Angiosarcoma and anaplastic carcinoma of the thyroid are two distinct entities: a morphologic, immunohistochemical, and genetic study.

Angiosarcoma and anaplastic carcinoma are the most lethal neoplasms of the thyroid worldwide and share some similarities, which have led to a longstanding controversy on their etiopathological relationship. Thyroid angiosarcomas are characterized by vessel formation and an immunophenotype common to endothelial cells, while anaplastic carcinomas are partially or wholly composed of mesenchymal-like cells that have lost the morphologic and functional features of normal thyroid follicular cells. To investigate whether angiosarcomas represent the endothelial extreme of the differentiation spectrum of carcinomas or they are bona fide vascular neoplasms, we studied the clinico-morphologic and genetic characteristics of a series of 10 angiosarcomas and 22 anaplastic carcinomas. Immunohistochemically, among the endothelial markers, CD31 and ERG were the most consistently expressed in angiosarcomas. Among the markers of thyroid origin, PAX8 was the most reliable in anaplastic carcinomas, while TTF-1 reactivity was found in only 5% of anaplastic carcinomas and thyroglobulin was always negative. Pankeratin reacted with most angiosarcomas and anaplastic carcinomas and is therefore not useful in the differential diagnosis. Interestingly a mutated pattern of p53 immunostaining prompted a diagnosis of anaplastic carcinoma. To compare the genetic profile, we used the NGS approach to sequence hotspot regions within a panel of 57 genes. As a result, only a few mutations were found in angiosarcomas and all of them were single events (no TP53 or TERT mutation). On the other hand, anaplastic carcinomas were characterized by a higher number of mutations, and TP53 and TERT promoter mutations were the most frequent genetic alterations. The lack in angiosarcomas of the common mutations identified in anaplastic carcinomas supports a different genetic origin and strongly suggests that, in spite of a shared sarcomatous morphology and a similar clinical aggressiveness, angiosarcomas and anaplastic carcinomas rely on a completely different set of genetic alterations during their evolution.

Cervicomediastinal Hematoma: Atypical Presentation of a Parathyroid Carcinoma.

Parathyroid carcinoma (PC) is a rare endocrine neoplasm that typically presents with osteopenia/osteoporosis, nephrolithiasis, asthenia, and neuropsychiatric symptoms. We describe the case of a 48-year-old woman, presenting with a large painful hematoma in the cervicomediastinal area. The neck ultrasound (US) demonstrated a solid lesion measuring 40 × 80 × 55 mm, markedly hypoechoic, which extended from the right thyroid lobe to the mediastinum. The blood tests showed elevated serum calcium and parathyroid hormone (PTH) concentrations, consistent with hypercalcemic primary hyperparathyroidism. The patient was rehydrated and treated with furosemide, cholecalciferol, and bisphosphonate, and underwent right lower parathyroidectomy, right hemithyroidectomy, and lymphadenectomy of the right VI cervical level. Histological examination was diagnostic for nonangioinvasive or neuroinvasive PC, and the thyroid lobe was the site of lymphocytic thyroiditis; all removed lymph nodes were benign. The postoperative course was regular. Postoperative neck US showed a hypoechoic left thyroid lobe without evidence of residual neoplasm in the right thyroid bed. Levothyroxine therapy of 50 mcg/day was started because of serum thyrotropin concentrations elevated at 18 mcIU/mL (normal reference range, 0.35-4.0 mIU/mL). Eight years after diagnosis, the patient is in good general condition, with no clinical, biochemical, or imaging evidence of disease persistence/recurrence.

Case Report: Papillary thyroid carcinoma in Goltz-Gorlin syndrome.

Goltz-Gorlin syndrome (GGS), also known as focal dermal hypoplasia, is a rare X-linked disorder caused by pathogenic variants in the PORCN gene and characterized by several abnormalities, including skin and limb defects, papillomas in multiple organs, ocular malformations, and mild facial dysmorphism. To date, only approximately 300 cases have been described in the literature. A 16-year-old female patient, born with multiple congenital dysmorphisms consistent with GGS and confirmed by genetic exam, was referred to our outpatient clinic for the workup of a thyroid nodule. A thyroid ultrasound showed a bilateral nodular disease with a 17-mm large hypoechoic nodule in the right lobe. Cytological exam of fine needle aspiration biopsy was suspicious for malignancy. Thus, she underwent total thyroidectomy plus lymphadenectomy of the right central compartment. A histological exam disclosed a papillary thyroid carcinoma (PTC) with lymph node micrometastases. Radioiodine (131-Iodine) therapy was performed. At 3- and 6-month follow-up, the patient did not present either ultrasound or laboratory PTC recurrence. To our knowledge, we report the first case of PTC in a patient with GGS. Since thyroid cancer is rare among children and adolescents, we hypothesize that the PORCN pathogenic variant could be responsible for tumor susceptibility. We also provide an overview of the clinical findings on GGS patients already reported and discuss the possible pathogenetic mechanism that may underlie this rare condition, including the role of PORCN in tumor susceptibility.

Neck Ganglioneuroma Mimicking a Thyroid Nodule in a Four-Year-Old Child: A Case Report and Review of the Literature.

Introduction: Ganglioneuromas are tumors of neurogenic origin usually located in the abdomen, the adrenal glands, and the mediastinum but infrequently found in the neck region. Case Presentation: We describe the case of a four-year-old Albanian girl presenting with an anterior neck mass initially suspected to be a thyroid nodule. From a clinical point of view, there was no evidence of compression on vital cervical structures. Lab tests detected normal serum thyrotropin, calcitonin, and parathormone concentrations. A neck ultrasound showed a huge mass apparently originating from the left thyroid lobe. Cytological examination of fine needle biopsy demonstrated a population of large cells with eosinophilic cytoplasm, regular nuclei, and prominent nucleoli and spindle cells without significant atypia, consistent with a benign lesion of neurogenic origin. Also, the neck MRI displayed a mass with well-defined margins, likely arising from the peripheral nervous system. The patient underwent surgical excision of the mass without complications. The histological exam was diagnostic for ganglioneuroma. Conclusions: We discuss the cytological and histological features peculiar to such a rare neck lesion and review the differential diagnosis.

LINE-1 hypomethylation is associated with poor outcomes in locoregionally advanced oropharyngeal cancer.

BACKGROUND AND PURPOSE: Currently, human papillomavirus (HPV) positivity represents a strong prognostic factor for both reduced risk of relapse and improved survival in patients with oropharyngeal squamous cell carcinoma (OPSCC). However, a subset of HPV-positive OPSCC patients still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse, are still lacking suitable prognostic biomarkers for clinical outcome. Here, we evaluated the prognostic value of LINE-1 methylation level in OPSCC patients and further addressed the relationship between LINE-1 methylation status and p53 protein expression as well as genome-wide/gene-specific DNA methylation. RESULTS: In this study, DNA was extracted from 163 formalin-fixed paraffin-embedded tissue samples retrospectively collected from stage III-IVB OPSCC patients managed with curative intent with up-front treatment. Quantitative methylation-specific PCR revealed that LINE-1 hypomethylation was directly associated with poor prognosis (5-year overall survival-OS: 28.1% for LINE-1 methylation < 35% vs. 69.1% for ≥ 55%; p < 0.0001). When LINE-1 methylation was dichotomized as < 55% versus ≥ 55%, interaction with HPV16 emerged: compared with hypermethylated HPV16-positive patients, subjects with hypomethylated HPV16-negative OPSCC reported an adjusted higher risk of death (HR 4.83, 95% CI 2.24-10.38) and progression (HR 4.54, 95% CI 2.18-9.48). Tumor protein p53 (TP53) gene is often mutated and overexpressed in HPV-negative OPSCC. Since p53 has been reported to repress LINE-1 promoter, we then analyzed the association between p53 protein expression and LINE-1 methylation levels. Following p53 immunohistochemistry, results indicated that among HPV16-negative patients with p53 ≥ 50%, LINE-1 methylation levels declined and remained stable at approximately 43%; any HPV16-positive patient reported p53 ≥ 50%. Finally, DNA methylation analysis demonstrated that genome-wide average methylation level at cytosine-phosphate-guanine sites was significantly lower in HPV16-negative OPSCC patients who relapsed within two years. The subsequent integrative analysis of gene expression and DNA methylation identified 20 up-regulated/hypomethylated genes in relapsed patients, and most of them contained LINE-1 elements in their promoter sequences. CONCLUSIONS: Evaluation of the methylation level of LINE-1 may help in identifying the subset of OPSCC patients with bad prognosis regardless of their HPV status. Aberrant LINE-1 hypomethylation might occur along with TP53 mutations and lead to altered gene expression in OPSCC.

Solitary fibrous tumor of the thyroid gland.

Solitary fibrous tumor (SFT) is a rare spindle-cell neoplasm more commonly involving the pleura, but recognized also in other tissues. Nineteen patients with SFT arising from the thyroid gland have been reported in the literature. The present report reviews these cases and discusses epidemiology, etio-pathogenesis, clinical-pathologic characteristics, differential diagnosis, therapy, and prognosis of thyroid SFT.

Primary spindle cell lesions of the thyroid gland; an overview.

Spindle cell lesions of the thyroid gland (T-SCL) are not encountered routinely in clinical practice or in the context of thyroid pathology. They commonly are classified as primary or secondary to metastatic disease. Primary T-SCL can be derivedfromfollicular, C-cell (parafollicular), or mesenchymal components and may be the result of reactive or neoplastic processes, including post-fine-needle aspiration spindle cell nodules, Riedel thyroiditis, solitary fibrous tumor, leiomyoma, peripheral nerve sheath tumor, hyalinizing trabecular tumor, spindle epithelial tumor with thymus-like differentiation, follicular dendritic cell tumor, medullary carcinoma, papillary carcinoma, anaplastic carcinoma, sarcoma, squamous cell carcinoma, and carcinoma showing thymus-like differentiation. Because T-SCL may represent the expression of benign and highly malignant neoplasms, distinction among these processes is crucial because it dictates therapy and defines prognosis. The present article reviews the clinical, imaging, pathologic, and immunohistochemical characteristics of primary T-SCL.

Combined small cell carcinoma and clear cell carcinoma of the gallbladder: report of a case and review of the literature.

We report a case of an incidental combined carcinoma of the gallbladder in a 66-year-old woman who underwent cholecistectomy for gallstones. The neoplasm was mainly constituted by a clear cell component and a small cell, chromogranin-positive one; it also showed some areas of conventional adenocarcinoma and foci of vascular invasion. The patient died after 3 years following treatment with combination chemotherapy. The histologic and immunohistochemical profile of the lesion is described, together with a brief review of the pertinent bibliography.

Parathyroid gland involvement by thyroid cancer: results from a large series of thyroidectomies performed in two italian university hospitals and review of the literature.

Objectives.Parathyroid involvement by thyroid cancer (TC) has not been frequently investigated in thyroidectomy-based studies. We aimed to detect cases of parathyroid invasion by TC in a large series of thyroidectomies and to review the literature on this topic. Study Design. A 10-yr period database research was made from the files of the Section of Pathology of two Italian University Hospitals. Out of 22,310 thyroidectomies, 10 patients with parathyroid involvement by TC were found. Results. The 10 patients, 7 females and 3 males, aged 55 ± 14 years (range 34-76, median 56) had papillary thyroid carcinoma and accounted for 0.4% of subjects affected by all TCs and submitted to thyroidectomy. The tumor invaded perithyroid soft tissues in 6 patients and central neck (level VI) lymph nodes in 3. Parathyroid involvement by TC occurred by infiltration in 6 cases, extension through an intervening pseudocapsule in 1, and both patterns in 3. All patients are alive and disease free at 5.6 ± 3-yr follow-up. Conclusion. Limited to thyroidectomy series, our results and literature data suggest that parathyroid involvement by TC has a 0.4-3.9% incidence rate; mainly affects women in their sixth-seventh decade of life; is associated to a good prognosis, unless massive extrathyroid extension of TC occurs.

Papillary thyroid carcinoma with predominant spindle cell component: report of two rare cases and discussion on the differential diagnosis with other spindled thyroid neoplasm.

Spindle cell transformation or metaplasia has been so far demonstrated in the context of both benign and malignant conditions. Spindle cell lesions of the thyroid gland of either primary or secondary origin to metastatic disease represent rare entities. We describe two patients with papillary thyroid carcinoma (PTC) showing spindle cell metaplasia, submitted to thyroidectomy due to euthyroid bilateral nodular thyroid disease. Cytological examination of fine-needle aspiration biopsy performed in the dominant nodules was consistent with follicular neoplasm in one case and with a hyperplastic/adenomatous nodule in the other patient. Histological examination disclosed unencapsulated follicular variant of PTC with spindle cell metaplasia in either cases. Both patients are doing well without clinical or laboratory evidence of PTC recurrence at 3- and 1-year follow-up, respectively. We present the clinical, pathological, and immunohistochemical aspects of these unusual cases and thoroughly discuss the differential diagnosis with other spindle cell lesions of the thyroid gland.

Nodular disease and parafollicular C-cell distribution: results from a prospective and retrospective clinico-pathological study on the thyroid isthmus.

OBJECTIVE: The isthmus represents a peculiar, as yet partially unexplored, thyroid gland area. AIM OF THE STUDY: To assess i) the prevalence and clinico-pathological features of solitary thyroid isthmic nodules (STIN); ii) the frequency of medullary thyroid carcinoma (MTC) arising from the isthmus; and iii) the C-cell distribution in the isthmus of patients with MTC and benign nodular thyroid disease (NTD). SUBJECTS AND METHODS: Patients referred from 2006 to 2008 for STIN were prospectively recruited, and underwent serum calcitonin (C(t)) measurement and fine needle aspiration cytology (FNAC). MTCs diagnosed from 1993 to 2005 were retrospectively searched. Immunohistochemistry was performed using anti-C(t) antibodies on lateral lobes and isthmi of 50 benign NTD and 50 MTC cases. RESULTS: From 1993 to 2005, 150 patients underwent surgery for MTC. All patients had the neoplasm located in lateral thyroid lobes, none in the isthmus. In the 3 years following, 192 STIN patients (40 (21%) males, 152 (79%) females; mean age: 46.2+/-7.1 years; 6.4% of NTD subjects) were recruited. All had normal C(t) concentrations. FNAC was malignant or suspicious for malignancy in 14 (7.3%) patients. Histology found malignancy in 17 (9%) cases, MTC in none. C cells were disclosed in lateral thyroid lobes of 100% MTC and 77% benign NTD patients; isthmi were free of C cells in either group. CONCLUSIONS: STINs are significantly less likely to be MTC in patients presenting with sporadic disease. Therefore, C(t) screening is not warranted in these subjects. Nonetheless, STINs are more likely to be neoplastic and deserve equal attention as those of the lateral lobes.

Metastases to the thyroid gland: prevalence, clinicopathological aspects and prognosis: a 10-year experience.

BACKGROUND: Metastases to thyroid (TM) are rarely observed in the clinical practice. OBJECTIVE: To assess the prevalence, clinicopathological aspects and prognosis of TM, and to evaluate the role of thyroidectomy in the management of TM. METHODS: The pathology files (databases) of two Italian Pathology Units were searched for thyroid cytology (FNAC) and histology reports covering the time period January 1993 through December 2003. RESULTS: Thirty-six cases of TM were found, accounting for 0.13% of thyroidectomies and 0.07% of FNAC. The main site of origin of TM was the lung, followed by oesophagus, breast and kidney. TM patients were divided into two groups, based on whether they were (Group 1) or were not (Group 2) submitted to surgery. Thirty-five subjects diagnosed with the same primary tumours as TM patients, but without TM, served as controls. The mean patient age, the mean time from diagnosis of primary tumour to TM detection, and the mean survival time did not significantly differ in Group 1 and Group 2 (63.2 +/- 1.6 vs. 66.6 +/- 2.9 years, 24.7 +/- 8.6 vs. 19.7 +/- 4.4 months and 24.3 +/- 4.9 vs. 39 +/- 9.9 months, respectively). In contrast, the mean time from detection of TM to death was longer in Group 1 than in Group 2 (14.3 +/- 2.5 vs. 4.5 +/- 0.5 months, respectively; P = 0.002). The overall survival of TM patients and control subjects was not significantly different (33.7 +/- 6.6 vs. 32.3 +/- 6 months). CONCLUSIONS: TM is a rare event, is more frequent in patients older than 60 years, and has the same impact on prognosis as nonthyroidal metastases. Although thyroidectomy may be useful to avoid further dissemination of the primary tumour in case of solitary TM, it does not contribute to prolonging patient's life.

Expression of p27kip1 in basal cell carcinomas and trichoepitheliomas.

Immunohistochemical analysis was used to evaluate p27kip1 expression in normal hair follicles and in a series of 39 basal cell carcinomas (BCC) (13 of superficial type, 7 infiltrating, 7 morphea-like, 12 nodular) and 20 trichoepitheliomas (TE) (9 of classic type, 9 immature, 2 desmoplastic). The labeling index (LI) was derived semiautomatically by means of a computer-assisted cellular image analyzer, and statistical analysis was carried out using the Student t test. A positive reaction for p27kip1 was detected in the hair germ papillae, in supramatrical cells, and in the inner pilar sheath, whereas matrical cells and the outer pilar sheath were negative. All BCC and TE cases showed a positive immunoreaction for p27kip1, but the staining pattern was different in the two groups of lesions, being patchy with focal peripheral accentuation in TE and more diffusely dispersed in BCC. The quantitative study showed lower p27kip1 expression in BCC (LI = 27.51 +/- 12.55) than in TE (LI = 45.27 +/- 20.27) (P < 0.0001). Statistically significant differences were also observed between TE subgroups and nodular or infiltrating BCC subtypes. The occurrence of a wide overlap of LI values hampers the practical application of a p27kip1 LI in the differential diagnosis between BCC and TE in difficult cases, however.