Chromogranin A expression in normal and malignant human tissues.

We used a recombinant cDNA probe for human chromogranin A to measure the expression of mRNA encoded by this gene in a variety of normal human tissues and tumor specimens using Northern blot and in situ hybridization analysis. With few exceptions, the expression of chromogranin A mRNA appears to be restricted to normal tissues and tumors of neuroendocrine lineage. However, we have detected mRNA expression of this gene in 1 of 14 cell lines and 2 of 13 tumor specimens of colon adenocarcinoma. The finding of chromogranin A expression in some colon carcinomas suggests that a previously unrecognized subgroup of these tumors has neuroendocrine features. The detection of this subgroup demonstrates the potential for improving tumor classification through the use of techniques and reagents developed by recombinant DNA technology.

Correlation of in vitro drug-sensitivity testing results with response to chemotherapy and survival in extensive-stage small cell lung cancer: a prospective clinical trial.

We devised a novel clinical protocol for extensive-stage small cell lung cancer (SCLC), selecting chemotherapy whenever possible on the basis of in vitro drug-sensitivity testing (DST) of individual patients' tumor specimens. Most of the specimens were obtained from metastatic sites during routine staging procedures. Increase of tumor cell number by culture in selective media usually was required before DST could be performed. We used the Weisenthal dye exclusion assay to place the seven drugs in rank order and to select the in vitro best regimen (IVBR), a three-drug combination of proved efficacy in SCLC. After initial staging and specimen acquisition, patients received etoposide and cisplatin (primary therapy) and were restaged after 12 weeks. Patients with partial or no responses and those relapsing after a complete response to primary therapy were switched to the IVBR if DST data were available. If DST data were unavailable, an empiric combination, vincristine-doxorubicin-cyclophosphamide, was administered as secondary therapy. Tumor-containing specimens were collected from 60 of the 80 patients (75%). One or more cell lines were established from 28 patients, and DST data were available from 26 patients (33% of total). Several parameters of in vitro drug sensitivity were significantly associated [two-sided P (P2) less than .05] with clinical response to primary therapy and also with response to the IVBR and were marginally associated with length of survival (.07 less than or equal to P2 less than or equal to .08). Sixteen patients (23%) received their IVBR as secondary therapy, and four of these (25%) attained a complete response, compared with three of 43 (7%) who received an empiric regimen (P2 = .16). We concluded that (a) selection of individualized chemotherapy is labor intensive but feasible in extensive-stage SCLC; (b) DST data are associated with clinical response to primary therapy and to secondary therapy with an IVBR; and (c) further observations will be required if we are to determine whether there is a modest therapeutic benefit to administering the IVBR as a secondary therapy.

Direct intralymphatic injection of radiolabeled 111In-T101 in patients with cutaneous T-cell lymphoma.

Direct intralymphatic administration of radiolabeled monoclonal antibody in targeting antigen-bearing lymphoma cells in regional lymph nodes of patients with cutaneous T-cell lymphoma was evaluated. Seven consecutive patients undergoing staging lymphangiography received intralymphatic infusions of 111In-T101 to evaluate lymph node involvement. This procedure was accomplished without significant complication. The 111In-T101 rapidly distributed throughout the regional lymphatic compartment and passed into the systemic circulation. Tumor-bearing sites in the inguinal-femoral lymph nodes retained from 0.42 to 4.8% of the injected dose of radiolabeled antibody. Three patients were upstaged to Stage IVA based on tumor involvement found after radiolymphoscintigraphy-directed biopsy of groin lymph nodes, selected because of intense radioactivity by gamma camera imaging. Compared with previously reported s.c. antibody administration, there was a marked reduction in the radioactive exposure of normal tissues at the injection sites in the lower extremities. Direct intralymphatic delivery of 111In-T101 appears to be a feasible, efficient method for delivering therapeutic doses of radiolabeled antibody.

Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sézary syndrome.

PURPOSE: This phase II study was undertaken to assess the efficacy and toxicity of alternating administration of pentostatin (deoxycoformycin [DCF]) and interferon alfa-2a (IFN) in patients with advanced or refractory mycosis fungoides (MF) or the Sézary syndrome (SS). PATIENTS AND METHODS: Forty-one patients underwent therapy with alternating cycles of DCF 4 mg/m2 intravenously (IV) days 1 through 3 and IFN 10 million U/m2 intramuscularly (IM) day 22, and 50 million U/m2 intramuscularly (IM) days 23 through 26. Twenty-nine patients had not responded to prior chemotherapy or total-skin electron-beam irradiation (TSEB), six had not responded to topical therapies, and six had no previous treatment. RESULTS: Two patients achieved a complete response (CR) and 15 achieved a partial response (PR), for an overall response rate of 41% (95% confidence interval, 26% to 58%). No responses were observed in the seven patients with visceral involvement. The median progression-free survival of patients who responded was 13.1 months. IFN-related constitutional symptoms were reported in 39% of patients; severe toxicities included cardiomyopathy in one patient, acute and chronic pulmonary dysfunction in four, and reversible mental status changes in two. Seven patients developed herpes zoster during therapy and six had staphylococcal bacteremia. CONCLUSION: These results suggest that the combination of DCF and IFN is an active regimen in MF patients without visceral involvement.

Phase II trial of fludarabine phosphate and interferon alfa-2a in advanced mycosis fungoides/Sézary syndrome.

PURPOSE: This phase II study was undertaken to assess the efficacy and toxicity of the addition of continuous low-dose interferon alfa-2a (IFN) to fludarabine in patients with advanced or refractory mycosis fungoides (MF) or the Sézary syndrome (SS). PATIENTS AND METHODS: Thirty-five patients were treated with fludarabine 25 mg/m2 intravenously (IV) on days 1 to 5 every 28 days along with IFN 5 x 10(6) U/m2 subcutaneously three times per week continuously for up to eight cycles. IFN doses were escalated to 7.5 x 10(6)/m2 at day 29 if constitutional toxicities were less than grade 3. Twenty-one patients had not responded to prior chemotherapy or total-skin electron-beam irradiation (TSEB), and 10 of these had received prior deoxycoformycin (pentostatin; DCF) and intermittent high-dose IFN; seven had received only topical therapies, and seven were untreated. RESULTS: Four patients achieved a complete response (CR) and 14 achieved a partial response (PR) for an overall response rate of 51% (95% confidence interval, 35% to 70%). Four of 11 patients with visceral involvement responded. The median progression-free survival duration of the patients who responded was 5.9 months, and three of the complete responders are in unmaintained response after 18 to 35 months. Grade 3 or 4 hematologic toxicity occurred in 21 patients, including two who developed persistent bone marrow aplasia. Eighteen patients developed infections during therapy, including five with herpes zoster, one with Pneumocystis carinii, one with extrapulmonary tuberculosis, and two with disseminated toxoplasmosis. CONCLUSION: The combination of fludarabine with continuous low-dose IFN is an active regimen in patients with advanced MF/SS, including patients with visceral involvement and patients who progressed after prior therapy with DCF and IFN. This regimen has induced unmaintained remissions in a small subset of patients.

Selective calcification of pancreatic islets of Langerhans. An unusual association with hypercalcemia and diabetes mellitus.

An unusual and extensive calcification of islets of Langerhans was found at autopsy in a man, 58 years old, who developed myeloma and, subsequently, hypercalcemia and diabetes. Although the islet cell calcification appears to be related to the hypercalcemia, the pathogenesis of the calcification is not clear, as primary metastatic calcification of pancreatic islets due to hypercalcemia does not occur. In support of this, a retrospective study of pancreatic tissue from 52 hypercalcemic patients with parathyroid adenoma and 34 patients with multiple myeloma, who frequently have hypercalcemia, did not reveal islet calcification. The islet calcification is ascribed to primary islet cell degeneration and necrosis, with hypercalcemia playing an augmenting but crucial role. It is considered that the combination of islet degeneration and calcification resulted in the diabetic state.

Allosensitization in patients receiving multiple blood transfusions.

Extended antigen (C, E, K) matching decreased the incidence of alloantibody (alloAB) and autoantibody (autoAB) formation, in addition to eliminating transfusion reactions in the multiply transfused sickle cell disease patients. AlloAB formation possibly transforms the immune system into a hyperactive state leading to further and earlier alloAB and autoAB formation. However, additional CEK matching results in marked overuse of Rh-negative packed red blood cell (pRBC) units, 30 minutes' extra time of a skilled technologist, and 153 dollars extra CEK reagent cost per unit to find CEK-matched pRBCs for every transfusion for these multiply transfused patients.

Clinical aspects of expression of inversion 16 chromosomal fusion transcript CBFB/MYH11 in acute myelogenous leukemia subtype M1 with abnormal bone marrow eosinophilia.

The pericentric inversion of chromosome 16 (inv(16)(p12q22)) is a characteristic karyotypic abnormality associated with acute myeloid leukemia, most commonly of the M4Eo subtype. It is increasingly appreciated as both a favorable prognostic factor and important guide to therapy. The breakpoints of the inversion have been cloned and a fusion transcript can be identified by RT-PCR. We expand upon our prior abstract of a case of AML subtype M1 with abnormal eosinophils that expressed the inversion 16 fusion transcript CBFB/MYH11. During remission, the transcript could not be detected. The patient relapsed twice during the first year after attaining a complete remission. Morphologically, the relapsed specimens were identical to the appearance of his diagnostic specimen. However, the CBFB/MYH11 fusion transcript was not detected in the relapsed specimen. We conclude that CBFB/MYH11 fusion transcript detection, as a surrogate for the favorable prognosis and treatment planning implied by inv(16) in AML M4Eo, should not be exclusively relied upon in AML M1 in the absence of prospective study of this specific (M1) category of AML. RT-PCR analysis should be correlated with cytogenetics when available and if used alone should be interpreted cautiously in cases of AML with atypical morphological features.

Low-grade astrocytomas: treatment results and prognostic variables.

Low-grade astrocytomas in adults are uncommon malignant neoplasms of the central nervous system which are fatal in the great majority of patients despite a lack of aggressive histologic features. Several series of such patients have been previously reported, but prognostic factors have not been fully identified. Between 1960 and 1986, 50 patients with low-grade astrocytomas have been treated with megavoltage radiation at the Naval Hospital, Bethesda, MD, following surgical biopsy or excision. Overall actuarial survival at 10 years for the entire treated group was 32%, similar to other series. The most significant prognostic factor was patient age, with decreasing survival for each age decade and a highly significant difference in survival between patients less than age 40 compared to older patients (p = .0017). The era of treatment (before or after 1978) was also an important prognostic indicator (p = .057), largely due to an effect of dose, although better tumor localization in the CT era may also have played a role. There was a trend toward increasing survival with increasing dose of radiation, although not reaching statistical significance at the p = .05 level on multivariate analysis. Patient sex, extent of surgical resection, use of whole brain irradiation, and tumor grade did not significantly affect survival. In comparison, in a separate group of 10 patients who received surgery without radiation during the same period, all patients who were completely resected were long-term survivors, whereas none of those with incomplete resections survived longer than 6 years.

Inflammatory pseudotumor of the spleen.

Two examples of an unusual splenic inflammatory pseudotumor are reported. Splenectomy followed detection of a mass lesion by CT scan in one case, and in the other, the pseudotumor was an unexpected and incidental pathologic finding. Despite the alarming gross appearance of these lesions, microscopic features were unequivocally inflammatory and benign. To our knowledge, this entity has not been described previously in the spleen.

Chronic lymphocytic leukemia with coexistent Hodgkin's disease. Implications for the origin of the Reed-Sternberg cell.

The association of chronic lymphocytic leukemia (CLL) and Hodgkin's disease has been controversial. Pleomorphic lymphoreticular cells resembling Reed-Sternberg cells have been observed in Richter's syndrome. Although most observers have favored the view that these cells are a component of a pleomorphic non-Hodgkin's lymphoma, some cases of histologically typical Hodgkin's disease have been described. We have studied two cases that appear to represent composite CLL and Hodgkin's disease, providing evidence for an interrelationship of these two disorders. Classic Reed-Sternberg cells and variants (RS-H) were seen in a background that was otherwise typical of CLL. Both patients initially presented with characteristic findings of CLL in the peripheral blood and bone marrow. The first patient was found to have RS-H cells within lymph nodes at initial presentation, and ultimately progressed to develop a disseminated lymphoma characteristic of Hodgkin's disease. In the second patient, RS-H cells were not discovered until 5 years later. Immunophenotypic studies confirmed these morphologic impressions. The predominant lymphocyte population had a phenotype consistent with B-cell CLL. By contrast, the RS-H cells were strongly positive for CD15 (Leu M1) with staining of the Golgi region and cell membrane. Additionally, the RS-H cells were surrounded by rosettes of lymphocytes that marked as T cells. In both of the patients, a small percentage of RS-H cells expressed positivity for the B-cell marker L-26, which may indicate an origin from the underlying CLL. These findings support a B-cell origin for the malignant cell in some cases of Hodgkin's disease and suggest that Hodgkin's disease in some patients may be related to or derived from a coexisting lymphoid malignancy.

T-cell lymphoblastic lymphoma with eosinophilia associated with subsequent myeloid malignancy.

Three patients with T-cell lymphoblastic lymphoma and peripheral blood eosinophilia are reported. At the time of diagnosis, all patients had lymphadenopathy, and one had a mediastinal mass. Lymph node biopsies revealed lymphoblastic lymphoma admixed with a variable number of mature eosinophils. Immunophenotypic studies demonstrated that each lymphoma had an immature T-cell immunophenotype. Bone marrow biopsies were hypercellular with myeloid hyperplasia and eosinophilia but were negative for lymphoma. All patients received multiagent chemotherapy; one patient achieved a complete remission, and two patients had partial remissions. All patients subsequently developed a myeloid malignancy. Two died of acute myeloid leukemia within 18 months of the diagnosis of lymphoblastic lymphoma. The third patient relapsed with a lymphoma that had histologic and immunophenotypic features of both T-cell lymphoblastic lymphoma and granulocytic sarcoma and also developed a poorly defined myeloproliferative disorder. These findings suggest that T-cell lymphoblastic lymphoma associated with eosinophilia may represent a distinct clinico-pathologic entity with a high risk of subsequent myeloid neoplasia.

Hepatolienal fusion: case report of an unusual lesion.

A unique fusion of liver and spleen was observed at autopsy between a tongue of hepatic parenchyma and the superolateral aspect of the spleen in an adult Caucasian male. No instance of hepatolineal fusion was found in the literature, prompting this report. An embryologic explanation is offered.

Bone marrow involvement in large-cell lymphoma. Prognostic implications of discordant disease.

Discordant lymphomas are those in which two different histologic subtypes of non-Hodgkin's lymphoma are present simultaneously in the same patient at two or more separate disease sites. Discordance usually involves a lower grade follicular lymphoma in one anatomic site and a higher grade diffuse lesion elsewhere. A common type of discordance is seen in patients with a primary diagnosis of diffuse large-cell lymphoma (DLCL) who demonstrate bone marrow involvement by a lower grade lesion, such as a small cleaved cell or mixed small cleaved and large cell lymphoma. This study was undertaken to assess retrospectively the clinical implications of such bone marrow involvement, as well as the possible biologic mechanisms. Of the 59 DLCL cases studied, 20 (33.9%) showed evidence of bone marrow involvement, 14 of which were discordant (70%). The most significant findings included the following: Overall treatment responses and survivals in discordant patients with predominantly small cleaved cells in the marrow were similar to those in patients with no marrow involvement (mean survivals, 47.7 and 49 months, respectively), and were significantly longer than in patients with concordant marrow involvement (mean survival, 13.1 months, P < .05). Patients with discordant marrow infiltrates composed of a mixed cell population tended to do as poorly as those with concordant involvement. No clear-cut pattern of relapse in discordant patients was found, but persistence of small cleaved cells in some was reminiscent of lower grade B-cell lesions. Other features associated with lower grade lesions included older age, less incidence of central nervous system involvement, and lesser extent and proportion of marrow infiltration. Finally, in approximately half the cases with discordant involvement, lymphoma was present unilaterally, emphasizing the need to perform bilateral biopsies for staging.

Neuroendocrine differentiation in endocrine and nonendocrine lung carcinomas.

Bronchial carcinoids and small cell lung cancer (SCLC) are currently recognized as neuroendocrine (NE) neoplasms. However, non-SCLC (NSCLC) may also express NE properties. Paraffin-embedded sections of a comprehensive panel of 113 lung carcinomas were analyzed for the expression of three general markers common to all NE cells, namely, chromogranin A, Leu-7 and neuron-specific enolase (NSE), five specific NE secretory products, and four other tumor markers by immunohistochemistry using the sensitive avidin-biotinylated peroxidase technique. The authors were able to demonstrate the following: (1) most, but not all carcinoids and SCLCs expressed multiple NE markers in a high percentage of tumor cells; (2) up to a half of NSCLC cases contained small subpopulations of cells expressing NE in a high percentage of tumor cells; (2) up to half of NSCLC cases contained small subpopulations of cells expressing NE markers; and (3) occasional NSCLCs showed staining patterns indistinguishable from SCLC. Specifically, 7 of 77 NSCLCs expressed four or more NE markers. NE markers in NSCLCs were more commonly expressed in adenocarcinomas and large cell carcinomas and rarely in squamous cell carcinomas. For comparison, the mean number of NE markers expressed by all cases of NSCLC was 1.5, carcinoids 6.0, and SCLCs 3.8. Individual "marker counts" were not useful in categorizing lung tumors as carcinoids and SCLC versus NSCLC. Instead, 95% of the tumors were correctly classified, applying a statistical model created from staining indices of the three general NE markers (chromogranin A, Leu-7, NSE) and three other tumor markers (carcinoembryonic antigen, keratin, vimentin). Because NSCLCs with NE features might have different clinical characteristics than other NSCLCs, immunohistochemistry provides an effective manner to identify this biologically interesting subset of NSCLCs in routine paraffin sections.

Acute erythroleukemia: evaluation of 48 cases with reference to classification, cell proliferation, cytogenetics, and prognosis.

We evaluated 48 archival cases of acute erythroleukemia and divided them into 3 groups: M6a, corresponding to the traditional French-American-British M6 category; M6b, which is pure erythroleukemia; and M6c, in which myeloblasts and pronormoblasts each account for more than 30% of cells by the French-American-British exclusion criteria. No significant differences were noted among the subtypes for ratio of males to females; age; or exposure to toxins, alcohol, or both. However, compared with the patients in the M6a group, patients in the M6b and M6c groups demonstrated a statistically significant increase in cytogenetic aberrations, proliferation markers (proliferating cell nuclear antigen and Ki67), and ringed (type III) sideroblasts. Marked survival differences were noted between the M6a (30.1 +/- 29.5 months) and M6b (3.15 +/- 4.2 months) groups, with patients in the M6c group demonstrating an intermediate prognosis (10.5 +/- 12.7 months). Chemotherapeutic regimens induced remission in all treated patients in the M6a and M6c groups but did not appear to affect the M6b group. However, the patients in the M6c group remained in remission for a significantly shorter period of time than did patients in the M6a group. Overall, survival appeared to depend on the ratio of pronormoblasts to myeloblasts at diagnosis and demonstrated a rapid decline with increasing pronormoblast and decreasing myeloblast counts. We must, therefore, devise chemotherapeutic regimens that target both blastic components of this disease.

Unusual metastasis to the cauda equina: case report.

A case of intradural metastasis from endometrial carcinoma to the cauda equina is presented. The clinical presentation and radiographic findings were misleading and suggested a herniated nucleus pulposus. Findings at operation were most suggestive of an ependymoma, but final pathological diagnosis revealed endometrial carcinoma. This has never been reported. Once again it demonstrates that surgeons managing lumbar disc disease must be prepared for possible intradural exploration with an appropriate team.

Myeloma cells in the urine.

We report two unusual manifestations of multiple myeloma in a 71-year-old man. Late in the course of his disease, myeloma cells were observed in the patient's urinary sediment. At post mortem, the source of the cells was found to be a plasmacytoma of the urinary bladder. To our knowledge, this appears to be the first report of a clearly demonstrable anatomic source for myeloma cells in the urine.

Inverted papilloma of the urinary bladder with granular eosinophilic cells. An unusual neuroendocrine variant.

We report the morphologic, immunohistochemical, and electron microscopic characteristics observed in a case of an inverted papilloma that contained neuroendocrine cells resected from the urinary bladder of a 77-year-old woman. Additionally, we evaluated the incidence of neuroendocrine cells in eight cases of inverted papillomas of the urinary bladder obtained from the files of the Armed Forces Institute of Pathology, Washington, DC. To our knowledge, an in-depth study of neuroendocrine cells in this neoplasm and a comparison of the same with neuroendocrine cells observed in other conditions in the lower genitourinary tract have not been previously published, prompting this report.

Whole-body pathologic analysis of a patient with Thorotrast-induced myelodysplasia.

An autopsy was performed on a 72-y-old Caucasian female who had received a carotid artery injection of thorium dioxide in 1953. The body was dissected in such a manner as to provide for radiobiological evaluation as well as to determine histologically the distribution of Thorotrast in the tissues and its complications. Thorotrast was identified within the liver, spleen, lymph nodes, bone marrow, and surrounding the right carotid artery (the injection site). The cause of death was gastric hemorrhage complicating pancytopenia secondary to refractory anemia with excess of blasts (myelodysplastic syndrome).