Kesavan Sittampalam

Angiomatoid fibrous histiocytoma: unusual sites and unusual morphology

Angiomatoid fibrous histiocytoma is a soft tissue neoplasm of low malignant potential, typically occurring in the superficial soft tissues of the extremities in children and young adults. Occurrence outside somatic soft tissues is most uncommon. This report describes eight such cases, involving the lung (three cases), mediastinum (one case), vulva (two cases), retroperitoneum (one case) and ovary (one case), with the latter three locations being hitherto unreported sites of occurrence. Patients had a median age of 48 years, and presented with symptoms related to the mass lesion (five cases) or were incidentally found to harbor a tumor (three cases). Besides the typical histological features such as an outer shell of lymphoid tissue, multinodular aggregates of dendritic-like tumor cells, blood-filled spaces and abundant admixed plasma cells, unusual features were found focally in some cases, including clear cells, rhabdomyoblast-like cells, pulmonary edema-like pattern and tumor cell cords lying in a myxoid stroma. Immunoreactivity for the epithelial membrane antigen, desmin, smooth-muscle actin, CD68 and CD99 was found in 100, 63, 43, 100 and 100% of cases, respectively. Molecular studies provided support for the diagnosis in all seven tested cases—EWS gene translocation in six cases (partner gene being CREB1 in three and ATF1 in two in which information was available) and FUS gene translocation in one case. Comparison of the reported cases of extrasomatic angiomatoid fibrous histiocytoma with their somatic soft tissue counterparts showed a number of differences: higher mean age, slight male predominance (particularly for bone lesions), larger tumors, higher frequency of systemic symptoms, higher recurrence rate, myxoid change being more common and a much higher frequency of EWS/ATF1 gene fusion.

Cribriform-morular variant of papillary carcinoma: the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma. A case report with clinical and molecular genetic correlation

&NA; The increased incidence of thyroid carcinomas in familial adenomatous polyposis (FAP) patients is well recognised. These thyroid neoplasms display distinctive clinicopathological features and generally show good prognostic outcome. Recently, unusual sporadic tumours that share the morphological features of FAP‐associated thyroid carcinomas have also been described. In this report, we document a case of a thyroid tumour in a previously well, 46‐year‐old female. Histology revealed a circumscribed neoplasm composed of tubular, papillary, cribriform and solid areas. The pseudostratified columnar tumour cells showed occasional nuclear grooves and rare nuclear inclusions. Immunohistochemistry showed positive staining with antibodies to cytokeratin AE1/AE3, oestrogen and progesterone receptor proteins. Focal immunoreactivity was also noted with antibodies to thyroglobulin, epithelial membrane antigen, 34betaE12 and cytokeratin CK7. The absence of polyps on colonoscopy and germline mutation in the adenomatous polyposis coli (APC) gene provides evidence that this tumour represents the sporadic counterpart of FAP‐associated thyroid carcinoma. The patient is well with no evidence of disease 7 months following resection of the tumour. The differential diagnoses and molecular genetics of this unusual tumour are discussed.

Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors.

Phosphaturic mesenchymal tumors typically cause paraneoplastic osteomalacia, chiefly as a result of FGF23 secretion. In a prior study, we identified FN1–FGFR1 fusion in 9 of 15 phosphaturic mesenchymal tumors. In this study, a total of 66 phosphaturic mesenchymal tumors and 7 tumors resembling phosphaturic mesenchymal tumor but without known phosphaturia were studied. A novel FN1–FGF1 fusion gene was identified in two cases without FN1–FGFR1 fusion by RNA sequencing and cross-validated with direct sequencing and western blot. Fluorescence in situ hybridization analyses revealed FN1–FGFR1 fusion in 16 of 39 (41%) phosphaturic mesenchymal tumors and identified an additional case with FN1–FGF1 fusion. The two fusion genes were mutually exclusive. Combined with previous data, the overall prevalence of FN1–FGFR1 and FN1–FGF1 fusions was 42% (21/50) and 6% (3/50), respectively. FGFR1 immunohistochemistry was positive in 82% (45/55) of phosphaturic mesenchymal tumors regardless of fusion status. By contrast, 121 cases of potential morphologic mimics (belonging to 13 tumor types) rarely expressed FGFR1, the main exceptions being solitary fibrous tumors (positive in 40%), chondroblastomas (40%), and giant cell tumors of bone (38%), suggesting a possible role for FGFR1 immunohistochemistry in the diagnosis of phosphaturic mesenchymal tumor. With the exception of one case reported in our prior study, none of the remaining tumors resembling phosphaturic mesenchymal tumor had either fusion type or expressed significant FGFR1. Our findings provide insight into possible mechanisms underlying the pathogenesis of phosphaturic mesenchymal tumor and imply a central role of the FGF1-FGFR1 signaling pathway. The novel FN1–FGF1 protein is expected to be secreted and serves as a ligand that binds and activates FGFR1 to achieve an autocrine loop. Further study is required to determine the functions of these fusion proteins.

Primitive neuroectodermal tumours of the uterus: a case report with cytological correlation and review of the literature

Summary A case of primitive neuroectodermal tumour (PNET) co‐existing with endometrial adenocarcinoma of the uterus is reported in a 48‐year‐old female. Histologically, the neoplastic cells formed neuroectodermal rosettes and displayed ependymal differentiation. Focal positive immunohistochemical staining for synaptophysin, chromogranin A, CD57 and cytokeratins was noted. Merging imperceptibly with the neuroectodermal component were areas of endometrial adenocarcinoma and, to the best of our knowledge, this report represents the second case of a uterine PNET with an admixed müllerian component. The patient was disease‐free 6 months following surgical resection of the tumour. The literature on this uncommon entity is critically reviewed and the histogenesis, differential diagnoses and cytomorphological features of PNET are also discussed.

Recurrent Dermatofibrosarcoma Protuberans of the Shoulder with Rare Distant Abdominal Metastasis detected by Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT).

A 56-year-old male patient with a rare dermatofibrosarcoma protuberans and fibrosarcomatous change (DFSPFS) presented with a solitary fluorodeoxyglucose (FDG)-avid tumour with no evidence of metastasis in the left upper extremity [Figure 1A]. This initial presentation was treated with wide excision, and then again at its recurrence 8 months later. At admission, the patient had symptoms of gastritis and underwent an oesophago-gastroduodenoscopy, which was normal. Almost 3 years after the initial presentation, the patient presented with a retroperitoneal mass measuring 1.4 x 0.8 cm. Investigation revealed the tumour, which was avid on FDG-PET/CT (standardised uptake value [SUV] max 11.3) and new compared to the previous study [Figure 2B]. Mild FDG uptake was also noted in a new pulmonary nodule (SUV max 1.9) and appeared malignant [Figure 3B]. Figure 4 shows the maximum intensity projection (MIP) images from the two studies. The retroperitoneal tumour was found to be dermatofibrosarcoma protuberans with extensive fibrosarcomatous transformation, histology grade 3 [Figures 5A and ​and5B5B]. Figure 1: Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) scans at the same trans-axial levels, showing mildly FDG-avid local recurrence in the shoulder (A), with no lesion subsequently identified in the same region (B). Figure 2: Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) scan at the same trans-axial level comparing the two scans at the time of local recurrence in 2006, when there was no retro-peritoneal lesion (A) and subsequently at ... Figure 3: Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) scan at the same trans-axial level comparing the two scans at the time of local recurrence in 2006 when there was no pulmonary lesion (A) and subsequently at the time ... Figure 4: Maximum intensity projection of the fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) scans at the time of the first presentation in 2006 with (A) a mildly FDG-avid local recurrence, and (B) subsequently, in 2009, with ... Figure 5: (A) Pathology slide of low-powered view of fibrosarcoma with herring-bone pattern; (B) Pathology slide showing areas of viable tumor fascicles with adjacent necrosis DFSP is a rare cutaneous tumour of low malignant grade characterised by a pattern of slow, infiltrative growth and a marked tendency to recur locally after surgical excision.1 DFSP is commonly found on the trunk (42–72%), occasionally in the proximal extremities (16–30%), and infrequently above the neck (10–16%).7 Rare distant metastases (in less than 5% of cases) may occur many years after the onset of disease and are limited mostly to the lungs, followed by regional lymph nodes, while the visceral organs and bones are rarely affected.2 Metastases are more likely with repeated incomplete surgical excisions and by tumour de-differentiation to higher grades.6 Metastases are associated with local recurrence and poor prognosis. The 5-year survival rate is estimated at 99.2%.7 DFSP is a fibrosarcoma originating from dermal fibroblasts.6 The genetic abnormalities in DFSP include a supernumerary ring chromosome related to the low amplification of sequences of chromosomes 17 and 22 which is a form of balanced reciprocal translocation.8 This rearrangement will cause fusion of alpha chain type A (COL1A1) located on 17q22 to the platelet-derived growth factor beta (PDGFB) located on 22q13. As a result, the COL1A1-PDGFB gene formation will result in up regulation of PDGFB expression, resulting in continuous autocrine activation of PDGF receptor beta (PDGFR-B) and propagation of the mitotic signal by formation of autocrine and paracrine loops.9 These transformed cells are inhibited by the tyrosine kinase inhibitor imatinib mesylate with reported cases of response often documented with FDG.10 The surgical objective in DFSP is complete tumour excision with maximal normal tissue preservation. Hence, a wide local excision with lateral margins of at least 3 cm and including the underlying fascia is recommended. In addition, micrographic controlled excision (MCE) showed favourable outcomes in treating DFSP.6 FDG-PET/CT findings in a case of recurrence of dermatofibrosarcoma in the surgical scar have been reported.3 FDG-PET/CT has also been used to monitor response to imatinib mesylate in 2 reported cases of unresectable metastatic DFSP, with a decrease in tumour uptake of FDG after treatment documented in both cases.4–5 In the former case, this decrease in uptake coincided with clinical improvement as early as 2 weeks after commencement of the therapy.4 In contrast to our case, where a FDG-avid pulmonary lesion was noted on PET/CT, a previous case reported a pulmonary nodule which was noted on CT but not on FDG-PET. It was thought this may have been due to the size (8 mm). A case has also been reported where DFSP response to imatinib was noted on FDG-PET but not on CT.10 This is similar to findings in other malignancies. DFSP is a rare cutaneous tumour of low malignant grade. FDG-PET/CT has been reported to be useful in DFSP imaging for delineating disease extent, both in staging and recurrence, which can be useful in planning surgery. FDG has also been documented as assessing DFSP response to imatinib, showing response when none was noted on CT. Given the rarity of the disease there are no large studies to date but the existing data appears promising. We suggest that FDG PET/CT be considered as an important component of the treatment plan of patients with DFSP.

Epibulbar Osseous Choristoma: A Report of Two Cases

Epibulbar osseous choristoma occurs rarely and is commonly mistaken for a dermoid or dermolipoma. We report two cases: an 8-year-old boy and a 79-year-old lady with epibulbar osseous choristomas where computed tomography showed an extraocular lesion in the temporal quadrant and diagnosis was confirmed by excision biopsy. The osseous component was adherent to the sclera in the young patient, while it was loosely attached to the surrounding tissue in the older patient. We believe that the 79-year-old lady is the oldest reported patient with an epibulbar osseous choristoma.

Germline hemizygous deletion of CDKN2A–CDKN2B locus in a patient presenting with Li–Fraumeni syndrome

Li–Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome usually associated with TP53 germline alterations. Its genetic basis in TP53 wild-type pedigrees is less understood. Using whole-genome sequencing, we identified a germline hemizygous deletion ablating CDKN2A–CDKN2B in a TP53 wild-type patient presenting with high-grade sarcoma, laryngeal squamous cell carcinoma and a family history suggestive of LFS. Patient-derived cells demonstrated reduced basal gene and protein expression of the CDKN2A-encoded tumour suppressors p14ARF and p16INK4A with concomitant decrease in p21 and faster cell proliferation, implying potential deregulation of p53-mediated cell cycle control. Review of 13 additional patients with pathogenic CDKN2A variants suggested associations of germline CDKN2A mutations with an expanded spectrum of non-melanoma familial cancers. To our knowledge, this is the first report of a germline gross deletion of the CDKN2A–CDKN2B locus in an LFS family. These findings highlight the potential contribution of germline CDKN2A deletions to cancer predisposition and the importance of interrogating the full extent of CDKN2A locus in clinical testing gene panels.

Brain metastasis in sarcoma: Does metastasectomy or aggressive multi-disciplinary treatment improve survival outcomes.

Brain metastasis is rare in sarcoma. Prognostic factors, optimal management strategies and therapeutic outcomes of such patients are not well studied. We aimed to evaluate the incidence, clinical characteristics and treatment outcomes of parenchymal brain metastasis in sarcoma patients.

Cardiopulmonary thromboembolism of epithelioid angiosarcoma arising from malignant phyllodes tumour of the breast

Phyllodes tumour is an uncommon fibroepithelial neoplasm of the breast with potential for aggressive biological behaviour manifesting as local recurrence or distant metastasis. Based on semiquantitative assessment of a constellation of histological parameters focusing on the stromal component, stromal cellularity and overgrowth, cellular atypia, mitotic activity and nature of tumour margin, these tumours are categorised into benign, borderline and malignant grades.1 Disease recurrence is mainly local, but malignant and rarely borderline tumours may develop distant metastases in a relatively small number of patients. While most metastases occur in the lung and skeleton, they have been described in almost every organ system. In this report, we document a rare case of cardiopulmonary tumour thromboembolism from a malignant phyllodes tumour with unusual histology and clinical course that posed diagnostic, clinical and management dilemmas. This was a patient who first presented with a left breast lump to another institution in February 2012, which was investigated with core biopsy that disclosed a phyllodes tumour. A lumpectomy ensued, which confirmed a 9.5 cm malignant phyllodes tumour that abutted the resection margin. Completion mastectomy was performed 2 months later, and CT scans did not show any metastatic lesions. She was seen in October 2012 for prolonged fever and was diagnosed with left-sided pneumonia as well as lobar thromboembolism. Echocardiogram and thrombophilia scan were within normal limits and did not identify any deep vein thrombosis or cardiac thrombus. CT scans of her thorax, abdomen and pelvis were also negative for tumour recurrence. She was commenced on warfarin anticoagulation. She continued to have intermittent low-grade fever but was otherwise well. However, she developed sudden onset of cough with shortness of breath, and her fever worsened 3 months later. CT thorax showed no change in the left-sided pulmonary thromboembolism; however, a mass was detected in the right atrium and ventricle associated …

Metabolic and reactive lesions simulating neoplasms

The skeleton can be affected by a wide variety of processes including infections, growth and development disturbances, circulatory disorders, metabolic diseases, reactive conditions, and neoplasms. All of these processes can occasionally produce a mass in bone that can clinically, radiographically and pathologically simulate a benign or malignant neoplasm. In this article, we discuss a select group of interesting metabolic and reactive lesions including brown tumor, osteomalacic fracture, hemophilic pseudotumor, reactive mixed mesenchymal pseudotumors of periosteal origin, avulsion injuries of bone, and pubic osteolysis, which are prone to be misinterpreted as neoplasms because of their peculiar clinical and morphologic features.