CIC‐NUTM1 fusion: A case which expands the spectrum of NUT‐rearranged epithelioid malignancies

NUT carcinoma (NC) shows very aggressive clinical behavior, occurs predominantly in the thorax and head and neck region of children and adults, and is defined by the presence of NUT (aka NUTM1) rearrangement, mostly BRD4‐NUTM1 fusion resulting from t(15;19)(q13; p13.1). So‐called “NUT variants” harbor alternate fusions between NUTM1 and BRD3, NSD3, ZNF532, or unknown partners. Rare cases of pediatric tumors with CIC‐NUTM1 fusion were recently reported in somatic soft tissue, brain, and kidney. However, such cases have not been identified in adult patients and the presence of a fusion between CIC, characteristic of CIC‐rearranged sarcoma, and NUTM1—a defining feature of NC—poses a diagnostic challenge. We herein report a case of malignant epithelioid neoplasm with myoepithelial features harboring CIC‐NUTM1 fusion arising in soft tissue of the head in a 60‐year‐old man. Immunohistochemistry revealed strong expression of NUT, but only weak ETV4 staining and negativity for keratins, EMA, p40, CD99, and WT1. SMARCB1 expression was retained. Fluorescence in situ hybridization and targeted next‐generation sequencing identified a CIC‐NUTM1 fusion resulting from t(15;19)(q14;q13.2). In light of morphologic features that overlap with those of NC from typical anatomical sites we have seen previously, the tumor was best classified as falling within the NC spectrum rather than CIC‐associated sarcoma. This case highlights the emerging diagnostic challenges generated by newly detected gene fusions of unknown clinical and biologic significance. Careful integration of cytogenetic, molecular, and immunohistochemical findings with morphologic appearances in the diagnostic workup of undifferentiated neoplasms is essential.     

NUT carcinoma presenting in the palate – a case report

NUT carcinomas (NC) are rare and aggressive tumours characterized by chromosomal rearrangements of the gene encoding for nuclear protein of the testis (NUT) located on chromosome 15q14. This article presents a case of a 60‐year‐old woman diagnosed with NC presenting as a fast growing primary tumour in the right palate. Further evaluation revealed a tumour mass in the lungs and widespread metastases. A review of the literature did not reveal earlier cases presenting in the palate. In order to improve early diagnosis it is suggested to perform immunohistochemical testing for NUT in all poorly differentiated carcinomas without glandular differentiation arising in the chest, and head and neck (Clin Cancer Res, 18, 2012, 5773).     

Primary malignant epithelioid and rhabdoid tumor of bone harboring ZNF532‐NUTM1 fusion: the expanding NUT cancer family

NUTM1 gene rearrangement is the genetic hallmark of NUT carcinoma, an aggressive tumor that most commonly affects the thoracic and head and neck regions and often exhibits squamous differentiation. The most common fusion partner gene is BRD4, followed by BRD3 and NSD3. Recently, NUTM1 gene rearrangement has been identified in rare tumors from soft tissues, intracranial locations, and other visceral organs. These tumors often show high grade malignant epithelioid to round cell histomorphology and lack evidence of squamous and/or epithelial differentiation. Therefore, their relationship with classic NUT carcinoma is still uncertain. Here, we present a primary mandible bone tumor of a 21‐year‐old female exhibiting monotonous epithelioid and rhabdoid cytomorphology, vesicular chromatin, and prominent nucleoli. The initial immunohistochemical workup was non‐specific, showing only CD34 positivity while being negative for cytokeratin (AE1/AE3), EMA, p63, etc. INI‐1 expression was retained. RNA sequencing was performed and identified a rare ZNF532‐NUTM1 gene fusion, which had only been reported in a single case of pulmonary NUT carcinoma. The fusion was confirmed by FISH for NUTM1 gene rearrangement and supported by diffuse and strong NUT immunoreactivity. MYC mRNA up‐regulation and immunoreactivity, a common finding in NUT carcinoma, was also observed in this tumor, suggesting a possible common pathogenetic mechanism and potential treatment target. The patient presented with a non‐metastatic disease status and received hemimandibulectomy, selective neck dissection (level Ib), and post‐operative radiation therapy. She remained disease free 3.6 years after the initial diagnosis.     

Genomic Landscape of poorly Differentiated and Anaplastic Thyroid Carcinoma

Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are aggressive thyroid tumors associated with a high mortality rate of 38–57 % and almost 100 % respectively. Several recent studies utilizing next generation sequencing techniques have shed lights on the molecular pathogenesis of these tumors, providing evidence to support a stepwise tumoral progression from well-differentiated to poorly differentiated, and finally to anaplastic thyroid carcinomas. While BRAF ^V600E and RAS mutations remain the main drivers in aggressive thyroid carcinoma, PDTC and ATC gains additional mutations, e.g., TERT promoter mutation, TP53 mutation, as well as frequent alterations in PIK3CA-PTEN-AKT-mTOR pathway, SWI-SNF complex, histomethyltransferases, and mismatch repair genes. RAS-mutated PDTCs are commonly associated with a histologic phenotype defined by Turin proposal, high frequency of distant metastasis, high thyroid differentiation score, and a RAS-like gene expression profile, whereas BRAF-mutated PDTCs are usually defined solely by the Memorial Sloan Kettering Cancer Center (MSKCC) criteria with a propensity for nodal metastasis and are less differentiated with a BRAF-like expression signature. Such demarcation is largely lost in ATC which is characterized by genomic complexity, heavy mutation burden, and profound undifferentiation. Additionally, several molecular events, e.g., EIF1AX mutation, mutation burden, and chromosome 1q gain in PDTCs, as well as EIF1AX mutation, chromosome 13q loss, and 20q gains in ATCs, may serve as adverse prognostic markers predicting poor clinical outcome.     

Macrofollicular Variant of Papillary Thyroid Carcinoma with Extensive Lymph Node Metastases

The macrofollicular variant of papillary thyroid carcinoma is a rare subtype of the follicular variant of papillary thyroid carcinoma and is usually characterized by an indolent clinical course. The tumors are prone to be misdiagnosed as benign due to their macrofollicular architecture and bland cytologic features. We report a rare case of the macrofollicular variant of papillary thyroid carcinoma with extensive lymph node metastases. The patient was a 48-year-old female with a right thyroid nodule and multiple enlarged lymph nodes in the right neck. It was not possible to make a definitive diagnosis of malignancy on fine-needle aspiration cytology and intraoperative frozen section. She underwent total thyroidectomy with right modified radical neck dissection. The surgical specimen showed a 2.5?×?1.5?×?10 cm, well-circumscribed macrofollicular variant of papillary thyroid carcinoma in the right lobe and multiple central and right lateral neck lymph node metastases. Molecular testing for BRAF, NRAS, HRAS, and KRAS was all negative. We then reviewed the demographic and clinicopathologic characteristics of 71 patients with the macrofollicular variant of papillary thyroid carcinoma. The cytologic or histopathologic diagnosis of macrofollicular variant of papillary thyroid carcinoma can be difficult. Extensive lymph node metastases caused by the macrofollicular variant of papillary thyroid carcinoma may occur even in the absence of capsular or lymphovascular invasion. This review will help to better understand the nature of the macrofollicular variant of papillary thyroid carcinoma.     

A rare Japanese case with a NUT midline carcinoma in the nasal cavity: A case report with immunohistochemical and genetic analyses

Background

NUT (nuclear protein in testis) midline carcinoma (NMC) is a recently described aggressive malignancy that is genetically defined by rearrangements of the NUT locus at 15q14. In approximately two-thirds of cases, the characteristic t(15;19) results in the fusion oncogene BRD4-NUT. Only 10 sinonasal NMCs have been documented, none of which were Japanese cases.

Case presentation

An 18-year-old woman was admitted because of a rapidly progressing tumor in the nasal cavity. A biopsy revealed an undifferentiated neoplasm without squamous differentiation. The tumor cells had round to oval nuclei with vesicular chromatin, prominent nucleoli, and scant cytoplasm. Immunohistochemical staining demonstrated a strong positivity for vimentin and NUT, with focal CD138 and only spotty EMA and cytokeratin AE1/AE3 staining. Cytogenetic and fluorescence in situ hybridization analyses revealed a t(15;19) and BRD4-NUT gene rearrangement. Direct sequencing identified the in-frame fusion of exon11 of BRD4 with exon2 of NUT. The patient was transferred to another hospital for chemoradiotherapy.

Conclusion

We herein describe the first Japanese case with an NMC of the sinonasal cavity, providing detailed and unambiguous cyto- and molecular genetic information on BRD4-NUT-rearrangement. The accumulation of cases with well-documented genetic data should provide clues to the treatment of this tumor entity.     

Midline carcinoma expressing NUT in malignant effusion cytology

Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare and aggressive subset of poorly differentiated squamous cell carcinoma that is defined by t(15,19) and typically presents in the midline structures of the head, neck, and mediastinum. We report two cases of NMC that presented uniquely with malignant pleural and pericardial effusions including one with cardiac tamponade at presentation. The first case is of a 25‐year‐old male patient who presented with progressive dyspnea associated with palpitations and dizziness on standing, found to have large bilateral pleural effusions. The second case is of a previously healthy 29‐year‐old male patient who presented with progressive dyspnea, cough with expectoration, and a large right lower neck mass of 3 months onset, and a large left pleural effusion and left lung infiltrate on imaging studies. Both cases showed malignant cells on cytology suggestive of poorly differentiated carcinoma. Subsequent histopathological and immunochemistry studies were consistent with the diagnosis of NMC. Both patients had a rapid decline in status and suffered comorbidities secondary to their carcinoma, inevitably leading to their death. It is important to consider NUT midline carcinomas can present in a variety of clinical scenarios, and it is important to consider in the differential diagnoses when evaluating malignant effusion cytology. Utilization of ancillary testing with a broad immunostain profile including NUT studies, as well as fluorescent in‐situ hydridization (FISH) studies are helpful and necessary in making the appropriate diagnosis.     

Primary angiosarcoma of the thyroid gland with recurrence diagnosed by fine needle aspiration: A case report

Angiosarcoma of the thyroid is a rare and aggressive primary malignant tumor of the thyroid originally reported in patients from the Swiss Alpine region. Diagnosis of this tumor rests mainly on characteristic histopathological features of a malignant vascular tumor supported by immunopositivity for vascular markers e.g., CD31, Factor VIII, and CD34. Its cytological features, however, are not well‐defined. We describe a case of primary angiosarcoma of the thyroid in a 48‐year‐old female, who presented with a rapidly enlarging neck mass associated with compressive symptoms. She had a history of hypothyroidism. The initial fine needle aspiration cytology of the neck mass was negative. She then underwent left hemithyroidectomy. Histologically, the tumor showed poorly differentiated malignant cells with eccentrically‐placed nuclei, prominent nucleoli, and intracytoplasmic vacuoles admixed with mixed inflammatory cells. These showed immunopositivity for CD31 but were negative for CD34, Factor VIII, CK5/6, EMA, TTF‐1, Thyroglobulin, Calcitonin, Melan A, and Calretinin. A diagnosis of poorly differentiated malignant tumor consistent with angiosarcoma was made. The patient was treated with radiation therapy but developed recurrence of the tumor. Second aspiration cytology of the recurrent tumor yielded hypocellular smears containing singularly dispersed atypical cells having eccentrically‐placed nuclei with prominent macronucleoli and intracytoplasmic vacuoles within a background of inflammatory cells, consistent with recurrent angiosarcoma. Chemotherapy was started but she succumbed to the disease 7 months after diagnosis. The cytological, histopathological, immunohistochemical findings, and the clinical course are discussed. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Neoplastic thrombotic endocarditis of the tricuspid valve in a patient with carcinoma of the thyroid. Report of a case

A rare case of neoplastic thrombotic endocarditis of the tricuspid valve in a patient with poorly differentiated follicular carcinoma of the thyroid is described. Although some previous reports documented extension of the follicular thyroid carcinoma into the great veins of the neck to the right cardiac chambers, this seems to be the first report of a neoplastic thrombotic lesion of the tricuspid valve in a patient with thyroid carcinoma. In our institute, where about 2,500 autopsies are performed yearly, and about 600 valvular lesions are discovered, such a lesion was never detected. In patients with carcinoma, a neoplastic thrombotic endocarditis may be a source of microembolic neoplastic spread leading to a possible pulmonary colonisation.     

NUT carcinoma of the lung

NUT carcinoma of the thorax is a rare and very aggressive tumor, whose definition is based on the demonstration of a nuclear protein in testis (NUTM1; also known as NUT) gene fusion on 15q14 with different partners from the bromodomain-containing proteins gene family. This fusion results in an activation of MYC oncoprotein responsible for the tumor's aggressivity. NUT carcinoma arises preferentially in young adults, presenting a large thoracic mass frequently associated with lymph nodes, bone or pleural metastases. At histology, this tumor is often poorly differentiated, mainly composed of sheets of small cells with scant cytoplasm, a round nucleus with a central nucleolus. Focal areas of squamous differentiation can be observed. Mitoses and necrosis are frequent, as well as neutrophilic infiltrate. The diagnosis is based on the detection of NUT protein expression by immunohistochemistry using the rabbit monoclonal antibody C52B1 in more than 50% of the tumor nuclei. This technique offers 87% sensitivity and nearly 100% specificity with reference to FISH or RT-PCR, which confirm the NUTM1 rearrangement. The differential diagnoses include basaloid carcinoma of the lung, small cell carcinoma, thymic carcinoma (basaloid variant), SMARCA4_deficient thoracic sarcoma, other NUTM1 rearranged undifferentiated tumors, small round cell tumors, non-Hodgkin lymphoma/leukemia, and melanoma. The prognosis of NUT carcinoma remains very poor, with a median survival of 6.7 months, and 1- and 2-year overall survival rates of 30% and 19%, respectively. NUT carcinoma is often refractory to conventional chemotherapy, but ifosfamide-based regimens or BET inhibitors could represent promising therapies.     

Immunohistochemical expression of CXCR4 in thyroid carcinomas and thyroid benign lesions

In different tumor entities, expression of the chemokine receptor 4 (CXCR4) has been linked to tumor dissemination and poor prognosis. The aim of this study was to examine the immunohistochemical expression of CXCR4 in thyroid carcinomas and thyroid benign lesions. Using monoclonal anti-CXCR4 antibody, we performed immunohistochemical staining on tissue sections from 134 cases obtained from Ruijin Hospital affiliated with Shanghai Jiaotong University School of Medicine (Shanghai, China) between 2000 and 2007. In our study, the CXCR4 expression of the thyroid carcinoma group (including 16 papillary thyroid carcinomas, 18 follicular thyroid carcinomas, 9 poorly differentiated thyroid carcinomas, and 7 medullary thyroid carcinomas) was found to be higher than in the benign lesion group (including 19 cases of Hashimoto's thyroiditis, 15 nodular goiters, and 50 follicular adenomas) (p < 0.0001). Within the carcinoma group, the more malignant thyroid carcinoma group (including 9 poorly differentiated thyroid carcinomas and 7 medullary thyroid carcinomas) showed a higher ratio of CXCR4 positivity compared to the less malignant thyroid carcinoma group (including 16 papillary thyroid carcinomas and 18 follicular thyroid carcinomas) (p < 0.0001). Our study suggests that CXCR4 expression might be a frequent and cancer-specific event in thyroid carcinoma, and it might be involved in malignancy transformation during the progression of thyroid carcinoma.     

The association of well-differentiated thyroid carcinoma with insular or anaplastic thyroid carcinoma; evidence for dedifferentiation in tumor progression

The sequence of tumorigenesis in the thyroid is unclear. It has been proposed that anaplastic carcinomas of the thyroid develop by dedifferentiation in pre-existing differentiated carcinomas. We reviewed all anaplastic and insular (poorly differentiated) thyroid carcinomas in a consultation practice of thyroid pathology that included more than 400 thyroid cancers. Sixteen tumors (4%) were classified as anaplastic or insular (poorly differentiated) thyroid carcinomas. We examined these cases to determine whether these carcinomas were associated with well-differentiated neoplasms of follicular cell derivation. Ten patients were women and 6 were men, and ages ranged from 29 to 85 years; 10 patients with anaplastic carcinomas and 2 with insular carcinomas were 56 years or older, whereas 3 of the 6 patients with insular carcinomas were 31 years or younger. Four tumors were composed exclusively of anaplastic carcinoma; all were represented only by incisional biopsies. One insular carcinoma infiltrated and destroyed all underlying thyroid tissue. In the remaining total, subtotal, or hemithyroidectomy specimens, areas of well-differentiated papillary or follicular carcinoma were found. Some differentiated papillary lesions had a wide spectrum of morphologies, including Hurthle cell, tall cell, and columnar cell features. In the literature, simultaneous or previous occurrence of well-differentiated thyroid carcinomas with anaplastic carcinomas is extremely variable, ranging from 7–89% of cases. in experimental animals, serial transplantation of differentiated thyroid tumors has been shown to lead to anaplastic transformation. Our findings suggest that the majority of anaplastic thyroid carcinomas in humans arise from well-differentiated tumors. However, only a very small number of differentiated carcinomas progress to anaplastic lesions; the factors underlying this phenomenon remain to be identified.     

Scarring in papillary carcinoma of the thyroid: report of two new cases with exuberant nodular fasciitis-like stroma

AIMS: To describe two new cases of papillary carcinoma of the thyroid with exuberant nodular fasciitis-like stroma, one of which was characterized by previously unreported transformation into a poorly differentiated lesion. Moreover, we explore the presence of TGF-beta to help to clarify the pathogenesis of the collagen formation. METHODS AND RESULTS: The case characterized by an aggressive behaviour exhibited areas of transformation into a poorly differentiated (insular) carcinoma of the thyroid. In both cases, as revealed by immunohistochemistry, neoplastic cells produced and secreted high amounts of TGF-beta. On the contrary, TGF-beta immunoreaction was never present in the normal thyroid or in papillary carcinomas without collagen bundles, while a weak, exclusively intracellular reaction was present in a patchy manner in cases showing intratumoral fibrous bundles. CONCLUSIONS: The rare variant of papillary thyroid carcinoma characterized by exuberant stroma may give rise to more aggressive lesions, as do other histotypes of differentiated thyroid carcinomas. TGF-beta, the fundamental cytokine which mediates scarring and activation of myofibroblasts, most probably induces the exuberant stroma.     

Primary renal NUT carcinoma identified by next-generation sequencing: a case report and literature review

Background: NUT carcinoma is a rare aggressive squamous cell carcinoma subtype genetically characterized by NUTM1 rearrangements. NUT carcinoma can be easily misdiagnosed as an undifferentiated carcinoma or Ewing sarcoma due to its primitive differentiation. Case presentation: We report a case of renal-derived NUT carcinoma diagnosed as a malignant small round-cell tumor resembling Ewing sarcoma/primitive neuroectodermal tumor where the diagnosis was revised to NUT carcinoma with a characteristic NUTM1 rearrangement based on next-generation sequencing (NGS). The patient received a standard NUT carcinoma treatment after recurrence but died of first-line chemotherapy failure due to advanced neoplasm progression. Conclusion: Routine NUT immunohistochemistry staining, NGS, and/or fluorescent in situ hybridization for poorly differentiated carcinoma and sarcoma can help avoid misdiagnosis of NUT carcinoma-related tumors, allowing patients to benefit from bromodomain and extra-terminal motif inhibitor therapy.     

Carcinoma showing thymus like elements: Report of a case with EGFR T790M mutation

Carcinoma showing thymus‐like differentiation of the thyroid (CASTLE) is a rare tumor involving the thyroid and perithyroidal soft tissues. It shares morphological, immunohistochemical and molecular similarities with thymic carcinomas. Due to its relatively better prognosis, it needs differentiation from other primary and metastatic tumors of this region. A 40‐year‐old lady presented with a gradually progressive anterior neck swelling for one year. Imaging showed bulky right and left lobes of thyroid along with a solid soft tissue mass in the pretracheal region. Fine needle aspiration smears showed features of poorly differentiated carcinoma. Total thyroidectomy with excision of the mass revealed histopathological features characteristic of CASTLE, with evidence of thyroiditis in adjoining thyroid. Epidermal growth factor receptor (EGFR) assay revealed presence of EGFR T790M somatic mutation in exon 20. The same was not detectable on direct sequencing. We present a rare case of CASTLE, occurring in association with Hashimoto thyroiditis, with emphasis on cytological features and report for the first time the presence of a low level somatic mutation in EGFR (EGFR T790M mutation).     

Primary squamous cell carcinoma of the thyroid gland: an entity with aggressive clinical behaviour and distinctive cytokeratin expression profiles

AIMS: Primary squamous cell carcinoma of the thyroid gland is uncommon. This study aims to identify the clinicopathological features and the pattern of expression of cytokeratins and oncoproteins in this tumour. METHODS AND RESULTS: Histological slides from Chinese patients with thyroid cancer treated in our institution from 1980 to 1999 were reviewed. Patients with primary squamous cell carcinoma of the thyroid were identified and their clinical records were analysed. The expression of cytokeratins (CKs), p53 and p21 in these cases were also studied by an immunohistochemical method. Four women (mean age 71 years) with squamous cell carcinoma of thyroid were found. The main presenting features were signs and symptoms of airway obstruction in three patients and neck swelling in one. The tumours were located at the right lobe (n=2), left lobe (n=1) or in both lobes of the thyroid (n=1). One patient died shortly after admission and the other three died within 4 months after thyroidectomy. The p53 protein was positive in 50% (2/4) of the tumours and p53+ tumours were poorly differentiated. The tumours were negative for p21. CK19 was expressed in all the tumours while CK7 expression was noted in 3/4 of the tumours. One carcinoma showed focal positivity to CK18. The tumours were negative for CKs 1, 4, 6, 10/13 and 20. The pattern of cytokeratin expression in squamous cell carcinoma of the thyroid gland was different from carcinoma showing thymus-like differentiation (CASTLE) of the thyroid gland and oesophageal squamous cell carcinoma. CONCLUSIONS: Squamous cell carcinoma of the thyroid has aggressive clinical behaviour and characteristic CK expression pattern. p53 over-expression in these tumours was associated with tumour differentiation.