Re-thinking uterine fibroids in immunocompromised patients: adenomatoid tumors

Abstract

Background

Adenomatoid tumor (AT) is an ambiguous term used to describe benign mesothelial neoplasms, most often reported in organs of the reproductive system. Their neoplastic nature has been proven through the confirmation of pathogenic mutations in TRAF7. Several studies have proven an association between AToU and immunosuppression. Several groups have hypothesized immunosuppression causes an abnormal inflammatory state within mesothelial cells, increasing the likelihood of a selective activating mutations in TRAF7.

Case presentation

A 34 year old female patient with a history of systemic lupus erythematosus was seen in the Emergency Department due to abdominal pain. A diagnosis of uterine leiomyomatosis was made and she was surgically intervened. Macroscopically, several intramural and subserosal uterine nodules were identified. On microscopic examination, all of them except one corresponded to adenomatoid tumours. A somatic mutation in TRAF7 was identified.

Conclusions

Adenomatoid tumors have been associated with immunosuppression. A decrease in immunosurveillance may explain the association between adenomatoid tumours and immunosuppression. Confirming their neoplastic nature is crucial. Further studies are required to characterize the biological significance TRAF7 has in adenomatoid tumours and their association to immunocompromised states.

Background

Adenomatoid tumor (AT) is an ambiguous term used to describe benign mesothelial neoplasms found mainly in organs of the reproductive system. Any organ covered by mesothelium may develop it, as it has also been described in pleura, peritoneum, pericardium and adrenal glands (Chen et al. 2017). In women, it commonly involves the fallopian tubes and the uterus (Chen et al. 2017; Hafiz et al. 2021; Quick and Solomon 2021).

The term was coined by Golden and Ash in 1945, a term they considered neutral and thus correctly described a tumor of unknown origin. It was regarded as a neoplasm of lymphatic vessels (lymphangioma), a mixed tumor of lymphatic vessels and smooth muscle cells (leiomyoma and lymphangioma), a benign tumor of gland-like structures (adenoma) and even a low-grade adenocarcinoma (Hafiz et al. 2021).

With the help of electron microscopy and immunohistochemistry, the origin of the tumour was identified as being from mesothelial cells. ATs express mesothelial antigens (cytokeratin, calretinin) and lack endothelial antigens (factor VIII, Ulex europaeus I-lectin, CD34, CD31) (Hafiz et al. 2021; Quick and Solomon 2021; Stephenson and Mills 1986; Karpathiou et al. 2020; Contreras et al. 2009; Kawamura et al. 2000). Their neoplastic nature was confirmed with the finding of specific mutations in a gene member of the TNF receptor-associated factors, TRAF7 (Karpathiou et al. 2020; Itami et al. 2021; Zhu et al. 2018).

Adenomatoid tumors of the uterus (AToU) tend to occur in women of reproductive age. The detection rate in hysterectomy specimens is of 1–5% (Quick and Solomon 2021; Karpathiou et al. 2020). They are usually asymptomatic; however, they may be associated with vaginal bleeding, menorrhagia, and abdominal masses. In hysterectomy specimens, they are incidental findings, usually associated with other lesions of the genital tract, including, leiomyomas, adenomyosis, endometrial and ovarian cancer. Imaging features are non-specific. AToU are often misdiagnosed as leiomyomas (Hong et al. 2009; Mitsumori et al. 2000; Wakita et al. 2020). Most of the cases reported in the literature describe AToU with a cystic component, which may render them more conspicuous (Yorita et al. 2016; Kim et al. 2000; Manucha et al. 2015; Harada et al. 2012). Nevertheless, MRI may be helpful in the differential diagnosis (Meng et al. 2015).

Macroscopically, most AToU are solitary, well circumscribed lesions of small size located within the walls of the uterus. They are usually subserosal, found at the fundus and cornual region (Tiltman 1980; Quigley and Hart 1981). Multiple tumors are rare, with a frequency that ranges from 2.8 to 20% of cases (Quick and Solomon 2021; Nakayama et al. 2013; Young and Taylor 1967). Large lesions usually harbor a cystic component (Bisset et al. 1988; Nogales et al. 2001; Rosa et al. 1992). The cut surface appears firm, homogeneous, with a white to tan color and a whorled appearance. Histologically they are composed of solid, tubular, cord-like, nested, microcystic, trabecular or spindled cell morphology. The glandular cavities are composed of flat, cuboidal, or columnar cells with abundant, acidophilic or lightly stained cytoplasm (Chen et al. 2017; Quick and Solomon 2021; Karpathiou et al. 2020).

A recent finding is the association of AToU and immunosuppression. Though previous articles had reported ATs in immunosuppressed patients, none demonstrated a clear association, and they considered ATs fortuitous findings (Angeles-Angeles et al. 1997). The changing prevalence of immunocompromised states might explain the growing interest in proving the association. Several groups have hypothesized immunosuppression causes an abnormal inflammatory state within mesothelial cells, increasing the likelihood of selective activating mutations in TRAF7 (Itami et al. 2021; Goode et al. 2018).

We present here a case of a female patient with a history of immunosuppression who underwent a simple hysterectomy as a treatment for uterine leiomyomas. Pathological examination revealed multiple ATs, confirmed through immunohistochemistry and molecular pathology.

Case presentation

A 34 year old female patient with a history of systemic lupus erythematosus (diagnosed in 2011), lupus valvulitis and chronic kidney disease (KDIGO V), was seen in the Emergency Department due to an intermittent, periumbilical abdominal pain with irradiation to the pubis. At the time, she was receiving prednisolone, nebivolol, amlodipine, folic acid, calcitriol, and erythropoietin. A transvaginal ultrasound was made, which reported uterine nodules. Blood tests showed a beta-hCG of 5.41 mUI/mL. After administration of an anticholinergic (butylscopolamine), she was scheduled for a gynecological evaluation. She reported a regular cycle, with episodes of menorrhagia and dysmenorrhea, which had decreased after a recent dose of medroxyprogesterone. Her complete blood count showed a hemoglobin of 9.1 g/dl and a hematocrit of 27.3%. The CT scan showed several tumors within the anterior and posterior wall, the largest measuring 5 × 5 cm and 4 × 4.2 cm respectively. Both tumors had grown when compared to a pelvic ultrasound and CT scan (Fig. 1). The MRI showed similar characteristics. CA 125 levels were within range (15.4 IU/ml). The patient underwent a simple hysterectomy with minimal bleeding (50 ml). On follow-up, the patient has had an optimal evolution.

Fig. 1

Radiological findings: a-b A abdomino-pelvic CT scan taken 4 years before, evidenced three ovoid, hypodense uterine masses (two shown here, white arrows), with ill-defined borders, the largest measuring 2.5 × 1.9 cm (without contrast; axial and coronal sections). c-d The recent abdominopelvic CT scan showed an increase in the size and number of the uterine masses, the largest measuring 5 × 5 cm; some with a hypodense center suggesting necrosis (asterisk) (venous phase; axial and coronal sections)

On macroscopic evaluation, the uterus was of 4 × 5x6 cm and 140 gr of weight, with an irregular contour, and a homogenous pink hue (Fig. 2). Three subserosal tumors were identified, one in the anterior wall (1 cm in diameter) and two in the posterior wall (largest one, of 4.5 cm in diameter, smaller one 8 mm in diameter), as well as several intramural at the corpus, the largest of 2 cm in diameter. On cut-section, the uterine cavity measured 8 × 3 mm, the uterine wall measured 2 cm in its thickest dimension. The tumors were well-circumscribed, non-encapsulated, with a solid homogeneous cut-surface, a light brown hue and a rubbery appearance. No necrosis was identified.

Fig. 2

On macroscopic examination, a) the uterus is deformed by several tumors located in the anterior and posterior walls. b The posterior surface shows papillary projections on the serosal surface covering the tumor. c Upon section, there are three solid tumors within the myometrium, the largest showing a nodular surface, each of the nodules with a yellowish whorled appearance, similar to the rest of the tumors within the corpus

On microscopic examination, three of the tumors had a mixture of slit-like and tubular structures, alternating with smooth muscle fibers (Fig. 3). The pseudovascular channels were lined by a flat epithelium, with a bland cytology. Immunohistochemistry analysis for mesothelial antigens were positive (Fig. 3). A submucosal leiomyoma was also identified.

Fig. 3

On microscopic examination of the largest lesion, a the adenomatoid tumor is composed of infiltrating pseudovascular channels that alternate with smooth muscle fibers (H&E, 10x). b Some areas showed a mixture of pseudovascular channels, which were lined by a flat epithelia and had an empty lumen, and cords of cells with abundant, vacuolated cytoplasm and oval nuclei (H&E, 20x). The immunohistochemistry assay showed positivity for c) calretinin, d) CK and e) D2-40, and f) negativity to actin (10x)

Furthermore, mutations in the WD40 repeat region of TRAF7 gene were sought using Sanger sequencing (see Supplementary material & methods) (Itami et al. 2021). A somatic point mutation was identified in exon 18, c.1681A > C (Fig. 4). As described in the literature, the mutation peak is low, but it was identified in repeated assays (Goode et al. 2018; Tamura et al. 2018).

Fig. 4

Electropherogram representation of the Sanger sequencing of mutation S561R: a-b) histological sections of the tumor (largest in size) and normal tissue from where DNA was extracted; c-d) show the DNA electropherogram of exon 18 where a single nucleotide mutation was identified (c.1681A > C)

Discussion and conclusions

An exhaustive review of the literature was done to identify the characteristics of AToU in patients with history of immunosuppression. Search was done specifically for case reports and case series adenomatoid tumors in the uterus, using the following key terms: “multiple”, “diffuse” and “adenomatoid tumor of uterus”, using databases such as PUBMED and Scielo, including only indexed journals with articles written in English, Spanish, French and German.

The terms multiple and diffuse were used interchangeably in most of the literature found and thus were both considered key terms. Immunosuppression was not considered as a key term as few reports and series describe to detail the clinical history. Cases with multifocal lesions and solitary tumors were excluded, as multifocal cases considered AT in uterus, ovary, Fallopian tubes and fimbria. Cases without mention of the number of lesions were considered solitary tumors and therefore excluded. Twenty-two articles were retrieved from a total of 103, between the years 1950 and 2021 (Table 1). From these articles, 35 cases of multiple AToU were identified (Chen et al. 2017; Hafiz et al. 2021; Konishi et al. 1984; Kalidindi and Odejinmi 2010; Tiltman 1980; Nakayama et al. 2013; Young and Taylor 1967; Nogales et al. 2001; Goode et al. 2018; Tamura et al. 2018; Lerias et al. 2021; Ranjan et al. 2015; Duval et al. 2008; Saran et al. 2007; Amre et al. 2005; Cserni et al. 2003; Chee et al. 2003; Bulent Tiras et al. 2000; Livingston et al. 1992; Srigley and Colgan 1988; Luchs et al. 2000; Stefano et al. 1998). The clinical elements found in common are also shared with the case presented above.

Table 1 Articles presenting cases of multiple adenomatoid tumors of the uterus

The case series and case reports included women from age 25 to 60 years, with a mean of 41. Abnormalities in menstrual bleeding occurred in 62% of the cases (20 out of 32), which was considered the main reason for the surgical treatment. Most of them had a pre-surgical diagnosis of fibroids or a uterine mass compatible with uterine fibroids. Hysterectomy was the most frequent surgical procedure (24 out of 35 cases), with the rest undergoing enucleation. Secondary immunodeficiency due to immunosuppressive treatment for autoimmune diseases or solid organ transplantation was identified in 12 cases (37.5%) (Hafiz et al. 2021; Goode et al. 2018; Tamura et al. 2018; Lerias et al. 2021; Duval et al. 2008; Cserni et al. 2003; Chee et al. 2003; Bulent Tiras et al. 2000; Livingston et al. 1992). The rest had either no history of immunosuppressive treatment or no clinical information of the sort was provided.

In the cases where the number of tumors was reported, the average number calculated was of 3 tumors. The average size of each was of 3.77 cm, considering the largest size reported in the revised articles (diameter). The location of the tumors varied; however, an intramural location was the most frequent location (10 out of 35 cases), though our case presented intramural and subserosal. The histological pattern that predominated varied as well: about a third (10 out of 35) presented mixed patterns of which the combination of adenoid and angiomatoid patterns were the most frequent. Likewise, the second most frequent pattern was the cystic pattern alone (7 out of 35 cases). Cases with only adenomatoid, angiomatoid or solid patterns were less frequent. Immunohistochemistry assays were used in most of the cases. The preferred biomarker being pan-cytokeratin. Other markers used were D2-40, high molecular weight cytokeratins and calretinin. All the cases combined mesothelial antigens with endothelial antigens for differential diagnosis.

A characteristic of AToU is their morphological heterogeneity (Contreras et al. 2009; Quigley and Hart 1981; Canedo-Patzi et al. 2006). Morphological classifications have been proposed but none have been unified. In 1950, Lee et al. described three patterns: a) a plexiform pattern, which contains mostly cords of cuboidal cells; b) a canalicular pattern, which consists of slit-like structures lined by flat cells and c) a tubular pattern, which are lined by cuboidal cells (Tiltman 1980). Several years later, Quigley and Hart described four types: a) the adenoid type, which presented gland-like structures; b) the angiomatoid type, characterized by pseudovascular channels; c) the cystic type with large cavities replacing most of the tumor and d) the solid type, with cells arranged in cords and nests (Quigley and Hart 1981).

Parallel to our case, most of the cases revised presented two patterns of growth, the tubulo-canalicular or angiomatoid-adenoid patterns being the most frequent combinations. In their study, Quigley and Hart found these patterns did not correlate with the age of the patient, the phase of the endometrium, nor the size of the neoplasm. In the same line, our review showed that the microscopic pattern does not correlate with the clinical presentation nor the macroscopical characteristics, specifically the focality and number of ATs.

Interestingly, since first described, AToU are asymptomatic. However, most of the reports where ATs are incidental findings describe a single tumor. Considering our case and our review of multiple AToU, bleeding is a common sign, which may be related to number and size of the tumors.

We found immunosuppression in 13 cases of multiple AoT. The frequency of immunosuppression reported in the literature varies from 25 to 58%, which coincides with the calculated frequency within a population of multiple AToU (Karpathiou et al. 2020; Tamura et al. 2018; Mizutani et al. 2016). Considering the frequency of immunosuppression in multiple AToU (37%) to the overall frequency of multiple AToU (35 out of 242 cases, 14.46%), the immunological state does not seem to determine the number of lesions. Only a third of the multiple AToUs were associated with immunosuppression. One would expect an association of immunocompromise to all 14.46% cases revised (35 out of 242). Nevertheless, a reporting and a sampling bias must be considered. Taking this into consideration, identifying clonality in AToU becomes significant as it elucidates the neoplastic nature of the tumor. We sought mutations in TRAF7, which have been reported specifically in the WD-40 repeat region (Itami et al. 2021).

TRAF7 is a gene encoding a protein belonging to the family of TNF receptor-associated factors. Unlike the rest of the members of the TRAF family, it lacks a TRAF-C (also known as MATH) homology domain, having instead a WD40 repeat domain (Zhu et al. 2018). The TRAF domain is located at the C-terminus and contains a TRAF-N coiled-coil domain and a conserved TRAF-C domain (Soni et al. 2007). It allows protein–protein interactions with factors like NF-κB, MAPKs and IRFs (Zapata et al. 2007). Though TRAF7 lacks the MATH domain, the remaining TRAF-N seems sufficient for protein–protein interaction. There is data showing TRAF7 promotes ubiquitination and allows activation of NF-κB (Goode et al. 2018; Zotti et al. 2011). Mutations identified in ATs are mostly missense mutations and occur more frequently in the WD40 repeats region of the protein, in six specific amino acids, including S561R. These mutations are thus considered hotspots (Zhu et al. 2018). The mutation identified (c.1681A > C) has not been previously described in the literature nor in databases, including 1000G nor gnomAD (Goode et al. 2018; Tamura et al. 2018).

Considering the published data thus far, further studies are needed to characterize mutations in TRAF7, determine their significance in the development of AToU and identify promoters, not only in immunosuppressed patients but also in the general population. Indeed, adenomatoid tumors found in immunosuppressed patients could be another example of the role our immune system plays in clonal evolution.

Conclusion

Adenomatoid tumours of the uterus are infrequent. They are usually asymptomatic but are associated with other pathologies of the uterus. Most are incidental findings and are frequently misdiagnosed as uterine fibroids. Multiplicity is also infrequent but tends to be more common in patients with immunodeficiency. They present microscopically with a mixed pattern of growth. Mutations in the WD40 region of the gene TRAF7 confirm their neoplastic nature. Our case includes a mutation not previously described in AToU, TRAF7 c.1681A > C.