Homozygous G/G variant of SNP309 in the human MDM2 gene is associated with earlier tumor onset in Caucasian female renal cell carcinoma patients.

Human mouse double minute 2 (Mdm2) plays an essential role in the regulation of the tumor suppressor p53. The G/G variant of SNP309 was shown to increase Mdm2 mRNA/protein expression and to be associated with an increased risk and earlier onset of different cancers in Asian populations. However, the frequency and impact of these G/G variants have not been studied in Caucasian renal cell carcinoma (RCC) patients. Therefore, we analyzed an unselected German cohort of 197 consecutive RCC patients and detected the G/G variant in 18 (9.1%) patients, the G/T variant in 116 (58.9%) patients and the T/T variant in 63 (32.0%) patients. Studying the association between age at tumor onset and SNP309 genotypes, no correlation was detected in the entire RCC cohort or among the male RCC patients. However, the female G/G patients (median age 59.5 years) were diagnosed 13.5 years earlier than the T/T females (median age 73 years). When separating all females into two groups at their median age (68 years), 7 and 1 patients with the G/G variant and 9 and 13 patients with the T/T variant were noted in these age groups (P=0.024). To study the age dependency of tumor onset further, a second, age-selected cohort of 205 RCC patients was investigated, which comprised especially young and old patients. Interestingly, the G/G type occurred more often at lower tumor stages and tumor grades compared with higher stages (P=0.039 and 0.004, respectively). In females, the percentage of the G/G variant was only slightly higher in the younger age group, whereas in males, the percentage of the G/G variant was remarkably higher in the younger age group (19.4% vs 8.0%). In summary, female Caucasian RCC patients with the MDM2 SNP309 G/G genotype showed significantly earlier tumor onset than patients with the wild-type T/T genotype.

[Primary metastatic well-differentiated neuroendocrine tumor arising in a tailgut cyst]. / Primär metastasierter hochdifferenzierter neuroendokriner Tumor in einer Tailgut-Zyste.

Tailgut cysts are unusual benign cystic retrorectal malformations arising from persistent remnants of the postanal gut. Malignant transformation within this dysontogenetic lesion is very uncommon. We report the rare occurrence of a neuroendocrine tumor arising in a tailgut cyst with primary liver and lymph node metastases in a 55-year-old woman. The neuroendocrine differentiation of the tumor determines the therapeutic approach and prognosis.

[Mixed exocrine-endocrine gastric carcinoma: a rarity of little consequence?]. / Gemischtes exokrin-endokrines Karzinom des Magens - eine Rarität ohne Konsequenzen?

HISTORY AND ADMISSION FINDINGS: A 38-year-old woman was admitted for the diagnosis of joint pains. She had no gastrointestinal symptoms. INVESTIGATIONS: Barium contrast examination revealed a rigid gastric wall. Gastroscopy showed multifocal carcinoid (neuroendocrine) tumors, up to 3 mm in diameter, and a 2 cm tumor which had apparently not metastasised (as demonstrated by sonography and computed tomography), but had broken into the muscular layer. TREATMENT AND COURSE: A partial gastrectomy and lymphadenectomies were performed. Histology showed a mixed exocrine-endocrine carcinoma with submucosal infiltration and lymph node metastases. The postoperative course was without complications. CONCLUSION: Neuroendocrine tumors are rare diseases of the stomach for which therapeutic options are surgical resection or endoscopic removal. Tumors up to 1 cm diameter and concomitant type A gastritis, multiple endocrine neoplasms with infiltration or Zollinger-Ellison syndrome are removed endoscopically. Bigger tumors or tumors that have infiltrated the muscular layer are managed by partial gastrectomy In our opinion radical surgery is required in all carcinoids larger than 1 cm and other neuroendocrine tumors.

Gains of 12q are the most frequent genomic imbalances in adult fibrosarcoma and are correlated with a poor outcome.

Comparative genomic hybridization was used to analyze 41 adult fibrosarcomas from 34 patients. Thirty-one patients showed in their tumors DNA sequence copy number changes (mean 11, range 3-25). The minimal common regions for the most frequent gains were narrowed down to 12q21 (18 cases); 12q14-q15 and 14q22 (16 cases each); 4q22, 7q31, and 14q23-q24 (15 cases each); and 4q21, 4q23-q24, 8q22, and 12q22 (14 cases each). Twenty-five high-level amplifications were observed in 12 samples. 12q21 and 18p were affected three times each; and 1p21, 4q31.3, 7p21, 12q14-q15, Xp22.1-p22.2, and Xq22-q23 two times each. Losses were less frequent than gains. Early stages of adult fibrosarcomas were characterized by frequent gains of chromosomes 2, 4q, and 14q, whereas gains of chromosomes 7 and 8q were associated with progression. Gains of 12q were frequent in all of the developmental steps of this soft-tissue sarcoma. By investigation of several tumors of the same patient, a number of corresponding changes were always detected. Adult fibrosarcomas from patients who died during the observation time showed statistically significant more frequent gains of 8q, 12q, 13q, and 15q compared to the fibrosarcomas of patients who are alive. Gains and high-level amplifications of 12q14-q22, which were the most frequent genomic imbalances, partly reflected an MDM2 amplification, indicating the importance of this region in the tumorigenesis of sarcomas. In adult fibrosarcomas, a gain of 12q22 correlated significantly (P = 0.028) with a poor overall survival rate.

Surgery on the cervicovisceral axis for invasive thyroid cancer.

BACKGROUND AND AIMS: Invasion of the cervicovisceral axis (i.e., larynx trachea esophagus) by thyroid cancers still poses a surgical challenge. PATIENTS AND METHODS: Between November 1994 and October 1999, all patients who underwent surgery at this institution for differentiated (DTC) or medullary (MTC) thyroid carcinoma invading the cervicovisceral axis were recruited into this study. RESULTS: The cervicovisceral axis was invaded in 34 consecutive patients (19 DTC, 15 MTC). Of these, 20 patients underwent cervicovisceral resections. These resections were performed less often in MTC than in DTC patients (20% versus 89%; P<0.0001). Full-thickness invasion was present in 3 patients (2 DTC, 1 MTC). In the 20 resectional patients, tracheal wedge resection was the most common procedure followed by extramucosal esophageal resection. Surgical mortality was nil. There were five major complications, most of which occurred in either lateral tracheal or high-risk combined laryngo-tracheo-esophageal resections. CONCLUSION: The surgical approach to invasive thyroid carcinoma must balance surgical morbidity against the potential benefits of cervicovisceral resection. Individual factors must be considered, such as patient age and co-morbidity, the extent and nature of the tumor, and quality-of-life issues. Lateral resection of the trachea may cause significant tracheal instability and morbidity and, thus, be inferior to segmental tracheal resection.

Multivariate analysis of clinicopathologic parameters for the insular subtype of differentiated thyroid carcinoma.

HYPOTHESIS: Insular carcinoma represents a more aggressive subtype of differentiated thyroid cancer on multivariate analysis after controlling for various clinicopathologic parameters. DESIGN: Retrospective analysis. SETTING: Tertiary referral center at a university hospital. PATIENTS: One hundred twenty-seven consecutive patients having a histological diagnosis of the follicular variant of papillary thyroid carcinoma or follicular thyroid carcinoma. MAIN OUTCOME MEASURE: A logistic regression model was used to examine the relationship between various clinicopathologic parameters and the insular subtype. RESULTS: The insular subtype involved 14 of 127 tumors. Unlike extrathyroidal extension and nodal metastasis, primary tumor diameter (> 40 mm vs < or = 40 mm; P = .008) and distant metastasis (P = .003) correlated with the insular subtype. Both parameters were interrelated since tumors greater than 40 mm displayed distant metastasis more often (30% vs 8%; P = .008) than tumors measuring 40 mm or less. CONCLUSIONS: These findings suggest that an unidentified somatic event may induce an accelerated proliferation of the transformed thyrocytes, which may ultimately result in enhanced rates of distant metastasis with increasing tumor volume.

["Physiological" and "neoplastic" C-cell hyperplasia of the thyroid. Morphologically and biologically distinct entities?]. / "Physiologische" und "neoplastische" C-Zell-Hyperplasien der Schilddrüse. Morphologisch und biologisch distinkte Entitäten?

C-cell hyperplasia (CCH) occurs regularly in the setting of type 2 multiple endocrine neoplasia (MEN2), either separately or in association with medullary thyroid carcinoma (MTC). It can also accompany sporadic MTC and appear without any tumour association. To test the practicability of the terms "physiologic" and "neoplastic", 18 cases with incidental sporadic, non-MTC associated CCH were investigated and the morphological patterns were described. We found CCH of various degrees, including so-called neoplastic CCH. In 16 of the 18 cases, a MEN2 setting could be ruled out by mutation analysis of the RET proto-oncogene. Morphologically, one can not distinguish with certainty between sporadic and hereditary or reactive and tumour-associated CCH. While MEN2-associated CCH can be regarded as true preneoplasia, sporadic CCH possesses variable biologic potential. The preneoplastic potential of sporadic CCH is still obscure. A pure morphological distinction between "physiologic" and "neoplastic" CCH regardless of the RET status should not be used.

Cytogenetic characterization of six malignant peripheral nerve sheath tumors: comparison of karyotyping and comparative genomic hybridization.

We analysed six malignant peripheral nerve sheath tumors (MPNSTs) from four patients using metaphase preparations and compared the results with those obtained by using comparative genomic hybridization (CGH). All six tumors showed structural and numerical chromosomal aberrations, mostly of chromosomes 1, 5, 7-10, 14-17, 19, 21, and 22. The number of chromosomes per tumor cell ranged from 42 to 104. We could not find a recurrent specific pattern of structural changes after comparing the MPNSTs of different patients. However, aberrations of different tumors from the same patient were nearly identical. In the four patients, we found a total of 117 breakpoints, mostly in 21q11.2 (seven times), in 8q11.2 and 14q10 (six times each), in 5q11.2 and 15q26 (four times each), in 8p11.2, 10q11.2, 16q22, 19q13.3, and 22q10 (three times each). In three MPNSTs, double minute chromosomes (dmin) we detected with metaphase investigations and high-level amplifications by using CGH, respectively. C-MYC gene amplification and loss of the P53 gene could be ruled out by locus-specific probes for the common gain of 8q and for losses of 17p. When comparing the CGH results with those of karyotyping an overlap in the most frequent gains in 7q, 8q, 15q, and 17q was observed. However, we found more frequent losses in 19q in the metaphase investigations.

Extended surgery and early postoperative radiotherapy for undifferentiated thyroid carcinoma.

The current study was devised to evaluate the therapeutic potential of extended surgery for improving survival in undifferentiated thyroid carcinoma (UTC). An institutional retrospective survival analysis (July 1994 to December 1998) of 30 patients who underwent surgery for UTC with locally curative intent was done. Median and 1-year survival was 4 months and 37%, respectively. Primary patients were older (70 vs. 59 years; p = 0.026) and deceased earlier (median survival 4 vs. 20 months; p = 0.027, log-rank test) than their reoperative counterparts, suggesting a referral bias toward younger patients. Survival analysis was restricted to primary pT4 UTC, leaving 18 patients. On univariate analysis, pN and M category, degree of resection (R2 versus R0/1 and radiotherapy (0-30 Gy versus >30 Gy) were identified as parameters suitable for further testing. On multivariate analysis, pN1 was a significant prognosticator of decreased survival (RR = 5.9; p = 0.043), followed by R2 (RR = 4.1, p = 0.088) and M1 (RR = 3.6; p = 0.089). Because of low patient numbers after stratification for radiotherapy, only pN and degree of resection were analyzed on subsequent multivariate analysis. In the incomplete radiotherapy stratum, neither of the two parameters affected survival, whereas R2 and pN1 limited survival in the complete radiotherapy stratum. In primary pT4 UTC, a subset of pN0 patients with R0/1 resections and radiotherapy greater than 30 Gy seemed to benefit from extended surgery. Because pN1 and R2 patients with radiotherapy of 30 Gy or less comprised most UTC patients, only 1-year, but not median, survival improved compared to literature controls.

Prophylactic completion thyroidectomy for differentiated thyroid carcinoma: prediction of extrathyroidal soft tissue infiltrates.

Controversy exists on the extent of completion surgery for differentiated thyroid carcinoma (DTC). Between November 1994 and October 1999, 88 consecutive DTC patients who had no evidence of residual tumor after primary surgery underwent completion total thyroidectomy in conjunction with a systematic en bloc resection of the cervicocentral lymph node compartment. To identify individual parameters predictive of occult residual tumor, three separate logistic regression analyses were fitted for intrathyroidal tumor, extrathyroidal soft tissue infiltrate and cervicocentral nodal metastasis. Altogether, occult residual tumor was found in 22% (19/88) of patients. Occult intrathyroidal tumor, extrathyroidal soft tissue infiltrate, and cervicocentral nodal metastasis were encountered in 11%, (10/88), 6% (5/88), and 10% (9/88), respectively. On logistic regression analysis, patients with multifocal DTC on primary surgery had a 17.4 times higher risk (p = 0.026) on reoperation to harbor extrathyroidal soft tissue infiltrates within the cervicocentral compartment. At least in multifocal DTC, a systematic en bloc resection of the thyroid remnant and cervicocentral lymph node compartment is warranted to ensure clearance of occult extrathyroidal soft tissue infiltrates, setting the stage for radioiodine therapy. Selective lymph node dissection alone does not seem capable of eliminating these soft tissue infiltrates from the cervicocentral compartment.

Importance of early screening and prophylactic thyroidectomy in asymptomatic nonindex RET germline carriers.

Genetic testing for RET germline mutations affords rapid identification of germline carriers, offering the prospect of cure before C-cell hyperplasia (CCH) has progressed to medullary thyroid carcinoma (MTC). Although nonindex RET mutation carriers have a better prognosis than do the index patients, it remains to be ascertained whether age represents a risk factor for MTC when screening patients. The current institutional study (October 1994 through June 1999) was set up to compare asymptomatic nonindex patients who were grouped by age: < 20 years and > or = 20 years. Inclusion criteria were confirmed RET mutations in the germline, with no MTC being more advanced than pT1pN1M0. Adult patients (> or = 20 years) had MTC significantly more often (84% vs. 43%), significantly larger tumors (5 mm vs. 3 mm), and significantly higher basal calcitonin levels preoperatively (78.0 vs. 9.7 pg/ml) than their pediatric/adolescent counterparts (< 20 years). There was a close correlation between pT1 MTC and an elevated basal serum calcitonin level (r = 0.67; Spearman's rho). All three patients with lymph node metastases from MTC had elevated basal calcitonin levels. The two groups did not differ in terms of multifocality of MTC (pT1b), lymph node involvement (pN1) or bilateral lymph node metastasis (pN1b), or preoperative stimulated and postoperative basal and stimulated serum calcitonin. Prophylactic thyroidectomy should not be postponed beyond the age of 20, and it should be performed before basal serum calcitonin has turned positive. Pathologic conversion of stimulated serum calcitonin obviously marks the time in carriers of RET germline mutations when surgery should be scheduled at the latest to be prophylactic.

Over-representation of a germline variant in the gene encoding RET co-receptor GFRalpha-1 but not GFRalpha-2 or GFRalpha-3 in cases with sporadic medullary thyroid carcinoma.

In contrast to the hereditary form of medullary thyroid carcinoma (MTC), little is known about the etiology of sporadic MTC. Somatic gain-of-function mutations in the RET proto-oncogene, encoding a receptor tyrosine kinase, are found in an average of 40% of sporadic MTC. We analysed 31 sporadic MTC for somatic and germline variants in GFRA1, GFRA2 and GFRA3 which encode the co-receptors of RET. Although there were no somatic mutations in any of the three genes, a sequence variant (-193C>G) in the 5'-UTR of GFRA1 was found in 15% of cases. Three patients were heterozygous (het); another three patients homozygous (hom) for the G variant. The G allele was not observed in 31 race-matched normal controls. Hence, the relative frequency of this variant in sporadic MTC cases and controls differed significantly (P<0.05). Since this variant lies in the 5' UTR, likely at the transcriptional start site, we analysed for differential expression of GFRalpha-1 at the transcript and protein levels. At the mRNA level, GFRA1 was over-expressed in tumors harboring the rare variant (P=0.06). The presence of the G polymorphic allele seemed to be associated with increased expression by immunostaining for GFRalpha-1. Interestingly, cytoplasmic staining was stronger in intensity for het patients and nuclear staining predominant in hom cases. In conclusion, mutation analysis of GFRA1, GFRA2 and GFRA3 revealed over-representation of a rare variant in GFRA1 (-193C>G) in the germline of sporadic MTC cases. Our data suggest that the mechanism is related to over-expression of GFRalpha-1 and differential subcellular compartmentalization but the precise mechanism as to how it acts as a low penetrance susceptibility allele for the development of sporadic MTC remains to be elucidated.

Somatic mutation and germline variants of MINPP1, a phosphatase gene located in proximity to PTEN on 10q23.3, in follicular thyroid carcinomas.

Various genes have been identified to play a role in the pathogenesis of follicular thyroid tumors. Cowden syndrome is the only known familial syndrome with an increased risk of both follicular thyroid adenoma (FA) and carcinoma (FTC). Germline mutations in the tumor suppressor gene PTEN, which encodes a dual-specificity phosphatase, have been found in up to 80% of patients with Cowden syndrome suggesting a role of PTEN in the pathogenesis of follicular thyroid tumors. Although somatic intragenic mutations in PTEN, which maps to 10q23.3, are rarely found in follicular tumors, loss of heterozygosity (LOH) of markers within 10q22-24 occurs in about 25%. Recently, another phosphatase gene, MINPP1, has been localized to 10q23.3. MINPP1 has the ability to remove 3-phosphate from inositol phosphate substrates, a function that overlaps that of PTEN. Because of this overlapping function with PTEN and the physical location of MINPP1 to a region with frequent LOH in follicular thyroid tumors, we considered it to be an excellent candidate gene that could contribute to the pathogenesis of follicular thyroid tumors. We analyzed DNA from tumor and corresponding normal tissue from 23 patients with FA and 15 patients with FTC for LOH and mutations at the MINPP1 locus. LOH was identified in four malignant and three benign tumors. One of these FTCs with LOH was found to harbor a somatic c.122C > T or S41L mutation. We also found two germline sequence variants, c.809A > G (Q270R) and IVS3 + 34T > A. The c.809A > G variant was found in only one patient with FA but not in patients with FTC or normal controls. More interestingly, IVS3 + 34T > A was found in about 15% of FA cases and normal controls but not in patients with FTC. These results suggest a role for MINPP1 in the pathogenesis of at least a subset of malignant follicular thyroid tumors, and MINPP1 might act as a low penetrance predisposition allele for FTC.

Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties.

In hereditary medullary thyroid carcinoma (MTC), few genotype-phenotype correlations have been established. RET genotypes (exons 10, 11, 13, and 14) of 63 patients with hereditary MTC (from November 1994 to October 1999) were correlated with age at diagnosis, sex, the TNM system, and basal calcitonin levels. Mutations in exons 10, 11, 13, and 14 were demonstrated in 22% (14 of 63), 54% (34 of 63), 21% (13 of 63), and 3% (2 of 63). The median ages at diagnosis differed significantly (38, 27, 52, and 62 yr; P = 0.003). When grouped by cysteine codons (exons 10 and 11 vs. exons 13 and 14), this difference became even more evident (30 vs. 56 yr; P = 0.001). Apart from age at diagnosis, no other significant associations were noted. Based hereon, three MTC risk groups were devised according to genotype: a high risk group (codons 634 and 618) with the youngest ages of 3 and 7 yr at diagnosis; an intermediate risk group (codons 790, 620, and 611) with ages of 12, 34, and 42 yr; and a low risk group (codons 768 and 804) with ages of 47 and 60 yr, respectively. Age at diagnosis was unrelated to specific nucleotide and amino acid exchange within each codon. The current data demonstrate that there is a significant genotype-phenotype correlation, allowing for a more individualized approach to the timing and extent of prophylactic surgery.

Thyroid carcinoma invading the cervicovisceral axis: routes of invasion and clinical implications.

BACKGROUND: Controversy exists about the routes of invasion (extrathyroidal versus lymphogenic extension) when differentiated carcinoma (DTC) and medullary thyroid carcinoma (MTC) invade the cervicovisceral axis (ie, larynx, trachea, esophagus). METHODS: We carried out an institutional analysis, from November 1994 to October 1999, of 451 consecutive patients undergoing surgery for DTC and MTC. RESULTS: Irrespective of tumor entity, carcinomas with cervicovisceral invasion (n = 34) were significantly larger and displayed higher pT categories (mainly pT4) than noninvasive carcinomas. In invasive papillary thyroid carcinoma (PTC) and MTC, the rates of positive lymph nodes were significantly higher than in noninvasive controls. When separate logistic regression analyses were fitted for laryngeal, tracheal, and esophageal invasion, extrathyroidal growth (pT4) consistently was a significant factor predictive of invasion in both DTC and MTC, with relative risks of 10.9 to 67.8. As the routes of invasion are similar in DTC and MTC, all data were pooled for multivariate analyses. Herein, the pN1 category had a significant impact only on esophageal invasion, with a relative risk of 4.7. CONCLUSIONS: Invasion of the cervicovisceral axis is more often caused by extrathyroidal growth than by nodal metastasis. To keep nodal metastasis from encroaching onto the cervicovisceral axis, paratracheal and paraesophageal lymph nodes should be cleared from the cervicocentral compartment at the primary operation.

Hypercalcitoninemia in a sporadic asymptomatic neuroendocrine tumor of the pancreatic tail.

BACKGROUND/AIM: Asymptomatic neuroendocrine tumors of the gastroenteropancreatic tract represent a significant challenge in terms of postoperative monitoring. METHODS: A case report of a calcitonin-secreting asymptomatic neuroendocrine tumor of the pancreatic tail is presented. RESULTS: Hypercalcitoninemia was noted in the 76-year-old Caucasian man who had a recurrent neuroendocrine tumor of the pancreatic tail. Upon pentagastrin stimulation, basal calcitonin increased only moderately from 82.3 (<10) to 100.9 and 125 pg/ml after 2 and 5 min, respectively. Surgical removal of the neuroendocrine tumor resulted in postoperative normalization of both basal and stimulated serum calcitonin levels. On immunohistochemistry, the neuroendocrine tumor was positive for calcitonin. CONCLUSION: Routine measurements of serum calcitonin might be a highly sensitive adjunct capable of identifying a subset of neuroendocrine tumors in which calcitonin monitoring may aid in the early detection of postoperative recurrence.

Regulation of proliferation and apoptosis in sporadic and hereditary medullary thyroid carcinomas and their putative precursor lesions.

C-cell hyperplasia (CCH) and medullary thyroid carcinoma (MTC) in patients affected by germline mutations of the RET oncogene represent an exceptional opportunity to study the regulation of proliferation and apoptosis during tumour initiation and progression. In 56 specimens [CCH, n=1; MTC with CCH, n=26; MTC, n=20; lymph-node metastasis (LNM), n=9] from 46 patients [multiple endocrine neoplasia type 2a (MEN2a), n=24; MEN2b, n=2; familiar MTC (FMTC), n=4; sporadic MTC, n-16] and 3 cases of non-neoplastic CCH, proliferation activity (MIB1), the rate of apoptosis [dUTP nick end labelling (TUNEL)] and expression of p53, bcl-2, bcl-x and bax were investigated and compared with clinical data. In MEN-associated CCH and small MTC, bcl-2 was strongly expressed, bcl-x was moderately expressed and bax was only weakly expressed. Advanced tumours and LNM did show a more heterogeneous bcl-2 staining accompanied by an increased bax expression and accelerated proliferation. The rate of apoptosis was extremely low in all investigated tumours. P53 was detectable in three patients with rapidly growing and extensively metastasising MTC. No somatic p53 mutations were found. Hereditary MTC with germline RET mutations at codon 918 (MEN2b) and codon 634 revealed a bias towards a higher proliferation activity at a younger age and are more frequently accompanied by LNM. CCH and MTC are characterised with a preponderance of bcl-2 as a factor blocking the programmed cell death. While MTC, in general, is a slowly growing tumour, a minority of tumours do progress rapidly with high proliferation. The factors leading to an accelerated tumour progression do not seem to take their effect via the regulation of apoptosis. Certain alterations of RET are supposed to have a direct or indirect implication on proliferation and, because of this, an effect on the clinical course.

Lymphepithelioma-like carcinoma of the lacrimal gland.

In this report a patient with a lymphoepithelioma (LE)-like carcinoma of the lacrimal gland is described for the first time in the literature. LE-like carcinomas outside the nasopharynx rarely occur in the major and minor lacrimal glands of natives of Greenland, Inuit or natives of southern China. The patient's tumor was extirpated using a Kronlein approach followed by total parotidectomy and modified radical neck dissection on the ipsilateral side after the detection of suspicious lymph nodes by ultrasound transmission. Adjuvant radiochemotherapy with cisplatin and 5-fluorouracil was then carried out. Three years later there is no sign of recurrence. As a result of this case we recommend careful examination of the orbit and lacrimal gland in cases of LE-like cancer with an unidentified primary tumor.

Glycohistochemical monitoring of chemically induced sarcomas at different stages of tumorigenesis.

Malignant soft tissue tumors still represent a source of uncertainty and controversy concerning histogenetic origin and histological behavior. Considering this, chemically induced sarcomas furnish an attractive model for the elucidation of cellular alterations during tumorigenesis. This approach allows us to closely follow cyto- and histological changes within coherent stages of tumor development. The specimen under scrutiny comprised 35 rat tissue samples from day 10 up to day 200 after benzo[a]pyrene injection. Additionally, for comparison and validation two human malignant fibrous histiocytomas (MFH) were investigated. The essential biological significance of protein-carbohydrate interactions warranted the histochemical application of synthetic tools (neo-glycoproteins-NGP) and lectins in order to reveal phenotypical dynamics in this aspect throughout the process of tumor development. Namely, 6 plant lectins (carbohydrate-binding proteins with defined saccharide specificity), 7 custom-made synthetic NGP (as the corresponding ligands visualizing endogenous lectins) and additionally three antibodies were employed. Characteristic cell populations were histochemically demonstrated in four stages of tumor development: exudation (n = 5), mesenchymal proliferation (n = 7), atypical granulation tissue (n = 7) and sarcoma (n = 16). Changes of glycohistochemical binding patterns were in close phenotypic relation to cellular activity, differentiation, local distribution as well as malignant transformation and tumor progression. At present, the new glycobiological features of the malignant phenotype substantiate the assumption that not only glycosylation but also the receptor display is altered upon carcinogenesis. In conclusion, this chronological longitudinal study takes advantage of the combination of a coherent model of tumorigenesis with innovative histochemical tools whose ligands are supposed to act as mediators of cell-cell- and cell-matrix interactions. It clearly demonstrates the suitability of the glycohistochemical method for comparative approaches. The systematic analysis of glycohistochemical determinants will improve our understanding of the early tumor biological processes with potential implications for therapeutic interventions.

Simultaneously occurring liver metastases of pheochromocytoma and medullary thyroid carcinoma--a diagnostic pitfall with clinical implications for patients with multiple endocrine neoplasia type 2a.

Malignant pheochromocytoma is an exceptional complication in patients with Multiple Endocrine Neoplasia Type 2a (MEN2a). In this paper, we report on a 53-year-old male patient with an evident RET gene germline mutation, who simultaneously developed hepatic metastases of medullary thyroid carcinoma (MTC) and pheochromocytoma. Comprehensive immunohistochemical investigations were performed to elaborate markers which could be useful for differentiating between MTC metastases and pheochromocytoma, respectively. Calcitonin and CEA, in particular cytokeratins and trefoil factor family 1 (TFF1), were detectable exclusively in MTC, whereas all the other markers revealed a comparable expression in both MTC and pheochromocytoma. The only clues that could indicate a potential malignant course were size, a lack of sustentacular cells and hyaline globules, and a focal spindle cell pattern in pheochromocytoma. Owing to a wide agreement in cellular differentiation and a lack of specific, routinely applicable markers for pheochromocytomas, a comprehensive and goal-directed immunohistochemistry is required to rule out pheochromocytoma metastasis in patients with MEN2a. A misinterpretation could lead to harmful clinical complications, as shown in the present case.