Inês Vieira de Castro

BRAF mutations are associated with some histological types of papillary thyroid carcinoma

Mutations in the BRAF gene have recently been detected in a wide range of neoplastic lesions with a particularly high prevalence in melanoma and papillary thyroid carcinoma (PTC). The hot‐spot mutation BRAFV599E is frequently detected in PTC (36–69%), in contrast to its absence in other benign or malignant thyroid lesions. In order to unravel whether there is any association between the occurrence of the BRAF mutation and the histological pattern of PTC, in this study a previous series of 50 PTCs was extended to 134 cases, including ten cases of PTC‐related entities—hyalinizing trabecular tumour (HTT) and mucoepidermoid carcinoma (MEC). Using PCR/SSCP and sequencing, the BRAFV599E mutation was detected in 45 of the 124 PTCs (36%). No mutations were detected in any case of HTT and MEC. BRAFV599E was present in 75% of Warthin‐like PTCs and 53% of conventional PTCs, whereas no BRAFV599E mutations were detected in any of the 32 cases of the follicular variant of PTC. BRAFV599E was also detected in 6 of 11 cases of the oncocytic variant of PTC that displayed a papillary or mixed follicular–papillary growth pattern and in none of the four oncocytic PTCs with a follicular growth pattern. A distinct mutation in BRAF (codon K600E) was detected in three cases of the follicular variant of PTC. This study has confirmed the high prevalence of BRAFV599E in PTC and has shown that the mutation is almost exclusively seen in PTC with a papillary or mixed follicular–papillary growth pattern, regardless of the cytological features of the neoplastic cells. The results support the existence of an oncocytic variant of PTC that should be separated from the oncocytic variant of follicular carcinoma and suggest that the follicular variant of PTC may be genetically different from conventional PTC. Copyright

BRAF mutations typical of papillary thyroid carcinoma are more frequently detected in undifferentiated than in insular and insular-like poorly differentiated carcinomas

Somatic mutations of the BRAF gene (BRAFV599E and BRAFK600E) were found to be closely associated with different histotypes of papillary thyroid carcinoma (PTC). The V599E mutation is highly prevalent in PTC with a papillary or mixed papillary follicular growth pattern, and the K600E mutation is apparently restricted to the follicular variant of PTC. It is usually accepted that thyroid malignancies may follow a progression path from well-differentiated to poorly differentiated (PDC) and undifferentiated (UC) carcinomas. One would expect that at least some of the less differentiated carcinomas would harbour the genetic alterations of pre-existing well-differentiated tumours. In order to find the prevalence of BRAF mutations in PDC and UC, we screened a series of 19 PDCs and 17 UCs, as well as 3 UC-derived cell lines, for both mutation types. The group of PDCs was restricted to the so-called insular and insular-like PDCs, thus excluding PTCs with solid, insular or trabecular foci of growth and PDCs displaying typical PTC nuclei. No BRAF mutations were detected in any of the 19 cases of PDC, whereas 6 of the UCs (35%) and one UC-derived cell line presented the BRAFV599E mutation. The BRAFK600E mutation was not detected in any case. We conclude that UC may progress from BRAFV599E-mutated PTC. The absence of BRAF mutations in our series of PDC supports the assumption that pure insular and insular-like PDCs are more closely related to follicular carcinoma than to PTC.

Salivary gland tumors in a Brazilian population: a retrospective study of 124 cases

UNLABELLED Salivary gland tumors constitute a highly heterogeneous histopathologic group. There are few epidemiological studies of large series of benign and malignant salivary gland tumors in Brazil. MATERIAL AND METHODS Hospital records of 124 patients with salivary gland tumors diagnosed from January 1993 to December 1999 were reviewed. The patients were analyzed according to gender, age, size, location, and histopathology of the tumor. RESULTS AND CONCLUSIONS Patients with benign and malignant tumors presented with a mean age of 47.7 and 48.8 years, respectively. The frequency of benign tumors was 80% (n = 99) and malignant tumors 20% (n = 25). Tumors were localized in the parotid gland 71% (n = 88), in the submandibular gland 24% (n = 30), and in the minor salivary glands 5% (n = 6). The most common benign tumors were pleomorphic adenoma in 84% (n = 84) and Warthins tumor in 13% (n = 13). Among malignant tumors, mucoepidermoid carcinoma was the most common in 52% (n = 13), adenoid cystic carcinoma occurred in 20% (n = 5), and carcinoma ex pleomorphic adenoma was detected in 12% (n = 3).

Hürthle (Oncocytic) Cell Tumors of Thyroid: Etiopathogenesis, Diagnosis and Clinical Significance

The etiopathogenesis and the classification of oncocytic (Hurthle cell) tumors of the thyroid is reviewed with an emphasis on the role played by mitochondrial and nuclear genetic abnormalities that interfere with mitochondrial function. Oxyphilia is classified into primary or secondary and the so-called Hurthle cell carcinoma is divided into oncocytic (Hurthle cell) variants of papillary and follicular carcinoma.

Acquisition of BRAF gene mutations is not a requirement for nodal metastasis of papillary thyroid carcinoma

The putative relationship between BRAF mutations and metastatic potential of papillary thyroid carcinoma (PTC) has been addressed by studying paired samples of primary tumours and their respective metastases. 1–3 Oler and collaborators 1 reported in their series that only five of the eight primary lesions of conventional PTC were BRAF V600E -mutated (62·5%) while all the metastases harboured BRAF mutations (100%); three of these metastases had a different BRAF mutation: BRAF VK600–1E , an in-frame triplet deletion that was also detected by our group in a solid variant of PTC. 4 Oler and collaborators also reported that in one of the cases of the follicular variant of PTC (FVPTC) the BRAF V600E mutation was detected in the metastasis despite its absence in the respective primary lesion. 1 These results indicated that lymph node metastasization of PTC could be promoted by, or even require, the acquisition of BRAF mutations, namely of a specific type: BRAF VK600–1E . 1

Cytologic findings of epithelioid angiosarcoma of the thyroid: A case report

BACKGROUND Angiosarcoma of the thyroid is a rare and aggressive tumor and occurs mainly in patients from central Europe, especially the alpine region. The fine needle aspiration findings of a keratin-positive epithelioid angiosarcoma of the thyroid occurring in a nonmountainous area in South America is described. CASE A 65-year-old male from São Paulo, Brazil, presented with a mass in the anterior part of the neck with progressive enlargement for three months. The cytologic findings on the fine needle aspirate were a cellular smear composed of single cells and small clusters of neoplastic cells, oval and round. Cell borders were indistinct, and the cytoplasm was vacuolated. The nuclei were eccentrically located, with irregular nuclear membranes; single, prominent nucleoli; and a coarse chromatin pattern. Features suggestive of intracytoplasmic lumens were identified. Open surgical biopsy demonstrated a tumor infiltrating the thyroid gland and composed of large, round, atypical epithelioid cells lining vascular spaces. These neoplastic cells were immunoreactive for AE1:AE3, CK7, vimentin, CD31 and factor VIII. CONCLUSION Epithelioid angiosarcoma should be considered in the differential diagnosis of epithelioid neoplasms of the thyroid. An immunohistochemical panel should include vascular markers even in the presence of immunoreactivity for epithelial markers.

Vascular Endothelial Growth Factor Expression in Invasive Papillary Thyroid Carcinoma

BACKGROUND The vascular endothelial growth factor (VEGF) is a major promoter of endothelial growth and migration. Some studies have shown a correlation between expression of this growth factor and prognosis in several cancers, including well-differentiated thyroid cancer. AIM We studied VEGF expression, local invasiveness, and other prognostic factors in papillary thyroid carcinoma (PTC) to test the hypothesis that the expression of VEGF is correlated with the degree of invasion of PTC. PATIENTS AND METHODS Clinical and pathological data of 76 patients with PTC were retrospectively reviewed. Group 1 consisted of patients with gross locally invasive tumors, group 2 consisted of patients with only invasion of the thyroid capsule, and group 3 consisted of patients with noninvasive PTC. RESULTS VEGF expression was noted within the tumor in all groups of PTC patients but was absent in the surrounding normal tissue. Older patients had higher expression of VEGF than younger patients. The age of patients with strong reaction to VEGF was 46 +/- 14 (mean +/- standard deviation), and that in patients with a weaker reaction was 39 +/- 16 (p < 0.05). Only 20% of patients with a follicular variant of PTC had a strong reaction to VEGF compared with 68% of patients with classical PTC (p < 0.01). CONCLUSIONS VEGF expression appears to be an early event in the development of PTC. Whether VEGF expression promotes the progression of PTC is not known, but the answer to this question may be important in view of its greater expression in older patients, a group whose prognosis in PTC is worse.

Prognostic significance of lymph node reactivity in the control of pathologic negative node squamous cell carcinomas of the oral cavity

BACKGROUND Identification of high-risk patients and defining prognostic factors may be useful in the treatment of head and neck cancer. The role of the lymph node reactivity is still obscure. The value of the node reactivity pattern as a predictor of tumor control in oral cavity cancer was analyzed. METHODS Retrospective analysis of patients with oral cavity squamous cell carcinoma (OCSCC), submitted to tumor resection and neck dissection, with pathologic negative lymph nodes (pN0). Dominant node reactivity pattern was defined as lymphocytic predominance (LP), germinal centers (GC), normal (NL), sinus hystiocytosis (SH), and lymphocytic depletion (LD). Clinical and pathological characteristics of patients free of disease (DF) were compared with those of patients with control failure (CF), which included local, regional, and distant recurrences. RESULTS Of the 26 patients with pN0 OCSCC, prevalence of SH was found in 10 cases, GC in 13, and LD, NL and PL in 1 case each. Comparing CF and DF groups, there was no significant statistical difference regarding: age, gender, performance status index, weight loss, smoking and drinking habits, complementary treatment, average follow-up, tumor grade or thickness, margins, or tumor inflammatory and desmoplastic reaction. Although there was a higher proportion of perineural invasion and larger tumors in the CF group, the difference was not statistically significant either. Germinal centers or LP were noted in only 27% of the CF group and in 73% of the DF group. Collectively, NL, SH, or LD patterns were observed in 73% of CF. This incidence was statistically different from 27% of the DF group (P <0.05). CONCLUSIONS Lymph node reactivity pattern seems to be a prognostic index in pN0 OCSCC patients. Prospective analysis is advised to confirm these results. Prophylactic neck dissection as a staging procedure could select high-risk patients even when no metastasis is found.

Perineural Invasion in Aggressive Skin Carcinomas of the Head and Neck

Introduction: Perineural invasion is a well-recognized form of cancer dissemination. However, it has been reported only in few papers concerning cutaneous carcinomas (basal cell, BCC, and squamous cell, SCC). Moreover, the incidence is considered to be very low. Niazi and Lambert [Br J Plast Surg 1993;46:156–157] reported only 0.18% of perineural invasion among 3,355 BCCs. It is associated with high-risk subtypes, as morphea-like, as well as with an increased risk of local recurrence. No paper was found in the literature looking for perineural invasion in very aggressive skin cancers with skull base extension, with immunohistochemical analysis. Methods: This is a retrospective review, including 35 very advanced skin carcinomas with skull base invasion (24 BCCs and 11 SCCs, operated on at a single institution from 1982 to 2000). Representative slides were immunohistochemically evaluated with antiprotein S-100, in order to enhance nerve fibers and to detect perineural invasion. The results were compared to 34 controls with tumors with a good outcome, treated in the same time frame at the same Institution. Results: Twelve (50.0%) of the BCCs with skull base invasion had proven perineural invasion, as opposed to only 1 (4.6%) of the controls, and this difference was statistically significant (p < 0.001). Regarding SCCs, 7 aggressive tumors (63.6%) showed perineural invasion compared to only 1 (10.0%) of the controls, but this difference did not reach significance (p = 0.08), due to the small number of cases. Conclusions: In this series, it was demonstrated that immunohistochemically detected perineural invasion was very prevalent in advanced skin carcinomas. In addition, it was statistically associated with extremely aggressive BCCs with skull base invasion.

Metalloproteinase-9 immunoexpression and angiogenesis in thyroid follicular neoplasms: relation to clinical and histopathologic features.

Thyroid follicular neoplasms (adenoma and carcinoma) may pose considerable difficulties to the differential diagnosis. Because such a distinction is not possible at fine‐needle aspiration, surgery is often necessary. Clinical information such as age, sex, and node size is important in case of suspected carcinoma. Follicular carcinoma is characterized by capsular invasion, vascular invasion, and metastatic dissemination mainly by the hematogenic pathway. This invasion depends on collagen degradation in capsule and in subendothelial basement membrane. Collagen degradation has been widely researched in the angiogenesis process and in the hematogenic dissemination mechanism. In this study, we performed clinical and histopathologic assessment of 74 follicular neoplasms, as well as immunohistochemical reactions for CD‐34 protein to estimate angiogenesis and for metalloproteinase‐9, an enzyme that degrades type IV collagen.