Early granulomatous foreign body reactions to a novel alginate dermal filler: the system's failure?

BACKGROUND: Cutaneous granulomas after a soft filler injection represent one of the worst scenarios for both patient and injector. OBJECTIVES: To present clinical and histopathological features of granulomatous nodular reactions induced by a new alginate-based dermal filler (Novabel(®)), and put it in context of the process of injectable soft tissue fillers approval and promotion in the EU. METHODS: A case series of four patients injected with Novabel(®) for volume restoration of the face and hands, who developed severe foreign body reactions. RESULTS: Four patients injected with Novabel(®) into tear troughs and/or dorsa of hands developed severe granulomatous reactions within months after injections. As we injected with the new filler into a total of 10 patients, a high incidence of 40% of the disfiguring adverse effect was observed. The inadequate response of manufacturer to our reporting the side-effects along with the available data on registration process of dermal fillers confirmed that the area is not well-regulated. CONCLUSIONS: The status of dermal fillers as class III medical devices, and the process of their approval and marketing in the EU need to be seriously reconsidered to avoid unnecessary and serious adverse reactions.

Subcutaneous injection of liquid and foamed polidocanol: extravasation is not responsible for skin necrosis during reticular and spider vein sclerotherapy.

BACKGROUND: Cutaneous necrosis is one of the most annoying complications of reticular and spider vein sclerotherapy. The precise incidence of the complication is not known, although various sources reported incidence between 0.2% and 1.2%. Among a few mechanisms proposed to explain it, extravasation of the sclerosant into the perivascular tissue has been cited as the major cause. OBJECTIVES: The aim of the experimental study in rats was to examine the potential of various concentrations and volumes of polidocanol in both liquid and foam forms to cause cutaneous necrosis after superficial subcutaneous injection. METHODS: Twenty-four female Sprague Dawley rats were injected subcutaneously different concentrations (0.5%, 1%, 2% and 3%) of polidocanol as well as different preparations of polidocanol (liquid vs. foam) and volumes (0.1-0.5 mL). The animals were sacrificed 10 days after injections and biopsy specimens were obtained. RESULTS: Cutaneous necrosis was not seen at volumes <0.5 mL regardless of the concentration or form of polidocanol injected. Foam preparation was shown to be less potent in inducing necrosis with a minimal strength being 2% in comparison with the liquid form where 1% was sufficient to produce overt cutaneous necrosis. CONCLUSIONS: This experimental study shows that extravasation of polidocal in usual circumstances of sclerotherapy of spider and reticular veins cannot be a significant cause of cutaneous necrosis rarely observed in this setting. It is particularly true for the foamed polidocanol where 1% strength seems safe if injected extravascularly in volumes up to 0.5 mL.

[Minimally invasive follicular thyroid carcinoma : Not always total thyroidectomy]. / Minimal-invasives follikuläres Schilddrüsenkarzinom : Eine Thyreoidektomie ist nicht obligat.

Current treatment guidelines for follicular thyroid carcinoma (FTC) recommend total thyroidectomy, lymphadenectomy and radioiodine ablation. Considering the low malignant potential of minimally invasive follicular thyroid carcinoma (MIFTC), a limited radical therapeutic procedure may be adequate. MIFTC is an intensely discussed group of tumors and a review of the literature reveals disagreement among experts concerning the criteria for a distinct definition. Therefore, in 2005 Rosai proposed a clinically more significant classification of FTC based on the extent of capsular and vascular invasion: MIFTC with capsular invasion only, with limited (< or =3) vascular invasion, encapsulated FTC with extensive (>3) vascular invasion and broadly invasive FTC with extensive invasive growth.For the diagnosis of MIFTC a complete investigation of the encapsulated follicular lesion should be performed by the pathologist and examination of at least 10 tissue blocks is mandatory. Due to the excellent prognosis hemithyroidectomy constitutes an adequate therapeutic approach in MIFTC with capsular invasion only and may also be considered for MIFTC with limited vascular invasion. There are no indications for systematic lymphadenectomy.

[Ossification in the carpal tunnel as a rare cause for untypical carpal tunnel syndrome]. / Ossifikation im Karpalkanal als seltene Ursache für ein atypisches Karpaltunnelsyndrom.

There are typical causes for carpal tunnel syndromes as well as a series of rare causes. Furthermore, the clinical image can also be untypical. This report is about a 59-year-old female patient with an untypical clinical symptomatology and with a rare cause: there was no major pain during the night or in the morning, no paraesthesias and no impairment of the fine motor skills, nevertheless, there were rapid paraesthesias and pain in the first three fingers of the right hand immediately after hyperextension of the wrist. Although the discomforts had already existed for 2 years they were not recognised properly because they were untypical and incomplete and neurography was negative. 3 years later in a renewed examination X-ray pictures of the carpus were taken and a 4 x 6 x 8 mm big ossicle on the ground of the carpal canal was found, the computed tomography and the intraoperative situs confirmed the image. The histology gave the diagnosis of a loose osteochondral body. Postoperatively the patient was quickly was free of the symptoms.

Desmoplasia in medullary thyroid carcinoma: a reliable indicator of metastatic potential.

AIMS: To evaluate the reliability of desmoplasia as a reproducible morphological parameter indicating the metastatic potential of medullary thyroid carcinoma (MTC). METHODS AND RESULTS: One hundred and twenty cases of MTC of the Medical University of Vienna, Austria and 76 cases from the School of Medicine of Marseille, France were analysed for the presence of desmoplastic stroma reaction by four endocrine pathologists. Intra- and interobserver concordance was assessed. The Austrian cases were also analysed for various morphological parameters. Intra- and interobserver concordance were highly significant with a kappa value of 0.883 for intra-observer reliability and 0.837, 0.79 and 0.758, respectively, when pathologists N.N., C.D.M. and K.W.S. reviewed the Austrian cases. The cases from France were reviewed by C.D.M. and K.K. with a kappa value of 0.759. None of the cases that were categorized as desmoplasia negative by any of the investigators showed lymph node metastasis. No other distinct morphological characteristics could be assigned to the MTCs without desmoplasia. CONCLUSIONS: Our data indicate desmoplasia to be a reliable and highly reproducible parameter with regard to lymph node metastatic potential.

Sporadic versus familial medullary thyroid microcarcinoma: a histopathologic study of 50 consecutive patients.

By means of calcitonin screening programs, sporadic and hereditary medullary thyroid carcinoma (MTC) can be detected at an early stage. We investigated the histopathologic findings of 16 familial (mean age 32 +/- 21 years, female/male ratio 1.6:1) and 34 sporadic (mean age 58 +/- 15 years; female/male ratio 2.4:1) MTCs with stage T1 comparatively. Patients with hereditary tumors were younger. Hereditary tumors were more often found multifocal (13 of 16 vs 3 of 34; p < 0.001), bilateral (11 of 16 vs 3 of 34; p < 0.001), displaying desmoplastic stroma (14 of 16 vs 19 of 34; p = 0.02), and accompanied by C cell hyperplasia (16 of 16 vs 24 of 34; p = 0.01), but all of these factors were present in some sporadic patients. Only tumors with desmoplastic stroma showed lymph node metastasis, which was observed in eight of the 50 patients. After surgery all patients showed permanent normalization of calcitonin levels. We conclude that 1) morphologic parameters considered to indicate familial MTC risk are of no value in the individual patient, 2) many sporadic MTCs develop on the background of CCH, 3) tumors with desmoplastic stroma are more likely to develop lymph node metastasis, and 4) early detection of MTC permits curative surgery in the majority of patients.

Latent carcinoma of the thyroid in Austria: a systematic autopsy study.

Data concerning the incidence of latent thyroid carcinoma (LTC) in populations with endemic goiter are scarce. Despite the introduction of iodine goiter prophylaxis in the early sixties, iodine supply is still insufficient in Austria and goiter remains endemic. This is the first detailed study dealing with epidemiological features of LTC at autopsy in Austria. A total of 118 thyroid glands were included in the study. The glands were serially sectioned at 2- to 3-mm intervals, embedded in paraffin and histologically examined for the presence of LTC. In addition, the incidence and severity of lymphocytic thyroiditis (LT) were evaluated. Ten thyroids were found to contain LTC (8.6%). All were of the papillary type. The mean tumor dimension was 4.9 mm +/- 3.2, the smallest lesion measuring 1 mm. Only the largest tumor slightly exceeded the extent of a microcarcinoma and measured 10.5 mm. Multifocal disease was present in three cases (30%). The prevalence of latent papillary thyroid carcinoma (LPTC) was 6.6% (n = 4) in females and 10.5% (n = 6) in males. The mean age of the subjects with LPTC was 67.7 +/- 14.4 yr, range 37 to 77 yr. Goitrous thyroids were seen in 33 cases (28%): One gland was diffusely enlarged and 32 (27.1%) enlarged glands were nodular goiters. The overall prevalence of LT was 30.5% (n = 36) and the only type of thyroiditis observed was focal lymphocytic thyroiditis (FLT). There was no correlation between the presence of LPTC and goiter, the presence of FLT and the subjects' age and sex. The incidence of LPTC in Austria is similar to that in nongoitrous regions. The adult population at large seems to be uniformly exposed to factors involved in the initiation and early growth of papillary thyroid carcinoma (PTC). This suggests that the levels of iodine intake only play a minor role in the early phase of the carcinogenesis of PTC, but may be of some importance in the progression of LPTC to clinically evident PTC.

Primary invasive signet-ring cell melanoma.

The histopathological variants of malignant melanoma include the common type (lentigo maligna, superficial spreading melanoma, nodular melanoma, acrolentiginous melanoma), spindle cell, desmoplastic, balloon cell, pleomorphic (fibrohistiocytic), myxoid, small cell melanoma and malignant blue nevus. Recently, signet-ring cell melanoma was introduced as an additional cytologic variant. We describe a 72-year-old patient with a primary signet-ring cell melanoma of the skin located on the upper arm. Histopathologic examination disclosed a melanocytic tumor extending from the epidermis to the deep reticular dermis. Numerous pleomorphic tumor cells showed large, intracellular vacuoles and oval to spindle-shaped nuclei at their periphery. Mitotic figures and multinucleated melanocytes were also observed. Some of the signet-ring cells exhibited cytoplasmatic periodic acid-Schiff (PAS)-positivity. Immunohistochemistry showed positive reaction of the tumor cells for S-100, HMB-45 protein and vimentin, confirming their melanocytic differentiation. Tumor cells were negative for cytokeratins, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA). The signet-ring cell melanoma disclosed an invasion to Clark Level IV and tumor thickness of 2.2 mm. Signet-ring cell melanoma is a rare morphologic variant of melanoma. Its recognition is important for differentiation from other tumors featuring signet ring cells.

C-cell hyperplasia and medullary thyroid carcinoma in patients routinely screened for serum calcitonin.

Routine screening of calcitonin serum levels in patients with nodular thyroid disorders has led to an increased rate of total thyroidectomies. We investigated prevalence and interrelationship of C-cell hyperplasia (CCH) and medullary thyroid carcinoma (MTC) in patients with thyroid and parathyroid disorders that showed increased calcitonin serum levels detected by routine screening. Within two years, 30 (mean age, 60 +/- 14 years) of 667 patients had a pentagastrin-stimulated calcitonin level of more than 100 pg/mL. All 30 underwent total thyroidectomy and were tested for germ-line mutations of the ret protooncogene. Entire surgical specimens were blocked, and C-cell disorders were assessed using conventional histology and immunohistochemistry. C-cell hyperplasia was defined by the presence of more than 50 C cells/l low-power field in both lobes and was classified as focal, diffuse, nodular, or neoplastic. Nineteen patients (female/male = 14/5) had MTC, and 11 males but no females had CCH only. Six of 16 patients with sporadic MTC had concomitant CCH. Three patients were index cases of new MTC families. We conclude that MTC with concomitant CCH is an unreliable marker for hereditary MTC risk and that CCH has a preneoplastic potential in the absence of germ-line mutations. In this series, CCH alone was not found in females.

Establishment of primary cultures from human colonic tissue during tumor progression: vitamin-D responses and vitamin-D-receptor expression.

Primary cultures derived from pre-cancerous and cancerous human colon tissue are essential for understanding normal and abnormal growth function in the large intestine. Here presented are (i) the methodology for routine establishment of primary cultures of normal, adenoma- and carcinoma-derived cells, and (ii) data for the apparently protective role of vitamin-D compounds in colon carcinogenesis. The steroid hormone 1,25-dihydroxyvitamin D3 and some non-hypercalcemic analogs reduce the high mitotic rate of adenoma cells to that of normal colonocytes. After vitamin-D treatment, tumor cells are less proliferative and differentiation is enhanced. Primary-colon-cancer cultures display a mosaic pattern of vitamin-D-receptor expression, at the mRNA level and at the protein level, with varying intensity of expression in positive cells. This suggests that, in human colorectal tumors in vivo, a large fraction of cells will respond to genomic action of vitamin-D compounds.

Peritumoral tissue reaction at transrectal US as a possible cause of overstaging in rectal cancer: histopathologic correlation.

PURPOSE: To assess if peritumoral tissue reaction (PTR) can be differentiated from tumor with transrectal ultrasound (TRUS) to avert overstaging. MATERIALS AND METHODS: Preoperative TRUS results in 40 consecutive patients with biopsy-proved rectal cancer were compared with histopathologic reports on the specimens (study 1). To test the hypothesis that areas more anechoic than the tumor were deemed responsible for incorrect staging in study 1, a prospective study was undertaken in another 40 consecutive patients (study 2). The thickest part of PTR was measured, and results were compared with the histopathologic findings. RESULTS: In study 1, 28 (70%) of 40 rectal cancers were staged correctly with TRUS. PTR was responsible for the misinterpretation in six of seven overstaged cases. In study 2, 38 (95%) of 40 cancers were staged correctly, and the presence or absence of PTR was described in 39 cases (98%). A statistically significant positive correlation was noted between histopathologic classification of PTR and its thickness measured with TRUS (P = .0001). CONCLUSION: Because of its more anechoic appearance, PTR may be differentiated from the tumor by means of TRUS. This may lead to a statistically significantly higher accuracy of TRUS in the staging of rectal cancer due to the avoidance of overstaging.

In vitro and in vivo studies of three radiolabelled somatostatin analogues: 123I-octreotide (OCT), 123I-Tyr-3-OCT and 111In-DTPA-D-Phe-1-OCT.

Scintigraphy with long-acting somatostatin (SST) analogues may be useful for the localization of tumours expressing receptors (R) for SST. In this study we have analysed the in vitro and in vivo binding properties of three SST analogues, 123I-octreotide (OCT), 123I-Tyr-3-OCT and 111In-DTPA-d-Phe-1-OCT. In vitro binding studies performed with a variety of primary tumours (n=48) as well as with several tumour cell lines (A431, HT29, PANC1, COLO320, HMC1, KU812) indicated significant in vitro binding of these three radiolabelled SST analogues to two subpopulations of SSTR, high (Kd 0.2-2.0 nM) and low (Kd 5-15 nM) affinity ones. The number of SSTR on tumour cells was at least a 1000-fold higher as compared with normal peripheral blood cells. Comparative scintigraphic studies using 123I-OCT and/or 123I-Tyr-3-OCT and/or 111In-DTPA-d-Phe-1-OCT were performed in 21 patients with histologically verified intestinal carcinoid tumours. Corresponding scintigraphic results were obtained in 18 of 21 patients investigated with two different SSTR ligands, either 123I-OCT/123I-Tyr-3-OCT (four of five), 123I-OCT/111In-DTPA-d-Phe-1-OCT (eight of nine), or 123I-Tyr-3-OCT/111In-DTPA-d-Phe-1-OCT (six of seven). We conclude that various tumours express high amounts of SSTR which are recognized by three radiolabelled SST analogues: 123I-OCT, 123I-Tyr-3-OCT and 111In-DTPA-d-Phe-1-OCT. Differences between these SST analogues in their in vitro binding and/or in vivo scanning properties are observed in a minority of patients. Thus, the labelling of OCT with iodine may be an alternative approach for those nuclear medicine departments for which 111In-DTPA-d-Phe-1-OCT is not easily available, or is too expensive.

Technetium-99m-galactosyl-neoglycoalbumin combined with iodine-123-Tyr-(A14)-insulin visualizes human hepatocellular carcinomas.

UNLABELLED: Human hepatocellular carcinoma (HCC) is the most frequent primary hepatic malignancy and its diagnosis by conventional methods is still difficult. We hypothesized that the expression of specific receptors could possibly be used to improve in vivo localization of HCC with specific receptor-based radioligands. METHODS: In initial in vitro studies, receptor binding of 99mTc-galactosyl-neoglycoalbumin (99mTc-NGA) and 123I-Tyr-(A14)-insulin to HCC was investigated. Scintigraphy was performed in 45 patients with histologically confirmed HCC using either 99mTc-NGA (75-150 MBq; 25-50 nmole, n = 27) and/or 123I-Tyr-(A14)-insulin (100-150 MBq; 7.5-10 micrograms, n = 30). RESULTS: HCC (1256 +/- 290 pmole bound/mg protein, Kd = 3.4 +/- 2.9 nM) expressed a 1000-fold higher number of specific receptors for 123I-Tyr-(A14)-insulin compared to normal liver tissue (2.4 +/- 0.8 pmole bound/mg protein, Kd = 4.2 +/- 2.4 nM), whereas HCC did not express receptors specific for 99mTc-NGA. All HCC lesions were identified as cold spots after injection of 99mTc-NGA, whereas 123I-Tyr-(A14)-insulin accumulated in these lesions, indicating HCC-to-normal liver ratios of 1.6 +/- 0.4 in the mean. Subtraction images obtained from planar studies visualized 123I-Tyr-(A14)-insulin in HCC lesions detected by 99mTc-NGA as cold spots. CONCLUSION: This hepatocyte receptor-specific, double-tracer method using 99mTc-NGA and 123I-Tyr-(A14)-insulin could become clinically useful in the diagnosis of HCC.

The clinical value of urinary cytology: 12 years of experience with 615 patients.

AIMS: To analyse the diagnostic value of cytological examination compared with histological findings in a large series of patients (n = 615) with tumours of the urinary tract epithelium. METHODS: Cytological examinations (n = 785) after bladder washing and exfoliative cytology were retrospectively compared and correlated with histological findings. In addition, 1527 bladder washings were obtained during follow up of patients after transurethral resection of bladder tumours. RESULTS: Cytology in bladder washings (overall diagnostic accuracy 66%) provides considerably more information that exfoliative cytology (overall accuracy 49%). Cytological examinations (n = 1125) in patients with bladder tumours receiving intravesical cytostatic drugs (for example, mitomycin C) yielded suspicious or positive results in 28% of patients, without being confirmed by endoscopy during follow up. CONCLUSION: Our results illustrate two major drawbacks of urinary cytology. First, a high rate of false positive results in patients on intravesical chemotherapy. Second, a high rate of false negative results in highly differentiated carcinomas, stressing the need for additional diagnostic tests such as staining with monoclonal antibodies directed against tumour antigens or assessment of ploidy.

Aldosterone and testosterone producing adrenal adenoma in childhood.

An 8-year-old boy presented with precocious puberty and hypertension. He had hypokalemia, increased serum aldosterone and testosterone levels and low plasma renin activity. An adrenal adenoma was found using imaging methods and was removed. Postoperatively aldosterone, testosterone and blood pressure returned to normal. Renal ultrasonography findings were consistent with nephrocalcinosis, which might be explained by long lasting hypokalemic metabolic alkalosis and hypercalciuria. Precocious pseudopuberty progressed into true puberty due to the maturational effect of testosterone. Nephrocalcinosis was still present 8 years later and hypertension was recurring obviously as a consequence of increased peripheral resistance.

CD15 (LeuM1) immunoreactivity: prognostic factor for sporadic and hereditary medullary thyroid cancer? Study Group on Multiple Endocrine Neoplasia of Austria.

Patients treated for sporadic and hereditary medullary thyroid carcinoma (MTC) have varying rates of persistent disease, recurrence, and survival. The aim of this study was to correlate the immunoreactivity of the monoclonal antibody CD15 (LeuM1) to initial clinical findings and the outcome of treatment. The primary tumors of 75 patients with sporadic MTC, 7 with hereditary disease, and 3 members of MEN 2A families were studied. Of these subjects 74 (87%) showed no or little immunoreactivity (< 15% positive cells; score 0) in most tumors. The remaining 13% had surgery for tumors with more than 15% cells with positive staining (score I). There was no correlation between LeuM1 immunoreactivity and sex, age, and type of MTC. There was, however, a significant correlation with the pTNM classification and UICC staging. The prognosis for patients with score 0 was significantly better than score 1 patients. CD15 immunoreactivity appears to be a predictive factor in sporadic and hereditary MTC. Lymph node dissection seems to be more successful in patients with score 0 tumors than in those with score 1 tumors. The question of reoperation in patients with recurrence of disease (especially with biochemical recurrence or persistence) should be discussed on the basis of CD15 immunoreactivity.

[Histologic classification of epithelial salivary gland tumors]. / Histologische Klassifikation epithelialer Speicheldrüsentumore.

A precise and reproducible histopathological classification, in combination with grading and staging, is the basis for determining the prognosis and treatment of salivary gland tumors. The 2nd edition of WHO Histological Typing of Salivary Gland Tumors, as well as the staging according to UICC 1989, is oriented towards the routine work of surgical pathologists. Knowledge about the important entities of this classification is an indispensable foundation for successful therapy and interdisciplinary cooperation.

Cross-competition between vasoactive intestinal peptide and somatostatin for binding to tumor cell membrane receptors.

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide with a wide range of biological activities. Recent data suggest that functional VIP receptors are expressed on various tumor cells. Somatostatin (SST) and its long-acting analogue octreotide (OCT) are potent inhibitors of tumor cell growth and secretion. In the present study, the interactions between VIP and SST/OCT on primary tumors (insulinomas, n = 3; VIPomas, n = 2; intestinal adenocarcinomas, n = 5; neuroblastomas, n = 5; papillary thyroid cancers, n = 7; carcinoids, n = 5; ductal breast cancers, n = 8; small cell lung cancers, n = 3; ACTH-producing hypophyseal adenomas, n = 5; pheochromocytomas, n = 5) as well as on tumor cell lines (A431, HT29, PANC1, COLO320, HMC1, and KU812 cells) were analyzed by use of 123I-labeled VIP and 123I-labeled Tyr-3-OCT. Cross-competition between VIP and SST/OCT for binding to tumor cells was observed. The rank-order of potency for displacement of 123I-labeled VIP binding to intact A431 cells was VIP [concentration causing half-maximal inhibition (IC50) = 2.9 +/- 1.9 (SD) nM] > OCT (IC50 = 9.3 +/- 1.7 nM) = SST > substance P = secretin (IC50 = 1 microM). Binding of 123I-labeled Tyr-3-OCT to A431 cells, in turn, was inhibited by OCT = Tyr-3-OCT (IC50 = 1.5 +/- 0.3 nM) = SST > VIP (IC50 = 4.9 +/- 1.1 nM). This rank-order of potency was also obtained for primary tumors and tumor cell lines. Furthermore, SST and OCT inhibited VIP-induced [3H]thymidine incorporation, cyclic AMP formation, and tyrosine kinase activity with IC50 values < 10 nM. Together, these data provide evidence for functional interactions between SST and VIP on various tumor cells. These interactions may involve peptide cross-competition at cellular binding sites and may have implications for the biology and pathophysiology of respective cells and disease states.

[Ultrasound-guided fine-needle biopsy with an automatic full-incision system: the initial experiences and comparison with a conventional biopsy gun]. / Ultraschallgezielte Feinnadelbiopsie mit einem automatischen Vollschnittsystem: erste Erfahrungen und Vergleich mit einer konventionellen Biopsiepistole.

The purpose of this study was to evaluate the efficacy of a new automatic biopsy device (Autovac, Angiomed, Karlsruhe, Germany) in ultrasound (US) guided biopsies of focal abdominal lesions. 50 consecutive patients with focal abdominal lesions underwent US guided biopsies. In the first 24 patients, needle passes were performed with the Autovac system (outer diameter 0.95 mm) as well as with the Biopty gun (outer diameter 0.9 mm) (Bard Covington, USA). The size and the quality of the histologic and the cytologic material obtained by both systems were evaluated by histopathologists blinded to the system used. Autovac yielded significantly more material (defined as the area of the obtained tissue cores) and a significantly higher quality score than did the Biopty system. 96% of the histologic specimen and 100% of the cytologic smears obtained with Autovac were diagnostic, compared to 70 and 81% with Biopty, respectively. With the exception of a short-time elevation of the blood pressure in one patient, no complications occurred. The results indicate an advantage of the automatic full-cut type system Autovac over the tru-cut type Biopty gun in US-guided biopsies of focal abdominal lesions.

Secretogranin IV immunoreactivity in medullary thyroid carcinoma: an immunohistochemical study of 62 cases.

The presence and intracellular distribution of secretogranin IV (Sg IV) was determined on light microcop by the avidin-biotin peroxidase complex method with the monoclonal antibody (mAb) Hisl-19 in normal and hyperplastic C-cells, in 62 primary medullary thyroid carcinomas (MTCs) and in 17 MTCs in tissue from synchronous and/or metachronous lymph node metastases and in one liver metastasis. Sg IV immunoreactivity was present in almost all normal-looking and hyperplastic C-cells, in 59 of 62 (96%) of the primary tumours, in 18 of 26 (69%) lymph node metastases and in distant metastasis. Sg IV reactivity ranged from small foci of positive tumour cells to a reaction in virtually every malignant cell. Two different staining patterns were obvious: a granular cytoplasmic reactivity and a perinuclear cluster-type signal. Normal-appearing and hyperplastic C-cells were characterized by a uniform granular staining often coexisting with discrete cluster-type immunoreactivity. Various combinations of these staining patterns were observed in C-cell carcinomas. The pure cluster-type reactivity was restricted to malignant C cells and was not detected in normal-appearing and hyperplastic C-cells. In serial sections immunohistochemical results for Sg IV, calcitonin (Ct) and chromogranin A (Cg A) showed only partial correlation. Depending on the area of the tumour chosen, immunohistochemical reactivity for Ct and Cg A might not be demonstrated in neoplastic C-cells, while staining for Sg IV was retained. The amount and type of Sg IV reactivity of MTCs was not correlated with the biological behaviour of the tumours. These results indicate that mAb Hisl-19 is an excellent marker for normal, hyperplastic and neoplastic C-cells. MAb Hisl-19 is especially useful in cases with weak or questionable reactivity for Ct and Cg A. The switch from the granular pattern to the perinuclear distribution seems to indicate a malignant transformation of C-cells and might prove useful an an additional diagnostic clue.