ORUCUB is an extremely rare variant of undifferentiated high-grade UC. Usually, OCG tumors arise in bone, soft tissues or tendon sheath, but tumors with a similar morphology are also reported in various visceral organs, including skin, salivary gland, larynx, thyroid, breast, lung, heart, liver, gall bladder, pancreas, intestine and female genital tract. They are known as “extra-skeletal or extra-osseous giant cell tumor,” “giant cell tumor,” “osteoclast-like giant cell tumor” or “osteoclastoma-like giant cell tumor,” etc.
Despite the morphologic similarities between giant cell tumor of bone (primary osteoclastoma) and ORUCUB, both lesions show differences in various critical aspects. Giant cell tumor of bone is a slow-growing, benign but locally aggressive neoplasm of the epiphysis/metaphysis of long bone occurring in young adults with a slight female predominance. It typically shows neoplastic monomorphic, ovoid to polygonal or elongated mononuclear cells with uniformly interspersed large OCGs. Malignant transformation is very rare (<1% and can occur after radiation therapy). However, ORUCUB is malignant neoplasm of predominantly older males, with very aggressive behavior and poor prognosis, including extensive metastasis and short survival. This tumor is considered a variant of high-grade UC because, usually, it is intimately associated with conventional high-grade UC (carcinoma in situ, high-grade papillary UC or both in adjacent areas of the same specimen). It is composed of two types of cells, including pleomorphic (ovoid–polygonal or spindle shaped), mononuclear malignant epithelial cells expressing immnoreactivity for epithelial markers, e.g. CKs, which is identical to adjacent conventional UC, and benign-appearing, evenly dispersed OCGs, which morphologically appear similar to osteoclasts/macrophages with multinucleation. The latter has no mitoses, some have phagocytosis and are ultrastructurally similar to osteoclasts. They do not display any epithelial marker immunoreactivity (including CKs and EMA) and are diffusely positive for osteoclast/macrophage lineage markers, including CD-68, CD 51, CD 54 and, sometimes, leukocyte common antigen. They are benign and are thought to be reactive in origin.
To date, there are 14 cases of ORUCUB[1
] reported in the current literature. To the best of our knowledge, this is the first FNA cytology case report of ORUCUB to be published.
Making the diagnosis of an ORUCUB is important on a cytology specimen. The unusual stromal reaction of non-neoplastic, multinucleated, OCGs in a background of neoplastic mononuclear cells can be confused with so many benign and malignant entities. The differential diagnoses include giant cell carcinoma of the bladder, foreign body/granulomatous reaction, trophoblastic variant of UC, sarcomatoid carcinoma of bladder, pleomorphic giant cell carcinoma of prostate, sarcomatoid carcinoma of prostate, chemo/radiation therapy-induced giant cells in a treated prostate cancer and giant cell tumor of bone.
ORUCUB is different from giant cell variant of UC in which giant cells are epithelial and are neoplastic, showing nuclear pleomorphism and immunopositivity with CKs. ORUCUB, as mentioned earlier, has giant cells that are of osteoclast/macrophage lineage and are benign/reactive in nature, showing nuclear monomorphism and expressing immunoreactivity with CD-68 and other osteoclastic markers. In the trophoblastic variant of UC, which shows trophoblastic giant cells (syncytiotrophoblast), staining is positive for human chorionic gonadotropin. Trophoblastic differentiation is usually considered a more aggressive variant of UC rather than a germ cell tumor[10
Sarcomatoid carcinoma of bladder with or without heterologus elements is another variant of high-grade UC, which is a biphasic malignant neoplasm showing morphological and immunohistochemical evidence of both epithelial and mesenchymal differentiation. The epithelial component is usually urothelial, glandular or small cell component showing immunoreactivity for CKs, but the mesenchymal component is frequently an undifferentiated high-grade spindle cell neoplasm showing reactivity with vimentin. Both components can be segregated from each other, but histological transition between the two components is usually noted. Both spindle and giant cell components are overtly malignant and stain with epithelial markers. In the foreign body type or granulomatous reaction of urinary bladder, the giant cells are foreign body type or Langerhan’s type with non-neoplastic plump stromal cells. They lack the malignant-appearing mononuclear cells.
Our patient was also found to have conventional prostatic adenocarcinoma. Therefore, pleomorphic giant cell carcinoma of the prostate could be a differential diagnosis, in which the multinucleated giant cell component is very bizarre and anaplastic (same as giant cell carcinoma of other organs). Prostatic adenocarcinoma and pleomorphic giant cells, both variably express prostate-specific antigen and CKs.[11
] However, the possibility of metastatic pleomorphic giant cell carcinoma of prostate or metastatic sarcomatoid carcinoma of prostate was ruled out due to the benign appearance of the giant cells. Radiation therapy is reported as etiologic factor for giant cell carcinoma of urothelium, sacromatoid carcinoma of prostate[13
] and as local therapy effect in an orthotopic model in the form of tumor necrosis, fibrosis, multinucleated giant cell induction with condensed nuclei, apoptosis and dense eosinophilic cytoplasm.[14
] Our patient did not have any history of getting any radiation therapy prior to his ORUCUB.
It is known for giant cell tumor of bone to metastasize. However, in this case, there is no clinical history of bone tumor. In addition, the presence of malignant mononuclear cell is not inconsistent with a giant cell tumor of bone.
Based on the current literature, the clinical, histological and immunohistochemical features of this tumor were published in 14 cases, including one urine cytology case, and are summarized in . In almost all cases, the surface urothelium showed a non-muscle invasive UC component (either carcinoma in situ or high-grade papillary UC or both with or without lamina propria invasion). The UC component was focal and situated adjacent to or was overlying the giant cell tumor component (neoplastic mononuclear ovoid stromal cells and scattered reactive OCGs).
Literature review of osteoclast-rich giant cell urothelial carcinoma of urinary bladder
ORUCUB is considered an osteoclast-rich undifferentiated UC (a variant of high-grade undifferentiated UC) due to the intimate association of this tumor with high-grade conventional UC and similar IHC profile, including positivity with CKs, EMA, Ki- 67 and p 53 in neoplastic mononuclear cells as well as in the adjacent UC component with non-neoplastic reactive histiocytic lineage of OCGs that are CD-68 positive and Ki-67/p 53 negative. In our case, left groin mass excision showed neoplastic mononuclear cells to be markedly pleomorphic with bizarre nuclei and increased mitoses, expressing focal positivity for CKs AE1/AE3, CK 903 and CK 5/6 and multinuclear giant cells to be focally positive for Ki-67 and p 53. As described previously, these OCGs are seen in the background stroma due to benign immunological reaction, and their presence is not specific for ORUCUB. They can be seen in a variety of benign and malignant conditions of various organs. Some studies clearly identify a number of common factors necessary for the multinucleation (cell fusion), including vitronectin, an adhesion protein, dendritic cell-specific transmembrane protein (DC-STAMP), a fusion factor, and macrophage fusion receptor that contribute to giant cell formation and function. These multinucleated giant cell phenotypes vary depending on their local environment.[15
] The osteoclast is hematopoetic in origin, derived from monocyte–macrophage lineage cells that fuse to form a multinucleated osteoclast. Both locally produced cytokines and systemic hormones regulate normal osteoclast formation. The bone microenvironment plays a critical role in osteoclast formation. Marrow stromal cells or osteoblasts produce osteoclast differentiation, inducing factors that are receptor activators of the NF-kappaB ligand (RANKL), a member of the tumor necrosis factor (TNF) gene family. This factor is also called TRANCE or osteoprotegerin ligand. RANKL activity can be blocked by the soluble decoy receptor, osteoprotegerin (OPG/osteoclastogenesis inhibitory factor, a member of TNF family). The ratio of RANKL to OPG regulates osteoclast formation and activity. In neoplasia, several factors including IL-1, IL-6, PTHrP, RANKL and MIP-1alpha, have been implicated in osteoclast formation and bone destruction. PTHrP is the major factor produced by breast cancer cells that induce osteoclast formation through upregulation of RANKL. Enhanced RANKL expression is also implicated in bone destruction in multiple myeloma patients.[16
] OCGs are frequently seen in tenosynovial giant cell tumor, pigmented villonodular synovitis and giant cell tumor of bone. They are CD68 -postive monocytic cell lineage composed of predominantly macrophages recruited in response to macrophage colony-stimulating factor 1 (CSF1).[17
] Understanding of various molecular mechanisms responsible for osteoclast activation and osteoclast-like cell formation in certain neoplasms should lead to novel therapeutic approaches.[17
] However, due to the rarity of ORUCUB, the mechanism of multinucleated giant cell formation has not been investigated. In our case, it is difficult to say whether these giant cells are still benign/reactive or are of uncertain malignant potential. The fact that the patient expired 2 months later makes us speculate that the positivity in p 53 and Ki-67 may be associated with advanced disease course, aggressive behavior and bad clinical outcome. In our case, the CK stains were negative in MTCs on cellblock on comparing with the surgical specimen, which was positive for CK. This may be the result of tumor heterogeneity and limited nature of sampling by FNA. Prior clinical history and comparison with prior resection specimen was helpful in making a definitive diagnosis of ORUCUB.
Molecular testing in the diagnosis of conventional UC is promising. The role of fluorescence in situ
hybridization (FISH) such as Urovision is well established.[19
] Urovision FISH is designed to perform testing on cytospin slides prepared from fresh urine specimen. In the past, no Urovision study was carried out on our patient.
There are few studies reported on the activities and effects of MAPKs pathway,[21
] including MEK, ERK½, ELK and P38 in normal urothelial cells and UC. However, these studies used samples of the most common and conventional types of UC. Because ORUCUB is a rare variant of UC, no molecular study of this particular variant is reported so far.