Soft Tissues: Aggressive angiomyxoma

2007-04-01   Francesca Micci , Petter Brandal 

1.Section of Cancer Cytogenetics, Department of Medical Genetics, Rikshspital-Radiumhospital Medical Centre, 0310 Oslo, Norway.

Summary

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

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

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

Atlas Image
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 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.

Cytogenetics molecular

The 12q15 rearrangements lead to alterations of the high mobility group (HMG) gene HMGA2 (previously known as HMGIC).

Additional anomalies

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 (high mobility group AT-hook 2)

Location

12q14.3

Dna rna description

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 description

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 mutations

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

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 3¹ portion of the gene. This 3¹ 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 5¹ 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 HMGA2s 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.

Bibliography

Pubmed IDLast YearTitleAuthors
156703092005Aggressive angiomyxoma of the female genital tract: a clinicopathologic and immunohistochemical study of 12 cases.Amezcua CA et al
146085462003Aggressive angiomyxoma: a second case of metastasis with patient's death.Blandamura S et al
114941492001The expression of HMGA genes is regulated by their 3'UTR.Borrmann L et al
113013472001The tumor-associated gene HMGIC is expressed in normal and osteoarthritis-affected synovia.Broberg K et al
86467301996Aggressive angiomyxoma: a clinicopathologic study of 29 female patients.Fetsch JF et al
112776632001Primary medical management of recurrent aggressive angiomyxoma of the vulva with a gonadotropin-releasing hormone agonist.Fine BA et al
103984241999HMGIC expression in human adult and fetal tissues and in uterine leiomyomata.Gattas GJ et al
90235511997Aggressive angiomyxoma: reappraisal of its relationship to angiomyofibroblastoma in a series of 16 cases.Granter SR et al
168703902006Aggressive angiomyxoma: multimodality treatments can avoid mutilating surgery.Han-Geurts IJ et al
98242081998The expression pattern of the Hmgic gene during development.Hirning-Folz U et al
86377071996HMGI-C rearrangements as the molecular basis for the majority of pulmonary chondroid hamartomas: a survey of 30 tumors.Kazmierczak B et al
86896131996Loss of an X chromosome in aggressive angiomyxoma of female soft parts: a case report.Kenny-Moynihan MB et al
104323291999Clinical problem-solving. A little math helps the medicine go down.Kopelman RI et al
162464032006Aggressive angiomyxoma of the vulva: Dramatic response to gonadotropin-releasing hormone agonist therapy.McCluggage WG et al
165683092006Deregulation of HMGA2 in an aggressive angiomyxoma with t(11;12)(q23;q15).Micci F et al
115502852001Chromosomal translocation t(8;12) induces aberrant HMGIC expression in aggressive angiomyxoma of the vulva.Nucci MR et al
99307981999Aggressive angiomyxoma: findings on CT and MR imaging.Outwater EK et al
126491982003Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15.Quade BJ et al
169907202006HMGA2 rearrangement in a case of vulvar aggressive angiomyxoma.Rabban JT et al
116023452001Molecular biology of HMGA proteins: hubs of nuclear function.Reeves R et al
87803821996HMGI-C expression patterns in human tissues. Implications for the genesis of frequent mesenchymal tumors.Rogalla P et al
88895001996Translocation 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 et al
172554312007Case 106: aggressive angiomyxoma.Sinha R et al
66844031983Aggressive angiomyxoma of the female pelvis and perineum. Report of nine cases of a distinctive type of gynecologic soft-tissue neoplasm.Steeper TA et al
107440712000HMGI-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 et al
157359782005Aggressive angiomyxoma: a clinicopathological and immunohistochemical study of 11 cases with long-term follow-up.van Roggen JF et al

Citation

Francesca Micci ; Petter Brandal

Soft Tissues: Aggressive angiomyxoma

Atlas Genet Cytogenet Oncol Haematol. 2007-04-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5203/soft-tissues-aggressive-angiomyxoma