Biomedical subjects
Publications and source records attributed to Hans Starz.
Pathologists play a central role in the management of cutaneous melanoma in determining that a tumor is a melanoma, whether or not it is primary or metastatic, and whether or not the margins of excision are tumor free and in evaluating prognostic indicators from examination of the primary tumor and, where appropriate, lymph nodes, including the sentinel nodes.
Langerhans' cell histiocytosis summarizes a spectrum of diseases on the basis of histogenetic criteria. These are characterized by an accumulation of cells with Langerhans' cell phenotype in one or multiple organs. Up to 50% of patients with either single or multi-organ manifestation of Langerhans' cell histiocytosis initially present with cutaneous symptoms. Nevertheless, cutaneous Langerhans' cell histiocytosis is rare and heterogeneous in its clinical features and therefore prone to misdiagnosis. We report on five patients, two infants and three adults, suffering from cutaneous Langerhans' cell histiocytosis, either singly or as part of multi-organ disease. The different skin features morphologically mimicking other entities are shown and the differential diagnoses are discussed. The correct diagnosis in all presented cases is based on immunohistological examination, showing a histiocytic infiltrate positively staining with anti-S100 antibodies, CD1a and--apart from one case--with CD207 (langerin).
Downstream of Ras, the serine/threonine kinase B-raf has been reported to be mutated, amongst other carcinomas, in a substantial subset of primary melanomas, with a preponderance of mutations within the kinase domain, including the activating V599E and V599K transitions. We investigated a representative series of 54 resection specimens of melanoma lymph node metastases for the presence of mutations within the activation segment (exon 15) of the B-raf kinase domain by polymerase chain reaction (PCR) and single-strand conformational polymorphism (SSCP) gel electrophoresis. Sequencing of cloned PCR-SSCP amplicons resulted in 24 (44%) samples harbouring somatic mutations, which is not significantly different from the mutation frequency found in recently investigated primary cutaneous melanomas (Deichmann M, Thome M, Benner A, Näher H. B-raf exon 15 mutations are common in primary melanoma resection specimens but not associated with clinical outcome. Oncology 2004; 66:411-419). The activating mutation T1796A was present in 20 (83%) of these resection specimens, followed in frequency by the oncogenic g1795A mutation in five (21%) cases. With regard to the B-raf protein sequence, the acidic amino acid transitions V599E and V599K were predicted in 15 (62%) and five (21%) of the 24 positive metastases, respectively. The detection of mutations at this hot spot codon was significantly associated with subsequent visceral metastasis (P=0.03; Fisher's exact test). During the transition from primary melanomas (see reference above) to lymph node metastases, the spectrum of B-raf mutations narrows significantly (P=0.00047). The oncogenic B-raf mutations V599E and V599K, as early events in melanocyte transformation, persist throughout metastasis with important prognostic implications.
Malignant tumors are a frequent complication in the late phase after organ transplantation. Malignant lymphomas are the second most common tumor, exceeded only by cutaneous carcinomas. Compared to the general population, the organ transplant patients have a 30-60 fold increased risk of developing non-Hodgkin's lymphoma. A 55-year-old, hepatitis C-positive man developed an Epstein-Barr virus (EBV)- negative Burkitt lymphoma (BL) first appearing on the gingiva under immunosuppressive therapy nine years after allogenic renal transplantation. He died 37 days after the onset of polychemotherapy. Immediately before his death, meningeal involvement by the BL was diagnosed. BL after organ transplantation is often found at extranodal sites; it involves the central nervous system more frequently than it does in immunocompetent patients. In 70% of BL occurring after organ transplantation, genes or gene products related to EBV can be demonstrated within the tumor cells. The EBV status of the tumor is of important prognostic significance: EBV-positive BL occurring in organ transplant patients usually responds well to reduction or cessation of immunosuppressive therapy; in some cases permanent complete remissions can be achieved even without chemotherapy. In contrast, patients with EBV-negative BL have a very poor prognosis and hardly respond, even to aggressive chemotherapy protocols.
The most successful strategies in the management of melanoma have always been based on early diagnosis and timely surgical removal. Sentinel lymphonodectomy (SLNE) is the most reliable technique for the detection of melanoma micrometastases in regional lymph nodes. The micromorphometric S-classification, a routinely determinable surrogate of tumor burden in the sentinel lymph node (SLN), has high prognostic relevance. SIII metastases, defined by a depth of invasion (d) greater than 1 mm below the capsular level, imply a risk of more than 50% for the presence of nonsentinel lymph node metastases in the same basin and for the emergence of distant metastases within 5 years of follow-up. Corresponding risks with SI metastases (d </= 0.3 mm) and SII metastases (0.3 mm < d </= 1 mm) do not exceed 15%. The survival curve for patients with SIII metastases approaches that of patients in the pre-SLNE era who underwent delayed lymph node dissection for subsequently detected nodal macrometastases. The survival of patients with initially removed SI and SII metastases is much better, similar to that of patients with S0 metastases. This explains the significant survival benefit of SLN-guided surgery in the entire population of patients with melanomas thicker than 0.75 mm, although the outcome of the subgroup without nodal metastases is not influenced by SLNE.
The success and further evolution of the sentinel lymph node (SLN) concept decisively depend on histological techniques. Fundamental standards were agreed on by a panel of international experts from various disciplines in 1999 and published as "The Augsburg Consensus" in 2000. Conventional histology (hematoxylin and eosin [H&E]) has to be supplemented by immunohistochemistry (eg, S100 and HMB45) using adequate series of paraffin sections. Melanoma cells in SLNs must be carefully differentiated from capsular and trabecular nevocytes, from immigrated Langerhans cells, from interdigitating dendritic leukocytes, and from nerve sheath cells, which all share S100 positivity in the cytoplasm. The micromorphometric S classification is based on the maximum distance of intranodal melanoma cells from the interior margin of the SLN capsule. It has proven its practicability under routine circumstances, as well as its predictive value regarding further nodal and distant metastases as well as overall survival. This has to be considered in prospective randomized trials dealing with the issues of completion lymphadenectomy and adjuvant therapies of melanoma patients. Reverse-transcriptase polymerase chain reaction (RT-PCR) techniques, when performed as a supplement to histology on the basis of additional paraffin sections, can further enhance the diagnostic sensitivity for detecting melanoma cells in SLNs.
The detection of tyrosinase mRNA in sentinel lymph nodes (SLNs) by reverse transcription polymerase chain reaction (RT-PCR) is a sensitive indicator for the presence of melanoma or nevus cells, but it does not enable a distinction between both. We have established an efficient method for extraction and reverse transcription of tyrosinase mRNA from paraffin sections that permits the close correlation of the RT-PCR results with (immuno)histologic findings in adjacent sections. One hundred fifty-three SLNs and 6 non-SLN specimens originating from 92 melanoma and 4 nonmelanoma patients were studied to test the reliability of this approach. The predictive value of positive RT-PCR results was 0.98 for the presence of melanoma or nevus cells; the corresponding negative predictive value was 0.83. Furthermore, the detection rate of tyrosinase mRNA significantly correlated with tumor burden. Among the 33 melanoma-positive SLNs without nevus cells, positive RT-PCR results were obtained in all specimens with extended peripheral (S2) or deeply invasive (S3) micrometastases but in only 46% of the cases with few localized melanoma cells in the subcapsular zone (S1). Routine (immuno)histologic evaluation alone had missed microclusters of melanoma cells in one SLN and small nevus cell aggregates in six other SLNs. They were detected only during microscopic reexamination caused by a positive RT-PCR result. We conclude that histology and immunohistochemistry remain the indispensable gold standard for the identification of melanoma and nevus cells in SLNs. Additional molecular analyses using adjacent paraffin sections may further improve the diagnostic accuracy by sensitizing and guiding the microscopist's attention.
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