| Identity |
| ICD-Topo | C470-C476,C478-C479,C490-C496,C498-C499 CONNECTIVE & SOFT TISSUE |
| ICD-Morpho | 8841/0 Deep (aggressive) angiomyxoma |
| Phylum | Soft Tissue Tumors:Uncertain differentiation:Deep 'aggressive' angiomyxoma |
| Other names | Deep aggressive angiomyxoma |
| Note | The term aggressive was introduced to emphasize the locally aggressive behaviour and the high potential for local recurrence, it does not reflect a high probability for metastasis, as only 2 cases with metastatic disease have been reported. The name angiomyxoma was chosen because of the similarity to myxoma and the notable vascular component. |
| Classification |
| Aggressive angiomyxoma (AA) is a soft tissue neoplasm. The term AA was not coined until 1983 but similar tumours were described as early as in the 1860ies. In the latest WHO-classification AA is now classified under Tumours of uncertain differentiation. |
| Clinics and Pathology |
| Disease | AA is a neoplasm. It is defined as benign but has infiltrative potential into skeletal muscle and fat. The disease is therefore considered locally aggressive although it does not infiltrate surrounding viscus. Only 2 cases with metastatic disease have been published. |
| Etiology | No etiologic factors are known. |
| Epidemiology | AA is a rare neoplasm with about 150 reported cases. It is most often found in women in reproductive age with a peak incidence in the fourth decade of life. The female:male ratio is 6:1. |
| Clinics | AA is most often found in or in proximity to the lower pelvis, more specifically perineum, vulva, vagina or inguinal regions. The majority of patients present with a slow-growing mass which is otherwise asymptomatic and this is frequently the only symptom/sign. Observed accompanying symptoms and signs are regional pain, a feeling of local pressure, or dyspareunia. Tumour size is often underestimated by physical examination. It is worth noticing that the frequency of symptoms and signs attributable to local growth is lower than what would be expected from the relatively large size of most of these tumours. AA is often clinically misdiagnosed, most often mistaken for a Bartholin cyst. Radiographically, AA is isointense or has low signal intensity on T1-weighted MRI, and have a whorled pattern of high signal intensity on T2-weighted MRI. These tumours show contrast enhancement, reflecting their inherent vasculature, and tend to displace and grow around structures rather than infiltrate them. |
| Pathology | Most AA are big, often more than 10 cm in largest diameter. These tumours are macroscopically lobulated and may adhere to surrounding soft tissue. Microscopically, cells with a spindled or stellate morphology are seen, embedded in a loose matrix consisting of wavy collagen and oedema. Cellularity is generally low to moderate. Infiltration into fat, muscle, and nerves is seen. The hallmark of AA is vessels of varying calibre haphazardly scattered throughout the tumour parenchyma, whereas mitotic figures are scarce. Immunohistochemically, most AA are positive for desmin, smooth muscle actin, muscle-specific actin, vimentin, oestrogen receptor, and progesterone receptor. Some tumours are positive for CD34, whereas S100 is invariably negative. Based on these observations, a myofibroblastic differentiation of the neoplastic cells is suggested. |
| Treatment | Radical surgery with wide margins is the treatment of choice. Because most tumours are large, grow infiltrative and blends with adjacent soft tissue, and are located in close proximity to vital organs such as bladder and rectum, wide excision is not always possible and/or may cause significant morbidity. In such situations watchful waiting may be advisable because these tumours may be stable with no or very limited growth over long periods of time. Several reported attempts using chemotherapy and radiotherapy as part of the treatment for AA have been disappointing, probably due to the low mitotic activity/growth fraction of cells. Most AA express oestrogen and progesterone receptors and are likely to have a hormone-dependent growth. Because of this, treatment with GnRH agonists has been administered to AA patients, and some case reports with dramatic responses to such GnRH agonists have been reported |
| Prognosis | The prognosis is very good. Only 2 cases with metastatic disease followed by death have been reported. Recurrences are common, though, reported to be between 9 and 72 %. These numbers are uncertain because late recurrences may develop several years after the primary tumour was found, and long-term follow-up of the patients is therefore very important. The major problem posed by this tumour is the often mutilating surgery necessary to cure the patient. |
| Cytogenetics |
| Cytogenetics Morphological | Although only 6 cases of AA showing chromosomal aberrations have been described so far, a non-random involvement of chromosomal band 12q15 has been identified. The cytogenetic rearrangements hitherto described, involving this band, are: t(11;12)(q23;q15), t(7;12)(q22;q13-14), t(8;12)(p12;q15), and der(12)t(5;12)(q31;p11)inv(12)(p11q14). An additional case with 12q15 rearrangement has been described using fluorescence in situ hybridization. |
 | |
| Ideograms and G-banded images of chromosomes 11 and 12 from an AA are depicted. Normal chromosome homologs and rearranged chromosomes are shown. Arrows indicate breakpoint positions. | |
| Cytogenetics Molecular | The 12q15 rearrangements lead to alterations of the high mobility group (HMG) gene HMGA2 (previously known as HMGIC). Monosomy of the X chromosome has been reported in one AA, whereas another AA showed monosomy 12 among other abnormalities. |
| Genes involved and Proteins |
| Gene Name | HMGA2 |
| Location | 12q15 |
| Dna / Rna | The HMGA2 gene consists of 5 exons spanning 141 kb of genomic DNA. It is highly expressed in embryonic tissue. In normal adult tissues, only low gene expression levels have been detected, and only in kidney, lung, and synovia. In all other terminally differentiated cells, no expression of this gene has been detected. |
| Protein | The HMGA2 gene encodes a member of the high-mobility group A (HMGA) of small, non-histonic, chromatin-associated proteins. These proteins are believed to affect transcription in several ways. They act as architectural elements by bending the DNA, they interact with a large number of other proteins, mainly transcription factors, and they also influence upon chromatin changes during cell cycle. As all proteins in this family, HMGA2 contains three copies of a conserved DNA-binding peptide motif called AT-hook. This AT-hook preferentially binds to the minor groove of stretches of AT-rich sequences. |
| Somatic mutation | Increased protein levels of HMGA2 have been reported in a variety of benign mesenchymal tumours, including lipoma, leiomyoma, chondroid tumours, pulmonary hamartoma, endometrial polyps, and fibroadenoma of the breast. In all these neoplasms rearrangements of chromosomal band 12q15 have been found at the cytogenetic resolution level. |
| Result of the chromosomal anomaly |
| Hybrid Gene | |
| Description | In general, two types of HMGA2 rearrangement are known. In some cases, HMGA2 is interrupted after the end of the third exon, whereby the AT hook domains are separated from the 3 portion of the gene. This 3 portion of the gene, coding for the protein-binding domains of HMGA2, is thereby lost. In other cases, breakpoints outside the coding region of the gene are found. These extragenic breaks suggest a disruption of regulatory sequences, which lead to abnormal expression of HMGA2. Expression of the entire HMGA2 gene is achieved through alterations affecting 5 regulatory elements or the 3' untranslated region, leading to a stabilized mRNA. It is important to note that even if the fusion products mentioned above are in-frame, some of HMGA2's partner genes contribute with very few amino acids to the chimeric product. It has therefore been suggested that the minimal requirement for tumourigenesis would be activating HMGA2 rearrangements leaving at least exons 1-3 of HMGA2 intact. For the specific translocation t(11;12)(q23;q15), the result is the abnormal expression of an intact, full-length product of HMGA2. |
| Other genes implicated (Data extracted from papers in the Atlas) |
| Genes | HMGA2 |
| Translocations implicated (Data extracted from papers in the Atlas) |
| t(11;12)(q23;q15) HMGA2 | |
| t(7;12)(q22;q13-14) HMGA2 | |
| t(8;12)(p12;q15) HMGA2 | |
| External links |
| Bibliography |
| Aggressive angiomyxoma of the female pelvis and perineum. Report of nine cases of a distinctive type of gynecologic soft-tissue neoplasm. |
| Steeper TA, Rosai J |
| The American journal of surgical pathology. 1983 ; 7 (5) : 463-475. |
| PMID 6684403 |
| Aggressive angiomyxoma of the pelvis: Cytogenetic findings in a single case. |
| Horsman DE, Berean KW, Salski CB, Clement PB |
| Cancer Genet Cytogenet. 1991 ; 56 (numero 1) : 130-131. |
| Cytogenetic findings in a case of angiomyxoma of the vaginal wall. |
| Betz JL, Meloni AM, U Ren LA, Moore GE, Sandberg AA |
| Cancer Genet Cytogenet. 1995 ; 84 (numero 1) : page 157. |
| Cytogenic and molecular analysis of an aggressive angiomyxoma. |
| Kazmierczak B, Wanschura S, Meyer-Bolte K, Caselitz J, Meister P, Bartnitzke S, Van de Ven W, Bullerdiek J |
| The American journal of pathology. 1995 ; 147 (3) : 580-585. |
| PMID 7677171 |
| Aggressive angiomyxoma: a clinicopathologic study of 29 female patients. |
| Fetsch JF, Laskin WB, Lefkowitz M, Kindblom LG, Meis-Kindblom JM |
| Cancer. 1996 ; 78 (1) : 79-90. |
| PMID 8646730 |
| HMGI-C rearrangements as the molecular basis for the majority of pulmonary chondroid hamartomas: a survey of 30 tumors. |
| Kazmierczak B, Rosigkeit J, Wanschura S, Meyer-Bolte K, Van de Ven WJ, Kayser K, Krieghoff B, Kastendiek H, Bartnitzke S, Bullerdiek J |
| Oncogene. 1996 ; 12 (3) : 515-521. |
| PMID 8637707 |
| Loss of an X chromosome in aggressive angiomyxoma of female soft parts: a case report. |
| Kenny-Moynihan MB, Hagen J, Richman B, McIntosh DG, Bridge JA |
| Cancer genetics and cytogenetics. 1996 ; 89 (1) : 61-64. |
| PMID 8689613 |
| HMGI-C expression patterns in human tissues. Implications for the genesis of frequent mesenchymal tumors. |
| Rogalla P, Drechsler K, Frey G, Hennig Y, Helmke B, Bonk U, Bullerdiek J |
| The American journal of pathology. 1996 ; 149 (3) : 775-779. |
| PMID 8780382 |
| Translocation breakpoints upstream of the HMGIC gene in uterine leiomyomata suggest dysregulation of this gene by a mechanism different from that in lipomas. |
| Schoenberg Fejzo M, Ashar HR, Krauter KS, Powell WL, Rein MS, Weremowicz S, Yoon SJ, Kucherlapati RS, Chada K, Morton CC |
| Genes, chromosomes & cancer. 1996 ; 17 (1) : 1-6. |
| PMID 8889500 |
| Aggressive angiomyxoma: reappraisal of its relationship to angiomyofibroblastoma in a series of 16 cases. |
| Granter SR, Nucci MR, Fletcher CD |
| Histopathology. 1997 ; 30 (1) : 3-10. |
| PMID 9023551 |
| The expression pattern of the Hmgic gene during development. |
| Hirning-Folz U, Wilda M, Rippe V, Bullerdiek J, Hameister H |
| Genes, chromosomes & cancer. 1998 ; 23 (4) : 350-357. |
| PMID 9824208 |
| HMGIC expression in human adult and fetal tissues and in uterine leiomyomata. |
| Gattas GJ, Quade BJ, Nowak RA, Morton CC |
| Genes, chromosomes & cancer. 1999 ; 25 (4) : 316-322. |
| PMID 10398424 |
| Aggressive angiomyxoma: findings on CT and MR imaging. |
| Outwater EK, Marchetto BE, Wagner BJ, Siegelman ES |
| AJR. American journal of roentgenology. 1999 ; 172 (2) : 435-438. |
| PMID 9930798 |
| Clinical problem-solving. A little math helps the medicine go down. |
| Kopelman RI, Wong JB, Pauker SG |
| The New England journal of medicine. 1999 ; 341 (6) : 435-439. |
| PMID 10432329 |
| HMGI-C and HMGI(Y) immunoreactivity correlates with cytogenetic abnormalities in lipomas, pulmonary chondroid hamartomas, endometrial polyps, and uterine leiomyomas and is compatible with rearrangement of the HMGI-C and HMGI(Y) genes. |
| Tallini G, Vanni R, Manfioletti G, Kazmierczak B, Faa G, Pauwels P, Bullerdiek J, Giancotti V, Van Den Berghe H, Dal Cin P |
| Laboratory investigation; a journal of technical methods and pathology. 2000 ; 80 (3) : 359-369. |
| PMID 10744071 |
| The expression of HMGA genes is regulated by their 3'UTR. |
| Borrmann L, Wilkening S, Bullerdiek J |
| Oncogene. 2001 ; 20 (33) : 4537-4541. |
| PMID 11494149 |
| The tumor-associated gene HMGIC is expressed in normal and osteoarthritis-affected synovia. |
| Broberg K, Tallini G, Hglund M, Lindstrand A, Toksvig-Larsen S, Mertens F |
| Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2001 ; 14 (4) : 311-317. |
| PMID 11301347 |
| Primary medical management of recurrent aggressive angiomyxoma of the vulva with a gonadotropin-releasing hormone agonist. |
| Fine BA, Munoz AK, Litz CE, Gershenson DM |
| Gynecologic oncology. 2001 ; 81 (1) : 120-122. |
| PMID 11277663 |
| Chromosomal translocation t(8;12) induces aberrant HMGIC expression in aggressive angiomyxoma of the vulva. |
| Nucci MR, Weremowicz S, Neskey DM, Sornberger K, Tallini G, Morton CC, Quade BJ |
| Genes, chromosomes & cancer. 2001 ; 32 (2) : 172-176. |
| PMID 11550285 |
| Molecular biology of HMGA proteins: hubs of nuclear function. |
| Reeves R |
| Gene. 2001 ; 277 (1-2) : 63-81. |
| PMID 11602345 |
| World Health Organization classification of tumours. Pathology and genetics of tumours of soft tissue and bone. |
| Fletcher CDM, Unni KK, Mertens F eds |
| IARC Press. : page L. |
| Aggressive angiomyxoma: a second case of metastasis with patient's death. |
| Blandamura S, Cruz J, Faure Vergara L, Machado Puerto I, Ninfo V |
| Human pathology. 2003 ; 34 (10) : 1072-1074. |
| PMID 14608546 |
| Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15. |
| Quade BJ, Weremowicz S, Neskey DM, Vanni R, Ladd C, Dal Cin P, Morton CC |
| Cancer research. 2003 ; 63 (6) : 1351-1358. |
| PMID 12649198 |
| Aggressive angiomyxoma of the female genital tract: a clinicopathologic and immunohistochemical study of 12 cases. |
| Amezcua CA, Begley SJ, Mata N, Felix JC, Ballard CA |
| International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2005 ; 15 (1) : 140-145. |
| PMID 15670309 |
| Aggressive angiomyxoma: a clinicopathological and immunohistochemical study of 11 cases with long-term follow-up. |
| van Roggen JF, van Unnik JA, Briaire-de Bruijn IH, Hogendoorn PC |
| Virchows Archiv : an international journal of pathology. 2005 ; 446 (2) : 157-163. |
| PMID 15735978 |
| Aggressive angiomyxoma: multimodality treatments can avoid mutilating surgery. |
| Han-Geurts IJ, van Geel AN, van Doorn L, M den Bakker, Eggermont AM, Verhoef C |
| European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2006 ; 32 (10) : 1217-1221. |
| PMID 16870390 |
| Aggressive angiomyxoma of the vulva: Dramatic response to gonadotropin-releasing hormone agonist therapy. |
| McCluggage WG, Jamieson T, Dobbs SP, Grey A |
| Gynecologic oncology. 2006 ; 100 (3) : 623-625. |
| PMID 16246403 |
| Deregulation of HMGA2 in an aggressive angiomyxoma with t(11;12)(q23;q15). |
| Micci F, Panagopoulos I, Bjerkehagen B, Heim S |
| Virchows Archiv : an international journal of pathology. 2006 ; 448 (6) : 838-842. |
| PMID 16568309 |
| HMGA2 rearrangement in a case of vulvar aggressive angiomyxoma. |
| Rabban JT, Dal Cin P, Oliva E |
| International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists. 2006 ; 25 (4) : 403-407. |
| PMID 16990720 |
| Case 106: aggressive angiomyxoma. |
| Sinha R, Verma R |
| Radiology. 2007 ; 242 (2) : 625-627. |
| PMID 17255431 |
| REVIEW articles | automatic search in PubMed |
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| Contributor(s) |
| Written | 04-2007 | Francesca Micci, Petter Brandal |
| Section of Cancer Cytogenetics, Department of Medical Genetics, Rikshspital-Radiumhospital Medical Centre, 0310 Oslo, Norway. |
| Citation |
| This paper should be referenced as such : |
| Micci F, Brandal P |
| Soft Tissue Tumors: Aggressive angiomyxom |
| Atlas Genet Cytogenet Oncol Haematol. April 2007 |
| Free journal version : [ pdf ] [ DOI ] |
| URL : http://AtlasGeneticsOncology.org/Tumors/AggresAngiomyxomaID5203.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Tue Feb 17 19:15:36 CET 2015 |
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