Coronary artery myointimal dysplasia in patients with pheochromocytoma-possible causal relationship: pathophysiology and clinical implication with reference to Takotsubo cardiomyopathy and spontaneous coronary dissection.

Myocardial damage in catecholamine cardiomyopathy, characterized by patchy myocyte necrosis commonly with contraction band appearances, interstitial fibrosis, and varying degrees of inflammatory infiltrates, has been well documented. However, coronary vascular pathology has not been recognized. Autopsy of a 43-year-old housewife who died of acute apical anteroseptal myocardial infarction revealed the incidental finding of a left adrenal pheochromocytoma. The epicardial and intramyocardial median- and small-sized coronary arteries exhibited myointimal dysplasia in the form of fibroblastic proliferation in the intima and media, resulting in thickened dysplastic vessels with marked luminal narrowing, occasionally leading to near-total occlusion. The distal left anterior descending artery showed features of recanalization after prior embolic occlusion. The density and severity of vascular involvement revealed a decreasing gradient from apical to basal region, mainly affecting the left ventricle, but the proximal coronary arteries were minimally affected. Myointimal dysplasia was not seen in control cases of hypertensive heart, and despite its presence in hearts with hypertrophic cardiomyopathy, it lacked the distinctive pattern of distribution and the epicardial vessels are uninvolved. Myointimal dysplasia probably results from reactive fibroplasia in response to the vasoconstrictive effect of circulating or local neurosecretory catecholamine and appears crucial in the pathogenesis of various types of catecholamine cardiomyopathy, including Takotsubo or stress cardiomyopathy. Together with the direct catecholamine cardiotoxicity, they result in diffuse microscopic ischemic necrosis and fibrosis. Depending on the type of catecholamine overproduction and action, together with the characteristic anatomic distribution and density of the various types of adrenergic receptors in the ventricles, different regions of the heart are variously affected so that different patterns of ventricular dysfunction are produced, with the subsequent angiographic appearances ranging from apical through midventricular to basal ballooning. Additional complications from the myointimal dysplasia include spontaneous coronary dissection, acute myocardial infarction, and superimposed thrombus formation in the dysplastic vessels and dyskinetic ventricle, with the risk of further damage from embolic events.

Functional Ulnar Nerve Paraganglioma: First Documented Occurrence in the Extremity With Hitherto Undescribed Associated Extensive Glomus Cell Hyperplasia and Tumorlet Formation.

Extra-adrenal paraganglioma has never been described in the extremities. A 34-year-old woman complained of an enlarging mass in the right forearm for 18 months. Imaging showed a circumscribed vascular tumor attached to the ulnar nerve; biopsy revealed features of paraganglioma. The resected tumor consisted of zellballen pattern of chief cells staining positively for chromogranin with surrounding S100-positive sustentacular cells. The chief cells contained many neurosecretory granules and mitochondria, whereas the sustentacular cells contained a large amount of rough endoplasmic reticulum and some microfilaments. There was adjacent extensive glomus cell hyperplasia and tumorlet formation. The intraoperative blood pressure dropped abruptly on tumor removal. The serum normetanephrine level decreased from a preoperative level of 1987 pg/mL (normal < 149 pg/mL) to normal after operation. The patient admitted on questioning to a history of paroxysmal attacks of transient palpitation, hand tremors, and sweating; imaging showed no evidence of tumor in other parts of the body, and there was no family history of similar tumor; she remained well 33 months after the operation. This occurrence of functional ulnar nerve paraganglioma with the hitherto undescribed associated glomus cell hyperplasia and tumorlet formation attests to the probable existence of normal sympathetic paraganglia in the extremity and their intimate functional relationship with glomus bodies.

Giant cell rich osteosarcoma revisited-diagnostic criteria and histopathologic patterns, Ki67, CDK4, and MDM2 expression, changes in response to bisphosphonate and denosumab treatment.

Defining giant cell-rich osteosarcoma (GCRO) as "an osteosarcoma in which more than 50% of the tumor consists of numerous uniformly distributed osteoclastic giant cells amidst oval or spindle mononuclear cells embedded in a fibrovascular stroma," eight such cases identified among 265 cases of osteosarcoma were analysed. Their age ranges from 11 to 33 years, with peak incidence in the second decade and equal sex distribution. Seventy-five percent presented with pain, commonest in the knee, affecting the metaphysis. Most appeared radiologically as well-circumscribed expansile multiloculated osteolytic lesions, and many are displayed periosteal reaction. They showed several distinct histologic patterns: the stromal and giant cell, fibrohistiocytic, aneurysmal-cystic, osteoblastoma-like, and parosteal and fibrous dysplasia-like patterns. Focal subtle lacelike osteoid deposition, permeative infiltration into adjacent native bony trabeculae and over 30 % Ki67 proliferative index were characteristic. There was no CDK4 and MDM2 amplification. In those having bisphosphonate and denosumab treatment, there was limited focal necrosis with reduction in the number of giant cells and broad trabecular woven bone formation but no giant osteoclast was seen. Two patients with initial diagnosis of giant cell tumor treated by curettage and local resection pursued aggressive clinical courses, died after 14 and 21 months. The others survived 12 to 110 months. GCRO accounts for about 3 % of all osteosarcomas and apart from its more frequent diaphyseal location and associated normal bone-specific alkaline phosphate levels; it shares with conventional high-grade osteosarcoma the same patient demographics, sites of occurrence, absence of CDK4 and MDM2 amplification, and probably clinical course.

Metatarsal leiomyosarcoma masquerading as acute osteomyelitis - A diagnostic trap unveiled by vigilant clinical, radiologic and pathologic analysis.

Due to overlapping clinical and radiological features, the differentiation between osteomyelitis and bone tumor can be challenging. A 48-year-old lady presented with intermittent left foot pain for a few months. Plain radiographs showed an osteolytic lesion affecting the proximal diaphysis of the left fourth metatarsal bone, with thinning and irregularities of the cortex and focal periosteal reaction. Ultrasonography revealed diffuse subcutaneous edema in the dorsum of the left foot, cortical irregularities along the mid-shaft of the left fourth metatarsal bone, and surrounding periosteal collection. Computed tomography showed medullary expansion along the shaft and base of the left fourth metatarsal bone with cortical irregularities and defects suggestive of cloaca, and focal mild periosteal new bone formation. The clinico-radiologic diagnosis was acute osteomyelitis with periosteal collection. During open biopsy, the finding of intramedullary fleshy tissue in the absence of significant inflammatory edema and purulent discharge, and subsequent negative culture result prompted a review of the histologic slides which was initially reported as benign fibroblastic tissue proliferation. Careful analysis of the histomorphology disclosed a spindle cell sarcoma for which ray amputation of the fourth and fifth metatarsal was performed. The final diagnosis was grade 1 leiomyosarcoma and the patient remained well 33 months after the operation.

Delayed osseous metastasis from low-grade endometrial stromal sarcoma: Uncommon occurrence deserving recognition.

Despite excellent prognosis, low-grade endometrial stromal sarcoma (ESS) is notorious for late recurrence even in stage I disease. Bone metastases are distinctly rare and only six cases have so far been reported. Two patients presented with back pain due to spinal metastatic low-grade ESS after 15 and 9 years free of disease after resection of the stage 1 primary uterine tumor. Plain radiograph showed an ivory first lumbar vertebra in the first patient and an osteolytic lesion involving the second thoracic vertebra in the second. In both cases, magnetic resonance imaging showed vertebral tumor with intra-spinal extension and spinal cord compression; biopsy confirmed the diagnosis of metastatic low-grade ESS. The first patient received palliative radiotherapy and chemotherapy while the second underwent surgical decompression followed by adjuvant radiotherapy and chemotherapy. The neurologic symptoms in both patients returned 12 months afterwards and progressed relentlessly despite adjuvant chemotherapy and radiotherapy. The first patient developed multiple bone and lung metastasis, culminating in death 44 months after recurrence. While surviving at 24 months from recurrent disease, the second became paraplegic with double incontinence and was wheelchair bound. Delayed osseous metastatic low-grade ESS, although uncommon, deserves recognition given the predilection for spine as the site of involvement. In such a location, where complete surgical removal is notoriously difficult, if not impossible, the prognosis of spinal metastatic low-grade ESS appears grave with considerable morbidity and mortality.

Infiltrating hybrid mesenchymal tumor of skeletal muscle showing lipomatous, hemangiomatous, leiomyomatous and osseous features - An unusual soft tissue tumor providing insight into the pathogenesis of lipoma variants.

Infiltrating angiolipoma and osteolipoma of the hand are rare. A 40-year-old man presented with slowly enlarging swelling of his right hand for two and half years without functional deficit but it became painful with slight limitation of movement for the past few months. Plain radiograph showed a large soft tissue swelling with specks of calcifications. Ultrasonography and magnetic resonance imaging revealed an infiltrative mass in the right palm deep to the flexor tendons. As biopsy suggested infiltrative angiolipoma of skeletal muscle, debulking of the tumor was performed. The tumor showed coexistence of all four mesenchymal elements, fat, blood vessel, smooth muscle and bone in various combinations in the form of angiolipomatous, osteolipomatous, ossified intramuscular hemangiomatous, myolipomatous and angiomyolipomatous patterns throughout the entire tumor. Small meningothelial-like whorls of spindle cells were focally seen, some showed intramembranous ossification forming small woven bony spicules in their centers. There were no atypical cells or lipoblasts. Staining for CDK4, MDM2, p16, HMB45 and Melan A was negative. The diagnosis was "infiltrating hybrid mesenchymal tumor of skeletal muscle showing lipomatous, hemangiomatous, leiomyomatous and osseous features". The fairly even admixture of the various components supports the neoplastic participation of each individual element. Hybrid mesenchymal tumor most probably originates from multipotent neoplastic cells showing multidirectional differentiation.

Primary synovial epithelioid sarcoma of the knee: distinctly unusual location leading to its confusion with pigmented villonodular synovitis.

Epithelioid sarcoma (ES) is a rare malignant soft tissue tumor occurring in the distal extremities of young adults and is characterized histologically by nodules of epithelioid cells showing central necrosis. Intra-articular ES is extremely rare; only four cases have been reported, but their radiologic and histologic documentation of intra-articular origin have been imprecise. We report the first radiologically and histologically well-documented case of primary synovial ES. A 59-year-old woman presented with pain followed by swelling of her right knee for 6 months. MRI revealed an entirely intra-articular nodular synovial mass in the lateral part of the right knee joint in a background of diffusely thickened synovium. Synovectomy was performed under the clinical impression of pigmented villonodular synovitis (PVNS), a diagnosis erroneously confirmed by the reporting pathologist. The tumor rapidly recurred 3 months afterward and the diagnosis of primary synovial ES was made. Despite above-knee amputation, the tumor continued to spread proximally to the retroperitoneum. She developed multiple lung metastases and died 20 months after initial presentation. The nodular aggregates of tumor cells with central necrosis resulted in diffuse polypoid synovial thickening mimicking tuberculous synovitis and PVNS. The tumor cells showed positive staining for EMA, CK19, CD34, and complete loss of INI1 staining, establishing the diagnosis of primary synovial ES. The ES spread from the synovium to and along the joint capsule, and then extra-articularly into the soft tissue surrounding the knee joint, with lymphovascular permeation. Such pattern of spread calls for radical surgical excision as the treatment of choice.

Primary intraosseous hybrid nerve sheath tumor of femur: a hitherto undescribed occurrence in bone with secondary aneurysmal bone cyst formation resulting in pathological fracture.

Soft tissue perineurioma besides its pure form may coexist with schwannoma as hybrid nerve sheath tumor (HNST) which occurs in the limbs, head and neck, trunk and occasionally colon but origination in other organ sites has not been reported. We report the first case of primary intraosseous HNST. An 18-year-old man suffered from pathological fracture of his right femur after an impact which was preceded by a similar episode two weeks previously. Plain radiograph revealed a displaced fracture in the superior diaphysis of the right femur where an expansile osteolytic lesion with relatively well defined borders was seen. Histologic examination of the curetted lesion showed a well circumscribed spindle cell neoplasm displaying predominantly storiform but focally whorled patterns. In areas, the cells possessed thin wavy spindle nuclei and delicate elongated bipolar cytoplasmic processes supported in a fibromyxoid stroma. They stained positively for EMA, claudin, CD34, collagen 4 and focally for S100 but negatively for MUC4 and BCL-2, indicative of perineurial differentiation. Situated in the periphery of some of these perineurial whorls are spindle cells bearing plump tapering wavy nuclei and palely eosinophilic cytoplasm with indistinct cell borders. They stained intensely for S100 but negatively for EMA, claudin, CD34, collagen 4, MUC4 and BCL-2, consistent with schwannian differentiation. Focally, these two varieties of cells intimately intermingled with each other. Features of aneurysmal bone cyst (ABC) formation were present but no mitotic figures, establishing the final diagnosis of primary intraosseous HNST with secondary ABC formation. The patient remained well 7 months after curettage and internal fixation of his fracture.

Epiphyseal osteosarcoma revisited: four illustrative cases with unusual histopathology and literature review.

Osteosarcomas arising in the epiphysis are extremely rare and easily missed in the diagnostic consideration of epiphyseal tumors. It is the purpose of this study to delineate the clinical pathological characteristics of 'epiphyseal osteosarcoma' under the definition of 'a solitary long bone osteosarcoma radiographically considered an epiphyseal tumor for which the main radiologic differential diagnosis would encompass giant cell tumor, chondroblastoma and clear cell chondrosarcoma'. Four such cases with unusual histopathology were retrieved among 110 cases of osteosarcoma. Their clinical, radiological and pathological features, together with all 10 reported cases, were analyzed. The radiographic diagnoses of our four cases include two giant cell tumors, one chondroblastoma and one clear cell chondrosarcoma but turn out to be fibroblastic, giant cell rich, telangiectatic and epithelioid variant of epiphyseal osteosarcoma. Including our patients, the 14 reported epiphyseal osteosarcomas comprise 8 males and 6 females, the age at presentation ranges from 11 to 39 years, two-third in the second decade, 71.4% affect the femur. Due to their epiphyseal locations, many carry benign radiological diagnoses notably giant cell tumor and chondroblastoma. Epiphyseal osteosarcomas may not only masquerade as benign radiological bony lesions but also assume many histological patterns; orthopedic surgeons, radiologists and pathologists should be aware of such possibility. Their behavior and prognosis are dictated by the histologic types, grading and staging rather than location.

Primary osseous inflammatory malignant fibrous histiocytoma masquerading as chronic osteomyelitis.

Inflammatory malignant fibrous histiocytoma, in addition to a mass lesion, may present with fever and other constitutional symptoms, mimicking an infectious process. This article presents an extremely rare and unique case of primary osseous inflammatory malignant fibrous histiocytoma, highlighting retrospectively the subtle clinical, radiologic, and pathologic features that can suggest this diagnosis. A 63-year-old woman with a history of nephrectomy for right kidney tuberculosis 20 years ago presented with slowly increasing left hip pain for 6 months. The relatively benign-appearing radiograph and biopsy report of chronic inflammation resulted in curettage and nailing of the lesion. The pathologic diagnosis was chronic osteomyelitis, but culture findings for bacteria and tuberculosis were negative. The patient remained well until 4 months later, when left thigh pain returned with fever and leukocytosis (white blood cell count as high as 20.7×10(9)/L, 80% neutrophils). No source of infection was localized. The patient showed no response to broad-spectrum antibiotics and antituberculous drugs. Radiographs showed substantial enlargement of the femoral lesion and extraosseous extension; biopsy results and review of previous histopathologic findings led to a diagnosis of inflammatory malignant fibrous histiocytoma. The fever gradually resolved and the white blood cell count returned to normal within a few days after segmental resection of the proximal femur tumor and its soft tissue extension. However, deep venous thrombosis developed, resulting in left foot ischemia and toe gangrene, necessitating left below-the-knee amputation. Disseminated metastasis occurred 3 months after tumor resection. The patient declined further aggressive treatment and died 13 months after initial presentation.

Femur chondrosarcoma misdiagnosed as acute knee arthritis and osteomyelitis--further developing a hitherto unreported complication of tumor embolic ischemic ileal perforation after arthroscopic lavage.

The differentiation between osteomyelitis and bone tumor may be difficult due to their overlapping clinical and radiological features. A 25-year-old lady presented with left knee pain and joint effusion associated with redness and hotness. A sub-optimally taken plain radiograph showed mixed osteolytic and osteoblastic lesion in the left lower femur with surrounding soft tissue swelling. Since the clinical diagnosis was acute osteomyelitis and arthritis, arthroscopic lavage was performed as a diagnostic and therapeutic procedure. The removed loose bodies and fibrinous tissue showed pathological features suspicious of chondrosarcoma. Subsequent MRI revealed an infiltrative tumor eroding through the cortex and joint cartilage. En bloc excision of the left lower femur, upper tibia including the knee joint and patella was performed, and the final diagnosis was grade 2 chondrosarcoma. The patient developed bilateral pulmonary metastasis 33 months after operation. Five months later, she suffered from a hitherto undescribed complication of ischemic perforation of the terminal ileum secondary to tumor embolic arterial obstruction with no macroscopic intestinal or peritoneal tumor deposit. The patient developed multiple brain metastases and died 43 months after initial presentation. Our case illustrates that malignant bone tumor as a differential diagnosis of acute osteomyelitis and arthritis merits recognition and exclusion before arthroscopic lavage, which may enhance tumor dissemination and in our patient results in embolic ischemic ileal perforation.

Malignant schwannoma of the radial nerve with unusual presentation: a case report.

Malignant schwannoma (MPNST) is a rare tumor. Many of these cases occur in patients with neurofibromatosis type I (NF-1) and they usually present as a mass lesion which rapidly increase in size with or without neurological symptoms. Here we present an unusual case of MPNST along the radial nerve in which the patient has no underlying neurofibromatosis type I.

Novel nonsense CDC73 mutations in Chinese patients with parathyroid tumors.

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disease characterized by the occurrences of parathyroid tumors and ossifying fibroma of maxilla/mandible. It is caused by mutations in CDC73 gene and mutation carriers are at increased risk of parathyroid carcinoma. Hyperparathyroidism could be the sole manifestation. We reported two Chinese patients having parathyroid neoplasm with equivocal malignant potential and parathyroid carcinoma respectively with both germline and somatic CDC73 mutations detected. Both of them presented with severe hypercalcemia and primary hyperparathyroidism with no other HPT-JT associated tumors and negative family history. We identified one novel germline mutation CDC73 NM_024529.4: c.1475G > A; NP_078805.3: p.Trp492X and one novel somatic mutation CDC73 NM_024529.4: c.142G > T; NP_078805.3: p.Glu48X. The other germline mutation CDC73 NM_024529.4: c.226C > T; NP_078805.3: p.Arg76X and somatic mutation CDC73 NM_024529.4: c.85delG; NP_078805.3: p.Glu29SerfsX8 were previously reported. This is the first report of CDC73 mutations in the Chinese population. Genetic analysis is reliable to confirm the underlying hereditary basis of hyperparathyroidism. By identification of mutations, the patient and the family members could benefit from regular surveillance for early detection of tumors.