Background

This is a deep soft tissue tumor, which as the name suggests, may have a locally aggressive course. Most tumors occur in women and are large, usually greater than 10 cm, slowly growing, and painless. The most common location is in the pelviperineal region and may exert pressure on adjacent organs.

OUTLINE

Epidemiology
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
AGE RANGE-MEDIAN	3-5th decades
SEX (M:F)	95% females

 

PATHOGENESIS	CHARACTERIZATION
CHROMOSOMAL ABNORMALITIES
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. Division of Women's and Perinatal Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.	Genes Chromosomes Cancer 2001 Oct;32(2):172-6 Abstract quote Benign mesenchymal neoplasms associated with rearrangements of the DNA architectural factor gene HMGIC on chromosome 12 include lipomas, uterine leiomyomata, pulmonary chondroid hamartomas, endometrial polyps, salivary gland pleomorphic adenomas, and breast fibroadenomas. Although HMGIC also has been implicated in the pathobiology of aggressive angiomyxoma of the vulva, the molecular mechanisms pertaining to this neoplasm are unclear. Tissue from a recurrent aggressive angiomyxoma was investigated by cytogenetic and expression analysis for HMGIC and HMGIY. The trypsin-Giemsa-banded karyotype showed a clonal translocation between chromosomes 8 and 12 [46,XX,t(8;12)(p12;q15)]. Fluorescence in situ hybridization (FISH) analysis with whole chromosome paint probes for chromosomes 8 and 12 excluded cryptic involvement of other chromosomes. The chromosome 12 breakpoint was mapped with two-color FISH analysis using cosmid probes at the 5' and 3' termini of HMGIC. Both cosmid probes showed hybridization to the normal chromosome 12 and the der(12) chromosome, indicating that the breakpoint was 3' (telomeric) to the gene. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed HMGIC expression in the tumor, and immunohistochemistry localized HMGIC expression to the tumor's spindle cells. Like numerous benign mesenchymal tumors, this locally aggressive tumor is associated with rearrangements near or within HMGIC, but chimeric gene formation was not required for tumorigenesis. Inappropriate expression of this DNA binding protein, however, may be important in the pathobiology of this tumor. Understanding the pathogenetic mechanism may also be helpful in developing new diagnostic tools for identifying residual disease.

 

LABORATORY/ RADIOLOGIC	CHARACTERIZATION
RADIOLOGIC
Sonographic appearance of aggressive angiomyxoma of the scrotum. De la Ossa M, Castellano-Sanchez A, Alvarez E, Smoak W, Robinson MJ. The Arkadi M. Rywlin Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, 4300 Alton Road, Blum Building, Suite 201, Miami Beach, FL 33140, USA.	J Clin Ultrasound 2001 Oct;29(8):476-8 Abstract quote Aggressive angiomyxoma (AAM) is a rare, locally infiltrative tumor that occurs almost exclusively in the pelvic and perineal regions of women of childbearing age. We report the unusual case of a 26-year-old man with an AAM presenting as a slowly enlarging scrotal mass. Gray-scale scrotal sonography demonstrated a well-demarcated, hypoechoic, extratesticular, extraepididymal mass with multiple thin, echogenic internal septa. The mass arose inferior to the left testicle and displaced the testicle cephalad. Color Doppler sonography revealed surrounding vascularity but no Doppler signals within the mass. The testicles and epididymides demonstrated normal echogenicity and vascularity. Histologic examination of the excised mass revealed a well-demarcated, nonencapsulated lesion composed of spindle-shaped cells in a myxoid background with a prominent vascular component.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
VARIANTS
MALE
Aggressive angiomyxoma of male genital region. Report of 4 cases with immunohistochemical evaluation including hormone receptor status Idrees MT, etal. Department of Pathology, The Lilian and Henry M. Stratton-Hans Popper, Mount Sinai Medical Center, New York, NY 10029, USA.	Ann Diagn Pathol. 2006 Aug;10(4):197-204. Abstract quote   Aggressive angiomyxoma (AA), first described by Steeper and Rosai (Am J SurgPathol. 1983;7:463-475), is a rare locally infiltrative tumor that usually arises in the pelvic and perineal soft tissues of young women. Approximately 150 cases have been reported in women. Aggressive angiomyxoma has a high rate of local recurrence because of its infiltrative growth and anatomical location making complete excision with wide margins difficult. To our knowledge, 39 cases of AA occurring in men have been reported in the literature. Sites frequently involved include the scrotum, spermatic cord, inguinal region, and perineum. The gross and microscopic appearances and clinical course are similar to those described in female cases. Immunohistochemistry evaluating estrogen and progesterone receptors (ER and PR, respectively), although frequently positive in the female cases, has rarely been studied in the male cases. We report the clinicopathologic features of 4 additional cases of AA in men with particular emphasis on hormone (ER/PR) receptor status. Hormone reactivity is significant in that AA may arise from specialized hormonally responsive stromal cells of the perineum and may potentially play a therapeutic role in unresectable tumors. From our small series, hormone positivity (1 case of ER+, 3 cases of PR+) does occur in the male cases of AA, and a large number of cases should be examined to determine the frequency at which these tumors express hormone receptors.
Aggressive angiomyxoma in men. A report of two cases associated with inguinal hernias. Clatch RJ, etal.	Arch Pathol Lab Med 1993;117:911-913
Aggressive angiomxyoma in males. A report of four cases Iezzoni JC, etal.	Am J Clin Pathol 1995;104:391-396

 

HISTOLOGICAL TYPES	CHARACTERIZATION
General	Small uniform spindle to stellate cells with pale eosinophilic cytoplasm and bland vesicular nuclei Set in myxoid matrix with variable rounded medium to large sized vessels, often thickened or hyalizined Narrow bundles of smooth muscle spin off into the stroma from around vessels Infiltrative margins with entrapment of adipose tissue, nerves, smooth muscle, and glandular tissue

 

SPECIAL STAINS/ IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
Special stains
Immunoperoxidase	Positive for VIM, desmin, actin ER PR may be positive S100 negative
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. Department of Pathology, Leiden University Medical Centre, Building I, L1-Q, P.O. Box 9600, 2300RC, Leiden, The Netherlands.	Virchows Arch. 2005 Feb;446(2):157-63. Epub 2004 Nov 3. Abstract quote   AIMS: To report the clinicopathological and immunohistochemical features and longer term biological behaviour of aggressive angiomyxoma, an uncommon mesenchymal neoplasm occurring predominantly in the pelvi-perineal region of adults. Using immunohistochemistry, possible overexpression of CDK4 and MDM2 was analysed, which might point to (cyto)genetic alteration(s) in chromosome region 12q13-15, an area reported to be altered in this tumour entity. METHODS AND RESULTS: Cases (n=11) of aggressive angiomyxoma were retrieved from the consultation files of the Comprehensive Cancer Centre of the Middle Netherlands (IKMN) panel for soft tissue tumours. Clinical and follow-up information were obtained, and immunohistochemical analysis was performed using antibodies directed against vimentin, cytokeratin AE1/AE3, desmin, alpha-smooth-muscle actin, CD34, S-100 protein, oestrogen receptors, CDK4 and MDM2. Five patients were female (age range 24-47 years; median 39 years), and six patients were male (age range 36-69 years; median 44.5 years). Of 11 cases, 10 arose in the pelvi-perineal area and 1 arose in the abdominal cavity in close relation to the bladder. Morphology was consistent with previous reports of this entity. Immunohistochemically, 8 of 11 cases were desmin positive (5 of 5 positive in females; 3 of 6 positive in males), 6 of 11 cases were positive for alpha-smooth-muscle actin, 5 of 11 cases were CD34 positive, 11 of 11 cases, irrespective of gender, were positive for oestrogen receptors and 3 of 11 cases were positive for cytokeratin AE1/AE3. Strong, diffuse nuclear positivity for CDK4 expression was present in all 6 cases tested, while only 1 of 11 cases tested for MDM2 showed weak focal positivity. Clinical follow-up in all cases (range 1-216 months; median 72 months) showed one local recurrence (9%) after 36 months. No metastases or tumour-related deaths were noted. CONCLUSIONS: The sex distribution of cases reported in this study was roughly equal, in contrast to previous reports emphasising the predominance of this tumour in females. Our study confirms the local aggressive nature of aggressive angiomyxoma, although our local recurrence rate is lower than previous reports (9% versus 36-72%); no metastases and/or disease-related patient deaths were documented. All cases arising in females were positive for desmin, while three of the six cases arising in males were negative for desmin, supporting previous findings and indicating that the lesion may be somewhat different in males. The strong diffuse positivity for CDK4 in all six cases tested goes some way in implicating CDK4, either directly or indirectly, in tumourigenesis. The negative immunostaining for MDM2 would argue against functional amplification of this gene.
ESTROGEN/ PROGESTERONE RECEPTORS
Aggressive angiomyxoma of pelvic parts exhibits oestrogen and progesterone receptor positivity. McCluggage WG, Patterson A, Maxwell P. Department of Pathology, Royal Group of Hospitals Trust, Belfast, Northern Ireland.	J Clin Pathol. 2000 Aug;53(8):603-5. Abstract quote   AIMS: Aggressive angiomyxoma of pelvic parts is a distinctive soft tissue tumour that chiefly involves the vulvar and perineal region of female patients. Several previous reports have demonstrated oestrogen receptor (ER) and/or progesterone receptor (PR) positivity in this neoplasm. The aim of this study was to confirm whether ER and/or PR positivity is present in aggressive angiomyxoma. We also wished to ascertain whether positivity may be found in the stromal cells of normal vulval skin and in other lesions at this site that can cause diagnostic confusion with aggressive angiomyxoma. METHODS: Five aggressive angiomyxomas in female patients and one involving male pelvic soft parts were stained immunohistochemically with antibodies against ER and PR. Other samples studied were normal vulval skin (n = 7), fibroepithelial polyps of vulva (n = 7), vulval smooth muscle neoplasms (n = 5), vulval nerve sheath tumours (n = 2), vaginal angiomyofibroblastoma (n = 1), and pelvic myxoma (n = 1). Nuclear staining was classified as negative, weak, moderate, or strong and the proportion of positively staining cells was categorised as 0, < 10%, 10-50%, or > 50%. RESULTS: All five cases of aggressive angiomyxoma in female patients were positive for ER (two with weak intensity involving < 10% of cells and three with moderate intensity involving 10-50% of cells) and four of five cases were strongly positive for PR in > 50% of cells. The other case was negative for PR. There was no staining with antibodies to ER or PR in the single male patient with aggressive angiomyxoma. Other samples exhibiting positivity of the stromal cells for either ER or PR were normal vulval skin (five of seven, ER; two of seven, PR), fibroepithelial polyps (four of seven, ER; five of seven, PR), smooth muscle neoplasms (three of five, ER; four of five, PR), nerve sheath tumours (one of two, ER; one of two, PR), angiomyofibroblastoma (one of one, ER; one of one, PR), and pelvic myxoma (one of one, PR). CONCLUSIONS: All cases of aggressive angiomyxoma of pelvic soft parts in female patients exhibited positivity for ER and/or PR. Because of its propensity to occur in female patients during the reproductive years, it is possible that aggressive angiomyxoma is a hormonally responsive neoplasm. However, dermal fibroblasts in normal vulval skin and stromal cells in a variety of vulval lesions can also be positive. ER or PR immunoreactivity cannot be used to distinguish aggressive angiomyxoma and its histological mimics.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
ANGIOFIBROMA
Cellular angiofibroma of the vulva. Lane JE, Walker AN, Mullis EN Jr, Etheridge JG. Department of Surgery, Mercer University School of Medicine, Medical Center of Southern Georgia, Macon, GA 31207-0001, USA.	Gynecol Oncol 2001 May;81(2):326-9 Abstract quote BACKGROUND: The cellular angiofibroma is a benign mesenchymal neoplasm that clinically and histologically must be distinguished from biologically more aggressive lesions. It typically arises in women of late reproductive age and lends itself to cure by complete local excision. A report of an unusual case in a postmenopausal patient is presented. CASE: A 77-year-old woman presented with a painless vulvar mass that slowly enlarged over 3 years. Past history included a hysterectomy and bilateral salpingo-oophorectomy followed by estrogen replacement therapy. Surgical excision of the mass was performed and there is no evidence of recurrence 1 year postoperatively. Histopathologic examination revealed an admixture of hyalinized blood vessels and loose cellular stroma characteristic of a cellular angiofibroma. Immunohistochemical studies revealed stromal cell immunoreactivity for vimentin and CD34 and nonreactivity for desmin, actin, and S100 protein. The nuclei of the stromal cells demonstrated strong reactivity for estrogen and progesterone receptors. CONCLUSION: Mesenchymal lesions of the vulva and perineum include both benign and malignant neoplasms. The cellular angiofibroma is benign; however, other lesions including the aggressive angiomyxoma must be excluded when arriving at that diagnosis. The role of long-term estrogen therapy in the genesis of this tumor awaits further analysis.
ANGIOMYO-FIBROBLASTOMA	Am J Clin Pathol 1997;107:36-44 <5 cm Perivascular cells with rounded, epithelioid, or plasmacytoid appearance
CERVICOVAGINAL MYOFIBROBLASTOMA
Superficial cervicovaginal myofibroblastoma: fourteen cases of a distinctive mesenchymal tumor arising from the specialized subepithelial stroma of the lower female genital tract. Laskin WB, Fetsch JF, Tavassoli FA. Department of Pathology, Northwestern University Medical School, Chicago, IL, USA.	Hum Pathol 2001 Jul;32(7):715-25 Abstract quote The clinicopathologic features and immunohistochemical profiles of 14 cases of a distinctive mesenchymal tumor that arises in the superficial lamina propria of the cervix and vagina and is histologically distinguishable from mesodermal (fibroepithelial) stromal polyp, including the cellular (pseudosarcomatous) variant, angiomyofibroblastoma, aggressive angiomyxoma, and other well-recognized lesions that occur in this location, are described. The lesions presented as a polypoid (n = 10) or nodular (n = 4) mass in the vagina (n = 12) or cervix (n = 2) of women ranging in age from 40 to 74 years (median, 58 years). The tumors were subepithelial in location, were well circumscribed, and ranged in size from 1 to 6.5 cm. (mean, 2.7 cm). Microscopically, the process was moderately to highly cellular and composed of relatively bland spindled and stellate-shaped mesenchymal cells embedded in a finely collagenous stroma that was punctuated by myxoid and edematous foci in 9 cases. The lesions characteristically had a multipatterned architecture with tumor cells focally assuming a lacelike/sievelike growth pattern in the more stroma-rich areas of the tumor and a vague fascicular growth pattern in the more cellular foci. Mitotic activity was minimal, and no atypical mitotic figures were identified. The tumors were immunoreactive (in decreasing order of relative strength) for vimentin (5 of 5 cases), estrogen (10 of 10 cases), and progesterone (10 of 10 cases) receptors, desmin (13 of 13 cases), CD34 (11 of 13 cases), alpha-smooth muscle actin (5 of 11 cases), and muscle-specific actin (2 of 8 cases). The desmin and CD34 antibodies highlighted the interconnecting, dendritic processes associated with many of the tumor cells. No immunoreactivity was detected for S100 protein, epithelial membrane antigen, or keratins. Follow-up data for 11 patients (range, 1 to 20 years; median, 4 years) showed no recurrence or metastasis after local excision. The term "superficial cervicovaginal myofibroblastoma" is proposed because it reflects the distinguishing features of this benign, relatively site-specific mesenchymal tumor. The process probably arises as a neoplastic proliferation of hormonally responsive mesenchymal cells native to the unique subepithelial stromal layer normally found through the endocervix and vulva of adult women.
MYXOMA, CELLULAR
Cellular myxoma of soft tissue: a clinicopathological study of 38 cases confirming indolent clinical behaviour. van Roggen JF, McMenamin ME, Fletcher CD. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.	Histopathology. 2001 Sep;39(3):287-97. Abstract quote   AIMS: To characterize the clinicopathological features and biological potential of a group of soft tissue lesions with morphology intermediate between intramuscular myxoma and low-grade myxofibrosarcoma. METHODS AND RESULTS: Thirty-eight lesions in 37 patients were retrieved from the authors' consultation files. Clinical and follow-up data were obtained and the lesions were also studied immunohistochemically. Tumours occurred in adults aged 25-83 years (mean 51.9 years) with a slight predominance in females. All cases, except two, were solitary. The extremities were preferentially involved (18 lower limb; nine upper limb), with seven lesions arising around the upper (2/7) and lower limb (5/7) girdles and four lesions occurring at other locations. Twenty-nine of 31 of the tumours, for which the depth was known, were situated deep to the superficial fascia, although only 19 were strictly intramuscular. Histologically these lesions were both more cellular and more vascular than intramuscular myxoma, while lacking the cytological pleomorphism, nuclear atypia and curvilinear vascular pattern characteristic of low-grade myxofibrosarcoma. CD34 positivity in lesional cells was identified in 17/30 (57%) cases, probably reflecting their fibroblastic nature. Staining for alpha-smooth muscle actin was focally positive in 3/30 (10%) cases, while desmin and S100 protein staining were consistently negative. Clinical follow-up data (available in 22 cases; median duration 30 months) demonstrate that these lesions behave in a benign fashion with only a small risk of local recurrence if not excised completely; in this study only two tumours recurred, both of which originally had been incompletely excised. None metastasized. CONCLUSIONS: The risk of recurrence in this group of lesions which we have designated 'cellular myxoma' appears to be low. Consequently simple complete local excision is most often adequate treatment. Longer follow-up (5-10 years or more) in a larger number of cases will be important in more definitively confirming the natural history of these lesions.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
Recurrence	Incomplete excision leads to recurrence in 30% of tumors, sometimes repeatedly
Metastasis	No reported cases
TREATMENT	Wide excision

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