Long-term results of ultrasound guided fine needle aspiration cytology in conjunction with sentinel node biopsy support step-wise approach in melanoma.

BACKGROUND: US-FNAC is a common diagnostic tool in the work-up of many cancers. Results in melanoma were initially poor (sensitivity 20-40%). Introduction of the Berlin Morphology criteria has shown potential improvement up to 65-80% in selected patients. AIM: This cohort study evaluates the long-term survival outcome of melanoma patients undergoing Ultrasound (US) guided Fine Needle Aspiration Cytology (FNAC) prior to sentinel node biopsy (SNB) or direct lymphadenectomy. METHODS: Between 2001 and 2010 over 1000 consecutive melanoma patients prospectively underwent targeted US-FNAC prior to SNB. The Berlin US morphology criteria: peripheral perfusion (PP), loss of central echoes (LCE) and balloon shape (BS) were registered. FNAC was performed if any factor was present. All patients underwent SNB or lymphadenectomy in case of positive FNAC. RESULTS: Median follow-up was 61 months (IQR 40-95). SN positivity rate was 21%. Survival analyses demonstrated that patients with positive US-FNAC had poor survival. After adjustment for SN status and other known prognostic features, patients with positive US-FNAC (hazard ratio (HR) 1.80, 95% CI 1.10-2.96) had worse survival than patients with normal US (reference). Patients with suspicious US and negative FNAC (HR 1.13, 95% CI 0.71-1.78) had survival comparable to patients with normal US. CONCLUSIONS: The long-term US-FNAC results support this step-wise approach to melanoma patients. Patients with positive US-FNAC have a poor survival and can be spared a SNB. Patients with suspicious US and negative FNAC should undergo SNB to detect microscopic occult disease. Completely US-FNAC negative patients might only require follow-up and no SN staging at all.

Efficacy of ultrasound B-scan compared with physical examination in follow-up of melanoma patients.

BACKGROUND: The value of ultrasound B-scan for routine follow-up of melanoma patients still is not generally accepted. Therefore, the authors compared the efficacy of physical examination (PE) with ultrasound B-scan (UBS) for detection of regional tumor recurrence in melanoma patients. The aim of the current study was to evaluate whether early detection of metastases improves relapse-free and overall survival. METHODS: For a period of 4 years, 829 consecutive melanoma patients were followed prospectively. Physical examination of 3011 patients and concomitant UBS of in-transit routes and regional lymph node basins were performed. Suspicious lesions were diagnosed by fine-needle aspiration cytology and pathology. RESULTS: During the study period, 242 (90.6%) of 267 patients with melanoma recurrences were first recognized by PE or UBS within the routine follow-up program. The sensitivities of both methods differed significantly (P = 0.001). Metastases were detected by PE in only 61 of 242 recurrences (25.2%, 95% confidence interval [CI]: 19.9-31.2%), whereas UBS revealed 240 recurrences (99.2%, 95% CI: 97.3-99.6%). The specificity was 98.4% (95% CI: 97.8-98.8%) and 98.3% (95% CI: 97.7-98.7%), respectively. Survival of 103 patients who presented with a first nodal melanoma recurrence was followed and analyzed by multiple Cox regression. Overall survival was affected by the diameter of the largest metastasis (P = 0.001) and the number of metastatic lesions (P = 0.012). CONCLUSION: The study found that ultrasound B-scan was highly effective in the early detection of regional melanoma metastases compared with physical examination. Earlier detection of such metastases seemed to result in improved overall survival.

[Ultrasound-guided fine needle aspiration cytology (FNAC) of unclear lesions in melanoma patients]. / Ultraschallunterstützte Feinnadelaspirationszytologie (FNAC)unklarer Raumforderungen bei Melanompatienten.

AIM: Fine needle aspiration cytology (FNAC) is widely used in oncology to obtain the diagnosis of unclear tumours in cancer patients. However, because the method is established only in few melanoma centers, we performed this study to evaluate ultrasound guided FNAC in routine follow-up of melanoma patients. METHOD: Unclear tumours recognised during routine follow-up of melanoma patients underwent ultrasound guided fine needle aspiration with cytological examination. The results were then compared to subsequent histopathology or future clinical outcome. RESULTS: 275 unclear tumours received ultrasound guided fine needle aspiration with cytological examination. Sensitivity showed to be 95.6% [95% CI: 91.5-98.1], specificity was 100% [95% CI: 96.2-100.0]. The positive predictive value was 100.0% [95% CI: 97.9-100.0], the negative predictive value 92.2% [95% CI: 85.1%-96.9%]. In 89 cases lesions turned out to be cytologically benign thus diagnosis avoiding surgery. In lesions with diameters up to 10 mm sensitivity and specificity were 91.4% and 100.0%, respectively. CONCLUSION: Ultrasound guided FNAC proved to be a minimal invasive procedure in the diagnosis of unclear tumours in the follow-up of melanoma patients. It allows definite diagnosis and avoids unnecessary diagnostic surgery.

Ultrasound-guided fine-needle aspiration cytology in the early detection of melanoma metastases.

BACKGROUND: The early detection and treatment of tumor recurrences in melanoma patients is dependent on reliable, sensitive, and specific techniques to verify suspected tumor metastases. As of now, fine-needle aspiration cytology (FNAC) has yet to establish itself in the routine follow-up of melanoma patients. METHODS: FNAC procedures were performed in melanoma patients with palpable tumors or nonpalpable, ultrasonically suspicious lesions. Cytodiagnostic evaluation of fine-needle samples obtained from suspicious lesions was performed morphologically. Findings were validated either by histopathologic diagnosis or prolonged clinical follow-up. RESULTS: The cytologic examination of 739 FNACs from 330 melanoma patients was conducted within 1 day of sampling. Complications were not observed. This study showed a sensitivity of 97.9% and a specificity of 100.0%. Moreover, in 158 FNACs derived from lesions with a diameter less than 1 cm a sensitivity of 94.6% was achieved. Diagnosis of metastatic melanoma with unknown primary tumor was established in 20 cases. CONCLUSIONS: FNAC is very reliable for the early detection of melanoma metastases. FNAC is a swift method free of complications and is able to replace diagnostic surgery completely for nonmalignant lesions in a large number of patients. Moreover, FNAC is especially useful in combination with ultrasound in melanoma follow-up and can enable diagnosis of lesions smaller than 1 cm without impairment of sensitivity or specificity.

Detection of regional melanoma metastases by ultrasound B-scan, cytology or tyrosinase RT-PCR of fine-needle aspirates.

Physical examination and ultrasound B-scan screening are important follow-up procedures in melanoma patients with regional disease. However, they do not allow definite diagnosis of suspicious lesions. Fine-needle aspiration cytology (FNAC) enhances the diagnostic accuracy in such patients but, unfortunately, reaches its technical limits, particularly when very small or necrotic lesions are examined. We therefore tested whether tyrosinase reverse transcription polymerase chain reaction (RT-PCR) of fine-needle aspirates (FNA-PCR) could help to increase diagnostic sensitivity. With clinical follow-up in 69 melanoma patients 81 regional lymph nodes were detected by ultrasound B-scan examination, nine of whom appeared to be palpable. Technically, FNAC was successful in all 81 lymph nodes, while FNA-PCR failed to obtain RNA at detectable levels in two lymph nodes of two patients. Of 79 lesions which have been completely evaluated by B-scan, FNAC and FNA-PCR, 44 proved to be melanoma metastases by histopathology, while the remaining 35 lesions were finally classified as non-specific lymph nodes. Of the 44 melanoma metastases 80% (n = 35) have been detected by B-scan, 90% (n = 39) by FNAC and 100% (n = 44) by FNA-PCR (P < 0.05 vs FNAC, P < 0.005 vs B-scan). In the subclass of lesions with diameters below 10 mm the sensitivities were 72% (n = 13), 78% (n = 14) and 100% (n = 18) respectively. In 35 regional lymph nodes classified as benign lesions, FNAC was always negative while FNA-PCR produced one positive result. Neither of these methods did produce false positive results in 15 control lymph nodes of non-melanoma patients. We conclude, that FNA-PCR might have superior sensitivity as compared to FNAC or ultrasound B-scan, particularly in melanoma lesions with diameters below 10 mm.

[The fine-needle aspiration cytology of lymph nodes suspected of malignancy. Its diagnostic value and capacity to predict the histogenesis]. / Die Feinnadelaspirationszytologie malignomverdächtiger Lymphknoten. Diagnostischer Wert und Fähigkeit zur Vorhersage der Histogenese.

To examine the usefulness of fine needle aspiration cytology in the investigation of patients with enlarged lymph nodes, the authors made a retrospective evaluation of the results of 1158 aspirations in 838 patients (630 male, 208 female, mean age 44 [4-90] years). In these 1158 cases the diagnosis was verified histologically, serologically or by follow up extending over at least six months. In 94.6% (n = 1096) the aspirate gave an unequivocal diagnosis, in 4.2% (n = 48) the diagnosis was equivocal and in 1.2% (n = 14) no diagnosis was reached. There were 773 correct malignant results, 368 correct benign results and 16 false benign; in one case the assessment was false malignant. Sensitivity was 98% and specificity 99.7%. In benign lymphadenopathies the investigation achieved a specificity of 99.7%, and in metastases and malignant lymphomas the sensitivity was 97.8% and 98.2% respectively. In 211 out of 286 aspirations the cytological diagnosis correctly predicted the subsequent histological diagnosis; in 58 cases correct though imprecise expressions such as "highly malignant non-Hodgkin's lymphoma" were employed. No serious complications were encountered. Fine needle aspiration cytology enables the clinician to devise an exact diagnostic and therapeutic plan in nearly every patient with unexplained lymph node enlargement.

[The value of fine needle aspiration cytology in suspected neoplastic salivary gland enlargement]. / Der Wert der Feinnadelaspirationszytologie bei tumorverdächtigen Speicheldrüsenschwellungen.

Imaging offers little support in the management of salivary gland masses suggestive of a neoplastic lesion. There are also contraindications for a surgical biopsy in many cases. Fine-needle aspiration cytology (FNAC) is not yet widely recognized as a diagnostic tool. To date, 206 FNAC were carried out from 1986 through 1993 on 181 consecutive patients and were reviewed in the present study. Histological confirmation was possible in 174 tests, while 32 were confirmed on clinical follow-up. In sum, 192 samples were sufficient for interpretation, 10 were questionable by our standards and 4 were non-diagnostic. One hundred-seventy-one samples were true-negative, 27 true-positive, 4 false-negative and 4 false-positive. Sensitivity was 87.1% and specificity 97.7%. Out of 141 primary diagnostic procedures in which a final histologic diagnosis was available, FNAC was able to determine histogenesis in 113/124 benign lesions and 9/17 malignant masses. These included 65/67 pleomorphic adenomas and 21/22 adenolymphomas. In 8 cases a diagnosis of "adenoma" was made. Difficulties in interpretation were found in lesions that were mucoepidermoid carcinomas and, in part, adenoid cystic carcinomas. No complications occurred. Provided that there was sufficient experience in performing the aspiration technique and in cytologic interpretation, FNAC was found to be a quick, reliable, low-cost, easy-to-perform method with low risk in the management of nearly all benign and most malignant salivary gland lesions.

Immunoglobulin therapy for autoimmune neutropenia in Hodgkin's disease.

We describe a patient with recurrence of Hodgkin's disease and severe liver disease of unknown origin in whom autoimmune neutropenia developed. Because of possible seronegative viral hepatitis he was treated with high-dose intravenous immunoglobulin instead of steroids. He responded with a prompt but transitory increase of the neutrophil count and recovered completely after chemotherapy.

[Fine needle aspiration cytology of metastatic malignant melanoma. Improvement of results with ultrasound control]. / Feinnadelaspirationszytologie beim metastasierenden malignen Melanom. Verbesserung der Ergebnisse durch Ultraschallführung.

A review of 315 fine-needle aspiration cytologies (FNAC) carried out from 1984 through 1992 in 157 patients with suspected metastatic melanoma was carried out: 176 results were confirmed by histological examination and 139 by clinical follow-up. In the first period, from 1984 through 1988, we observed 5 false-negative results out of 123 evaluable FNACs. All were caused by technical failure. In the second period, from 1988 through 1992, all fine-needle biopsies of impalpable masses were done with ultrasound guidance. Thus, we were able to avoid further false-negative results. No errors in interpretation were found. We obtained 219 true-positive and 91 true-negative results with 97.8% sensitivity, 100% specificity, 98.4% accuracy, 100% positive and 94.8% negative predictive value. In 3 cases with metastatic melanoma the cytological diagnosis only was 'malignant tumor', while in another 5 patients the cytodiagnosis of melanoma was not definitive. Immunocytology was helpful in these cases in identifying melanoma. FNAC allowed the correct diagnosis of a second malignancy in 4 cases (one papillary thyroid cancer, one Hodgkin's disease, two non-Hodgkin's lymphomas). No complications occurred. In our opinion, FNAC--for poorly defined lesions with ultrasound guidance--is a very rapid, safe and accurate method that allows reliable diagnosis of metastatic melanoma.

[The value of fine-needle aspiration cytology in the after-care of malignant melanoma]. / Der Stellenwert der Feinnadelaspirationszytologie in der Nachsorge des malignen Melanoms.

In recent years, we have carried out 146 fine-needle aspiration cytologies (FNAC) for diagnostic clarification of putative metastases from melanomas. The cytodiagnostic appraisal was based on general criteria for the malignancy of tumour cells as well as on particular melanoma-specific findings. Different cell variants can be differentiated in cytological terms. Validation of the cytological diagnoses was possible in 118 of the 123 evaluable FNAC, either by histological examination of the subsequently excised lesions or on the basis of the further clinical progress observed. Statistical evaluation revealed a sensitivity of 93.8% for this method and a specificity of 100%. In our experience, FNAC is thus a diagnostic method that is of great value in the rapid and reliable diagnosis of suspected metastatic lesions in the clinical follow-up of melanoma patients.

Cryocrystalglobulinemia: pH-dependent precipitation of a monoclonal IgG-kappa-immunoglobulin.

Cryoglobulinemia is seen in a minority of patients with plasma cell dyscrasias and can be of clinical relevance if intravascular gelling or precipitate formation occurs at low temperatures. We observed a patient suffering from IgG-kappa multiple myeloma which was complicated by instability of the immunoglobulin forming crystalline precipitates at low pH and low temperature. Short exposure to extreme cooling initiated an unusual course terminating in disseminated vascular occlusion and fatal outcome which was connected with an adverse effect of blood exchange. Crystal formation was noticed in anticoagulated blood samples even at 37 degrees C. In vitro studies showed a critical pH dependency of solubility of the immunoglobulin close to the physiological pH of the blood. These observations suggest that the fatal outcome was due to a vicious circle of ischemia, metabolic acidosis and intravascular precipitations, initiated not only by low acral temperatures but by cold-induced ischemic tissue acidosis as well. Serum of patients with monoclonal gammopathy and cryoglobulinemia should be tested for pH dependent immunoglobulin insolubility.

[Fine needle aspiration of the skin: diagnosis of malignant lymphoma and of cutaneous manifestations of myeloid hemoblastosis]. / Feinnadelaspiration der Haut: Diagnostik von malignen Lymphomen und von kutanen Manifestationen myeloischer Hämoblastosen.

Fine-needle aspiration cytology of the cutis was carried out in 103 patients suffering from malignant lymphomas and myelogenous leukemias. All biopsies were performed using a novel aspiration device. Only in 7.8% of cases was it not possible to establish a cytological diagnosis because the biopsy specimens obtained were inadequate. The sensitivity of the method was 96.8%. There was a close correlation between the cytological and the final diagnosis (contingency coefficient C = 0.96). The method was equally efficient for primary evaluation as it was for the follow-up of patients with hematological neoplasms.

[Ultrasound guided fine- and coarse-needle puncture of the abdominal and retroperitoneal space]. / Sonographisch geführte Fein-und Grobnadelpunktion im abdominalen und retroperitonealen Raum.

Within a period of 21 months, 167 fine-needle and 86 cannula (1.67 mm external diameter) punctures of the abdominal or retroperitoneal space were performed under sonographic control. Sufficient material was obtained with 93.4% of fine-needle punctures. With regard to differentiation between malignant and benign lesions, fine-needle punctures had a sensitivity of 86% and specificity of 100%, if the material was examined by an experienced cytologist. Sensitivity dropped to 55,1% if the same material was interpreted by a less experienced cytologist, but specificity was still 98.1%. Sufficient material for histological examination was always obtained with the cannula, already at the first puncture. With cannula puncture there were two complications: bleeding requiring transfusion and peritonitis.

Lymphoplasmacytic/lymphoplasmacytoid lymphoma: a clinical entity distinct from chronic lymphocytic leukaemia?

Clinical data of 116 patients with chronic lymphocytic leukaemia (CLL) and of 114 patients with lymphoplasmacytic/lymphoplasmacytoid lymphoma (synonym: LP immunocytoma, IC) as diagnosed according to the Kiel classification were compared. This interim evaluation of a prospective multicenter study of the Kiel Lymphoma Study Group characterizes IC the less favorable lymphoma entity as evidenced by a more rapid lymph node enlargement, by a higher incidence of constitutional symptoms and of marked anaemia, and by a higher percentage of patients requiring early treatment. In addition, in IC autoimmune haemolytic anaemia was detected in 11.2% of investigated patients as compared to none of the patients with CLL, and monoclonal gammopathy was disclosed in 34.2% of investigated patients as compared to only three patients with CLL who could be, however, unrecognized cases of IC. Actuarial survival data after a follow-up period of 40 months are in favor of an overall better prognosis of patients with CLL than of patients with IC.

Germinal center cell lymphomas: prognostic significance of their histopathological differentiation.

Clinical data of 48 patients with centrocytic, 83 patients with centroblastic/centrocytic and 64 patients with centroblastic lymphoma who had entered a prospective multicenter study of the Kiel Lymphoma Study Group since October 1975 were compared. Advanced (stage IV) disease at time of diagnosis, predominantly due to bone marrow infiltration, was most frequent in centrocytic (69% of patients) and in centroblastic/centrocytic (51% of patients) lymphomas as compared to only 28% of patients with centroblastic lymphoma. High survival probability of patients with localized centrocytic and centroblastic/centrocytic lymphomas after radiotherapy, contrasting with a worse prognosis of corresponding patients with centroblastic lymphoma, is compatible with the classification of these lymphoma entities as neoplasias of low-grade malignancy. However, as shown by this prospective and previous retrospective trials overall survival probability of patients with advanced centrocytic lymphoma was inferior to that observed in corresponding patients with centroblastic/centrocytic lymphoma. These findings suggest the possibility that patients with advanced centrocytic lymphoma occupy an intermediate position between typical low-grade and typical high-grade malignant non-Hodgkin lymphomas.

Clinical and prognostic heterogeneity of non-Hodgkin lymphomas of high-grade malignancy.

Comparison of clinical data of 64 patients with centroblastic lymphoma, 55 patients with immunoblastic lymphoma and 31 patients with lymphoblastic lymphoma not only confirmed the original assumption of high-grade malignancy as proposed by the concept of the Kiel classification but also demonstrated distinct clinical differences, particularly between lymphoblastic lymphoma and the two other entities. Rapid lymph node enlargement as well as steep fall of survival curves within the first year after diagnosis were common characteristics. Bimodal age distribution, predominance of males and early generalization of disease were typical features of lymphoblastic lymphoma; elderly patients and patients with the unclassified subtypes of lymphoblastic lymphoma exhibited the worst prognosis. Whereas patients with centroblastic and immunoblastic lymphomas showed similar distribution of age, sex and initial stage of disease, patients with immunoblastic lymphoma presented more frequently with a reduced performance status and showed a poorer response to radio- and chemotherapy resulting in a worse prognosis discernible after the first year of follow-up. Generalization during course of the disease was significantly more frequent in immunoblastic than in centroblastic lymphoma.

[Haematological features of anorexia nervosa (author's transl)]. / Hämatologische Veränderungen bei Anorexia nervosa.

Nine patients with anorexia nervosa were studied, who had varying degrees of bone marrow failure ranging from a slight neutropenia to severe pancytopenia. In addition to routine laboratory work bone marrow biopsies were performed at admission and during the course of disease. In four of those patients erythropoietin excretion per 24 hours was measured by the bioassay in the polycythemic mouse at least twice during the course of treatment. At admission most bone marrow showed a marked although varying hypocellularity with grossly apparant background gelatinous material, which appeared to consist of acid mucopolysaccharides. Leukopenia and the changes of the bone marrow morphology reversed to normal after refeeding. Erythropoietin excretion was only elevated in patients who were anemic and returned to normal when the haematocrit reached normal levels. It seems therefore unlikely that an impaired production of erythropoietin or other postulated humoral factors cause the haemopoietic changes in anorexia nervosa. A direct effect of fat or carbohydrate depletion and/or of the increased mucopolysaccharides upon the proliferation of the haemopoietic cells can be suggested, but is an entirely speculative preposition.

[Immunoblastic lymphadenopathy--malignant neoplasia or hyperimmune reaction? (author's transl)]. / Immunoblastische Lymphadenopathie--maligne Neoplasie oder hyperimmunisatorische Reaktion

Six patients have been observed which exhibited the features of the so called immunoblastic lymphadenopathy. The histological and clinical findings allow to distinguish the disease from both the malignant lymphomas and other forms of benign pseudolymphomas. The most important clinical features are severe general symptoms, generalised lymphadenopathy, hepatosplenomegaly, skin rash and a variety of abnormal reactions in the B-cell system such as hypergammaglobulinaemia, a transient positive Coombs test and the appearance of plasma cells in the peripheral blood. Evidence for a neoplastic nature of the disease is lacking. Nevertheless, the course of the disease may be progressive and fatal, but spontaneous remissions and subsequent relapses have also been essential part of the therapeutic strategy. Immunosupressants such as corticosteroids may have a positive effect in cases with immunological complications.