The CD44 receptor is a molecular predictor of survival in ovarian cancer.

PURPOSE: CD44 is a cell surface receptor implicated in cancer progression and metastases. Malignant tumors may show a loss of CD44 splice control mechanisms. We investigated the role of CD44 splice variant expression in ovarian tumors and metastases, and its association with survival. EXPERIMENTAL DESIGN: We tested CD44 expression in 142 cases of epithelial carcinoma of the ovary and 265 metastatic sites by immunohistochemistry. RESULTS: Survival analysis showed that the expression of CD44s, CD44-v4, -v5, -v6, -v9, and -v10 are significant predictors for survival in univariate analysis. After stage, the expression of CD44-v10 in metastases was the strongest predictor of decreased survival in multivariate analysis (p = 0.0009). Conversely, CD44-v10 expression in the primary tumor was an independent predictor of improved survival in multivariate analysis (p = 0.0002). The expression of CD44s in the tumor/stroma interface of the primary tumor was associated with improved survival (p < 0.0001). CONCLUSIONS: CD44 variant expression is a molecular prognostic maker for epithelial ovarian carcinomas. CD44-v10 expression is an independent prognostic indicator and the site of expression determines a positive or negative influence in survival. Our results also indicate that CD44 may be involved in important tumor/stroma interactions.

Clear cell carcinoma of the ovary: characterization of its CD44 isoform repertoire.

OBJECTIVE: CD44 is a cell surface receptor implicated in tumor metastases. We have previously shown that there is a loss of CD44 splice control in clear cell carcinoma (CCCa) of the ovary. Our aim is to characterize the expression of CD44-3v, -5v, -7v, and -10v in clear cell ovarian tumors and to determine their prognostic value. METHODS: Twenty-two cases of ovarian CCCa were studied for CD44-3v, -5v, -7v, and -10v expression by immunocytochemistry. RESULTS: The primary tumors showed expression of CD44-3v, -5v, -7v, and -10v in 44, 55, 61, and 39% of the cases, respectively. We were able to compare the expression of CD44 in the primary tumor and metastatic sites from the same patient in 7 cases (metastatic sites n = 16). We observed decreased immunoreactivity of CD44-3v, -5v, -7v, and -10v in 67, 100, 93, and 92% of the sites, respectively. CD44-3v and -10v expression was absent in 100% of the nonaffected contralateral ovaries while -7v and -10v were expressed in 1/11 (9%) of them. When CD44-10v was not expressed in the primary tumor, only 18% of the women recurred or died of disease; in contrast, of the cases where it was present, 71% of the women recurred or died of disease (P = 0.049). CONCLUSIONS: There is aberrant alternative mRNA splicing in the development of CCCa of the ovary when compared to the contralateral nonaffected ovary. The expression of CD44-10v correlates with survival. Larger series are needed to further understand the role of CD44 isoforms in ovarian cancer metastases.

CD44-9v and CD44-10v are potential molecular markers for squamous cell carcinoma of the vulva.

OBJECTIVE: CD44 is a cell surface glycoprotein widely distributed in the extracellular matrix. CD44 isoforms arising from alternative mRNA splicing are implicated in tumor metastases. The aim of this study is to investigate the expression of CD44s and two splice variants, CD44-9v and CD44-10v, in squamous cell carcinoma (SCC) of the vulva as well as its correlation with lymph node (LN) metastases and disease-free survival. METHODS: Thirty-five SCC vulvar tumors were evaluated for CD44s, CD44-9v, and CD44-10v expression by immunocytochemistry. One nonmetastatic LN was studied also. In cases with LN metastases, the metastatic LN as well as a nonmetastatic LN from the same patient were evaluated. RESULTS: CD44s and CD44-9v were expressed in all epithelia--normal, dysplastic, and SCC. However, intensity and distribution of expression of 9v isoforms changed within the tissue containing invasive cancer. CD44-9v expression was downregulated in the most differentiated cells within the carcinoma, mainly in patients who had disease recurrence or eventually died of disease (P = .031). All metastatic tumor to LNs was immunoreactive also for CD44-9v. CD44-10v expression was present in 78% of tumors and 56% of normal epithelium. Interestingly, CD44-10v membrane expression, but not cytoplasmic expression, correlated with disease recurrence (P = .035). CONCLUSION: Our findings warrant larger multi-institutional studies to determine the potential of CD44-9v and CD44-10v as molecular markers of disease recurrence in vulvar carcinoma. We propose to test the use of anti-CD44-9v monoclonal antibody for radioimmunoimaging of occult LN metastases.

Prognostic value of CD44 expression in invasive squamous cell carcinoma of the vulva.

OBJECTIVE: CD44 is a cell adhesion molecule that binds extracellular matrix. CD44 isoforms arising from alternative mRNA splicing are implicated in tumor metastases. The aim of our study is to investigate the expression of CD44 splice variants and its correlation to lymph node metastases and disease-free survival in squamous cell carcinoma (SCC) of the vulva. METHODS: Thirty-five cases of SCC of the vulva were evaluated for CD44 splice variants -3v, -4v, -5v, and -7v expression by immunocytochemistry. When available one nonmetastatic lymph node (LN) was also studied. In cases with LN metastases, the metastatic LN as well as a nonmetastatic LN from the same patient were evaluated. RESULTS: All CD44 variants studied were expressed in all epithelium: normal, dysplastic, and SCC. CD44 variants showed decreased immunostaining in the tumor cells when compared to normal epithelium. Furthermore, intensity of expression of the CD44 isoforms changed within the tissue containing invasive cancer. Interestingly, CD44-4v expression was downregulated in the most differentiated cells within the carcinoma, mainly in patients who had disease recurrence or died of disease (P = 0.004). Confirming prior publications, CD44-5v and -7v expression did not correlate with survival. One hundred percent of metastatic tumors to LNs were immunoreactive with CD44-3v and only 1/30 normal LN had CD44-3v expression. Eighty percent of metastatic tumors to LNs were immunoreactive for CD44-4v. However, 3 LNs without tumor were also immunoreactive with CD44-4v. CONCLUSION: CD44-4v is a potential molecular marker of disease recurrence in vulvar carcinoma. A larger multiinstitutional study is needed to evaluate the specificity of CD44-3v expression in LN metastasis. If a larger scale study confirms our findings, a CD44-3v antibody could be used for radioimmunoimaging of occult lymph node metastases in patients with vulvar cancer.

The role of fine-needle aspiration biopsy in the management of thyroid nodules in children, adolescents, and young adults: a multi-institutional study.

Thyroid nodules in children are extremely uncommon and in most cases present as asymptomatic neck masses. The significance of a thyroid nodule in a child involves the underlying risk of malignancy. The purpose of this study was to assess the validity of results of fine-needle aspiration biopsy (FNAB) of thyroid nodules in the pediatric population and its usefulness in pediatric patient management. FNAB was performed on a total of 57 thyroid nodules from 57 patients between 1992 and 1997. The patients included 46 females and 11 males ranging in age from 9 to 20 years (average 16.5 years). Surgical and/or clinical follow up was available in all patients. FNAB diagnoses included papillary thyroid carcinoma (PTC) (12.3% [7/57]), follicular neoplasm (FN) (15.8% [9/57]), atypical cytology (8.8% [5/57]) and nonneoplastic thyroid (63.2% [36/57]). Surgical follow-up available in all patients with cytological diagnoses of PTC, FN, and atypical cytology revealed malignancy in 13 cases. Of the 36 patients with nonneoplastic cytological diagnosis, surgical excision was performed in 3 patients and the rest were followed up clinically. Surgical excision in these 3 patients revealed follicular carcinoma (FC) (1 case) and multinodular goiter (2 cases). Overall, 14 patients (24.6%) had malignant thyroid lesions, including 11 PTC and 3 FC. In conclusion, the majority of pediatric thyroid nodules are benign. The prevalence of malignancy in pediatric patients with thyroid nodules in our series was 24.6%. High diagnostic accuracy of thyroid FNAB improves selection of pediatric patients requiring surgery.

CD44 splice variant expression in clear cell carcinoma of the ovary.

OBJECTIVE: CD44 is a surface glycoprotein widely distributed among different tissues. Malignant tumors may show a more complex pattern of CD44 expression, indicating a loss of splice control. The aim of our study is to investigate the expression of CD44 splice variants (CD44v) and its metastatic potential in clear cell carcinoma of the ovary. METHODS: Twenty-two cases of clear cell carcinoma of the ovary were evaluated for CD44 standard form (CD44s) and splice variants: -4v, -6v, and -9v expression by immunocytochemistry. RESULTS: Twenty-one primary ovarian tumors and 23 metastatic sites were available for evaluation. Eighteen of 21 (86%) of ovarian sections studied expressed CD44s; 15/21 (71%) expressed CD44-4v; 14/21 (67%) expressed CD44-6v; and 12/21 (57%) expressed CD44-9v. Of 23 metastatic sites evaluated, 87% expressed CD44s. In contrast, only 5 (22%) metastases had CD44-4v and CD44-6v expression and 8 (35%) had CD44-9v immunoreactivity. None of 10 normal contralateral ovaries expressed CD44s or any splice variants. In 2 cases we had tumor available from the primary surgery, and subsequent recurrences. Both recurrences showed decreased expression of CD44-4v and CD44-6v. CONCLUSIONS: Clear cell carcinoma of the ovary shows an abnormal pattern of CD44s expression and mRNA splicing when compared to the contralateral normal ovary in the same patient. Metastases of clear cell carcinoma show a downregulation in expression of some splice variants. Furthermore, we have data that suggest that as the tumors recur, CD44s and its isoforms are downregulated. Our results suggest that alternative mRNA splicing of CD44 may be important in the development of metastases from clear cell carcinoma of the ovary.

Fine-needle aspiration of the macrofollicular and microfollicular subtypes of the follicular variant of papillary carcinoma of the thyroid.

BACKGROUND: The follicular variant of papillary carcinoma of the thyroid (FVPCT) is being increasingly diagnosed on excised thyroid nodules. However, the fine-needle aspiration (FNA) and intraoperative diagnosis is often that of a follicular neoplasm, especially in papillary carcinomas with a pure or predominantly follicular pattern. The authors undertook this study in an attempt to refine the cytologic criteria for the diagnosis of FVPCT. METHODS: The authors reviewed 16 cases with cytologic diagnoses of FVPCT (9 cases), suspicious for FVPCT (6 cases), or cellular adenomatoid nodule (1 case) based on aspirates stained with Papanicolaou stain or a Giemsa-type stain (Diff-Quik). All cases had been confirmed histologically as pure or predominantly (>80%) FVPCT in 13 cases and as follicular adenoma in 3 cases. Cytologic features evaluated included cellularity, cell arrangement, nuclear features, cytoplasm, and colloid. RESULTS: Twelve of 13 cases of FVPCT were correctly diagnosed cytologically. Features that proved useful in the diagnosis of FVPCT were the concomitant and conspicuous presence of ovoid or pear-shaped nuclei with hypochromasia and nuclear grooves. Soft features included nuclear overlap and eccentric, small nucleoli. Cytoplasmic features were not useful in making this diagnosis. Based on cell arrangement and colloid, it was possible to predict microfollicular and macrofollicular variants. The microfollicular subtype showed rosettes or microfollicles and scant, thick colloid in casts and blobs. The macrofollicular subtype had predominantly sheets or spherules with abundant, thick background colloid. Nuclear pseudoinclusions and psammoma bodies were absent and multinucleated giant cells rarely found. Pitfalls leading to a "false-positive" FVPCT diagnosis included oncocytic adenoma (in 2 cases) and atypical adenoma (in 1 case). A cytologic diagnosis of cellular adenomatoid nodule was made in one case of macrofollicular FVPCT. CONCLUSIONS: The authors present improved cytologic criteria for the diagnosis of pure FVPCT on smears stained with Papanicolaou stain or Diff-Quik, and they elaborate on the clues and pitfalls associated with this diagnosis. The cytologic features of the macrofollicular and microfollicular subtypes of FVPCT are also described.

The role of ultrasonography-guided fine-needle aspiration biopsy in the management of nonpalpable and palpable thyroid nodules.

The introduction of highly sensitive imaging techniques has made it possible to detect many nonpalpable thyroid nodules (non-PTN). We investigated the value of ultrasound-guided fine-needle aspiration biopsy (US-guided FNAB) as a diagnostic tool in the management of non-PTN as well as palpable thyroid nodules (PTN) that were considered difficult to aspirate without guidance. US-guided FNAB was performed on a total of 119 nodules (71 palpable and 48 nonpalpable) from 119 patients between 1992 and 1996. All available clinical and follow-up data were reviewed. Surgical follow-up was available in 24 cases. The patients included 100 females and 19 males ranging in age from 9 to 81 years (average, 51 years). FNA diagnoses (PTN versus non-PTN) included papillary carcinoma (12.7% [9/71] versus 4.2% [2/48], follicular neoplasm (16.9% [12/71] versus 0%), medullary carcinoma (1.4% [1/71] versus 0%), atypical cytology (5.6% [4/71] versus 2.1% [1/48], non-neoplastic thyroid (63.4% [45/71] versus 85.4% [41/48]) and unsatisfactory (0% versus 8.3% [4/48]). In 2 cases of occult papillary carcinoma, risk factors included radiation exposure (1 case) and a newly developed nodule during follow-up for hypothyroidism (1 case). Subsequent surgical follow-up (24 cases) confirmed the FNA findings, except for a case of Hürthle cell adenoma and 1 of Hashimoto's thyroiditis diagnosed as papillary carcinoma and follicular neoplasm, respectively. US-guided FNAB in most non-PTN are diagnosed as benign. For most patients with non-PTN and without any high-risk factors, a conservative approach such as clinical follow-up may be a more cost effective and logical approach. In contrast, US-guided FNAB is more useful in diagnosing biologically significant lesions in PTN that may be difficult to aspirate without guidance.

Tolerance induction by intrathymic inoculation prevents chronic renal allograft rejection.

BACKGROUND: These experiments investigated the ability of the donor-specific unresponsiveness created by the intrathymic inoculation of donor alloantigen to effectively prevent chronic rejection in an established rat model of chronic renal allograft rejection. METHODS: Three study groups were examined: (1) Allograft controls--F-344 rats received a Lewis renal allograft plus 10 days of low-dose cyclosporine (CsA); (2) isograft controls--F-344 rats received an F-344 renal isograft and low-dose CsA; (3) experimental group--F-344 rats received a T-cell depleted syngeneic bone marrow transplant and intrathymic injection of Lewis bone marrow. Twenty-one days after bone marrow transplant, these animals received a Lewis renal allograft. RESULTS: Allograft controls demonstrated severe parenchymal fibrosis; isograft controls and intrathymic (IT) animals failed to develop this lesion. Immunohistochemical analysis revealed increased CD4+ T cells infiltrating the cortex of the allograft controls. Cytokine interferon-gamma and interleukin-2 transcripts were strongly positive in allograft controls and were absent from isograft controls and IT allografts as determined by reverse transcriptase-polymerase chain reaction. Analysis of tolerant grafts by flow microfluorimetry and genomic DNA amplification could not detect chimerism to a level of < 0.1%. CONCLUSION: IT inoculation of donor alloantigen can confer long-term unresponsiveness and prevent the development of the characteristic lesions of chronic rejection.

Induction of specific tolerance through mixed hematopoietic chimerism prevents chronic renal allograft rejection in a rat model.

BACKGROUND: Chronic rejection is the leading cause of late graft loss in kidney transplantation. We tested the ability of mixed hematopoietic chimerism to prevent chronic renal allograft rejection in an established rat model and described possible mechanisms responsible for this tolerance. METHODS: Mixed hematopoietic chimerism was established in lethally irradiated F-344 rats by reconstitution with Lewis bone marrow. Four groups (n = 5 each) received orthotopic kidney transplants: (1) allograft controls, (2) isograft controls, (3) experimental chimeras, and (4) specificity control. After 120 days kidney grafts were examined histologically, immunohistochemically, and for cytokine interferon-gamma, interleukin-2 (IL-2), IL-4, and IL-10 gene transcripts by means of reverse transcriptase polymerase chain reaction techniques. RESULTS: Allograft control group exhibited severe parenchymal fibrosis; isograft control and chimera groups failed to develop this lesion. Immunohistochemical analysis revealed increased CD8+ lymphocytes and ED-1+ monocyte-macrophages infiltrating the tubulointerstitium of control allografts. Interferon-gamma and IL-2 were absent in isografts. IL-4 was absent and IL-10 was positive in all grafts. Chimeras promptly rejected third-party allografts. CONCLUSIONS: Induction of specific tolerance through mixed hematopoietic chimerism prevents chronic renal allograft rejection. These results support the hypothesis of an immunologic basis of chronic rejection and advance previous observations that the induction of specific tolerance enables long-term solid organ transplantation without the use of immunosuppression.

Fine-needle aspiration cytology of ductal adenoma: report of a case associated with a mucocele-like lesion.

Ductal adenoma (DA) is an uncommon breast lesion that can histologically and clinically mimic carcinoma. We performed a fine-needle aspiration (FNA) of a DA. Cytologically, the lesion had features overlapping with those of mucinous carcinoma (MC), mucocele-like lesion, lactating adenoma (LA), and in retrospect with intraductal papilloma (IP). The smears were highly cellular and contained numerous monolayered sheets of ductal cells with prominent punched-out, small vacuoles distending the cytoplasm. The nuclei were mostly round to oval and had bland chromatin. Occasionally cells with enlarged nuclei and conspicuous nucleoli were present. The background showed large mucin pools, scattered single cells with mild nuclear atypia, some with apocrine metaplasia, rare stripped nuclei, and a fibrovascular stromal component. Calcifications were also present. We compare our cytologic findings with those of the lesions considered in the differential diagnosis. Due to its rare incidence and unusual features. DA may represent a diagnostic pitfall on FNA. Increased awareness of its cytologic appearance may help prevent a misdiagnosis.

Cells from ejaculatory ducts and seminal vesicles and diagnostic difficulties in prostatic aspirates.

In some smears from prostatic aspirates we have observed atypical epithelial cells similar to those of seminal vesicles; however, the site of aspiration was nowhere close to the seminal vesicles. We presumed those cells corresponded to ejaculatory duct epithelium. To confirm this assumption, we compared the cytology of seminal vesicles and ejaculatory ducts based on smears obtained from 10 autopsy cases. The aspects analyzed were types and arrangements of the cells, cytoplasmic and nuclear features, presence of pigment, and background of the smear. The only differences observed were the greater amounts of proteinaceous material in smears from seminal vesicles and the presence of transitional epithelial cells in smears from ejaculatory ducts. We would like to make pathologists aware of atypical cells from ejaculatory ducts as a source of diagnostic difficulties in prostatic aspirates. This subject has received no attention in the literature.

Human papilloma virus in uterine cervix: a comparison of detection by morphology and by dot-blot hybridization.

Colposcopically directed cervical biopsies, smears, and swabs obtained from 210 women with a previous abnormal cervical cytology were evaluated for the presence of human papilloma virus (HPV) using morphology and dot-blot hybridization. The diagnosis of HPV infection in biopsies and smears examined morphologically was rendered using established criteria for condyloma/cervical intraepithelial neoplasia (CIN). In hybridization studies, DNA was isolated from cells obtained from cervical swabs and annealed with probes that detected HPV types 6/11, 16/18, and 31/33/35 using a dot-blot procedure. Ninety-five cases demonstrated morphologic evidence of condyloma/CIN; 51 of these (54%) were positive for HPV DNA (five cases 6/11, 21 cases 6/18, 20 cases 31/33/35, and five cases two different probes). HPV DNA was also detected in 6 of the 115 cases (5.2%) that were morphologically negative (three cases 16/18, three cases 31/33/35). The results demonstrated that morphology was more sensitive than dot-blot hybridization for detection of HPV-related lesions. The dot-blot hybridization did detect HPV DNA in a small percentage of the cases that showed no morphologic abnormality and was useful for typing of the HPV. At this juncture, however, the clinical significance of the latter findings is unclear.

[Oncologic protocol for solid tumors of the upper aerodigestive tracts. Protocol for collection of computerized data]. / Protocolo oncológico para los tumores sólidos de las vías aerodigestivas superiores (VADS). Protocolo de captura de datos informatizados.

We present our method for treatment and follow up in patients with head and neck cancer. We have modified Laennec's Hospital Protocole (Paris), and afterwards we have developed a new computerized database system.

[A clinical study of cisplatin ototoxicity]. / Estudio clínico de la ototoxicidad del cisplatino.

To evaluate the ototoxicity of CDDP an audiological study was made to 18 patients, treated with this drug, for 4 cycles. The audiological test was made at the beginning of treatment, after the cycles and the end of it. The ototoxicity was found in 50% of the patients.

[Malignant non-Hodgkin's lymphoma in cervicofacial pathology]. / Linfomas malignos no hodgkinianos en patología cervicofacial.

114 non-Hodgkin's lymphomas (NHL) have been studied in HCU of Salamanca during a ten years period (1977-1987). Fifty seven of them had a head and neck location. According to this we divided this group of patients in primary or secondary sitting in relation to the head and neck affectation. We also distinguish which are the most frequently involved areas; lymph nodes and extranodal presentations, divided into Waldeyer's and no-Waldeyer's one. We present the clinical features and first affects symptoms. Histological materials was reviewed by a pathologist and a diagnosis aspect according to the working formulation of the National Cancer Institute for the NHL.