Jan Hastka

Hepatoid Adenocarcinoma – Review of the Literature Illustrated by a Rare Case Originating in the Peritoneal Cavity

Hepatoid adenocarcinoma (HAC) is a rare and aggressive extrahepatic tumour, morphologically mimicking hepatocellular carcinoma (HCC). However, immunophenotype and location are heterogeneous. We report the case of a 21-year-old man with HAC of the peritoneal cavity and summarize data from the 261 HAC cases published so far. The most common HAC locations were stomach (63%), ovaries (10%), lung (5%), gallbladder (4%), pancreas (4%), and uterus (4%). With the exception of gallbladder HAC, there was a male predominance (M:F = 2.4:1). Median age was 65 years (range 21–88). Fatigue, weight loss, abdominal masses, and pain were common findings. One-year survival was 55% and median overall survival 11 months (range 0.1–102). The outstanding diagnostic feature of HAC is positivity for alphafetoprotein (AFP) (88%), HepPar1 (63%), and EpCAM antibodies HEA125 or MOC31 which show no reactivity with hepatocytes. Due to the beneficial effect of sorafenib in HCC and strong activation of EGFR, ERK1 and AKT1, our patient received sorafenib. Despite temporary clinical improvement, he died 6 months after the diagnosis. The diagnostic panel of HAC should include AFP, HepPar1, and EpCAM antibodies. EpCAM reactivity excludes HCC. HAC has a poor prognosis.

Soluble transferrin receptor and zinc protoporphyrin – competitors or efficient partners?

Abstract:  Objectives: Soluble transferrin receptor (sTfR) and zinc protoporphyrin (ZPP) are both parameters of iron deficient erythropoiesis (IDE), the sTfR measurement is commonly regarded to be the more sensitive test. sTfR also reflects erythropoietic activity, it is increased in enhanced erythropoiesis. Methods: We investigated the diagnostic accuracy of sTfR in assessment of iron deficiency (ID) and compared it with ZPP. The study was performed on 174 subjects, in which ID has been precisely staged. Results: Individuals without ID and patients with storage iron depletion only, had normal sTfR values. Patients classified as IDE and patients with iron deficiency anemia had significantly increased sTfR. There was a good correlation between sTfR and hemoglobin (r = −0.86; P < 0.0001) and between sTfR and ZPP (r = 0.86; P < 0.0001). When diagnosing ID, ZPP was the more sensitive test. In mildly developed IDE associated with ZPP‐ratios between 40 and 70 μmol/mol heme, the sTfR concentration was elevated in only 25% of the cases. Reliably elevated sTfR values were observed only in more advanced IDE, associated with ZPP > 70 μmol/mol heme. Conclusions: ZPP is not inferior to sTfR when diagnosing IDE. Given the good correlation between sTfR and ZPP and because ZPP is uninfluenced by the erythropoietic activity, sTfR and ZPP are not competitors, rather efficient partners in diagnosing anemias. By measuring ZPP and sTfR simultaneously, the diagnostic uncertainty inherent in each of them individually can be eliminated. In particular, the simultaneous determination of ZPP and sTfR enhances the diagnostic power of sTfR in assessment of the erythropoietic activity.

Diagnostic accuracy of cytology and immunocytology in carcinomatous effusions

Background:  Immunocytology substantially improves the diagnostic accuracy of conventional cytology in the diagnosis of carcinomatous effusions. Due to the unequivocal characterization of the various cell populations, a sensitivity of 92% and specificity of 100% was achieved by immunocytology, examining samples of 1234 serous effusions.

bcl‐2 expression in non‐Hodgkin's lymphomas is not associated with bcl‐2 gene rearrangements

Previous reports have associated bcl‐2 gene rearrangements found in non‐Hodgkins lymphomas with an inappropriately elevated bcl‐2 expression compared with the mature B‐cell stage of development. This study investigates bcl‐2 expression in non‐Hodgkins lymphomas (NHL) without bcl‐2 gene rearrangements. Molecular analysis in 168 patients with NHL revealed 45 patients without bcl‐2 gene rearrangements in which additional immunostaining for bcl‐2 protein was possible. An unexpectedly high prevalence (39/45) of bcl‐2 expression was found. The levels and patterns of bcl‐2 expression were not specific for the histological type of NHL and were similar to those shown in comparable cases with bcl‐2 gene rearrangements. In conclusion, bcl‐2 expression is not specific for NHL bearing bcl‐2 gene rearrangements. This finding implicates the existence of other deregulating control mechanisms of bcl‐2 expression, more important than bcl‐2 gene rearrangements.

The importance of granulocyte elastase in haematological diagnosis

SummaryPMN elastase is a useful additional parameter in the differential diagnosis of the leukaemias. In all patients with myelocytic leukaemias there were elevated levels of elastase-α1-proteinase inhibitor (E-α1PI), while in the lymphatic leukaemias complexed elastase levels were decreased. The highest values were found in the peripheral blood plasma and bone marrow plasma of patients with CML. Despite high E-α1PI concentrations there were no signs of bleeding or consumption of plasmatic coagulation factors. In AML a wide range of E-α1PI levels was observed, extending from slightly elevated to four hundred-fold increased. In myeloblastic leukaemias without maturation (FAB M1) the concentrations of complexed elastase remained below 150 ng/ml. In myeloblastic leukaemias with maturation (FAB M2) the E-α1PI values ranged between 214 ng/ml and 850 ng/ml (x= 402 ± 69), and in myelo-monoblastic leukaemias (FAB M4) between 450 ng/ml and 720 ng/ml (x = 663 ± 72). The only case of promyelocytic leukaemia (FAB M3) exhibited an extremely high value of 4,550 ng/ml, while a monocytic leukaemia (FAB M5) showed an extremely low value of 5 ng/ml. During cytostatic therapy there was a rapid decrease in levels of complexed elastase, with E-α1PI values returning to normal in remission. In recidivating cases there was an increase of E-α1PI levels in AML and a decrease in ALL. There was a correlation between the E-α1PI concentrations in peripheral plasma and leukaemic bone marrow infiltration, so providing a good basis for monitoring remission from leukaemia and indicating relapse. It was also interesting to observe an extremely low E-α1PI level (5 ng/ml) in patients with myelodysplasia. Under Decortin/Plenastril therapy the concentration rose to 50 ng/ml. An E-α1PI level of 10 ng per ml was observed in one case of Ranitidine agranulocytosis. Under corticoid therapy the value returned to normal within eight days.

The soluble transferrin receptor (TfR)-F-Index is not applicable as a test for iron status in patients with chronic lymphocytic leukemia

Abstract Background: The soluble transferrin receptor (sTfR) is established as a test for iron deficiency (ID). In chronic lymphocytic leukemia (CLL), sTfR is not reliable for screening for ID as the latter is strongly dependent on tumor burden. Methods: We investigated whether the influence of the tumor load can be excluded or minimized using the sTfR/log ferritin ratio (TfR-F-Index) and the C-reactive protein (CRP)-adjusted TfR-F-Index in 87 patients with CLL. sTfR was measured nephelometrically (normal: 0.81–1.75 mg/L). A cut-off value of 1.5 for the TfR-F-Index and 0.8 for the CRP-adjusted TfR-F-Index, in patients with a CRP >5 mg/L, was used. Results: All Binet A patients had normal sTfR values (1.34±0.2 mg/L), TfR-F-Index (0.67±0.2) and a CRP-adjusted TfR-F-Index. In Binet B and C, sTfR and the TfR-F-Index were significantly increased compared to Binet A patients (p<0.0001). The differences between Binet B and C were not significant. sTfR was increased in 85%, TfR-F-Index in 46% and the CRP-adjusted TfR-F-Index in 54% of the Binet B patients, in Binet C patients, 80%, 50% and 60% showed increases, respectively. sTfR and the TfR-F-Index decreased or even normalized following successful treatment. Conclusions: Similar to sTfR, the TfR-F-Index is strongly associated with tumor burden in patients with CLL. Thus, these parameters do not allow for a reliable diagnosis of ID in this patient group. Clin Chem Lab Med 2009;47:1291–5.

The soluble transferrin receptor reflects tumor load in chronic lymphocytic leukemia

Abstract Background: The soluble transferrin receptor (sTfR) is a parameter of erythropoietic activity and iron deficiency. Increased levels have also been described in hematological malignancies, especially in chronic lymphocytic leukemia (CLL). Methods: We investigated the value of sTfR in the assessment of tumor mass in 61 previously untreated CLL patients. Both hemolysis and iron deficiency were excluded. sTfR was measured nephelometrically (normal 0.81–1.75 mg/L). Results: All Binet A patients had normal sTfR values (1.36±0.22 mg/L). In Binet B patients, the sTfR was increased (3.08±1.70 mg/L, p<0.0001) compared to Binet A patients. Binet B patients with normal sTfR had a small tumor load and no abdominal involvement. A further increase of sTfR in Binet C (3.75± 2.32 mg/L) was not significant compared to Binet B patients. sTfR values decreased or even normalized after successful treatment, whereas relapse or disease progression was associated with another increase of sTfR. Conclusions: The sTfR concentration directly reflects the tumor burden in CLL. Therefore, sTfR may be of clinical value in monitoring disease activity, response to treatment and disease progression. Clin Chem Lab Med 2007;45:1313–8.

Intracellular expression of CD61 precedes surface expression

Abstract We report a case of acute myeloid leukemia which we have classified as acute megakaryoblastic leukemia because of intracytoplasmic expression of CD61. Light microscopy demonstrated agranular blasts which, by cytochemical staining, were negative for myeloperoxidase. Using flow cytometry, the blast cells were seen to be positive for HLA-DR, CD7, CD13, CD33, and CD34, thus revealing their myeloid origin. Immunophenotyping on fixed blood smears additionally showed positive reaction with the CD61 antibody, demonstrating the megakaryoblastic differentiation of the blasts. After permeabilization of the cell membrane, the intracytoplasmic CD61 expression was confirmed by flow cytometry. Cytogenetic analysis disclosed a del(7)(q21–22). Our findings suggest that cytoplasmic expression of CD61 may precede the cell-surface expression of this antigen and should therefore be investigated in all cases of acute leukemias with undifferentiated morphology and negative cytochemistry to set apart early FAB-M7 from FAB-M0.

The soluble transferrin receptor in dysplastic erythropoiesis in myelodysplastic syndrome

Objectives: In individuals without iron deficiency, the soluble transferrin receptor (sTfR) directly reflects the erythropoietic activity. This study investigated sTfR concentrations in ineffective, dysplastic erythropoiesis in myelodysplastic syndrome (MDS). Methods: To exclude influences of other myeloid cells on sTfR, only patients with refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS) and 5q– syndrome were included. sTfR was measured nephelometrically (normal range 0.81–1.75 mg/L). Results: Thirty‐four untreated MDS patients (RA = 14, RARS = 10, 5q– syndrome = 10) were enrolled and analysed. The mean sTfR value of all MDS patients (1.30 ± 0.8 mg/L, range 0.2–3.8) did not differ from our control group. In 5q– syndrome, the mean sTfR concentration (0.80 ± 0.5 mg/L) was significantly lower than in RA (1.32 ± 0.4 mg/L, P = 0.02) and RARS (1.75 ± 1.1 mg/L, P = 0.03). Subdividing MDS according to their amount of erythroid mass in bone marrow a significant difference of sTfR between patients with decreased (0.70 ± 0.4 mg/L), normal (1.32 ± 0.4 mg/L) and increased (2.06 ± 0.9 mg/L) erythropoiesis was observed. MDS patients with sTfR values below the reference range of 0.81 mg/L required transfusions in 90% of cases and showed higher erythropoietin levels compared to MDS patients with sTfR levels ≥0.81 mg/L (P = 0.01). There was a good agreement between sTfR and the amount of polychromatic erythroblasts observed (r = 0.68, P < 0.001). Conclusion: In conclusion, the serum concentration of sTfR reflects erythropoietic activity in MDS, but it is in particular determined by the degree of erythroid maturation and the severity of ineffective erythropoiesis. Low sTfR values in MDS are associated with a reduced, poorly differentiated erythropoiesis and requirement of blood transfusions.

Reliable identification of small cell lung cancer in cytological specimens by immunocytology.

A reliable diagnosis of small cell lung cancers (SCLC) is of high clinical relevance. We investigated whether immunocytology substantially improves the diagnostic accuracy of conventional cytology in diagnosing SCLC. Patients and Methods: 162 carcinomatous specimens clinically suspected to originate from pulmonary neoplasms were investigated by cytology and immunocytology. Immunocytology was performed on smears using HEA125 and pancytokeratin antibodies as epithelial markers and MOC-1 as SCLC probe. Results: As histologically clarified, 114 specimens corresponded to pulmonary neoplasms (SCLC = 51; non-small cell lung cancer: NSCLC = 59; mixed SCLC/NSCLC = 2; carcinoid = 2), 48 to nonpulmonary adenocarcinomas. By conventional cytology tumor cells were clearly detected in 93 (57.4%) and suspected in another 43 (26.5%) cases (83.9% overall sensitivity). Considering SCLC samples, tumor cells were diagnosed or suspected in 36 (70.5%), not identified in 10 (19.6%), and misdiagnosed as hematological malignancy in 5 cases. Only 2 specimens were accurately diagnosed as SCLC. Using the epithelial antibodies all samples were identified as carcinomatous. MOC-1 stained all but one SCLC, both SCLC/NSCLC, and both carcinoids. One SCLC brush smear was MOC-1 negative, containing only squamous epithelium. 3 pulmonary adenocarcinomas stained falsely positive, all nonpulmonary carcinomas MOC-1 negative. Conclusion: Immunocytology substantially improves the diagnostic accuracy of cytology in diagnosing SCLC with a diagnostic sensitivity of 98% and specificity of 97%.