Eva Sigstad

Risk Markers of Oral Cancer in Clinically Normal Mucosa As an Aid in Smoking Cessation Counseling

PURPOSE Quitting smoking may prevent oral cancer. Behavioral intervention to quit smoking may be more efficient if persons are assigned an individual risk of cancer. PATIENTS AND METHODS In this prospective study, we provided counseling and behavioral intervention toward smoking cessation, supplemented by genetic analyses in clinically normal oral mucosa of heavy smokers. Measurement of serum cotinine was used to assess changes in smoking habits. RESULTS In cytologic scrapings from 275 heavy smokers with clinically normal mucosa, we found tetraploidy in four and aneuploidy in 19 persons (23 of 275; 8%). Twenty one (91%) of 23 persons with aneuploidy had quit or reduced their smoking habits at the 3-month follow-up, 20 (87%) of 23 persons had done so at 12 months, and 21 (91%) of 23 persons had done so at 24 months. Fifty-one (20%) of the 252 persons without genetic changes in their mucosa had quit or reduced their tobacco habits at the 3-month follow-up, 23 (9%) had done so at 12 months, and 17 (7%) had done so at 24 months (P < .001). After 24 months, normalization of DNA content to diploidy was observed in two of four persons with tetraploid (50%), and in 11 of 19 persons (58%) with aneuploid scrapings. One patient developed an oral carcinoma in the floor of the mouth: this patient had an aneuploid scraping obtained 43 months earlier and developed a leukoplakia 28 months before the carcinoma. CONCLUSION Risk markers of oral cancer are present in clinically normal mucosa of heavy smokers, and such findings enhance the adherence to smoking cessation on counseling. Cytogenetic aberrations may normalize after quitting smoking.

Survey of 548 oncogenic fusion transcripts in thyroid tumors supports the importance of the already established thyroid fusions genes

Neoplasms frequently present structural chromosomal aberrations that can alter the level of expression of a protein or to the expression of an aberrant chimeric protein. In the thyroid, the PAX8‐PPARG fusion is present in the neoplastic lesions that have a follicular architecture—follicular thyroid carcinoma (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC), and less frequently in follicular thyroid adenoma (FTA), while the presence of RET/PTC fusions are largely restricted to papillary thyroid carcinoma (PTC). The ability to detect fusion genes is relevant for a correct diagnosis and for therapy. We have developed a new fusion gene microarray‐based approach for simultaneous analysis of all known and predicted fusion gene variants. We did a comprehensive screen for 548 known and putative fusion genes in 27 samples of thyroid tumors and three positive controls—one thyroid cancer cell line (TPC‐1) and two PTCs with known CCDC6‐RET (alias RET/PTC1) fusion gene, using this microarray. Within the thyroid tumors tested, only well known, previously reported fusion genes in thyroid oncology were identified. Our results reinforce the pathogenic role played by RET/PTC1, RET/PTC3, and PAX8‐PPARG fusion genes in thyroid tumorigenesis.

The new molecular markers DDIT3, STT3A, ARG2 and FAM129A are not useful in diagnosing thyroid follicular tumors

Preoperative characterization of thyroid follicular lesions is challenging. Fine-needle aspiration specimens cannot differentiate follicular carcinomas from benign follicular neoplasias. Recently, promising markers have been detected using modern molecular techniques. We conducted a retrospective study to confirm the usefulness of immunohistochemical staining for the protein markers, DDIT3, STT3A (ITM1), ARG2 and FAM129A (C1orf24) in separating benign and malignant thyroid follicular lesions. Formalin-fixed, paraffin-embedded thyroid tissue from 30 in-house cases (15 follicular carcinomas and 15 follicular adenomas), as well as 8 follicular carcinomas and 21 follicular adenomas on tissue microarray slides were stained immunohistochemically for DDIT3, STT3A, ARG2 and FAM129A expression. Control tissue consisted of thyroid parenchyma adjacent to the tumors and 11 separate cases of normal thyroid parenchyma. All in-house cases of follicular adenomas, follicular carcinomas and adjacent normal thyroid tissue showed positive immunostaining with anti-DDIT3 and anti-STT3A. Anti-ARG2 and anti-FAM129A polyclonal antibodies showed positive staining in 20 and 60% of in-house follicular adenomas, and 40 and 87% of in-house follicular carcinomas, respectively. Monoclonal anti-FAM129A demonstrated positive staining in 13 and 33% of in-house follicular adenomas and follicular carcinomas, respectively. Polyclonal anti-DDIT3, -STT3A and -FAM129A antibodies showed positive staining in all tissue microarray slides of follicular carcinoma and in 76, 85 and 81% of the follicular adenomas, respectively. Monoclonal anti-STT3A stained 81% of the follicular adenoma cores. Anti-ARG2 stained positive in 13% of follicular carcinomas and 10% of follicular adenomas on the tissue microarray slides. In conclusion, DDIT3, STT3A, ARG2 and FAM129A immunohistochemistry does not appear to be useful in the diagnosis of thyroid follicular neoplasias, as they do not reliably distinguish follicular thyroid carcinoma from follicular thyroid adenoma.

Regional Lymph Node Metastases

Regional lymph node metastases are a common finding in papillary and medullary carcinomas, but they are very rare in follicular carcinoma because this tumor usually spreads hematogenically. Lymph node affection is often seen in thyroid lymphomas, and reactive lymph nodes are found in thyroiditis. Reactive lymph nodes are usually enlarged, but metastatic infiltration does not necessarily cause enlargement. Thus, lymph node size is not a reliable criterion in the differential diagnosis [6,23].

Follicular Variant of Papillary Thyroid Carcinoma

Morphologically,follicular variant of papillary thyroid carcinoma (FVPTC) may appear partially or completely encapsulated and can be misdiagnosed as follicular adenoma or follicular carcinoma pathologically and on (ultrasound) examination. They can be hyper-, iso-, hypoechoic, or mixed with an uneven hypoechoic capsule that is hypervascular with a “spoke-and-wheellike” appearance. Some have sharply marginated areas of different echogenicity within the tumor, a feature we introduce as geographic echo pattern (see page 9). If microcalcifications are found inside the tumor, FVPTC is more likely the diagnosis.These encapsulated FVPTC are often solitary. If they are not encapsulated, they often look like an ordinary PTC both pathologically and on US examination [17].

En kvinne i 30-årene med brystkreft og bilateral struma

A woman in her late thirties was electively hospitalised on suspicion of a locally advanced carcinoma of the right breast. Her medical history showed that she had had type 1 diabetes mellitus since she was 11 and had been found to have an extra, non-functioning renal system. A couple of years previously, ultrasound and CT throat had been used at a local hospital to examine her for bilateral goitre. The conclusion of these tests was colloid nodular goitre with no suspicion of malignancy. There is no information as to whether cytology tests were carried out. The patient had two children. Several of the patient’s maternal aunts and uncles had died of cancer. Suspicion of locally advanced carcinoma of the right breast arose following mammography conducted by a private X-ray institute. The patient suffered from breast tenderness and had requested the examination. The examination of breasts and axillae revealed possible malignant changes in the right breast, possible lymph node metastasis in the right axilla and non-specific changes in the left breast. The radiological diagnosis was regarded as certain, and the patient was referred directly for hospitalisation. Biopsies taken in connection with hospitalisation revealed ductal mammary carcinoma in the right breast and lymph node metastasis in the right axilla. A cytological sample from a radiologically benign-seeming lesion in the left mamma revealed papillary cell groups without atypical signs. No biopsy was taken from this lesion. A further X-ray examination of the thyroid yielded an image consistent with nodular colloid goitre, but cytological samples contained too little material and were non-diagnostic. The patient received preoperative chemotherapy and lost her hair. It proved difficult to find a wig that was large enough for her head. Seven months after the start of chemotherapy, ablatio of the right breast was performed with subsequent post-operative radiotherapy.

Nodular or Colloid Goiter, Hyperplasia, and Cysts

These thyroid nodules are often described as hyperplastic, adenomatous, or colloid. Most cystic thyroid lesions are hyperplastic nodules that have undergone extensive liquefactive degeneration. The common features of a nodular goiter are multinodular inhomogeneous, well-circumscribed solid, semi-solid or mostly cystic tumors. Some are hyperechoic compared with the echogenicity of the normal thyroid tissue, some are isoechoic, and still others hypoechoic. The hyper- and isoechoic nodules are often partially circumscribed by a thin hypoechoic halo. The nodules may contain coarse calcifications within the tumor, or peripheral “eggshell” calcifications. The cystic areas are often purely anechoic, but they may also be hypoechoic or show fluid-fluid levels due to intracystic bleeding, often with avascular internal debris. Many, even tiny cysts, contain small, strongly hyperechoic foci, often with “comet tail” artifacts. These foci represent crystallized colloid. Some cysts have intracystic avascular septae and/or papillary solid tissue protruding from the wall. Some cystic nodules have a spongy or honeycomb-like appearance. The vascularity varies a lot when evaluated on color Doppler imaging. Sometimes only spreading, faint vascularity is observed throughout the nodule, but often there is strong vascularity inside the nodule combined with a distinct peripheral border flow.

Ultrasound Features of Thyroid Lesions

There are many different features indicating a certain benign or malignant tumor type, but many of these are overlapping signs. Combining several features is considered to give the best result. Ultrasound features of benign lesions are often described as a diffusely enlarged gland, a well-circumscribed inhomogeneous hyper- or isoechoic solid lesion, a semi-solid or predominantly cystic lesion, multinodular lesions, and so forth. US features suggestive of malignant thyroid tumors have been described as follows: microcalcifications, hypoechogenicity, a taller than wide lesion, predominantly solid composition, irregular borders, absence of peripheral halo, intranodular hypervascularity, and regional lymphadenopathy [4,8,9]. No US feature has both a high sensitivity and a high positive predictive value for thyroid carcinoma. The different malignant tumors have to some degree a different appearance on US.

Physical and Technical Essentials

There are confusing, and to a certain degree misleading, discrepancies between different countries, different medical centers, anddifferent specialties in the terminology concerning the sampling of specimens for cytology and histology. In the United States, samplingof specimens for cytology and histology are called biopsy: fine needle aspiration biopsy (FNAB or FNA biopsy), which gives a specimen for cytology, and coarse or core needle biopsy (CNB), which gives a specimen for histology. In Europe, most often anotherterminology is used: fine needle aspiration cytology (FNAC or FNAC cytology), cutting biopsy (CB), core needle biopsy (CNB),or just biopsy. Large needle biopsy (LNB) is also used by some authors. Some regard an 18-gauge needle as a fine needle.

Papillary Thyroid Carcinoma

Papillary thyroid carcinomas (PTCs) are solid, usually hypoechoic tumors with inhomogeneous echo structure. They usually have irregular margins and often contain discrete echogenic foci, ie, microcalcifications. They may be solitary or multifocal. In our experience the vascularity varies from avascular to strongly vascularized. In our opinion, the ultrasound findings with highest accuracy for PTC show low echogenicity, microcalcifications, irregular margins, and neck lymph node metastases [4,6–10]. Uncommon features include hyperechoic or mixed echo texture, cysts, hypovascularity, and coarse or peripheral calcifications [18].