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1.  The Multifaceted Granulosa Cell Tumours—Myths and Realities: A Review 
ISRN Obstetrics and Gynecology  2012;2012:878635.
Background. Granulosa cell tumors (GCTs), representing ~2% of ovarian tumours, are poorly understood neoplasms with unpredictable and undetermined biological behaviour. Design. 5 unusual presentations of GCT and a retrospective 14-year (1997–2011) surgical pathology review based on patient sex, age, tumour type and concurrent pathology findings are presented to discuss the “myths and realities” of GCTs in the context of relevant evidence-based literature. Results. The 5 index cases included (1) a 5 month-old boy with a left testicular mass, (2) a 7-day-old neonate with a large complex cystic mass in the abdomen, (3) a 76-year-old woman with an umbilical mass, (4) a 64-year-old woman with a complex solid-cystic pelvic mass, and (5) a 45 year-old woman with an acute abdomen. Pathological analysis confirmed the final diagnosis as (1) juvenile GCT, (2) macrofollicular GCT, (3) recurrent GCT 32 years later, (4) collision tumour: colonic adenocarcinoma and GCT, and (5) ruptured GCT. Conclusion. GCT is best considered as an unusual indolent neoplasm of low malignant potential with late recurrences that can arise in the ovaries and testicles in both the young and the old. Multifaceted clinical presentations coupled with the unpredictable biological behaviour with late relapses are diagnostic pitfalls necessitating a high degree of suspicion for accurate clinical and pathological diagnosis.
doi:10.5402/2012/878635
PMCID: PMC3449135  PMID: 23008780
2.  Recent Advances in Granulosa Cell Tumor Ovary: A Review 
Granulosa cell tumors constitute less than 5 % of all ovarian tumors. Unlike epithelial ovarian tumors, they occur in a younger age group, are usually detected in an early stage and often have features of hyperestrogenism. The presenting symptoms are usually nonspecific with abdominal pain or distension. They follow an indolent course and are characterized by a long natural history. Mutation of FOXL2 (402C->G) seen in 97 % of adult GCT may be pathognomonic for adult GCT. Only stage of the disease has been consistently shown in various studies to affect survival of patients with GCT. The initial management of patients, for whom fertility is not an issue, is total abdominal hysterectomy, bilateral salpingo-oophorectomy and removal of all gross disease. Nodal dissection is not a significant factor for survival and is not recommended in surgical staging of GCT. Fertility preserving surgery with unilateral salpingo-oophorectomy is feasible in young patients with stage Ia GCT. Patients with early stage disease (stage I and II) have a very good prognosis with 5 year DFS and OS of 89 % and 99 % respectively and these groups of patients usually don’t require any postoperative treatment. Patients with stage Ic disease associated with poor prognostic factors like large tumor size or high mitotic index and stage II, have a higher chance of relapse, and may benefit with postoperative treatment but role of chemotherapy is still debatable. In advanced stage disease (stage III and IV) the 5 year DFS and OS disease was 72 % and 80 % respectively hence the option of postoperative treatment with 6 cycles of BEP should be considered in this group. Recently paclitaxel is being investigated as an effective tool in GCT. The efficacy of radiation in GCT is not well defined but in optimally debulked cases postoperative radiation is a viable option. Due to high chance of recurrence even years after apparent clinical cure of the primary tumor, lifelong follow up with clinical examination and tumor markers like inhibin B is recommended. About 25 % GCT develop recurrence and the median time to recur is usually 4–5 years. Most recurrences are intraperitoneal and usually a complete debulking of the disease is feasible even in the recurrent setting. Postoperative chemotherapy (platinum based) is usually given after surgery more so in cases with widespread disease or after suboptimal cytoreduction. Recurrent chemoresistant, progressive non-responding GCT or patients with high surgical risk are ideal candidates for targeted therapy.
doi:10.1007/s13193-012-0201-z
PMCID: PMC3578540  PMID: 24426698
Granulosa cell tumor; Inhibin B
3.  Serum Müllerian Inhibiting Substance/anti-Müllerain Hormone levels in patients with adult granulosa cell tumors directly correlates with aggregate tumor mass as determined by pathology or radiology 
Gynecologic oncology  2009;114(1):57-60.
Objectives
Granulosa cell tumors (GCTs) comprise 2–5% of ovarian tumors. Serum Müllerian Inhibiting Substance (MIS, also known as anti-Müllerian Hormone, or AMH) levels have been validated as a marker of GCT recurrence and progression. There has been little correlation between serum MIS/AMH levels several clinical parameters in GCTs, including tumor burden. We have performed a retrospective review correlating aggregate tumor mass as reported by pathologic examination or by radiology with serum MIS/AMH levels drawn on the date of examination.
Methods
We retrospectively identified 32 GCT patients at our institution over the last 15 years who had serum MIS/AMH measurements. Patients who had serum MIS/AMH measurements within three days of surgery or on the same day as abdominal computerized tomography scan (CT) or magnetic resonance imaging (MRI) were further evaluated.
Results
We found a significant direct correlation between patient serum MIS/AMH levels and gross aggregate tumor mass determined by pathology (slope=15.4±6.06, r=0.65, p<0.04) or by radiographic aggregate tumor mass for all data points identified (slope=0.07±0.03, r=0.33, p<0.04) and after correcting for selection bias (slope=1.45±0.17, r=0.93, p<0.01). We also identified a significant difference between serum MIS/AMH levels between samples drawn the same day as negative and positive abdominal CT or MRI scans (8.16±1.54 vs. 158.7±32.2 ng/ml, p<0.0001).
Conclusions
These data indicate a significant direct correlation between serum MIS/AMH levels and both gross and radiographic aggregate tumor mass in GCT patients. Together with the current literature, the present data argues for a more prominent role for serum MIS/AMH in the management of GCTs.
doi:10.1016/j.ygyno.2009.02.023
PMCID: PMC2756071  PMID: 19359032
4.  Transforming Growth Factor Alpha (TGFα) Regulates Granulosa Cell Tumor (GCT) Cell Proliferation and Migration through Activation of Multiple Pathways 
PLoS ONE  2012;7(11):e48299.
Granulosa cell tumors (GCTs) are the most common ovarian estrogen producing tumors, leading to symptoms of excessive estrogen such as endometrial hyperplasia and endometrial adenocarcinoma. These tumors have malignant potential and often recur. The etiology of GCT is unknown. TGFα is a potent mitogen for many different cells. However, its function in GCT initiation, progression and metastasis has not been determined. The present study aims to determine whether TGFα plays a role in the growth of GCT cells. KGN cells, which are derived from an invasive GCT and have many features of normal granulosa cells, were used as the cellular model. Immunohistochemistry, Western blot and RT-PCR results showed that the ErbB family of receptors is expressed in human GCT tissues and GCT cell lines. RT-PCR results also indicated that TGFα and EGF are expressed in the human granulosa cells and the GCT cell lines, suggesting that TGFα might regulate GCT cell function in an autocrine/paracrine manner. TGFα stimulated KGN cell DNA synthesis, cell proliferation, cell viability, cell cycle progression, and cell migration. TGFα rapidly activated EGFR/PI3K/Akt and mTOR pathways, as indicated by rapid phosphorylation of Akt, TSC2, Rictor, mTOR, P70S6K and S6 proteins following TGFα treatment. TGFα also rapidly activated the EGFR/MEK/ERK pathway, and P38 MAPK pathways, as indicated by the rapid phosphorylation of EGFR, MEK, ERK1/2, P38, and CREB after TGFα treatment. Whereas TGFα triggered a transient activation of Akt, it induced a sustained activation of ERK1/2 in KGN cells. Long-term treatment of KGN cells with TGFα resulted in a significant increase in cyclin D2 and a decrease in p27/Kip1, two critical regulators of granulosa cell proliferation and granulosa cell tumorigenesis. In conclusion, TGFα, via multiple signaling pathways, regulates KGN cell proliferation and migration and may play an important role in the growth and metastasis of GCTs.
doi:10.1371/journal.pone.0048299
PMCID: PMC3498304  PMID: 23155381
5.  Extraovarian Granulosa Cell Tumor of Mesentery: A Case Report 
Extraovarian granulosa cell tumor (GCT) is a very uncommon tumor, assumed to arise from the ectopic gonadal tissue along the embryonal route of the genital ridge. A 54 years old female patient presented with a mass and acute pain in abdomen. Exploratory laparatomy revealed hemoperitoneum with a large mesenteric mass measuring 13 × 12 cm in size, showing extensive areas of haemorrhages. Histopathological examination of the excised mass showed features of adult-type GCT. As the patient had a history of hysterectomy with bilateral salpingo-oophorectomy 10 years ago for ‘‘leiomyoma” with no evidence of GCT of the ovary in the histopathology report, a diagnosis of extraovarian GCT was made. A diagnosis of extraovarian GCT should be carried out after excluding any previous history of GCT of the ovary. Tumor rupture with haemoperitoneum is a well-known complication of GCT. Extraovarian GCT is a rare tumor with only 10 cases reported in literature. The case is presented for its rarity.
doi:10.4061/2010/292606
PMCID: PMC2997286  PMID: 21152176
6.  TLR4 activates NFkB in human ovarian granulosa tumor cells 
Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (OSE) and in epithelial ovarian tumors. Most notably, OSE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-κB) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to IκB degradation and activation of NF-κB. NF-κB activation was confirmed by nuclear localization of NF-κB p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-κB signaling attenuated LPS-induced TNFαplus increased doubling time in both cell lines. Contradictory to reports using human OSE cell lines, inhibition of NF-κB signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to OSE-derived cancers, inhibition of NF-κB does not sensitize GCTs to TRAIL or cisplatin.
doi:10.1016/j.bbrc.2011.05.063
PMCID: PMC3118942  PMID: 21616060
Granulosa cell tumor; Toll-like receptor; TLR; ovary; LPS; lipopolysaccharide
7.  P32 - A Case of Multicentric Giant Cell Tumours with 25-Year Follow Up 
Giant cell tumour of bone (GCT) is a relatively rare benign bone tumour more frequent in young people (20–40 years). Histologically, two cell types are represented, stromal cells of osteoblastic origin and a distinctive osteoclast-like population probably of monocytic origin. GCTs can be aggressive and they recur locally in up to 50% of cases; up to 5% of GCTs metastasise to the lungs and spontaneous transformation to a high-grade malignancy occurs in 1–3% of patients. The aetiology of GCT is not known, and no risk factors have been recognised, although familial clustering of both Paget’s disease and GCT has been reported.
GCTs account for approximately 3–5% of primary bone tumours. GCT is rarely multicentric and usually occurs at the epiphyses of long bones, but may also affect other bones.
There are few randomised, prospective clinical trials available to guide clinical management of GCT. Recent developments have led to evaluation of newer therapeutic agents, including biphosphonates and denosumab, with encouraging results. We report the case of a 66-year-old woman affected by GCT. In 1985 the patient, then 41 years old, presented a cystic lesion on her left tibia, which was removed surgically. This lesion relapsed two years later. Therefore the patient was hospitalised and received a diagnosis of “multicentric giant cell bone lesions” (limb-girdle, sternum, mandible, ribs), confirmed by histological examination. These lesions showed hyperactivity on bone scintigraphy. Plain radiographs demonstrated destructive lytic lesions. Blood and urinary examinations showed markedly elevated levels of bone alkaline phosphatase and urine pyridinoline and there was persistent bone pain. In 1993 normocalcaemic primary hyperparathyroidism was diagnosed and an adenoma was removed, with no relapse of the disease. Subsequently the patient started clodronate therapy, i.v., followed by alendronate-neridronate per os and clodronate i.m. for about nine years. Biphosphonate therapy caused a modest and transient decrease in bone indexes. Initial bone lesions were unchanged on computed tomography 25 years after diagnosis, but new bone lesions had appeared. MEN1 gene and CasR analyses were negative.
This is a rare case of a patient affected by multicentric giant cell tumours with a 25-year follow up. A slow progression of the lesion is documented, as well as the absence of significant effect of biphosphonate therapy.
PMCID: PMC3213768
8.  Granular Cell Tumor of the Cervical Esophagus: Case Report and Literature Review of an Unusual Cause of Dysphagia 
Head and Neck Pathology  2012;7(3):274-279.
Granular cell tumors (GCT) of the head and neck are not uncommon; however, involvement of the cervical esophagus is rare. Characterized by an infiltrative growth pattern, these benign tumors are historically difficult to surgically excise and are radioresistant. We present here a case of dysphagia caused by a GCT of the cervical esophagus. Work up with ultrasound-guided fine needle aspiration was suggestive of a GCT due to the presence of cohesive cells with granular cytoplasm that were S-100 and CD68 positive with immunostaining, and PAS positive with histochemistry. Resection required removal of a portion of the muscular wall of the esophagus sparing the overlying mucosa. The patient is currently asymptomatic and without recurrence after 10 month follow-up. Review of the literature revealed 19 reports of cervical esophageal GCTs. There is a female preponderance (75 %), with an average age of 41 years. Dysphagia and weight loss are the most common presenting symptoms. The average tumor size on presentation was 2.7 cm, with symptomatic tumors being significantly larger than asymptomatic lesions; the latter was present in 25 % of patients. Concurrent GCTs in the upper aerodigestive tract were identified in 35 % of cases. Approximately 30 % of tumors required segmental cervical esophageal resection. The purpose of this report is to describe the epidemiology and treatment of GCTs of the cervical esophagus. Lesions should be addressed early with complete surgical excision to prevent growth necessitating more morbid surgery. Due to the high rate of concurrent GCTs, upper endoscopy is advised in the workup of these patients.
doi:10.1007/s12105-012-0408-x
PMCID: PMC3738753  PMID: 23143390
Granular cell tumor; Cervical esophagus; Management; Dysphagia
9.  Chromosome X loci and spontaneous granulosa cell tumor development in SWR mice 
Epigenetics  2013;8(2):184-191.
Females of the SWR/Bm (SWR) inbred mouse strain possess a unique susceptibility to juvenile-onset tumors originating from the granulosa cells (GC) of the ovarian follicles. Tumor susceptibility is an inherited, polygenic trait in SWR females, minimally involving an oncogenic Granulosa cell tumor susceptibility (Gct) locus on chromosome (Chr) 4 (Gct1), and two GC tumor susceptibility modifier genes mapped to distinct regions of Chr X (Gct4 and Gct6). Shifts in the frequency of GC tumor initiation in the SWR female population from low penetrance to moderate penetrance, or phenotype switching between GC tumor-susceptible and GC tumor-resistant, is strongly influenced by the allelic contributions at Gct4 and Gct6. In addition to the allele-specific effects, GC tumor susceptibility is controlled by the mode of X-linked transmission with a dominant, paternal parent-of-origin effect. We took advantage of the robust paternal effect with a recombinant male progeny testing strategy to resolve the Gct4 locus interval to 1.345 million base (Mb) pairs. Based on the mapping resolution and the phenotype sensitivity to endogenous and exogenous androgen exposure, a promising candidate for Gct4 identity is the androgen receptor (Ar) gene. We explored the mechanism of allelic variation for Ar between SWR (low penetrance allele) and SJL/Bm (SJL) (moderate penetrance allele) using an SWR.SJL-X congenic strain resource and a quantitative gene expression method. We report the low GC tumor penetrance allele of the SWR strain correlates with significantly reduced Ar transcript levels in the female ovary at the pubertal transition.
doi:10.4161/epi.23399
PMCID: PMC3592904  PMID: 23299801
granulosa cell tumor; tumor susceptibility allele; parent-of-origin effect
10.  Sequential bilateral testicular tumours presenting with intervals of 20 years and more 
BMC Urology  2013;13:71.
Background
About 3 – 5% of all patients with testicular germ cell tumour (GCT) develop a contralateral cancer, the majority of which arise within 10–15 years. Little is known about the risk of second GCTs after more than two decades. Here we present 3 cases with very late presenting contralateral GCT and provide a summary of similar cases reported previously.
Case presentations
(1) This white Caucasian man underwent right-sided orchiectomy for a nonseminomatous GCT at the age of 22 years. Additional treatment consisted of retroperitoneal lymph node dissection (RPLND) and chemotherapy with 4 cycles of vinblastin / bleomycin. 36 years later, contralateral seminoma clinical stage 1 developed. Cure was achieved by orchiectomy. Histologically, testicular intraepithelial neoplasia (TIN; intratubular germ cell neoplasia) was detected in the tumour-surrounding tissue.
(2) This white Caucasian male had right-sided orchiectomy for nonseminomatous GCT at the age of 29 years. Pathological stage 1 was confirmed by RPLND. 25 years later, he received left sided orchiectomy for seminoma stage 1. Histologically, TIN was found in the tissue adjacent to seminoma. Two brothers had testicular GCT, too, one with bilateral GCT. (3) This 21 year old white Caucasian man underwent left-sided orchiectomy for nonseminomatous GCT. Pathological stage 1 was confirmed by RPLND. 21 years later, he received organ-preserving excision of a right-sided seminoma, followed by BEP chemotherapy for stage 3 disease. Histologically, TIN was found in the surrounding testicular tissue.
22 cases of bilateral GCT with intervals of 20 or more years have previously been reported, thereof three with intervals of more than 30 years, the longest interval being 40 years.
Conclusion
Apart from increased risks of cardiovascular diseases and non-testicular malignancies, patients with GCT face the specific probability of a second GCT in the long run. This risk persists life-long and is not eliminated by chemotherapy. Contralateral testicular biopsy can identify patients at risk by revealing precursor cells of GCT though false-negative biopsies may occur sporadically. However, in view of the multi-facetted late hazards of GCT patients, this minor surgical procedure might somewhat simplify the long-time care of these patients.
doi:10.1186/1471-2490-13-71
PMCID: PMC4028980  PMID: 24321309
Testicular germ cell neoplasms; Bilateral tumours; Testicular biopsy; Seminoma; Familial germ cell tumours
11.  Either Kras activation or Pten loss similarly enhance the dominant-stable CTNNB1-induced genetic program to promote granulosa cell tumor development in the ovary and testis 
Oncogene  2011;31(12):1504-1520.
WNT, PI3K or RAS signaling pathways control specific stages of ovarian follicular development. To analyze the functional interactions of these pathways in granulosa cells during follicular development in vivo, we generated specific mutant mouse models. Stable activation of the WNT signaling effector beta-catenin (CTNNB1) in granulosa cells results in the formation of premalignant lesions that develop into granulosa cell tumors (GCTs) spontaneously later in life or following targeted deletion of the tumor suppressor gene Pten. Conversely, expression of oncogenic KRASG12D dramatically arrests proliferation, differentiation and apoptosis in granulosa cells, and consequently, small abnormal follicle-like structures devoid of oocytes accumulate in the ovary. Because of the potent anti-proliferative effects of KRASG12D in granulosa cells, we sought to determine if KRASG12D would block precancerous lesion and tumor formation in follicles of the CTNNB1 mutant mice. Unexpectedly, transgenic Ctnnb1;Kras mutant mice exhibited increased GC proliferation, decreased apoptosis and impaired differentiation and developed early-onset GCTs leading to premature death in a manner similar to the Ctnnb1;Pten mutant mice. Microarray and RT-PCR analyses revealed that gene regulatory processes induced by CTNNB1 were mostly enhanced by either KRAS activation or Pten loss in remarkably similar patterns and degree. The concomitant activation of CTNNB1 and KRAS in Sertoli cells also caused testicular granulosa cell tumors that showed gene expression patterns that partially overlapped those observed in GCTs of the ovary. Although the mutations analyzed herein have not yet been linked to adult GCTs in humans, 1) other components of these pathways may be altered or mutated, 2) these mutations may relate to juvenile GCTs or 3) they may occur in tumors of other tissues where CTNNB1 is mutated. Importantly, our results provide strong evidence that CTNNB1 is the driver in these contexts and that KRASG12D and Pten loss promote the program set in motion by the CTNNB1.
doi:10.1038/onc.2011.341
PMCID: PMC3223552  PMID: 21860425
CTNNB1; KRAS; PTEN; granulosa cell tumor; ovary; testis
12.  Adult Type Granulosa Cell Tumor: A Very Rare Case of Sex-Cord Tumor of the Testis with Review of the Literature 
Case Reports in Pathology  2013;2013:932086.
Granulosa cell tumor (GST) is a sex-cord/stromal neoplasm of the gonads, more commonly arising in the ovaries, while approximately 80 cases have been reported in the testes. Out of these, 30 cases were of the adult type, while the remainder 50 cases were of the juvenile type. The latter mostly concerned infants and followed a benign course. However, the adult type testicular GCTs may be potentially malignant as it also happens in female patients with such neoplasms. We present a case of an adult type GCT located at the left testis. The patient was subjected to total orchiectomy and received no further treatment. Histology showed typical GCT histomorphology with Call-Exner bodies in some places. The immunoprofile of the tumor was CD99 (+), calretinin (+), inhibin (+), alpha smooth muscle actin (+), vimentin (+), ER (−), PR (−), keratin AE1/AE3 (−), alpha fetoprotein (−), CD117 (−), and placental alkaline phosphatase (−). Two years after surgery, the patient is alive and well with no signs of recurrence.
doi:10.1155/2013/932086
PMCID: PMC3670554  PMID: 23762714
13.  Predictors of viable germ cell tumor in postchemotherapeutic residual retroperitoneal masses 
Urology Annals  2014;6(1):27-30.
Objective:
The aim of this study was to identify predictors of viable germ cell tumor (GCT) in postchemotherapeutic residual retroperitoneal masses.
Materials and Methods:
The pertinent clinical and pathologic data of 16 male patients who underwent postchemotherapeutic retroperitoneal lymph node dissection (PC-RPLND) at King Faisal Specialist Hospital and Research Centre between 1994 and 2005 were reviewed retrospectively. It was found that all patients received cisplatin-based chemotherapy for advanced testicular GCT.
Results:
Out of the 16 male patients, 2 (13%), 8 (50%), and 6 (37%) had viable GCT, fibrosis, and teratoma, respectively. Ten (10) of the patients with prechemotherapeutic S1 tumor markers did not have viable GCT, and two of the six patients who had prechemotherapeutic S2 tumor markers have viable GCT. All tumor marker levels normalized after chemotherapy even in patients with viable GCT. Four patients had vascular invasion without viable GCT. Furthermore, four patients had more than 60% embryonal elements in the original pathology, but only 1 had viable GCT at PC-RPLND. Four of the five patients with immature teratoma had teratoma at PC-RPLND but no viable GCT; however, out of the four patients with mature teratoma, one had viable GCT and two had teratoma at PC-RPLND. Of the two patients with viable GCT, one had 100% embryonal cancer in the original pathology, prechemotherapeutic S2 tumor markers, history of orchiopexy, and no vascular invasion; the other patient had yolk sac tumor with 25% embryonal elements and 40% teratoma in the original pathology, and prechemotherapeutic S2 tumor markers.
Conclusion:
None of the clinical or pathological parameters showed a strong correlation with the presence of viable GCT in PC-RPLND. However, patients with ≥S2 may be at higher risk to have viable GCT. Further studies are needed to clarify this.
doi:10.4103/0974-7796.127017
PMCID: PMC3963339  PMID: 24669118
Chemotherapy; germ cell tumor; predictor; retroperitoneal lymph node dissection
14.  Granular cell tumor of the appendix: a new case and review of the literature 
SpringerPlus  2013;2:649.
Granular cell tumor (GCT) is a rare and usually benign lesion of neural / schwannian origin, most frequently found in middle-age women. The appendicular involvement is extremely rare: in over half a century only twelve cases have been reported in the literature, the patients living in America and Europe. Hitherto, no cases are documented from Africa, Asia and Oceania and no cases of malignant GCTs of the appendix have been reported.
Most patients were diagnosed preoperatively as having acute appendicitis, whereas in three patients the tumor was incidentally detected during major abdominal surgery. The GCTs were equally distributed between mid-appendix and tip, where lymphoid tissue is more abundant and the anatomical nerve supply is progressively reduced. Moreover, the appendix surrounding the GCTs is characterized by the presence of chronic inflammatory cells (histiocytes, plasmocytes, eosinophils, mastocytes) and, therefore, a chronic inflammation of the appendix may be an antecedent condition favouring the appearance of GCTs. The GCT of the appendix appears so to be a lesion that reflects local reactive changes in the neural / schwannian cells, rather than being a genuine neoplasm. We describe the smallest GCT of the appendix ever reported, with a detailed literature review supporting its reactive origin in the lymphatic tissue-rich sites, such as ileo cecal appendix.
doi:10.1186/2193-1801-2-649
PMCID: PMC3862858  PMID: 24349953
Granular cell tumor; Ileocecal appendix; Chronic appendicitis; Segmented peritonitis; Oncologic management
15.  The new molecular biology of granulosa cell tumors of the ovary 
Genome Medicine  2009;1(8):81.
Granulosa cell tumors (GCTs) of the ovary belong to the group of ovarian sex-cord stromal tumors and represent 5 to 10% of ovarian malignancies. GCTs exhibit several morphological, biochemical and hormonal features of normal proliferating pre-ovulatory granulosa cells, such as estrogen biosynthesis. Prognostic factors of this condition are lacking, and alternative treatment options to preserve future fertility are needed. Several groups have shown that two genetic factors implicated in GCTs are of particular interest. The gsp oncogene is a constitutive activating mutation of the prognosis of the tumor. FOXL2 is a transcription factor gene involved in ovarian development and function, whose expression is reduced and which is mutated in the majority of GCTs. FOXL2 appears to play a major role in cell cycle regulation. These recent findings open new pathophysiological insights into GCT development as well as revisitation of granulosa cell and ovarian function.
doi:10.1186/gm81
PMCID: PMC2768967  PMID: 19725933
16.  Multifocal Metachronous Giant Cell Tumor: Case Report and Review of the Literature 
Case Reports in Medicine  2014;2014:678035.
Introduction. Giant cell tumors (GCTs) of bone are known for their local aggressiveness and high recurrence rate. There are rare cases of multicentric GCT and most are synchronous. We herein review metachronous multicentric GCT reported in the literature. Material and Methods. A MEDLINE, Cochrane, and Google Scholar search was done to collect all cases of multicentric metachronous GCT specifying the clinical, radiological, and histological characteristics of each location and its treatment. Results. A total of 37 multifocal giant cell tumors were found in the literature. 68% of cases of multicentric giant cell tumors occur in less than 4 years following treatment of the first lesion. Thirty-seven cases of multifocal metachronous GCT were identified in the literature until 2012. Patients with multicentric GCT tend to be younger averaging 23. There is a slight female predominance in metachronous GCT. The most common site of the primary GCT is around the knee followed by wrist and hand and feet. Recurrence rate of multicentric GCT is 28.5%. Conclusion. Multicentric giant cell tumor is rare. The correct diagnosis relies on correlation of clinical and radiographic findings with confirmation of the diagnosis by histopathologic examination.
doi:10.1155/2014/678035
PMCID: PMC3912820  PMID: 24511316
17.  FOXL2, GATA4, and SMAD3 Co-Operatively Modulate Gene Expression, Cell Viability and Apoptosis in Ovarian Granulosa Cell Tumor Cells 
PLoS ONE  2014;9(1):e85545.
Aberrant ovarian granulosa cell proliferation and apoptosis may lead to granulosa cell tumors (GCT), the pathogenesis of which involves transcription factors GATA4, FOXL2, and SMAD3. FOXL2 gene harbors a point mutation (C134W) in a vast majority of GCTs. GATA4 is abundantly expressed in GCTs and its expression correlates with poor prognosis. The TGF-β mediator SMAD3 promotes GCT cell survival through NF-κB activation, and interacts with FOXL2. Here, we find that the expression patterns of these factors overlap in the normal human ovary and 90 GCTs, and positively correlate with each other and with their mutual target gene CCND2, which is a key factor for granulosa cell proliferation. We have explored the molecular interactions of FOXL2, GATA4, and SMAD3 and their roles in the regulation of CCND2 using co-immunoprecipitation, promoter transactivation, and cell viability assays in human GCT cells. We found that not only SMAD3, but also GATA4 physically interact with both wild type and C134W-mutated FOXL2. GATA4 and SMAD3 synergistically induce a 8-fold increase in CCND2 promoter transactivation, which is 50% reduced by both FOXL2 types. We confirmed that wild type FOXL2 significantly decreases cell viability. Interestingly, GATA4 and SMAD3 caused a marked reduction of GCT cell apoptosis induced by wild type FOXL2. Thus, the effects of GATA4 and SMAD3 on both cell viability and apoptosis are distinct from those of wild type FOXL2; a perturbation of this balance due to the oncogenic FOXL2 mutation is likely to contribute to GCT pathogenesis.
doi:10.1371/journal.pone.0085545
PMCID: PMC3887065  PMID: 24416423
18.  A clinicopathological study of giant cell tumor of small bones 
Upsala Journal of Medical Sciences  2011;116(4):265-268.
Background and purpose
Giant cell tumor (GCT) of the small bones (small-bone GCT) is usually rare and considered somewhat different from conventional GCT. The purpose of this study was to investigate and report the clinicopathological features of 11 cases with small-bone GCT.
Materials and methods
Patient information was obtained with the help of questionnaires. X-rays and paraffin blocks obtained from several institutions were clinically, radiographically, and histologically evaluated.
Results
Small-bone GCT was observed in younger patients compared to conventional GCT; 5 of the 11 (45%) patients were below 20 years of age, whereas the corresponding figure for all GCT patients is 16% in Japan. Excessive cortical bone expansion is a special feature. There were two cases of recurrence and one case of lung metastasis; the primary lesion was in the hand for all three cases. In contrast, no primary lesion of the foot recurred or metastasized. Varying degrees of positive p63 immunostaining were observed in all examined cases (n = 9) of small-bone GCT but were negative in case of giant cell reparative granuloma (GCRG) and solid variant of aneurysmal bone cyst (ABC). One case that demonstrated high-intensity positive staining had two episodes of recurrence.
Conclusion
Small-bone GCT tends to develop in younger patients than does conventional GCT. Primary GCTs of the hand may be biologically more aggressive than those of the feet. The p63 immunostaining may be useful not only for differential diagnosis but also for prognostication of small-bone GCT.
doi:10.3109/03009734.2011.596290
PMCID: PMC3207302  PMID: 21919814
clinicopathological study; giant cell tumor; p63 immunostaining; small bone
19.  Nearly 30 Years of Treatment for Recurrent Granulosa Cell Tumor of the Ovary: A Case Report and Review of the Literature 
Case Reports in Oncology  2010;3(1):14-18.
A 30-year-old woman was diagnosed with a stage IA granulosa cell tumor (GCT) of the ovary in 1979. Following removal of the adnexal mass and complete surgical staging, she remained disease-free for 12 years. In 1991 she underwent a resection of a retroperitoneal mass, confirmed to be a recurrent GCT. Despite adjuvant radiation treatment at the time of recurrence, the patient presented five years later with abdominal pain, and was found to have a second recurrence. Over the next 10 years the patient had multiple recurrences and progressive disease despite surgical resection, cytotoxic, hormonal and targeted chemotherapy treatments. In conclusion, there is no standard management for recurrent GCT of the ovary. We review this patient's treatment in the context of the current literature.
doi:10.1159/000274590
PMCID: PMC2918836  PMID: 20740152
Granulosa cell tumor; Hormonal therapy; Ovarian cancer; Chemotherapy
20.  Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression 
Carcinogenesis  2008;29(11):2062-2072.
The mechanisms of granulosa cell tumor (GCT) development may involve the dysregulation of signaling pathways downstream of follicle-stimulating hormone, including the phosphoinosite-3 kinase (PI3K)/AKT pathway. To test this hypothesis, a genetically engineered mouse model was created to derepress the PI3K/AKT pathway in granulosa cells by conditional targeting of the PI3K antagonist gene Pten (Ptenflox/flox;Amhr2cre/+). The majority of Ptenflox/flox;Amhr2cre/+ mice featured no ovarian anomalies, but occasionally (∼7%) developed aggressive, anaplastic GCT with pulmonary metastases. The expression of the PI3K/AKT downstream effector FOXO1 was abrogated in Ptenflox/flox;Amhr2cre/+ GCT, indicating a mechanism by which GCT cells may increase proliferation and evade apoptosis. To relate these findings to spontaneously occurring GCT, analyses of PTEN and phospho-AKT expression were performed on human and equine tumors. Although PTEN loss was not detected, many GCT (2/5 human, 7/17 equine) featured abnormal nuclear or perinuclear localization of phospho-AKT, suggestive of altered PI3K/AKT activity. As inappropriate activation of WNT/CTNNB1 signaling causes late-onset GCT development and cross talk between the PI3K/AKT and WNT/CTNNB1 pathways has been reported, we tested whether these pathways could synergize in GCT. Activation of both the PI3K/AKT and WNT/CTNNB1 pathways in the granulosa cells of a mouse model (Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+) resulted in the development of GCT similar to those observed in Ptenflox/flox;Amhr2cre/+ mice, but with 100% penetrance, perinatal onset, extremely rapid growth and the ability to spread by seeding into the abdominal cavity. These data indicate a synergistic effect of dysregulated PI3K/AKT and WNT/CTNNB1 signaling in the development and progression of GCT and provide the first animal models for metastatic GCT.
doi:10.1093/carcin/bgn186
PMCID: PMC2577137  PMID: 18687666
21.  The epidemiology of malignant giant cell tumors of bone: an analysis of data from the Surveillance, Epidemiology and End Results Program (1975–2004) 
Rare Tumors  2009;1(2):e52.
Malignant giant cell tumor (GCT) of bone is a rare tumor with debilitating consequences. Patients with GCT of bone typically present with mechanical difficulty and pain as a result of bone destruction and are at an increased risk for fracture. Because of its unusual occurrence, little is known about the epidemiology of malignant GCT of bone. This report offers the first reliable population-based estimates of incidence, patient demographics, treatment course and survival for malignancy in GCT of bone in the United States. Using data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program, we estimated the overall incidence and determinants of survival among patients diagnosed with malignant GCT of bone from 1975–2004. Cox proportional hazards regression was used to evaluate demographic and clinical determinants of survival among malignant GCT cases. Based on analyses of 117 malignant GCT cases, the estimated annual incidence in the United States was 1.6 per 10,000,000 persons per year. Incidence was highest among adults aged 20 to 44 years (2.4 per 10,000,000 per year) and most patients were diagnosed with localized (31.6%) or regional (29.9%) disease compared to distant disease (16.2%). Approximately 85% of patients survived at least 5 years, with survival poorest among older patients and those with evidence of distant metastases at time of diagnosis. The current study represents the largest systematic investigation examining the occurrence and distribution of malignancy in GCT of bone in the general U.S. population. We confirm its rare occurrence and suggest that age and stage at diagnosis are strongly associated with long-term survival.
doi:10.4081/rt.2009.e52
PMCID: PMC2994468  PMID: 21139931
giant cell tumor of bone; surveillance; epidemiology and end results; descriptive epidemiology; incidence; survival; osteosarcoma.
22.  Giant Cell Tumor of Bone: Risk Factors for Recurrence 
Background
Many surgeons treat giant cell tumor of bone (GCT) with intralesional curettage. Wide resection is reserved for extensive bone destruction where joint preservation is impossible or when expendable sites (eg, fibular head) are affected. Adjuvants such as polymethylmethacrylate and phenol have been recommended to reduce the risk of local recurrence after intralesional surgery. However, the best treatment of these tumors and risk factors for recurrence remain controversial.
Questions/purposes
We evaluated the recurrence-free survival after surgical treatment of GCT to determine the influence of the surgical approach, adjuvant treatment, local tumor presentation, and demographic factors on the risk of recurrence.
Methods
We retrospectively reviewed 118 patients treated for benign GCT of bone between 1985 and 2005. Recurrence rates, risk factors for recurrence and the development of pulmonary metastases were determined. The minimum followup was 36 months (mean, 108.4 ± 43.7; range, 36–233 months).
Results
Wide resection had a lower recurrence rate than intralesional surgery (5% versus 25%). Application of polymethylmethacrylate decreased the risk of local recurrence after intralesional surgery compared with bone grafting; phenol application alone had no effect on the risk of recurrence. Pulmonary metastases occurred in 4%; multidisciplinary treatment including wedge resection, chemotherapy, and radiotherapy achieved disease-free survival or stable disease in all of these patients.
Conclusion
We recommend intralesional surgery with polymethylmethacrylate for the majority of primary GCTs. Because pulmonary metastases are rare and aggressive treatment of pulmonary metastases is usually successful, we believe the potential for metastases should not by itself create an indication for wide resection of primary tumors.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-010-1501-7
PMCID: PMC3018195  PMID: 20706812
23.  Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations 
BMC Genomics  2010;11:132.
Background
Intracranial pediatric germ cell tumors (GCTs) are rare and heterogeneous neoplasms and vary in histological differentiation, prognosis and clinical behavior. Germinoma and mature teratoma are GCTs that have a good prognosis, while other types of GCTs, termed nongerminomatous malignant germ cell tumors (NGMGCTs), are tumors with an intermediate or poor prognosis. The second group of tumors requires more extensive drug and irradiation treatment regimens. The mechanisms underlying the differences in incidence and prognosis of the various GCT subgroups are unclear.
Results
We identified a distinct mRNA profile correlating with GCT histological differentiation and prognosis, and also present in this study the first miRNA profile of pediatric primary intracranial GCTs. Most of the differentially expressed miRNAs were downregulated in germinomas, but miR-142-5p and miR-146a were upregulated. Genes responsible for self-renewal (such as POU5F1 (OCT4), NANOG and KLF4) and the immune response were abundant in germinomas, while genes associated with neuron differentiation, Wnt/β-catenin pathway, invasiveness and epithelial-mesenchymal transition (including SNAI2 (SLUG) and TWIST2) were abundant in NGMGCTs. Clear transcriptome segregation based on patient survival was observed, with malignant NGMGCTs being closest to embryonic stem cells. Chromosome copy number variations (CNVs) at cytobands 4q13.3-4q28.3 and 9p11.2-9q13 correlated with GCT malignancy and clinical risk. Six genes (BANK1, CXCL9, CXCL11, DDIT4L, ELOVL6 and HERC5) within 4q13.3-4q28.3 were more abundant in germinomas.
Conclusions
Our results integrate molecular profiles with clinical observations and provide insights into the underlying mechanisms causing GCT malignancy. The genes, pathways and microRNAs identified have the potential to be novel therapeutic targets.
doi:10.1186/1471-2164-11-132
PMCID: PMC2837036  PMID: 20178649
24.  Granular cell tumor of hand presenting as subcutaneous nodule mimicking dermal adnexal tumor: A diagnosis by cytology 
Granular cell tumor (GCT) is an uncommon tumor and is believed to be of schwannian origin. GCT is benign but rare malignant cases are recorded. GCT occurs in almost any part of the body. The common sites are the tongue, skin, and subcutaneous tissue. GCT of hand is an extremely rare. Till date only 17 cases are reported in the literature. Preoperative diagnosis of GCT is important, because GCT mimics dermal adnexal tumor in subcutaneous tissue, other soft tissue tumor or inflammatory lesions. GCT is composed of large polygonal cells with eosinophilic granular cytoplasm and these cells are often immunoreactive for the S-100 protein. Fine-needle aspiration cytology has been suggested to be diagnostic modality of choice and this would undoubtedly aid the correct diagnosis. Excision with wide surgical margins is curative for benign GCT. Recurrence and malignant transformation requires regular follow-up. Here, this communication documents a case of cytological diagnosis of the granular cell tumor of hand in a 21-year-old female, clinically suspected to be a dermal adnexal tumor.
doi:10.4103/2229-5178.105467
PMCID: PMC3573450  PMID: 23439997
Fine-needle aspiration cytology; granular cell tumor; hand; histology; immunohistochemistry
25.  Improved Outcome of Central Nervous System Germ Cell Tumors: Implications for the Role of Risk-adapted Intensive Chemotherapy 
Journal of Korean Medical Science  2010;25(3):458-465.
To determine the impact of treatment protocols on the outcome of central nervous system germ cell tumors (CNS-GCTs), we reviewed the medical records of 53 patients who received front-line chemotherapy from September 1997 to September 2006. Pure germinoma, normal alpha-fetoprotein level and beta-human chorionic gonadotropin level <50 mIU/mL were regarded as low-risk features and the others as high-risk. Patients from different time periods were divided into 3 groups according to the chemotherapy protocols. Group 1 (n=19) received 4 cycles of chemotherapy comprising cisplatin, etoposide and bleomycin. Group 2 (n=16) and group 3 (n=18) received 4 cycles of chemotherapy with cisplatin, etoposide, cyclophosphamide and vincristine in the former and with carboplatin, etoposide, cyclophosphamide and bleomycin in the latter. In group 2 and group 3, high-risk patients received double doses of cisplatin, carboplatin and cyclophosphamide. Radiotherapy was given after chemotherapy according to the clinical requirements. The event-free survivals of groups 1, 2, and 3 were 67.0%, 93.8%, and 100%, respectively (group 1 vs. 2, P=0.06; group 2 vs. 3, P=0.29; group 1 vs. 3, P=0.02). Our data suggest that risk-adapted intensive chemotherapy may improve the outcome of patients with malignant CNS-GCTs.
doi:10.3346/jkms.2010.25.3.458
PMCID: PMC2826748  PMID: 20191048
Neoplasms, Germ Cell and Embryonal; Central Nervous System; Drug Therapy; Survival

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