Uterus Adenofibroma/Adenosarcoma Pathology

Updated: May 01, 2017
Author: Peggy S Sullivan, MD; Chief Editor: Ramya Masand, MD 


Adenosarcoma is a biphasic neoplasm composed of malignant stroma and benign epithelium,[1]  whereas adenofibroma is a biphasic neoplasm composed of benign stroma and benign epithelium. Adenofibromas are exceedingly rare, and there is a concern whether they truly exist or whether most cases are well-differentiated adenosarcomas.

See the image below.

Intraglandular polypoid projections characterize a Intraglandular polypoid projections characterize adenofibroma/adenosarcoma at low power (hematoxylin and eosin stain, x200).


Adenosarcoma occurs in females aged 15-90 years, with a median age at diagnosis of 58 years.[2, 3, 4, 5, 6, 7, 8, 9] Most patients diagnosed with adenosarcoma are postmenopausal, but one third are of reproductive age. Although almost all adenosarcomas occur in women, mesodermal adenosarcoma has been reported in a boy with persistent müllerian duct syndrome and, rarely, in the testis, seminal vesicle, and prostate.[10, 11, 12, 13, 14]

Adenosarcomas that arise in the cervix tend to occur at a younger age than those that arise in the uterine corpus,[15, 16, 17, 18] with an age range from 13 to 67 years (mean age, 37 years).

Adenofibroma is an uncommon neoplasm, comprising 5% of a large series of adenosarcomas/adenofibromas.[5] Patients diagnosed with adenofibroma range in age from 19 to 80 years[19] ; however, they are generally perimenopausal or postmenopausal, with a median age of 68 years.[8]



Adenosarcomas have been reported in women treated with tamoxifen[20, 21, 22] and after prior pelvic radiation.[4, 5] No association of adenosarcoma with obesity or hypertension has been reported.[2]

Occasional cases of adenofibroma have been associated with tamoxifen therapy.[23]

No known racial or other epidemiologic features associated with endometrial carcinoma have been linked to adenosarcomas.[24]



Approximately 90% of adenosarcomas arise in the uterine corpus, but cervical, vaginal, tubal, ovarian, and primary peritoneal adenosarcomas have also been reported.[16, 25, 26, 27] Rare tumors arise within the myometrium, presumably owing to adenomyosis,[5] and 5%-10% arise in the cervix.[6, 28] Multifocal tumors have been reported within the uterine corpus.[5] Rare cases of synchronous uterine and extrauterine adenosarcoma may represent a multicentric origin linked to endometriosis rather than metastatic disease. Adenofibromas may occur anywhere in the uterine corpus or cervix.


Clinical Features and Imaging

The most common clinical feature of adenosarcoma is abnormal vaginal bleeding, many times associated with an enlarged uterus, pelvic pain, and tissue protruding from the cervical os. In many cases, patients have a history of recurrent cervical or endometrial "polyps," which, upon retrospective review, are found to be adenosarcoma.[5] Most patients with cervical adenosarcomas present during the reproductive years with abnormal uterine bleeding that is initially misdiagnosed as benign endocervical polyps.

Adenofibromas have a clinical presentation similar to that of adenosarcomas.


Gross Findings

Adenosarcomas are typically polypoid masses ranging in size from 1cm to 17 cm, with an average maximum dimension of 5 cm. Occasionally, they grow as multiple papillary or polypoid masses.[5, 6] They may be either soft or firm. The cut surface is tan, brown, or gray with microcystic architecture and occasional foci of hemorrhage and necrosis (approximately 25% of cases).[24] The mass typically grows into the endometrial cavity, enlarging the uterus, and less commonly invades the myometrium.[5] Primary cervical adenosarcomas may be ectocervical or endocervical in location and range in size from 2 cm to 8 cm or more. A sarcoma botryoides appearance has been reported.[29]

Adenofibromas have gross findings that are similar to those of adenosarcoma. They range in size from 2 cm to 20 cm (median, 7 cm). They are lobulated, polypoid, broad-based masses that vary from soft to firm and fibrous in consistency. The cut surface is spongy or cystic with watery to mucoid fluid. The tissue is white or tan. Like adenosarcoma, they grow into the endometrial cavity and enlarge the uterus.[24]


Microscopic Findings

The classic adenosarcoma has a frondlike growth pattern: Thin papillae or broad polypoid fronds project into glands or from the surface of tumor, as shown below,[5, 8] closely resembling phyllodes tumor of the breast.

Intraglandular polypoid projections characterize a Intraglandular polypoid projections characterize adenofibroma/adenosarcoma at low power (hematoxylin and eosin stain, x200).

When the asymmetric growth of stroma is extreme, polypoid invaginations are produced. The glands are usually uniformly distributed, often cystic, irregularly contoured, or compressed into thin slits and scattered throughout a variably cellular stroma. The epithelium usually resembles proliferative endometrium. It is not unusual for the glandular component to be active, even when the adjacent endometrium is atrophic.

Endocervical (mucinous), tubal (ciliated), secretory endometrial, hobnail, metaplastic squamous (nonkeratinizing), or indifferent epithelium can also be seen, as well as mixed forms.

The epithelium typically appears benign or less commonly atypical (approximately one-third of cases), simulating complex hyperplasia or adenocarcinoma in situ. However, by definition, the epithelium is not malignant. It should be noted that small foci of adenocarcinoma have been reported and, in such cases, atypical hyperplasia or carcinoma was seen in the adjacent endometrium.[5, 7]

The stromal component is typically a low-grade sarcoma that contains varying amounts of fibrous tissue and smooth muscle.[30, 31] The stromal cells form a characteristic hypercellular collar or cuff (so-called "cambium layer") around the glands and clefts (see the image below); in other areas, they may be sparsely cellular or may be replaced by myxoid or hyalinized fibrous tissue. The stroma is generally homologous, resembling a low-grade endometrial stromal sarcoma, fibrosarcoma, or a combination of both.[5]

Periglandular cuffing (ie, increased stromal cellu Periglandular cuffing (ie, increased stromal cellularity around glands) is noted around cystic, cleftlike spaces or compressed glands (hematoxylin and eosin stain, x200).

Focal sex-cord–like elements are seen in a minority (approximately 5%) of tumors,[32] as well as foamy stromal cells resembling those seen in endometrial stromal sarcoma. Heterologous elements (seen in 10%-25% cases) include fat, cartilage, or rhabdomyoblasts. There is a variable degree of atypia, but it is generally mild to moderate and is limited to the foci of stromal condensation surrounding the glands and clefts. It is in these areas where mesenchymal mitotic figures are stated to be more than one per 10 high-powered fields (hpf)[5] but, generally, most neoplasms have four or more mitotic figures per 10 hpf.[6, 8] In many cases, the stromal component is largely bland-appearing, requiring a meticulous search for the sarcomatous component.

Sarcomatous overgrowth is diagnosed if a pure sarcomatous component comprises greater than 25% of the total tumor. It is seen in 10% of cases[4, 6, 32] and, generally, the purely sarcomatous areas show increased cellularity, higher nuclear grade, and more mitotic figures (see the first image below) compared to the adjacent adenosarcoma.[6, 30, 33] Heterologous elements such as rhabdomyosarcoma may be seen in (and limited to) these areas (see the second image below). Lymphatic and vascular space invasion is most often seen in areas of sarcomatous overgrowth.[6]

A higher-power image shows nuclear atypia and mito A higher-power image shows nuclear atypia and mitotic figures within the periglandular stroma (hematoxylin and eosin stain, x400).
The sarcomatous stroma shows rhabdomyoblastic diff The sarcomatous stroma shows rhabdomyoblastic differentiation in some cases (hematoxylin and eosin stain, x400).

Approximately 15% of all uterine corpus adenosarcomas are myoinvasive; deep myoinvasion occurs in less than 5% of cases.[5] The invasive border is usually well-circumscribed, but irregular tongues are seen occasionally. Rarely, myometrial vessel invasion is seen. Both benign glands and sarcomatous stroma are seen in areas of myometrial invasion. Recurrences, conversely, are usually a pure sarcoma (approximately 70%) or adenosarcoma (approximately 30%) and may be higher grade than the primary tumor. Rare cases may recur as carcinosarcoma[34] or may have heterologous elements not previously seen in the primary tumor.[5] Hematogenous metastases typically occur in the lung and almost always contain pure sarcomatous elements.[25]

Adenofibroma is a benign polypoid mass composed of broad papillary fronds projecting from the surface and into cystic spaces. Cleftlike spaces are often present. It is covered by epithelium that is most often endometrioid, ciliated, or nondescript columnar to cuboidal cells. Rarely, squamous metaplasia is seen. The epithelium can be stratified and hyperplastic; if so, an atypical polypoid adenomyoma should be considered.[35]

The benign stromal component is usually fibroblastic, sometimes with endometrial stromal cells, smooth muscle cells, or a mixture. Stromal atypia, mitotic activity, and periglandular cuffing should be absent or inconspicuous (see the image below).

Intraglandular polypoid projections characterize a Intraglandular polypoid projections characterize adenofibroma/adenosarcoma at low power (hematoxylin and eosin stain, x200).

Rare benign heterologous elements such as fat or skeletal muscle may be present.[36, 37] Adenofibromas are usually confined to the mucosa (endometrial or cervical) and do not invade the underlying myometrium or stroma, although two cases of myometrial invasion and myometrial vein involvement have been reported.[38] It is unresolved whether the definition of adenofibroma may be restricted to a limit of mitotic activity (no more than 2 per 10 hpf) or atypia (no more than mild). Some regard any mitotic activity as indicative of adenosarcoma.[5] Microscopic examination of the entire lesion is necessary to rule out the more common adenosarcoma; hence, a definitive diagnosis of adenofibroma may not be possible based on a biopsy or curettage specimen.



The epithelial component for adenosarcoma/adenofibroma is positive for broad-spectrum cytokeratins and epithelial membrane antigen. The stroma of adenosarcomas is often CD10-, estrogen receptor–, and progesterone receptor–positive, which may be lost in cases of sarcomatous overgrowth, high-grade sarcoma, or recurrence.[39, 40, 41] Variable staining for smooth muscle markers desmin and caldesmon is also seen in the stromal component.



A complex karyotype involving multiple chromosomes was identified by cytogenetic and molecular cytogenetic analysis of an adenosarcoma from a 15-year-old girl.[15] TP53 mutations are not common[4, 42] and, along with ATRX mutations and MYBL1 amplification, may be associated with stromal overgrowth. Frequent low-level amplification of MDM2 and CDK4 is also observed[43] and appears to be restricted to the mesenchymal component.[44] HER-2/neu appears to play a significant role in this disease.[42]


Tumor Spread and Staging

Patients with uterine adenosarcoma are staged according to the International Federation of Gynecology and Obstetrics (FIGO) (2009)[45] or American Joint Committee on Cancer (AJCC) tumor/node/metastasis (TNM) staging for adenosarcomas (2010).[46]  Most patients present at stage I at the time of diagnosis.[4, 5, 42] Occasional patients with sarcomatous overgrowth have pelvic lymph node metastases[6, 7] ; however, this is rare.[9] Hematogenous spread occurs in less than 5% of cases and is typically to the lung. Local vaginal or abdominopelvic recurrence occurs in approximately 25% of cases, often more than 5 years after hysterectomy.

Adenofibroma is a benign entity that is not invasive. Rare examples of endocervical wall invasion, myometrial invasion, or myometrial vessel involvement have been reported.[5]


Prognosis and Predictive Factors

Most patients are considered cured of adenosarcoma after simple hysterectomy[1] ; however, they require long-term follow-up, as recurrences generally occur more than 5 years later. Recurrences tend to occur in the pelvis, with distant metastases (eg, to the lung) following local recurrence.

Factors associated with recurrence and subsequent metastases include extrauterine extension at diagnosis, high-grade heterologous stroma, myometrial invasion (especially to the outer half of myometrium), lymphatic and vascular space invasion, and sarcomatous overgrowth. The overall recurrence rate is 15%-25% for tumors without stromal overgrowth and 45%-77%[47] for those with stromal overgrowth.

Uterine preservation surgery may be a potential option in patients with early-stage uterine adenosarcoma who wish to maintain their fertility; however, clinicians must have a detailed, thorough discussion with patients regarding the tumor recurrence risk.[48]

Approximately 10%-25% of patients with uterine adenosarcoma die of their disease. This figure rises to 54% in those whose tumors contain stromal overgrowth.[5, 6, 8, 33, 49]  A 2016 retrospective study (1998-2011) that evaluated the survival of 2205 women with müllerian adenosarcoma based on data from the National Cancer Data Base found that independent negative prognostic factors for overall survival included distant metastasis, positive surgical margin, older age, a higher composite comorbidity score, and adjuvant radiotherapy.[50]  Moreover, each 1-cm increase in uterine adenosarcoma tumor size was associated with an increased risk for death.[50]

A large 2010 study based on Surveillance, Epidemiology, and End Results (SEER) Program data showed a 63%-69% survival rate among women with myoinvasive disease and a survival of less than 50% among those with extrauterine disease.[9]  SEER data from a 2017 retrospective study (1973-2013) revealed that uterine adenosarcomas had the lowest incidence of lymph node metastasis among the three sarcoma subtypes evaluated (including endometrial stromal sarcoma and uterine leiomyosarcoma); however, the impact of lymph node metastasis on cause-specific survival (CSS) was similar among these subtypes (independently associated with a decreased CSS in all three tumor types).[51]

Of the few reported cases of primary cervical adenosarcomas, hysterectomy appears to be curative, possibly owing to the early detection of low-stage disease in most patients. Recurrences have been reported in 18%, wheras deaths due to disease occurred in 12%.[17, 18, 52] Similar to uterine corpus tumors, depth of invasion and sarcomatous overgrowth are adverse prognostic indicators.

Adenofibromas are benign neoplasms with little risk for recurrence once completely excised. No tumor-related deaths have been reported, and conservative therapy with repeated curettages may help preserve fertility. It should be noted that incomplete excision may result in local recurrences.[19]  Occasional tumors may superficially invade the myometrium, and invasion of the myometrial veins has also been described,[38] but metastases have not been reported. Occasional cases have been focally involved by adenocarcinoma, but the association is probably incidental.[53]


Differential Diagnosis

The following conditions should be considered in the differential diagnosis of uterine adenosarcomas and uterine adenofibromas:

  • Atypical polypoid adenomyoma

  • Endometrial Hyperplasia

  • Endometrial polyp

  • Polypoid endometriosis

  • Uterus Carcinosarcoma

  • Uterus Smooth Muscle

  • Uterus Stromal Tumors

  • Embryonal rhabdomyosarcoma