Immunohistochemical demonstration of ceruloplasmin in follicular adenomas and thyroid carcinomas

The presence of ceruloplasmin in follicular adenomas (15 cases) and thyroid carcinomas (39) and two Hürthle cell tumours was investigated by immunohistochemical methods. Follicular adenomas were all negative whereas Hürthle cell tumours, follicular and papillary carcinomas exhibited various degrees of cytoplasmic positivity for ceruloplasmin. Highly atypical multinucleated cells and incorporated follicular structures observed in anaplastic carcinomas were positively stained; the spindle cell variety of these cancers was always negative for ceruloplasmin. Medullary carcinomas and normal thyroid tissue were constantly unstained. The distribution pattern of ceruloplasmin is the same as that of lactoferrin, a marker recently proposed for the differential diagnosis between follicular adenomas and thyroid carcinomas; these two glycoproteins are structurally related.     

The differentiation of atypical adenomas and encapsulated follicular carcinomas in the thyroid gland

Summary From 1968 to 1977 a total of 1,394 follicular neoplasms were seen in surgical material containing 4,612 thyroid glands. 1,159 tumors were obviously benign adenomas. All remaining follicular tumors with equivocal histological appearances were extensively re-examined, together with all apparently invasive follicular carcinomas. Thereby, 125 atypical adenomas, 55 encapsulated and 55 widely invasive follicular carcinomas were diagnosed. In 102 tumors a definite diagnosis was reached after excision and histological examination of ten tissue blocks from preserved wet material. In each case the number of blood vessel invasions and penetrations of tumor capsule was recorded. Among these tumors, 17/36 (47%) encapsulated carcinomas proved to be only slightly invasive. All their tissue blocks were cut into sequential sections and in 6/17 cases additional vascular invasions found. It was shown by this study that the proof of vascular invasion is more often successful than the proof of capsular penetration and therefore a better indication of malignancy in encapsulated follicular tumors. Examination of 10 tissue blocks represents the minimum effort to estimate the invasive capability of a follicular tumor, whereas sequential sections through less than 10 blocks are of little help in most cases. A follow-up study of all patients included here seems to justify the distinction we have made between atypical adenomas and encapsulated follicular carcinomas.

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Zusammenfassung In den Jahren 1968–1977 wurden insgesamt 1394 follikuläre Tumoren der Schilddrüse in einem Operationsgut von 4612 Strumen diagnostiziert. 1159 follikuläre Tumoren waren zweifelsfrei als Adenome einzuordnen. Alle übrigen follikulären Tumoren mit zunächst unklarer Dignität aber auch solche mit eindeutig invasivem Wachstum wurden histologisch eingehend nachuntersucht. Daraus resultierten 125 atypische Adenome, 55 weitgehend abgekapselte follikuläre Carcinome und 55 ausgedehnt invasive Carcinome. Bei 102 Tumoren stützte sich die endgültige Diagnose auf die histologische Nachuntersuchung von 10 Gewebsentnahmen aus dem kapselnahen Bereich. Dabei wurde die Zahl der Tumoreinbrüche in prae- oder postcapilläre Blutgefäße und die Zahl der kompletten Kapseldurchbrüche registriert. Bei 17/36 (47%) abgekapselten Carcinomen waren jeweils nur ein oder zwei Gefäßeinbrüche festzustellen. In diesen Fällen wurden die vorhandenen 10 Gewebsblöcke pro Tumor in 20 weiteren Schnittstufen aufgearbeitet und bei 6/17 zusätzliche Gefäßeinbrüche gefunden. Die quantitative Auswertung hat ergeben, daß der Nachweis von Gefäßeinbrüchen häufiger gelingt als der von Kapseldurchbrüchen und damit ein besserer Hinweis für die Malignität eines abgekapselten follikulären Tumors ist. Allerdings ist die Untersuchung von 10 Entnahmestellen das Minimum für eine zuverlässige Diagnose und mit Sicherheit nicht durch Schnittstufen mit weniger Gewebsblöcken zu erreichen. Der bisherige postoperative Verlauf aller in dieser Studie erfaßten Patienten rechtfertigt die nach den angegebenen Kriterien vorgenommene Unterscheidung zwischen atypischen Adenomen und abgekapselten follikulären Carcinomen.

     

Computerized nuclear morphometry in thyroid follicular neoplasms

Differential diagnosis of follicular adenoma (FA) and follicular carcinoma (FC) of the thyroid can be challenging in the routine practice of surgical pathology because the diagnosis of FC is strictly defined and identification depends on the presence of invasion of the capsule or blood vessels. These features may be equivocally presented in the histological sections and interpreted subjectively by different pathologists, so an objective approach to solve this problem is essential. Computerized morphometry is a scientific tool to evaluate cellular changes and it can enhance the interpretation of morphological features by the transformation of pathological changes in cells to a qualitative form. The present study investigated the diagnostic role of objective computerized nuclear morphometry in follicular neoplasms. Thirty-six cases of thyroid FC and 36 cases of FA from patients who were matched by age and sex were studied. Four nuclear parameters were selected and analyzed: mean nuclear area, mean nuclear perimeter, largest to smallest diameter ratio of the nuclei, and coefficient of variation of the nuclear area. The results indicate that all the chosen nuclear variables were significantly correlated with the FA and FC studied. In conclusion, computerized nuclear morphometry can be considered a helpful ancillary tool for differential diagnosis of FA and FC.     

Expression of matrix metalloproteinases in benign and malignant follicular thyroid lesions

AIMS: To examine expression of matrix metalloproteinases (MMPs) and related proteins in follicular thyroid lesions (FTLs) and to determine their usefulness for differential diagnosis of FTLs, particularly between minimally invasive carcinoma and adenoma. METHODS AND RESULTS: Six widely invasive follicular carcinomas (WIFCs), 15 minimally invasive follicular carcinomas (MIFCs), 19 follicular adenomas (FAs) and 10 adenomatous goitres (AGs) were analysed immunohistochemically for MMP-1, MMP-2, MMP-7, MMP-9, membrane-type 1-MMP (MT1-MMP) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2). MMP-1 was positive in all FTLs. MMP-2 and MMP-7 were positive in more than 80% of WIFC and MIFC cases, whereas they were negative in all FA and AG cases except one MMP-2+ FA (P < 0.001). MMP-9 stained positive significantly more in MIFC than FA or AG cases (P < 0.05, respectively). The positivity of MT1-MMP and TIMP-2 was different among some of the FTLs, but with no significant difference between MIFC and FA cases. In-situ hybridization of MMP-2 and MMP-7 mRNA in selected cases demonstrated the expression of these enzymes in the tumour cells as well as in some stromal cells. CONCLUSIONS: Our results confirm MMP expression mainly in malignant FTLs and suggest that MMP-2 and MMP-7 may be useful markers to distinguish MIFC from FA.     

Tumor-to-tumor metastasis to a thyroid follicular adenoma as the initial presentation of a colonic adenocarcinoma

The incidence of thyroid involvement by metastatic disease from distant organs ranges from an average of 3.1% in surgical series to 5.3% in autopsy series. However, the metastasis of one tumor into another (traditionally referred to as 'tumor-to-tumor metastasis') is distinctly uncommon. Typically, they are identified as new manifestations or necropsy findings of a known, pre-existing donor tumor. Herein is described the case of a 59-year-old woman whose thyroid nodule (a follicular adenoma) was resected and found to contain foci of a well-differentiated adenocarcinoma with a morphologic and immunohistochemical profile consistent with origination from the lower gastrointestinal tract. Subsequent diagnostic work-up revealed a sigmoid colon tumor with metastases to the liver. This is, to the authors' knowledge, the first reported example of a colon adenocarcinoma whose initial clinical manifestation was a metastasis to a thyroid neoplasm and only the third reported example of a colonic adenocarcinoma metastatic to a thyroid tumor. In a review of previously reported examples of tumor-to-tumor metastases involving a thyroid neoplasm as the recipient, the following features were present in the majority: (i) multifocality of the metastatic tumor aggregates; (ii) a total lack of, or only minimal amounts of reaction (desmoplastic, inflammatory or myxoid) of the recipient tumor to the metastatic deposits; and (iii) retention of the histopathologic characteristics of the donor tumor in the metastatic deposits. In general, strikingly divergent morphologic features in an otherwise typical thyroid neoplasm should elicit a differential diagnosis that takes into consideration the possibility of metastasis.     

Role of GPER1, EGFR and CXCR1 in differentiating between malignant follicular thyroid carcinoma and benign follicular thyroid adenoma

It is extremely difficult to discriminate between follicular thyroid carcinoma (FTC) and follicular thyroid adenoma (FTA) before surgery, because the morphologies of carcinoma cells and adenoma cells obtained by fine needle aspiration biopsy (FNAB) are similar. Molecular markers may be helpful on this issue. The purpose of this study was to assess the role of GPER1, EGFR and CXCR1 in differential diagnosis between FTC and FTA. GPER1, EGFR and CXCR1 mRNA expression levels were examined in 15 FTCs and 10 FTAs using real-time RT-PCR. FTC showed to have significantly increased mRNA levels of the three molecules compared to FTA (P < 0.001 for all the three molecules). GPER1, EGFR and CXCR1 protein expression in 106 FTCs and 128 FTAs were analyzed using immunohistochemistry. The rates of GPER1, EGFR and CXCR1 high expression were 73.6%, 72.6% and 70.8% in FTC and 30.5%, 28.1% and 27.3% in FTA, respectively. Statistical analysis showed that GPER1, EGFR and CXCR1 protein expression were correlated with one another in FTC and concomitant high expression of the three molecules had stronger correlation with the occurrence of FTC than did each alone. The positive predictive values (PPV) for concomitant high expression of the three molecules for discriminating between FTC and FTA were 91.0% for GPER1/EGFR, 93.8% for GPER1/CXCR1, 92.3% for EGFR/CXCR1 and 98.2% for GPER1/EGFR/CXCR1, respectively. These results indicated that the evaluation of GPER1, EGFR and CXCR1 concomitant high expression may be helpful in differential diagnosis between FTC and FTA.     

Capsular collagen staining of follicular thyroid neoplasms by picrosirius red: role in differential diagnosis

A key criterion in the diagnosis of thyroid follicular carcinoma is capsular invasion, but invasion cannot always be demonstrated histologically. Since invasion is likely to evoke reactions in the capsular collagen, we examined the effects of invasion on capsular collagen with the picrosirius orange-red (PSR) staining technique for collagen. Under polarized light, the color of PSR-stained collagen varies as a function of the structural and biochemical properties of the collagen fibers. Capsules of widely invasive carcinomas (n = 10), minimally invasive carcinomas (n = 10), and adenomas (n = 28) were stained with the PSR method. Carcinomas were assessed along the thickened capsule for sites of definite invasion, minimal invasion, and no evidence of invasion. In adenomas, sites of thickened capsules (similar to carcinomas) were compared to sites of thin capsules. All foci were evaluated for the color and color intensity of collagen fibers. We found a significantly higher frequency of yellow-green collagen fibers than of orange-red fibers at sites of invasion, whereas orange-red fibers significantly predominated at non-invaded sites. In a minority of cases both colors occurred but the non-dominant color was of lesser intensity in all but 1 case. There were no significant differences in staining between minimally and widely invasive carcinomas. Thick capsules of adenomas consistently stained with an intense orange-red color, although weakly stained yellow-green fibers were also observed in some of these cases. We conclude that PSR staining can provide diagnostically useful information in capsular samples of carcinomas, when both color and color intensity of PSR staining are evaluated at the same site. Specifically, intense yellow-green birefringence of collagen in a thickened capsule is additional evidence for capsular invasion.     

Cell proliferation marker MCM2, but not Ki67, is helpful for distinguishing between minimally invasive follicular carcinoma and follicular adenoma of the thyroid

AIMS: To compare cell proliferation markers, minichromosome maintenance protein 2 (MCM2) and Ki67, in minimally invasive follicular carcinoma (MIFC) and follicular adenoma (FA) of the thyroid and among MIFCs with different diagnostic criteria. METHODS AND RESULTS: Twenty-two MIFCs and 20 FAs were immunohistochemically stained for MCM2 and Ki67. The MIFCs were subdivided into six Group 1 tumours with both capsular and vascular invasions, seven Group 2 tumours with vascular invasion only and nine Group 3 tumours with capsular invasion only. The MCM2 and Ki67 indices were calculated, counting more than 1000 tumour cells in the most frequently positive areas. In total and Groups 1-3 MIFCs and in FAs, the average MCM2 index was 26.7 +/- 11.0, 28.4 +/- 8.6, 26.3 +/- 14.8, 25.9 +/- 8.4 and 10.7 +/- 4.5, respectively, whereas the average Ki67 index was 2.07 +/- 1.65, 1.93 +/- 2.02, 2.49 +/-1.38, 1.84 +/- 1.5 and 1.78 +/- 0.92, respectively. There was a significant difference in the MCM2 index, but not in the Ki67 index, between each category of MIFCs and FA (P < 0.01). However, neither the MCM2 index nor the Ki67 index showed a statistically significant difference among the subgroups of MIFC. CONCLUSIONS: MCM2, but not Ki67, is a helpful marker for differentiating MIFC from FA. The tumour cell proliferative activity supports the histological criteria based on diagnosing MIFC by either capsular or vascular invasion only.     

Late bone metastasis from an encapsulated follicular carcinoma of the thyroid withoutcapsular and vascular invasion

A unique case of encapsulated follicular carcinoma of the thyroid, which lacked histologic evidence of capsular and vascular Invasion but developed a late bone metastasis, is described. The thyroid tumor was found in a 42-year-old man. It was relatively small (2.5 cm) and totally encapsulated. Histologically, the thyroid tumor showed a microfollicular growth pattern of follicular cells and revealed no histologic evidence of nuclear atypia, mitotic figures or capsular and vascular invasion. The diagnosis of microfollicular adenoma was made and partial thyroidectomy was performed. Bone (rib) metastasis of the thyroid tumor developed 22 years after the thyroidectomy. The present case suggested that capsular and/or vascular invasion is not always sufficient for the diagnosis of encapsulated follicular carcinoma of the thyroid.     

Synchronous papillary thyroid carcinoma and follicular thyroid carcinoma: case report and review of literature

Collision tumor is a term denoting two histologically distinct tumor types occuring at the same anatomic site, which is a rare clinical entity. In the thyroid gland, collision tumors are rare. Here we report a case of the synchronous occurrence of follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC). The current case report describes a 40-year-old woman with synchronous FTC and PTC. Pathologists and surgeons should be aware of collision tumors to avoid possible misdiagnosis.     

Cathepsin B and Cathepsin D Expression in Follicular Adenomas and Carcinomas of the Thyroid Gland

Biologic features that distinguish follicular adenomas (FAs), minimally invasive follicular carcinomas (MICs), and extensively invasive follicular carcinomas (EICs) of the thyroid gland are not well understood. Endogenous proteases, including cathepsin B (CB) and cathepsin D (CD), have been linked to tumor progression in other malignancies and may be important in the different biologic behavior of these follicular thyroidal lesions. Archival paraffin-embedded tissue sections from 16 FAs, 12 MICs, and 4 EICs were studied for immunohistochemical expression of CB and CD. Percent of tumor staining, intensity of staining, and intracytoplasmic staining pattern were assessed. Increased intensity of staining with CD was observed in follicular carcinomas compared to adenomas and was greatest in the EIC (p<0.04). An increase in diffuse cytoplasmic staining pattern with CD (p<0.008) and CB (p<0.02) was observed in follicular carcinomas compared to FAs. The increased intensity of staining with CD in the follicular thyroid carcinomas and the increased diffuse cytoplasmic staining pattern with CD and CB in these carcinomas suggest that these proteinases may play a role in their propensity to invade and metastasize and, therefore, their more aggressive behavior. Furthermore, this diffuse cytoplasmic staining suggests an altered intracellular processing of these proteinases in the carcinomas.     

Identification of chromosomal copy number changes associated with transformation of follicular lymphoma to diffuse large B-cell lymphoma

The histological transformation from a follicular lymphoma (FL) to a diffuse large B-cell lymphoma (DLBL) occurs in 22% to 30% of all cases of FL. The aim of this study was to identify specific chromosomal gains/losses associated with transformation of FL to DLBL, in addition to the well-known mechanisms like p53 mutation and protein expression and c-myc translocation and up-regulation. This is the first study to meet 2 important conditions for such a comparison. First, we demonstrate that the FL and the DLBL were clonally related, based on identical immunoglobulin gene rearrangements in 5 of the 6 cases. Second, we used laser microdissection microscopy to isolate only the neoplastic cells from the initial FL samples. The results indicate that no single chromosomal abnormality seems to be responsible for the transformation of FL to DLBL. P53 protein overexpression was found in 4 and c-myc translocation in 3 of the 6 transformed DLBLs, but not in the initial FL samples. Additional chromosomal abnormalities were detected by comparative genomic hybridization in all 6 cases when the DLBL was compared with the FL. In the 5 cases with transformation of grade 1 or 2 FL to DLBL, gains at chromosomes 7 (5 of 5 cases), 10p1 (3 of 5 cases), 12 (3 of 5 cases), and 20p13 (2 of 5 cases) and loss at 9q (4 of 5 cases) were the most frequently found abnormalities. A gain on chromosome 7p, in combination with a loss on 9q, was found in 4 of the 5 DLBL that transformed from FL grade 1 or 2.