conditions. Further characterization indicated that VEGF bound more avidly to HEEC than to other endothelial cell types. CONCLUSIONS: Human endometrial endothelial cells were isolated to homogeneity by a two-part protocol and successfully passaged under culture conditions similar to those used for other endothelial cell types. The HEEC were very responsive to VEGF growth-stimulation likely due to elevated affinity, or increased levels of, KDR and FLT-1 on the cell surface. These results indicate that HEEC are capable of maintaining a mature phenotype in culture and might provide a model for understanding the response of these cells to the recurrent cycles of proliferation imposed on the endometrium during menstruation.

Differential expression of frpHE: a novel human stromal protein of the secreted frizzled gene family, during the endometrial cycle and malignancy.

By using the differential display technique to identify genes that are differentially expressed in human endometrial carcinoma compared with normal endometrium, we have cloned frpHE, a novel member of the secreted frizzled gene family. By in situ hybridization, we have determined that frpHE is expressed by mesenchymal cells but not by epithelial cells. The expression of frpHE is modulated during the endometrial cycle: it is expressed in the stroma of proliferative endometrium and not significantly detectable in secretory or menstrual endometrium, suggesting that frpHE is under hormonal regulation. In addition, the expression of frpHE mRNA is markedly up-regulated in the stroma of endometrial hyperplasia and carcinoma and in the stroma of in situ and infiltrating breast carcinomas. Injection of frpHE mRNA in Xenopus embryos inhibited the Wnt-8 mediated dorsal axis duplication. These results indicate that frpHE functions as a regulator of the Wnt-frizzled signaling pathway and is involved in endometrial physiology and carcinogenesis.

Cytologic features of neoplastic lesions in endocervical glands.

Cytologic criteria for classifying atypical endocervical cells on Pap smears are poorly defined. In this study we evaluated cytologic parameters that are useful in predicting the presence of neoplastic lesions (NL) and those that help distinguish squamous intraepithelial lesion (SIL) from glandular neoplastic lesions. The recently proposed Bethesda System (TBS) terminology for reporting atypical glandular cells of undetermined significance (AGUS) was also evaluated for its significance on patient management. Sixteen cases of biopsy-proven endocervical glandular NL that had cytologic smears available for review were included. Thirty-five smears with atypical endocervical cells and follow-up biopsies showing benign/reactive change (n = 22) and SIL involving glands (n = 13) were reviewed for comparison. Our results show that squamous NL often coexist with glandular NL. The presence of rosettes, hyperchromasia and increased N/C ratio is useful in distinguishing NL from benign/reactive conditions. Architectural features are helpful in distinguishing SIL from glandular NL. While a haphazard arrangement is more often seen with SIL, glandular NL are more likely to maintain polarity and to show glandular rosettes. Using TBS criteria, a conservative management seems justified in patients with AGUS-favor reactive and AGUS diagnosis on Pap smear, and colposcopy is indicated for patients with AGUS-favor NL.

Uterine smooth muscle cells express functional receptors (flt-1 and KDR) for vascular permeability factor/vascular endothelial growth factor.

Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is an angiogenic factor with important roles in tumor growth, wound healing, and inflammation. VPF/VEGF interacts with endothelial cells by way of two high-affinity receptor tyrosine kinases: flt-1 and KDR. The vast majority of published studies have described expression of the VPF/VEGF receptors only in endothelial cells, and the statement is frequently made that these receptors are endothelial-cell-specific. In this study, we detected mRNA for flt-1 and KDR by in situ hybridization in smooth muscle cells in sections of the wall of the uterus. To confirm these unexpected findings, smooth muscle cells from the uterus and, as a control, from the colon were isolated, characterized, and cultured. Both uterine and colonic smooth muscle cells in culture expressed VPF/VEGF, but only smooth muscle cells from the uterus expressed mRNA for flt-1 and KDR by Northern analysis and in situ hybridization. Cell culture extracts of uterine but not colonic smooth muscle cells were also positive for flt-1 by Western analysis. Moreover, cultured uterine but not clonic smooth muscle cells phosphorylated the flt-1 receptor and proliferated strongly in response to added VPF/VEGF. This is one of the first rigorous demonstrations that a normal cell type other than endothelial cells can express functional receptors for VPF/VEGF in vivo and in vitro, suggesting that VPF/VEGF may have important, previously unsuspected roles on cell types other than endothelium.

Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in endometrial carcinoma.

BACKGROUND: Solid tumors, including endometrial carcinomas, must induce a vascular stroma to grow beyond a minimal size. The mechanisms responsible for angiogenesis in endometrial carcinoma, however, are not well defined. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine that is an important regulator of tumor angiogenesis. We evaluated VPF/VEGF mRNA and protein expression, as well as VPF/VEGF receptor mRNA expression, in endometrial carcinoma. METHODS: Fourteen examples of endometrial carcinoma were evaluated by in situ hybridization; in 7 cases, benign atrophic endometrium from the same patient was also examined. Histologic sections were subjected to in situ hybridization using 35S-labeled riboprobes specific for VPF/VEGF and, in a subset of cases, riboprobes specific for the VPF/VEGF receptors flt-1 and KDR. In addition, ten examples of endometrial carcinoma were evaluated for VPE/VEGF protein expression by immunohistochemistry. RESULTS: All 14 examples of endometrial carcinoma studied by in situ hybridization exhibited focal strong VPF/VEGF mRNA expression by tumor cells. In addition, the endothelial cells of surrounding microvessels strongly expressed flt-1 and KDR mRNAs in all ten cases examined. In contrast, no strong expression of VPF/VEGF, flt-1, or KDR mRNA was observed in the seven examples of benign atrophic endometrium studied. All ten cases of endometrial carcinoma studied by immunohistochemistry exhibited strong VPF/VEGF protein expression by tumor cells. CONCLUSIONS: These observations suggest that VPF/VEGF is an important angiogenic factor in endometrial carcinoma.

Qualifiers of atypical squamous cells of undetermined significance help in patient management.

According to the recommendations of the Bethesda System, the diagnosis of atypical squamous cells of undetermined significance (ASCUS) should be further qualified, when possible, as to whether a reactive or a squamous intraepithelial lesion (SIL) is favored. To determine the utility of this recently proposed terminology, we undertook this study to correlate the diagnosis of ASCUS (with or without qualifiers) with results obtained from examination of biopsy specimens. All patients were identified for the study who had a coloposcopically obtained cervical biopsy specimen or endocervical curettage specimen recorded in the surgical pathology files at Beth Israel Hospital, Boston, Massachusetts, from April 1994 through September 1994 and had either prior or concurrent Pap smear(s) reported as ASCUS, ASCUS-favor reactive, ASCUS-favor SIL, or SIL-low grade (SIL-LG). Patients with a cytologic diagnosis of SIL-LG served as a reference group. A total of 435 patients with 485 Pap smears were included. The prevalence rates of biopsy-proven SIL in patients with a cytologic diagnosis of ASCUS-favor reactive, ASCUS, ASCUS-favor SIL, and SIL-LG were 10, 28, 36, and 55%, respectively. The difference between cases diagnosed as ASCUS (with or without qualifiers) and SIL-LG, with respect to the presence of SIL at examination of the biopsy specimen, was statistically significant (P < 0.001 for all correlations). Cases diagnosed as ASCUS-favor reactive had a significantly lower rate of biopsy-proven SIL compared with those diagnosed as ASCUS and ASCUS-favor SIL (P < 0.01 for both correlations). A significant proportion of biopsy specimens with Pap smear diagnosis of ASCUS-favor SIL had SIL-high grade (15%). In contrast, an underlying SIL-high grade is much less likely in patients with ASCUS (unqualified) (3%) or when a reactive process is favored (3%). It seems justified to manage patients with ASCUS-favor SIL in a manner similar to those with SIL-LG. A conservative management seems appropriate for patients with ASCUS and ASCUS-favor reactive.

Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms.

Angiogenesis is a critical factor in the growth, progression, and metastatic spread of solid tumors. Furthermore, angiogenesis has been correlated with prognosis in patients with ovarian cancer. The pathogenesis of the angiogenic events in ovarian cancer, however, are not well defined. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine that has been shown to be an important regulator of tumor angiogenesis. The purpose of the present study was to define the expression of VPF/VEGF and its receptors flt-1 and KDR in ovarian tumors. Four specimens of normal ovarian cortex and 41 specimens of benign (4), borderline (8), and malignant (29) ovarian tumors were studied by in situ hybridization, and in some cases by immunohistochemical analysis. VPF/VEGF protein was also determined by an immunofluorometric assay in cyst fluids obtained from 11 patients, including 7 benign, 2 borderline, and 2 malignant tumors. VPF/VEGF mRNA and protein were expressed by the neoplastic cells in all of the malignant tumors evaluated, with the majority of tumors (28 of 29) showing strong expression of mRNA. Serous borderline tumors had variable VPF/VEGF mRNA expression, with two of six cases showing focal strong expression and four showing low-level expression. No definite expression of VPF/VEGF was seen in two cases of mucinous borderline tumors. No strong expression of VPF/VEGF mRNA was observed in normal ovarian cortex, including surface epithelium, or benign tumors. Substantially higher VPF protein concentrations were detected in cyst fluids of the two malignant (60, 440 pM) and two borderline tumors (210, 590 pM) than in the seven benign serous cysts (mean, 10 +/- 3 pM). In addition, microvascular endothelial cells strongly expressed mRNA of the VPF/VEGF receptors flt-1 and KDR and immunostained for VPF/VEGF protein in the majority of malignant and borderline tumors examined. These findings suggest that VPF/VEGF plays an important role in the angiogenesis associated with ovarian neoplasms.

Estrogen receptor expression is a common feature of ovarian borderline tumors.

PURPOSE: The presence of estrogen receptor (ER) and its therapeutic significance in ovarian borderline tumors (OBT) have not been established. We recently observed a response to tamoxifen therapy given empirically to a patient with unresectable, recurrent serous borderline tumor (SBT). In view of this observation the present study was undertaken to assess ER expression in 51 cases of OBT. MATERIALS AND METHODS: ER expression was determined retrospectively, using an immunohistochemical method on formalin-fixed, paraffin-embedded specimens, from 35 cases of SBTs, 6 cases of mucinous mullerian (MMBT), and 10 cases of mucinous intestinal borderline tumors (MIBT). ER was considered positive if > 5% of tumor epithelial cell nuclei were immunostained. Both SBTs and mucinous borderline tumors (MBTs) were included to determine the influence of histologic type on ER expression. RESULTS: The patients ranged in age from 25 to 77 years (median 43 years for SBTs, 36 years for MMBTs, and 37 years for MIBTs). The stage distribution for the SBTs was stage I in 27 patients (77%), stage II in 4 patients (11.5%), and stage III in 4 patients (11.5%). All patients with MBTs were stage I. ER expression was observed in the majority of cases and correlated with histologic type: 94% (33/35) of SBTs and 100% (6/6) of MMBTs were ER positive compared to 0% (0/10) of MIBTs (P < 0.01). In the SBT category the presence of ER did not correlate significantly with stage or age. In addition, ER was positive in all four SBT implants (including one involved lymph node) and two recurrent SBTs analyzed. CONCLUSION: ER expression is a common feature of SBT and MMBT, but not MIBT. The relevance of ER expression in the pathogenesis and treatment of OBTs requires further investigation.

ThinPrep processing of endoscopic brushing specimens.

To evaluate ThinPrep (Cytyc, Marlborough, MA) processing of endoscopic brushing specimens for cytologic examination, ThinPrep slides and direct smears of 29 gastrointestinal (GI) and 22 bronchial brushings were compared. Clinicians prepared the direct smears. The brush was then immersed in CytoLyt (Cytyc) and one ThinPrep slide made. All cases had corresponding biopsies. Smears and ThinPrep slides were screened and reviewed independently. Screening time per case was recorded. All slides were evaluated for cellularity, quality, cellular preservation, and quantity of diagnostic cells. A diagnosis was rendered for each case. Cytologic and histologic diagnoses were correlated. Follow up was obtained for cases with discrepant histologic and cytologic diagnosis. Twenty-three brushings were from esophagus, 5 stomach, 1 duodenum, and 22 lung. An average of 3.6 direct smears (range 2-6) was made for each case. Average screening time per case was 12 minutes for GI direct smear, 15 minutes bronchial direct smear, 4 minutes GI ThinPrep slide, and 9 minutes bronchial ThinPrep slide. ThinPrep slides were superior to direct smears in cellularity, quantity of diagnostic cells, and quality of slides. ThinPrep slides and direct smears showed comparable cellular preservation. The sensitivity of detecting malignancy by biopsy, direct smears, and ThinPrep slides was 81%, 75%, and 75%, respectively. One false-positive diagnosis was made on cytology with both direct smear and ThinPrep slide, a case with radiation atypia. In conclusion, ThinPrep slides are at least comparable to direct smears in cytologic examination of brushings. However, false-positive diagnosis is a possible potential pitfall.

Recombinant BCG therapy suppresses melanoma tumor growth.

BACKGROUND: Melanoma is the fastest rising cancer in the United States. Bacillus Calmette-Guerin (BCG) has been genetically engineered to actively express and secrete the cytokine interleukin-2 (IL-2). Both BCG and IL-2 have known potent antitumor and immunomodulatory properties. METHODS: This recombinant BCG (rBCG 3A) has been tested as an intratumoral injection and a vaccine therapy in conjunction with irradiated tumor cells against melanoma in the murine B16 melanoma model. RESULTS: The transfection process did not adversely alter the function of the wild-type (WT) BCG. rBCG 3A and WT BCG are equally effective intratumoral and vaccine therapies against melanoma when compared with normal saline control groups. Tumor burdens were significantly smaller (p < or = 0.01 and 0.05) for the treatment groups for both intratumoral and vaccine administration of therapy. Immunization with rBCG 3A and WT BCG 14 days before a B16 challenge resulted in an approximately 45% smaller tumor burden when compared with controls. CONCLUSIONS: Novel therapies based on the immunogenic properties of melanoma combined with molecular technologies may offer promise for an effective and safe treatment of melanoma.

Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia.

BACKGROUND: Angiogenesis is a critical factor in the progression of solid tumors, including cervical cancers. The mechanisms responsible for angiogenesis in cervical neoplasia, however, are not well defined. PURPOSE: Our goal was to determine the relationship between angiogenesis and the expression of the angiogenic cytokine vascular permeability factor (VPF), also known as vascular endothelial growth factor, and its receptors in cervical neoplasia. METHODS: Sixty-six cervical biopsy specimens were evaluated; among these, 16 samples were designated as benign, 17 as low-grade squamous intraepithelial lesions, 18 as high-grade squamous intraepithelial lesions, and 15 as invasive squamous cell carcinomas. Histologic sections immunostained for factor VIII-related antigen were evaluated quantitatively for microvessel density and for the presence of epithelial-stromal vascular cuffing. Sections were also evaluated for VPF messenger RNA (mRNA) expression by in situ hybridization. RESULTS: VPF mRNA expression, epithelial-stromal vascular cuffing, and microvessel density counts were significantly increased in invasive carcinoma and in high-grade intraepithelial lesions as compared with low-grade intraepithelial lesions and benign squamous epithelium. Vascular cuffing and increased microvessel density counts were also significantly associated with increased VPF mRNA expression. CONCLUSIONS: These observations suggest that VPF is an important angiogenic factor in cervical neoplasia.

CD44 variant expression is a common feature of epithelial ovarian cancer: lack of association with standard prognostic factors.

PURPOSE: CD44 is a hyaluronic acid receptor that exists as a standard 90-kd form (CD44S) as well as several CD44 variant isoforms produced through alternative splicing. Expression of CD44 variants is associated with clinically aggressive behavior in some human tumors. The purpose of the present study is to define the expression of CD44 variant isoforms in ovarian cancer and to investigate whether the expression of these molecules is associated with adverse prognosis. MATERIALS AND METHODS: Six specimens of normal ovarian surface epithelium (NOSE) and 31 separate cases of newly diagnosed ovarian cancer were studied by a combination of reverse-transcription polymerase chain reaction (RT-PCR) and immunoperoxidase staining. Clinical correlation was made between CD44 variant expression and stage (I/II v III/IV), residual disease (< or = 2.0- v > 2.0-cm mass), age (< or = 65 v > 65 years), histology (papillary serous v other), grade, and survival. RESULTS: RT-PCR analysis revealed that NOSE predominantly expressed transcripts for CD44S, as well as a restricted pattern of transcripts characteristic of CD44 splice variants. CD44S and CD44 variant exon nine sequences (CD44-9v) were focally expressed in one of two NOSE specimens examined by immunoperoxidase staining. In comparison, the majority (71%) of ovarian cancer specimens expressed a complex pattern of CD44 splice variants by RT-PCR analysis. Immunoperoxidase studies revealed that the majority of ovarian cancer specimens expressed both CD44S and CD44-9v, whereas expression of sequences from variant exons 3, 4, and 6 was uncommon. There was no association between CD44 variant expression (transcript or protein) and stage, residual disease, age, histology, grade, or survival. CONCLUSION: Expression of CD44S and CD44-9v is a common feature of epithelial ovarian cancer cells. The lack of a significant association between CD44 variant expression and prognosis suggests that other factors may be more important in determining the clinical behavior of this disease.

Histocytological study of squamous atypia on Pap smears.

UNLABELLED: The significance of squamous atypia on Pap smears is currently unclear and its management is controversial. We undertook this study to determine whether cytological parameters on Pap smears with a diagnosis of squamous atypia could be useful in predicting the presence of a squamous intraepithelial lesion (SIL). METHODS: For a 3-mo period, all patients who had a colposcopically directed biopsy and or endocervical curettage (ECC) with a simultaneous or a previous Pap smear showing squamous atypia were identified. All biopsies were reviewed and all cytological smears were evaluated for the following cytological parameters: inflammation, parakeratosis, atypical parakeratosis, number of atypical cells, nuclear size, chromatin pattern (fine, coarse, or hyperchromatic), as well as presence of metaplasia, nuclear membrane irregularity, multinucleation, and nuclear halo in the atypical cells. RESULTS: a total of 97 patients were eligible for the study. The average interval between the Pap smear and colposcopy was 96 days (range, 0 to 364 days). Thirty patients (31%) had SIL on biopsy or ECC, of which 17 (18%) were SIL, low grade, and 13 (13%) were SIL, high grade. Of the 67 that showed no SIL on histology, 24 had inflammatory reactive changes, five had squamous metaplasia with atypia, one had parakeratosis, and 37 had essentially normal biopsies. Most of the cytological features, except coarse chromatin, were equally predictive of SIL with approximately 30% of the patients with any particular feature showing SIL on histology. However, 46% (17/37) of those that had coarse chromatin showed SIL on histology (P < 0.02). Based on this study, squamous atypia on Pap smears appears a marker of an underlying SIL in a considerable number of cases, and coarse chromatin seems most helpful in predicting the presence of SIL.

Large loop excision of the transformation zone in patients with exocervical squamous intraepithelial lesions.

This study was undertaken to determine factors influencing the success of loop excisions. One hundred twenty-seven women with exocervical intraepithelial lesions underwent large loop excision of the transformation zone (LLETZ); 102 returned for evaluation at 3 months. The pretreatment biopsies were low grade squamous intraepithelial lesions (LGSIL) in 37 cases and high grade squamous intraepithelial lesions (HGSIL) in 90. For the 37 women with LGSIL, the LLETZ specimen revealed no residual SIL in 13 (35%), LGSIL in 16 (43%), and HGSIL in 8 (22%). For the 90 women with HGSIL on pretreatment biopsy, 17 (19%) had no SIL, 10 (11%) had LGSIL, and 63 (70%) had HGSIL. Of the 102 women who returned for reevaluation, colposcopy was satisfactory in 89. There were 9 failures and all of these occurred in women with HGSIL in the LLETZ specimen. In the 17 women with involved margins there were 6 failures (35%); in the 85 women with uninvolved margins there were 3 failures (4%) (p = 0.005). The success of loop excisions is influenced by the grade of intraepithelial neoplasia and status of the margins of the LLETZ specimen.

Rat urate oxidase produced by recombinant baculovirus expression: formation of peroxisome crystalloid core-like structures.

Urate oxidase (EC 1.7.3.3), which catalyzes the oxidation of uric acid to allantoin, is present in most mammals but absent in humans and hominoid primates. In rats and most other mammals that catabolize uric acid to allantoin, this enzyme is localized within the crystalloid cores of peroxisomes present in liver parenchymal cells. To determine whether urate oxidase forms these crystalloid cores or whether core-forming protein(s) exist in association with urate oxidase, a baculovirus expression vector system was used to overproduce the full-length rat urate oxidase in Spodoptera frugiperda cells. Urate oxidase was expressed to a level of approximately 30% of the total protein in this system. Immunoblot analysis demonstrated that the baculovirus-generated protein had electrophoretic and immunologic properties similar to those of urate oxidase expressed in rat liver. Immunofluorescence and electron microscopic examination revealed that the overexpressed recombinant urate oxidase is present in both the cytoplasm and the nucleus of infected insect cells as numerous 1- to 3-microns discrete particles. These insoluble protein aggregates, which were positively stained for urate oxidase by protein A-gold immunocytochemical approach, did not appear to be delimited by a single membrane. They revealed a crystalloid structure reminiscent of rat peroxisomal core consisting of bundles of tubules with an inner diameter of approximately 50 A. The recombinant urate oxidase particles, isolated by a single-step procedure, were composed entirely of 35-kDa urate oxidase subunit. These studies indicate that rat urate oxidase is capable of forming insoluble crystalloid core-like structures.

Amyloidosis in association with human immunodeficiency virus infection.

Amyloidosis has not been previously reported in association with human immunodeficiency virus (HIV) infection. An HIV-infected patient with hemophilia who developed nephrotic syndrome due to amyloidosis is described. Amyloid disease has been observed in monkeys with AIDS, and patients with AIDS have had elevated levels of amyloid A protein, findings that suggest a pathogenetic linkage between the two disorders. Amyloidosis should be considered in the differential diagnosis of HIV-associated nephropathy and the nephrotic syndrome in HIV-infected patients.