Bilateral infiltrating lobular carcinoma of the breast with osteoclast-like giant cells

Abstract: A case of bilateral infiltrating lobular carcinoma of the breast containing osteoclast-like giant cells is presented. Notable pathologic features include prominent tumor-associated angiogenesis and the presence of osteoclast-like giant cells in axillary lymph node metastases. Immunohistologic and ultrastructural examination support a nonepithelial, histiocytic origin for the giant cells, and results are similar to previous reports of osteoclast-like giant cells associated with breast carcinoma. This is the first report of bilateral pure infiltrating lobular carcinoma of the breast with osteoclast-like giant cells and the first case of pure lobular carcinoma with osteoclast-like giant cells present in lymph node metastases.     

Osteoclast-like giant cell tumor arising in the soft tissue of the breast: Report of a case

Extraosseous manifestations of osteoclast-like giant cell tumors (OGCTs) in soft tissue are unusual, especially in the breast. However, multinucleated osteoclast-like giant cells have been described in association with epithelial malignancy, as a variant of breast carcinoma. We report a case of OGCT of the soft tissue of the breast, not associated with epithelial elements. To the best of our knowledge, this is only the second such case reported.     

Undifferentiated carcinoma of the lung with osteoclast-like giant cells

We treated a patient with undifferentiated carcinoma of the lung, with osteoclast-like giant cells resembling those of the giant cell tumor of bone. The clinical and morphologic characteristics of this case are documented, and the literature concerning this type of tumor is reviewed. The tumor differed histologically from the pleomorphic carcinoma, which occurs most commonly in the lung, and showed diverse pleomorphic manifestation with benign looking osteoclast-like multinucleated cells and bizarre giant cells. In addition, and undifferentiated carcinoma with a sarcoma-like appearance containing small areas of papillary adenocarcinoma was evident in the tumor.     

Undifferentiated carcinoma of the lung with osteoclast-like giant cells

We treated a patient with undifferentiated carcinoma of the lung, with osteoclast-like giant cells resembling those of the giant cell tumor of bone. The clinical and morphologic characteristics of this case are documented, and the literature concerning this type of tumor is reviewed. The tumor differed histologically from the pleomorphic carcinoma, which occurs most commonly in the lung, and showed diverse pleomorphic manifestation with benign looking osteoclast-like multinucleated cells and bizarre giant cells. In addition, and undifferentiated carcinoma with a sarcoma-like appearance containing small areas of papillary adenocarcinoma was evident in the tumor.     

Papillary Urothelial Bladder Carcinoma Associated with Osteoclast-Like Giant Cells

We report the case of a papillary urothelial carcinoma associated with osteoclast-like giant cells. A 60-year old woman presented with hematuria. A papillary neoplasm was detected by cystoscopy and removed transurethrally. Histological examination revealed a papillary urothelial carcinoma (grade I) associated with multiple stromal giant cells, which displayed morphological, ultrastructural and immunohistochemical characteristics of osteoclast-like giant cells. The formation of osteoclast-like giant cells in association with urothelial bladder carcinoma is a rare event, of which only six cases have been reported in the Anglo-American literature. It may cause diagnostic problems because primary giant cell tumor, giant cell carcinoma and foreign body stromal reaction have to be considered. Immunohistochemistry and electron microscopy may help to rule out these differential diagnoses.     

Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas. A case report

Undifferentiated carcinoma with osteoclast-like giant cells is a rare pancreatic neoplasm, with a possible cystic pattern, includes an adenocarcinoma component and giant cell mimicking osteoclastic bone tumor. We report the case of a 72-year woman admitted for jaundice and epigastric pain. Abdominal ultrasound and computed tomography scan revealed a 6 x 5 cm cystic and solid tumor of the pancreatic head with both bile duct and pancreatic duct dilatation. A pancreaticoduodenectomy was performed and pathologic examination revealed an undifferentiated carcinoma with osteoclast-like giant cells of the pancreatic head. The patient was alive and disease-free with a 18-month follow-up.     

Breast carcinoma with osteoclast-like giant cells: morphological and ultrastructural studies of a case with review of the literature

Primary carcinoma with osteoclast-like giant cells is a very rare tumour of the female breast. The clinical course, histological, immunohistochemical and ultrastructural features of 61 cases of invasive duct carcinoma with osteoclast-like multinucleated giant cells (OMGCs) are reviewed and a new case is presented. The median patient age of all patients included in the review was 42 years, the tumour was located in the upper outer quadrant and the mammographic and gross findings were of a well-defined tumour of dark-brown colour, resembling a metastatic melanoma. Follow-up data in the literature have shown that 86% of patients with these tumours are still alive after 5 years. Histologically, these tumours are invasive ductal carcinomas with OMGCs next to the neoplastic glands and within their lumen. Signs of recent and past haemorrhage are ubiquitously present in the highly vascularized stroma. Immunohistochemical and ultrastructural studies have claimed a benign histiocytic nature of the OMGCs; they may represent a special type of polykaryon, distinct from both osteoclasts and inflammatory giant cells.     

Surgically resected undifferentiated carcinoma with osteoclast-like giant cells of the periampullary region involving the orifice of the papilla of vater: Report of a case

Undifferentiated carcinomas with osteoclast-like giant cells are rare periampullary neoplasms, which morphologically mimic giant cell tumors of the bone. The terminology, histogenesis, biological behavior, and chemosensitivity of these tumors, and their treatment protocol, remain controversial. We report the case of a 71-year-old man with periampullary carcinoma who underwent pancreaticoduodenectomy under the diagnosis of periampullary carcinoma. Histologically, the neoplasm was composed of undifferentiated cells and evenly spaced osteoclast-like giant cells. Liver and paraaortic lymph node metastases were detected 6 months later and were treated effectively with intravenous gemcitabine. The patient remains in remission 2 years after surgery.     

Giant cell tumor of the extrahepatic biliary tree: a clinicopathologic study of 4 cases and comparison with anaplastic spindle and giant cell carcinoma with osteoclast-like giant cells

We report four previously undescribed primary giant cell tumors of the extrahepatic biliary tree and morphologically compare them with 10 anaplastic spindle and giant cell carcinomas with osteoclast-like giant cells of the gallbladder. Two giant cell tumors were located in the distal common bile duct; one in the cystic duct and one in the gallbladder. The 3 patients with bile duct tumors were male, and the only patient with a gallbladder tumor was a female. The age of the patients ranged from 45 to 60 years with an average of 55 years. The patients with bile duct tumors presented with biliary obstruction, and the patient with a gallbladder tumor presented with symptoms of cholelithiasis and a gallbladder mass. Histologically, the tumors were similar to giant cell tumors of bone. They consisted of a mixture of mononuclear and multinucleated osteoclast-like giant cells. The mononuclear cells showed no atypical features, and their nuclei were similar to those of the multinucleated giant cells. CD163 immunoreactivity was restricted to the mononuclear cells, whereas CD68 and HAM 56 labeled only the multinucleated osteoclast-like giant cells. The mononuclear cells were EMA-positive but did not express cytokeratins. Follow-up showed that 3 patients were alive and disease-free 3.7 to 7 years after surgery. The anaplastic spindle and giant cell carcinomas contained a fewer number of osteoclast-like giant cells, and their mononuclear cells showed considerable variation in size and shape, marked cytologic atypia, and numerous mitotic figures. They were focally cytokeratin positive (AE1/AE3; CAM 5.2) and did not label with CD163, CD68, and HAM 56. The benign osteoclast-like giant cells showed immunoreactivity for CD68 and HAM 56 but were negative for CD163 and cytokeratins. Giant cell tumors of the extrahepatic biliary tree are benign true histiocytic neoplasms that should be distinguished from the highly lethal anaplastic spindle and giant cell carcinomas with osteoclast-like giant cells by detailed cytologic analysis and immunohistochemical stains for CD163, CD68, HAM 56, and cytokeratins.     

地诺单抗通过STAT3信号通路抑制骨巨细胞瘤的初步研究

目的 研究STAT3信号通路及其下游相关分子在地诺单抗治疗骨巨细胞瘤过程中的表达变化及其意义。方法 收集我院2013年1月至2018年12月手术治疗的31例骨巨细胞瘤病人,其中28例未经地诺单抗治疗（对照组）,3例经地诺单抗治疗（研究组）。通过苏木素-伊红（hematoxylin and eosin, HE）染色检测骨巨细胞瘤组织经地诺单抗治疗前后的病理学变化;通过免疫组化法检测研究组和对照组的骨巨细胞瘤组织中RANKL、STAT3及其下游分子Bcl-2、Cyclin D1分子的表达差异;通过TUNEL法检测上述两组石蜡切片组织中肿瘤细胞的凋亡情况。结果 HE染色结果：对照组中骨巨细胞瘤组织主要由肿瘤基质细胞和多核破骨样巨细胞组成;研究组中破骨样巨细胞消失,残留部分细长形肿瘤基质细胞,大量网状纤维组织及编织骨形成并替代肿瘤组织;免疫组化检测结果：RANKL主要表达于肿瘤基质细胞;STAT3主要表达于多核破骨细胞胞浆和肿瘤基质细胞胞膜;Bcl-2主要表达于多核破骨样巨细胞胞浆、散在分布于细胞核;Cyclin D1表达于多核破骨样巨细胞的细胞核中。RANKL、STAT3、Bcl-2和Cyclin D1在对照组肿瘤组织中的阳性表达率分别为70%、53%、77%、73%;研究组肿瘤组织中多核破骨样巨细胞消失,残留的肿瘤基质细胞中RANKL表达量明显减少,未见STAT3、Bcl-2、Cyclin D1分子表达;TUNEL法凋亡结果：对照组中仅有少量的肿瘤细胞凋亡,研究组中可见残留的肿瘤细胞明显凋亡。结论 地诺单抗可能通过抑制STAT3 信号通路抑制多核破骨样巨细胞的形成及促进肿瘤基质细胞凋亡。     

Mucoepidermoid and squamous cell carcinomas of breast with reference to squamous metaplasia and giant cell tumors

Clinical and pathologic features of five low-grade mucoepidermoid and a similar number of squamous cell carcinomas of breast are presented. Three of each were retrieved from 55 cases of invasive breast cancer previously assessed to exhibit squamous metaplasia. Although the estimated incidence of low-grade mucoepidermoid cancers is approximately 0.2%, they may be more frequent, masquerading under designations of squamous metaplasia or intracystic carcinomas. All patients with low-grade mucoepidermoid cancer, and the two recorded previously, were free of recurrence for 4-10 years. No high-grade mucoepidermoid cancers were found. Squamous cell cancers frequently have a phyllode configuration (carcinoma phyllodes). Two examined by electron microscopy revealed a commonality of ultrastructural features with similar tumors of other sites. None exhibited glandular differentiation or tinctorial evidence of mucin secretion. One squamous cell carcinoma contained both malignant epithelial and banal, osteoclast-like, stromal giant cells. Only the latter were identified in tissue culture. This experience and review of the literature prompted a nosologic characterization of giant cell lesions of breast. One patient with squamous cell carcinoma succumbed because of her disease; the remainder are either free of or alive with recurrence at 4 and 10 years.     

Bisphosphonates Induce Apoptosis of Stromal Tumor Cells in Giant Cell Tumor of Bone

Giant cell tumour of bone (GCT) is an aggressive primary neoplasm that results in the production of osteolytic lesions. Stromal cells, which form the main neoplastic component of this tumor, regulate the formation of osleoclast-like giant cells that are ultimately responsible for bone destruction. Bisphosphonates prevent bone resorption by inhibiting osteoclast activity and promoting osteoclast apoptosis, and they have been known to induce apoptosis of primary neoplastic cells such as those in breast and prostate cancers. We hypothesized that in bisphosphonates may induce apoptosis not only in osteoclast-like giant cells but also in neoplastic stromal cells of GCT both in vitro and in vivo. Twelve patients with GCT were treated with weekly injections of pamidronate for a period of 6 weeks prior to surgery. GCT specimens were collected at the time of biopsy and during definitive surgery. TUNEL assay was used to evaluate apoptotic DNA fragmentation in cells. In addition, twelve GCT primary cultures from these patients were treated with zoledronate, pamidronate, or alendronate for 48 hours at different doses (3, 30, or 150 M) and subjected to apoptosis assay by flow cytometry following fluorescent Annexin-V labeling. The results showed that pamidronate significantly induced apoptosis in both osteoclast-like giant cells and stromal tumor cells, in vivo. All three bisphosphonates caused substantial apoptosis of stromal tumor cells in cultures. Zoledronate was the most potent reagent, resulting in an average cell death of 27.41% at 150 M, followed by pamidronate (22.23%) and alendronate (15.3%). Our observations suggest that these drugs may be considered as potential adjuvants in the treatment of GCT.Both authors (Y.Y. Cheng and L. Huang) contributed equally to this work.     

Osteoclastic giant cell tumor of the pancreas

INTRODUCTION

Pancreatic giant cell tumors are rare, with an incidence of less than 1% of all pancreatic tumors. Osteoclastic giant cell tumor (OGCT) of the pancreas is one of the three types of PGCT, which are now classified as undifferentiated carcinoma with osteoclast-like giant cells.

PRESENTATION OF CASE

The patient is a 57 year old woman who presented with a 3 week history of epigastric pain and a palpable abdominal mass. Imaging studies revealed an 18 cm × 15 cm soft tissue mass with cystic components which involved the pancreas, stomach and spleen. Exploratory laparotomy with distal pancreatectomy, partial gastrectomy and splenectomy was performed. Histology revealed undifferentiated pancreatic carcinoma with osteoclast-like giant cells with production of osteoid and glandular elements.

DISCUSSION

OGCT of the pancreas resembles benign-appearing giant cell tumors of bone, and contain osteoclastic-like multinucleated cells and mononuclear cells. OGCTs display a less aggressive course with slow metastasis and lymph node spread compared to pancreatic adenocarcinoma. Due to the rarity of the cancer, there is a lack of prospective studies on treatment options. Surgical en-bloc resection is currently considered first line treatment. The role of adjuvant therapy with radiotherapy or chemotherapy has not been established.

CONCLUSION

Pancreatic giant cell tumors are rare pancreatic neoplasms with unique clinical and pathological characteristics. Osteoclastic giant cell tumors are the most favorable sub-type. Surgical en bloc resection is the first line treatment. Long-term follow-up of patients with these tumors is essential to compile a body of literature to help guide treatment.     

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??Pancreatic undifferentiated carcinoma with osteoclast-like giant cells: An analysis of 5 cases and literature review TAN Xiao-kai*, LI Le, CHEN Hua, et al. *Department of Pancreatic and Biliary Surgery, the First Affiliated Hospital of Harbin Medical University,Harbin 150001, China
Corresponding author: SUN Bei, E-mail: sunbei70@tom.com
Abstract Objective To investigate the clinicopathological feature, diagnosis and treatment of pancreatic undifferentiated carcinoma with osteoclast-like giant cells (PUC-OGC). Methods The clinical and follow-up data of 5 patients with PUC-OGC who were admitted to the First Affiliated Hospital of Harbin Medical University from October 2014 to December 2017 were analyzed and studied retrospectively. Results As for chief complaint, 4 patients had epigastric pain while one had chill and fever. Four of five patients were normal in CEA and CA19-9 preoperatively and only one was slightly elevated in CA19-9. Four patients underwent distal pancreatectomies with splenectomies and 1 choledochojejunostomy and gastrojejunostomy. Pathological features: Four tumors were located at the body and tail of pancreas while one at the head and neck. The median diameter of the tumor was 4.0 (3.2—10.0) cm. Cystic-solid sections with hemorrhage or necrosis was found in 3 cases and solid section in another one, and no metastasis was seen in the lymph nodes of the whole series. There were a huge number of spindle-shaped mononuclear neoplastic cells and distributed large multinucleated non-neoplastic osteoclast-like giant cells(OGCs) microscopically. One of the 5 PUC-OGC cases was accompanied by mucinous cystadenocarcinoma. Another one received chemotherapy of gemcitabine and S-1 postoperatively. Follow-up to December 2017, 4 patients survived without diseases, 1 had died, and the postoperative survival time was 8 (1—28) months. Conclusion The clinical manifestations of PUC-OGC are not specific, and the diagnosis is mainly based on pathological examination. The optimal treatment may be en-bloc resection and postoperative adjuvant therapy, and the prognosis is inconclusive.     

Papillotubular carcinoma with an invasive micropapillary carcinoma component of the breast,characterized by a rapid increase in size due to intra-tumoral hemorrhage: A case report

IntroductionRapidly enlarging mammary tumors, including invasive breast tumors, are clinically rare. Invasive micropapillary carcinoma (IMPC) of the breast is known to have aggressive behavior and poor clinical course compared to invasive ductal carcinoma.Case presentationAn 87-year-old woman presented with a rapidly enlarging tumor of the right breast over the course of 3 weeks. Ultrasonography and computed tomography of the chest revealed a giant tumor located on the right chest wall, with heterogeneous parenchymal components and several cystic lesions. Emergency mastectomy was performed because of rapid tumor enlargement complicated by hemorrhage. Histopathological diagnosis confirmed a papillotubular invasive ductal carcinoma with an IMPC component. Tumor cells were negative for estrogen and progesterone receptors, and the human epidermal growth factor receptor 2 score was 2+.DiscussionThere has been only one report of breast carcinoma with rapid enlargement caused by spontaneous intratumoral hemorrhage to date. IMPC is associated with a high incidence of axillary lymph node metastases, frequent local recurrence, and a poor clinical outcome. In the present case, the specific breast cancer type can be considered as potential factors responsible for hemorrhage induction within the tumor that further enhanced rapid tumor growth.ConclusionIMPC is a rare, clinically aggressive variant of invasive ductal carcinoma. Owing to its aggressive clinical behaviors, surgeons should readily recognize the morphology of IMPC.     

Osteoclast-type giant cell neoplasm of salivary gland. A microdissection-based comparative genotyping assay and literature review: extraskeletal "giant cell tumor of bone" or osteoclast-type giant cell "carcinoma"?

Primary salivary gland tumors resembling giant cell tumor of bone are very rare and have unsettled histogenesis. Both mesenchymal and epithelial origins have been suggested. We review 14 cases in the English-language literature and report another case, the first of which to be studied by microdissection-based microsatellite analysis. One-half of the tumors have been associated with a carcinoma, usually salivary duct carcinoma and carcinoma ex pleomorphic adenoma. Significant differences between this tumor and giant cell tumor of bone were observed. Unlike giant cell tumor of bone, in which the nuclei of the mononuclear and giant cells are similar, those of salivary gland show obvious differences between the nuclei of mononuclear cells and osteoclastic giant cells. In addition and in contrast to giant cell tumor of bone, the mononuclear cells of giant cell tumor of salivary gland express epithelial markers (epithelial membrane antigen, EMA; carcinoembryonic antigen, CEA) and androgen receptor. Genotypically, the microsatellite pattern of the giant cell component is more akin to the carcinomatous component and does not resemble giant cell tumor of bone. Biologically, giant cell tumor of salivary gland tends to be more aggressive than giant cell tumor of bone. We conclude that giant cell tumor of salivary gland is an unusual carcinoma that is not related to giant cell tumor of bone.     

Pathomorphologic study of undifferentiated carcinoma in seven cases: relationship between tumor and pancreatic duct epithelium

Background/purpose  By the time undifferentiated carcinoma is detected, it has formed a large mass, and it is reportedly difficult to pathologically observe its relationship with the pancreatic duct. In this study, we examined the pancreatic ducts of seven patients of surgical samples, and pathomorphologically investigated the relationship between the adenocarcinomatous and sarcomatous components and the pattern of tumor extension. In addition, we evaluated the usefulness of pancreatic juice cytology by comparison with the findings of the main pancreatic duct (MPD). Methods  Seven primary undifferentiated carcinomas of the pancreas (from three male and four female patients with a mean age of 59 years) were analyzed. Histopathological evaluation was based on the WHO diagnostic criteria. Pancreatic juice cytology was performed and evaluated in two patients. Results  All the undifferentiated carcinomas contained adenocarcinomatous and sarcomatous components, and two had a distinct glandular structure. However, we could not pathomorphologically confirm the continuity of the adenomatous with the sarcomatous components in any of the patients. Three undifferentiated carcinomas contained osteoclast-like giant cells. Pathological observation of the tumor and MPD was possible in three of the seven undifferentiated carcinomas. PanIN-3 was observed in the MPD of three patients, suggesting extension into the MPD. In one of these three, the tumor presented intraductal growth in the MPD, and preoperative pancreatic juice cytology revealed atypical cells with osteoclast-like giant cells. In the remaining two, the tumor extraductally compressed the MPD upward. Conclusions  Undifferentiated carcinoma showed two patterns of cancer extension: (1) invasion and expansive growth during the sarcomatous transformation of adenocarcinoma, and (2) intraductal extension. In addition, some undifferentiated carcinomas showed extension in the MPD. Of note, postoperative pancreatic juice cytology may be useful for the diagnosis.     

Giant cell tumor of bone: A basic science perspective

Comprehending the pathogenesis of giant cell tumor of bone (GCT) is of critical importance for developing novel targeted treatments for this locally-aggressive primary bone tumor. GCT is characterized by the presence of large multinucleated osteoclast-like giant cells distributed amongst mononuclear spindle-like stromal cells and other monocytes. The giant cells are principally responsible for the extensive bone resorption by the tumor. However, the spindle-like stromal cells chiefly direct the pathology of the tumor by recruiting monocytes and promoting their fusion into giant cells. The stromal cells also enhance the resorptive ability of the giant cells. This review encompasses many of the attributes of GCT, including the process of giant cell formation and the mechanisms of bone resorption. The significance of the receptor activator of nuclear factor-κB ligand (RANKL) in the development of GCT and the importance of proteases, including numerous matrix metalloproteinases, are highlighted. The mesenchymal lineage of the stromal cells and the origin of the hematopoietic monocytes are also discussed. Several aspects of GCT that require further understanding, including the etiology of the tumor, the mechanisms of metastases, and the development of an appropriate animal model, are also considered. By exploring the current status of GCT research, this review accentuates the significant progress made in understanding the biology of the tumor, and discusses important areas for future investigation.     

PTHrP increases RANKL expression by stromal cells from giant cell tumor of bone

Giant cell tumor of bone (GCT) presents with numerous osteoclast-like multinucleated giant cells that are principally responsible for the extensive bone resorption by the tumor. Although the precise etiology of GCT remains uncertain, the accumulation of giant cells is partially due to the high expression of the receptor activator of nuclear factor-κB ligand (RANKL) from the neoplastic stromal cells. Here, we have investigated whether parathyroid hormone-related protein (PTHrP) plays a role in the pathogenesis of GCT. Immunohistochemistry results revealed PTHrP expression in the stromal cells of the tumor, and that its receptor, the parathyroid hormone type 1 receptor (PTH1R), is expressed by both the stromal cells and giant cells. PCR and Western blot analyses confirmed the expression of PTHrP and PTH1R by isolated stromal cells from five patients presenting with GCT. Treatment of GCT stromal cells with varying concentrations of PTHrP (1-34) significantly increased both RANKL gene expression and the number of multinucleated cells formed from RAW 264.7 cells in co-culture experiments, whereas inhibition of PTHrP with a neutralizing antibody decreased RANKL gene expression. These results suggest that PTHrP is expressed within GCT by the stromal cells and can contribute to the abundant RANKL expression and giant cell formation within the tumor.