Charles L. Hitchcock

Merkel cell carcinoma: Analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival

BACKGROUND Merkel cell carcinoma (MCC) is an uncommon malignancy of the skin and has a high rate of recurrence and metastasis. There have been few large studies of the biologic behavior of MCC. OBJECTIVE Our purpose was to determine whether there were clinical or histologic features of MCC that predict its biologic behavior. METHODS We reviewed 132 cases of MCC. Clinical and histologic features were correlated with follow-up information to determine whether any of these were associated with prognosis. RESULTS Clinical information was available on 126 patients; 57 were alive, 1 was alive with tumor, 28 died of tumor, 27 died from other causes, and 14 were lost to follow-up. MCC on the buttock/thigh area or trunk had the worst prognosis, and those on the distal extremities had the best prognosis; however, the difference was not statistically significant. Sex and age were not significant factors. Small cell size, high mitotic rate, and large tumor size were associated with a low survival rate. When cell size was excluded, male sex and depth of invasion were associated with a worse survival, although these were not statistically significant. CONCLUSION Cell size, mitotic rate, and tumor size are significant factors in relation to the biologic behavior of MCC.

Metastasizing mixed tumor of salivary glands. A clinicopathologic and flow cytometric analysis

Among salivary gland neoplasms are a group of rare tumors that are histologically identical to benign mixed tumors that inexplicably metastasize; they have been called metastasizing mixed tumor (MZMT) of salivary glands. We report the clinicopathologic features and flow cytometric findings for 11 cases of MZMT. At the time of discovery of metastatic disease, the patients, six women and five men, ranged in age from 20 to 83 years. Primary sites of involvement included the parotid gland (eight cases), submandibular gland (two cases), and the nasal septum (one case). With one exception, all the patients had at least a single recurrence of their primary mixed tumor, but two or more recurrences were the norm before development of metastatic foci. The metastases were discovered from six to 52 years following the occurrence of the primary tumor. Metastatic deposits were identified in bone, lung, regional lymph nodes, skin, kidney, retroperitoneum, oral cavity, pharynx, calvarium, and central nervous system. The metastases either occurred simultaneously with an episode of recurrent mixed tumor (n=5) or from 5 to 29 years after a recurrence (n=6). The treatment of the primary, recurrent, and metastatic neoplasms was surgical excision. Follow-up, ranging from 8 months to 16 years following the diagnosis of MZMT, revealed seven patients to be alive without disease (64%) and two dead of causes unrelated to metastatic disease (18%). Two patients (18%) died as a direct result of metastatic tumor at 3 and 2 years after metastasis of their mixed tumors. Flow cytometric analysis revealed a diploid DNA cell population in the primary and/or metastatic tumors in nine cases. Aneuploid DNA cell content was identified in two of the cases. DNA ploidy levels and cell proliferation rates were compared with those of conventional benign mixed tumors and also with malignant mixed tumors. Retrospective analysis of histologic parameters (mitotic rate, cellular pleomorphism, infiltrative growth, vascular or lymphatic invasion) and flow cytometric analysis failed to identify criteria to predict the development of metastasis in these neoplasms.

Melanotic neuroectodermal tumor of infancy. Clinicopathological, immunohistochemical, and flow cytometric study.

Twenty cases of melanotic neuroectodermal tumor of infancy (MNTI) are reported. The patients (13 females, seven males), whose ages ranged from 1 to 9 months (mean, 5 months), typically presented with a rapidly growing mass. Tumor sites included the maxilla (13 cases), mandible (three cases), dura (two cases), brain (one case), and skull/orbit (one case). The mean tumor size was 3.5 cm (range, 1.0-10.0 cm). Follow-up was obtained on 12 cases. Five tumors (45%) recurred within 4 months of diagnosis, but none metastasized. One surgical death occurred Histologic appearance was distinctive, with tubular or alveolar formations of large melanin-containing cells around nests of smaller neuroblastic cells possessing scant or fibrillar cytoplasm. Twelve tumors were studied immunohistochemically; tumor was positive for cytokeratin in 12 of 12, for HMB 45 in 12 of 12, for vimentin in seven of eight, and for epithelial membrane antigen (EMA) in four of nine tumors, mainly in the large cells. Neuron-specific enolase (NSE) (seven of 12) and Leu 7 (nine of 12) were positive in small and large cells; some tumors also expressed synaptophysin (four of 12), glial fibrillary acidic protein (GFAP, three of 12 tumors), or S-100 protein (two of 12 tumors). No staining was found for chromogranin, desmin, or carcinoembryonic antigen (CEA). Eight of 10 tumors studied had interpretable results on flow cytometry (FCM) (four DNA diploid, three DNA aneuploid, and one DNA diploid with a prominent shoulder). Tumor recurred locally in two of five cases with follow-up, and we were unable to demonstrate the usefulness of FCM in predicting recurrences. Further studies are necessary to define better the potential usefulness of FCM in predicting aggressive behavior. Distinctive morphology and multiphenotypic (epithelial, neural, melanocytic) expression distinguish MNTI from melanoma and metastatic neuroblastoma

Hepatoblastoma: the prognostic significance of histologic type.

The clinicopathologic features of 105 hepatoblastomas accessioned to the Armed Forces Institute of Pathology between 1967 and 1987 were reviewed. DNA content was analyzed by flow cytometry. A multivariate analysis using the Cox proportional hazards model was performed to evaluate the effect of stage, histologic type, and DNA content on the prognosis for survival. The relative risks of death for a given stage compared to the other stages combined were 0.1637, 0.5672, 2.8742, and 3.5148 for stages I-IV, respectively. The relative risk of death for a given histologic type adjusted for age, sex, and stage compared to the other types was 1.0739 (p = .8850) for the fetal pattern, 1.7409 (p = .1662) for the embryonal pattern, 0.5292 (p = .0754) for the mixed pattern, 1.1980 (p = .7729) for the macrotrabecular pattern, and 3.7096 (p = .1061) for the small-cell undifferentiated pattern. Of 19 hepatoblastomas analyzed for DNA content, 5 were DNA diploid and 11 were DNA aneuploid; 3 could not be classified. The stage of disease at presentation proved to be a significant prognostic factor, whereas histologic type and DNA content did not have a significant effect.

Diagnostic considerations in molar gestations

Hydatidiform moles (HMs) are classified as partial or complete based on a combination of gross, histologic, and karyotypic features. Adherence to strict and reproducible diagnostic criteria is needed to ensure accurate diagnosis and minimize interpathologist variability. Using the kappa statistic as a measure of agreement, the morphologic, flow cytometric, and clinical features of 80 cases of HM or suspected HM were analyzed sequentially by three pathologists to evaluate intrapathologist and interpathologist variability. Poor interpathologist agreement was obtained when histology alone was used for diagnosis. The combination of gross morphology and histology resulted in poor to good agreement. Good interpathologist agreement was obtained, however, when objective data (DNA content determined by flow cytometry) were included in the analysis. Our data indicate that pathologist concordance is maximized when the diagnosis is based on a combination of morphology and DNA content.

Flow cytometric analysis of granulosa tumors

Paraffin blocks from 17 granulosa tumors, nonmetastatic (n = 10) and metastatic (n = 7), were analyzed by flow cytometry. Three neoplasms, one with and two without metastases, were found to have cells with an abnormal DNA (DNA aneuploid) content. The occurrence or absence of DNA aneuploid cells did not predict behavior. In addition, there was no correlation of tumor DNA content with tumor size or patient age at the time of surgery. There was no significant difference in cell proliferation (%S + %G2/M) between metastatic and nonmetastatic DNA diploid tumors, however, there was an increase in cell proliferation in tumors with a DNA aneuploid stemline. Granulosa tumors are low‐grade neoplasms. At least 90% are seen in Stage I, and metastasis occurs subsequently in 5% to 15% of these cases. Features of Stage I neoplasms associated with subsequent metastasis in some reports, but not all, are involvement of the capsule (Stage IC), large size, and high mitotic rate.1–5 Providing definitive statements about the behavior of granulosa tumors is hampered by their rarity, the subjectivity of the diagnosis, and their sluggish behavior. We attempted to determine if flow cytometric analysis of DNA could identify granulosa tumors with metastatic potential. We compared DNA histograms from ten Stage IA granulosa tumors that did not metastasize during 22 to 47 years of follow‐up with seven granulosa tumors that showed malignant behavior.

DNA flow cytometric analysis of serous ovarian tumors of low malignant potential

Background. Ovarian serous tumors of low malignant potential (STLMP) occasionally progress; a small percentage of patients die of the tumor. There is no known way to predict which tumors will progress.

Flow Cytometric and Quantitative Histological Parameters to Predict Occult Disease in Clinical Stage I Nonseminomatous Testicular Germ Cell Tumors

The goal of this study was to determine if deoxyribonucleic acid (DNA) flow cytometric and quantitative histological parameters could predict occult metastases in clinical stage I nonseminomatous testicular cancer. Archival paraffin primary tumor tissue was available from 36 clinical stage I nonseminomatous germ cell testicular cancer patients who all had retroperitoneal lymphadenectomy and followup defining 2 groups: pathological stage I (23) and occult pathological stage II (13). Archival blocks were microdissected and individual histological components were subjected to flow cytometry. In addition, the primary histology was reevaluated for vascular invasion and per cent composition of histological components of embryonal carcinoma and other histologies. For flow cytometry parameters, no tumor was uniformly diploid, and the DNA index and per cent S phase cells were not useful in differentiating stages. Although mean per cent S phase for the aneuploid cell population and proliferative index were significantly greater for stage II cases by univariate logistic regression analysis, they are approximately 70% accurate in predicting occult disease as single tests and were not significant by multivariate analysis. The calculation of per cent embryonal carcinoma was also significantly greater in stage II cancer by univariate logistic regression testing and remained significant by multivariate analysis. Vascular invasion was marginally predictive of occult disease but was also not significant by multivariate analysis. Calculating the percentage of embryonal carcinoma of a primary testicular tumor may be a useful method to assess clinical stage I cancer patients for risk of occult disease. A larger study is needed to confirm the importance of per cent embryonal carcinoma and to clarify further if flow cytometry in combination is useful.

DNA Analysis of cardiac myxomas: Flow cytometry and image analysis

Cardiac myxoma is the most common primary tumor of heart, but there is a longstanding controversy over whether it is a true neoplasm or a reactive lesion. We analyzed 24 cardiac myxomas from 22 patients: 22 by DNA flow cytometry and five by image analysis. Two myxomas were aneuploid; one of those analyzed by flow cytometry, and the other by image analysis. Proliferative fractions (S + G2/M) were high in three tumors from patients with multiple myxomas (mean, 15.9%; SD, 4.0%) as compared with 12 solitary uncomplicated myxomas (mean, 7.7%; SD, 6.0%). S-phase and proliferative fractions were low in embolic, recurrent, and solitary myxomas. The presence of aneuploidy in some myxomas supports a neoplastic origin for this tumor.