Adenomatoid Tumors of the Uterus: An Analysis of 60 Cases

Francisco F. Nogales, M.D., Mara Alejandra Isaac, M.D., David Hardisson, M.D.,Luisanna Bosincu, M.D., Jos Palacios, M.D., Jaume Ordi, M.D., Eladio Mendoza, M.D.,

Flix Manzarbeitia, M.D., Helena Olivera, M.D., Francisco OValle, M.D., Maja Krasevic, M.D., andManuel Mrquez, M.D.

Summary: Sixty cases of uterine adenomatoid tumors (ATs) are reported. All exceptfour were incidental findings in hysterectomy specimens, three of these being discov-ered preoperatively as large multicystic tumors. ATs were classified into two distinc-tive macroscopic patterns: small, solid tumors and large, cystic ones. The 56 small,solid ATs ranged from 0.2 to 3.5 cm, (average 2.1 cm); 48 were nodular and 8 diffuse.The four large, cystic tumors ranged from 7 to 10 cm. Inflammation occurred in 65%of the tumors, and a smooth muscle reaction, identified by an increased Ki-67 index,was present in most cases. Both types were histologically similar except for thepresence of short papillae in cystic tumors, which also showed serosal involvement.Both were immunoreactive for cytokeratins, calretinin, HMBE-1, and vimentin. Es-trogen and progesterone nuclear receptors and EMA were negative. These tumorsrepresent a spectrum ranging from small and solid to large and cystic ATs in the femalegenital tract, whereas outside the genital tract they are morphologically similar tomulticystic mesothelioma. Although a reactive origin for ATs often seems plausible,especially when inflammation is present, their neoplastic nature should not be ignored.Key Words: Adenomatoid tumorUterusMesotheliomaMulticysticImmuno-histochemistry.

Adenomatoid tumors (ATs) are specialized benignmesothelial tumors (13) preferentially found in thegenital systems of both males and females and onlyrarely reported in other sites, such as the adrenal gland(4) and peritoneum (5). In the female genital system theyare found in the fallopian tube, uterus, and ovarian hilus(6,7). With respect to uterine ATs, most publicationshave reported isolated cases, although some have beenshort series (79). This collaborative study reports thelargest number of ATs to date and provides a histologicaland immunohistochemical insight into these tumours.

MATERIALS AND METHODS

Fifty cases of uterine ATs were collected from thefiles of the hospitals involved in this study and 10 casesfrom the consultation files of one of us (F.F.N.). Basicclinical and pathological data as well as paraffin blockswere available. The follow-up for patients with largecystic tumors ranged from 4 to 12 years. Routine immu-nohistochemistry was performed in all cases using thefollowing antibodies: cytokeratins (CAM 5.2 clone)(Becton Dickinson, San Jose, CA), thrombomodulin(1009 clone), mesothelial antigen (HMBE-1 clone), Ki-67 (MIB-1 clone), epithelial antigen (Ber-EP4 clone) (allfrom Dako, Glostrup, Denmark), polyclonal calretinin,epithelial membrane antigen (EMA, ZCE 113 clone),vimentin (V9 clone), estrogen (6F11 clone) and proges-terone (1A6 clone) receptors (all from Master Diagnos-tica, Granada, Spain), and inhibin A (RI clone) (Serotec,Oxford, UK).

From the Departments of Pathology, University Hospital (F.F.N.,M.A.I., F.O.), Granada, Spain; University Hospital La Paz (D.H., J.P.),Madrid, Spain; Virgen del Rocio Hospital (E.M.), Sevilla, Spain; Hos-pital Clinic (J.O., M.M.), Barcelona, Spain; Fundacin Jimenez Daz(F.M.), Madrid, Spain; Condes Castro Hospital (H.O.), Guimaraes,Portugal; University Hospital (L.B.), Sassari, Sardinia, Italy; and Medi-cal Faculty of Rijeka (M.K.), Croatia.

Address correspondence and reprint requests to F. F. Nogales, M.D.,Departamento de Anatoma Patolgica, Facultad de Medicina, 18012Granada, Spain.

International Journal of Gynecological Pathology21:3440, Lippincott Williams & Wilkins, Baltimore 2001 International Society of Gynecological Pathologists

34

RESULTS

Clinical DataThe youngest patient was 28 and the oldest 65 years

of age, the average age being 45 years. All except fourwere incidental findings in hysterectomy specimens usu-ally performed for uterine leiomyomas (60%), pelvicpain (15%), and metrorrhagia (20%). In only three in-stances were large multicystic tumors preoperatively di-agnosed by ultrasonography either as uterine (one case)or as adnexal solid masses with cystic changes. All thetumors behaved in a benign fashion with no subsequentcomplications.

PathologyAll the ATs were single, except for one case where

two independent tumors were found. They were situatedin the immediate subserosal areas in 60% of cases, andthe remaining were found in various intramural loca-tions, involving the subendometrial myometrium in onlyone case. Subdivision into various histopathologic pat-terns was not attempted, classification being simplifiedinto two distinctive macroscopic patterns: small, solidtumors and large, cystic ones.

Small, solid tumorsFifty-six of these tumors were studied and ranged

from 0.2 to 3.5 cm in size, with an average of 2.1 cm, andconsisted of white-grey, nodular, nonencapsulated neo-

plasms in 48 cases. In the remaining eight cases, thetumors were neither nodular nor macroscopically evidentand were found in routine sections of the myometrium inthe vicinity of coexistent leiomyomas. The tumor borderswith the surrounding myometrium were not as sharplydefined as in leiomyomas (Fig. 1). On histologic exami-nation, the tumors consisted of complex slit-like, tubularor cystic branching spaces situated between fascicles ofsmooth muscle cells without a surrounding fibrousstroma (Fig. 2A). They were lined by eosinophilic cu-boidal or flattened cells; occasionally, nests of epitheli-oid or squamoid cells were present. A constant feature inthe lining cells was a hairy, basophilic apical surface

FIG. 1. Nodular, subserous adenomatoid tumor showing border withsurrounding myometrium that is less distinct than that of a typicalleiomyoma.

FIG. 2. (A) Tubular, mildly dilated adenomatoid spaces amongsmooth muscle fibers. Scattered lymphocytes are present. (B) Highermagnification of a tubular space showing cuboidal, eosinophilic cellswith extensive hairy apices.

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(Fig. 2B) corresponding to the specialized, bushy micro-villi observed on electron microscopy (1,1012). Innodular tumors, the growth pattern of the tubular branch-ing spaces was best seen at low-power examination of acytokeratin-stained slide and consisted of an organizednodular, concentrically arranged, targetoid structures in22% of cases (Fig. 3) and randomly oriented tubules in60% of cases. In these patterns, the surrounding andintervening smooth muscle fascicles seemed to react in aproliferative fashion as demonstrated by a 5% (Ki-67)proliferation index (PI) that was invariably higher thanthe surrounding uninvolved myometrium. In the caseswhere the AT was not nodular, it involved the myome-trium in a diffuse manner without an apparent prolifera-tive reaction within the myometrium.

Papilla, atypia, and mitoses were not found in thesmall solid tumors. The Ki-67 index of mesothelial cellswas

papillae were noted throughout most of the tumor in twocases (Fig. 8), and numerous intraluminal foam cellswere present in another tumor.

In both types of tumors, associated lesions weremainly coexistent uterine leiomyomas (60%) and endo-metrial carcinomas of endometrioid (two cases) and clearcell types (one case). No associated ATs were found inany other location in the female genital tract.

ImmunohistochemistryBoth types of tumors revealed identical immunohisto-

chemical features with the cells lining the branching andcystic spaces showing consistently strong positivity tolow molecular weight cytokeratins (CAM 5.2), calreti-nin, and the mesothelial antigen, HMBE-1, with less in-tense staining for vimentin. Focal weak positivity wasoccasionally noted (2/60) to either thrombomodulin orBer-EP4. Estrogen and progesterone nuclear receptors,inhibin, and EMA were consistently negative.

DISCUSSION

In the past, a major argument against a mesothelialorigin of ATs was the fact that they are most often foundin the genital tract organs. However, their specializedmesothelial identity has been clearly established in vari-ous ultrastructural and immunohistochemical studies(1,1012), and cases have been reported in the perito-neum, which would further support this origin (5). Inthe female genital tract, ATs occur, in order of fre-quency, in the uterus, tube, and ovarian hilus, whereasin the male they are found in the epididymis, spermatic

cord, tunica albuginea, prostate, and ejaculatory duct.Apart from their typical location in genital areas, ATshave also been reported in the adrenal gland (4). It wouldseem that the common denominator of these locations isthat all these organs have a common embryological ori-gin that is a celomic thickening, the so-called steroidalcrest, and are thus influenced by different steroid hor-mones. For these reasons, ATs could be expected tohave a special susceptibility to hormonal stimulation,which in turn may be responsible for their specializedmesothelial morphology. However, no estrogen or pro-gesterone receptors have been identified in the mesothe-lial cells of ATs, something that would have supportedthis hypothesis. The absence of receptors is analogousto the pattern found in normal peritoneum and othermesotheliomas (13).

The true incidence of these tumors is unknown, be-cause they are almost always merely incidental findingsin hysterectomy specimens from adult women. Further-more, they are frequently mistaken macroscopically for

FIG. 6. Cystic protrusion into the serosal surface of adenomatoidtumor.

FIG. 5. Fragment of large cystic tumor in myometrium. Note exten-sive cystic change and spongy appearance.

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leiomyomas, with which they are associated in a highproportion of cases (60% in this study). It is reasonableto expect that they would be found much more frequentlyif thorough macroscopic analysis and sampling were per-formed on a routine basis.

Macroscopically, they appear most often as nodularformations with ill-defined margins with the surroundingmyometrium, an observation that helps differentiatethem from leiomyomas, which are much more clearlydelineated. Only a small proportion of cases (15% in thepresent study) were not identified macroscopically, be-cause they diffusely involved the myometrial wall(14,15) and lacked a nodular arrangement. Multiplicityor multifocality is unusual (15), and on rare occasionsATs may involve the superficial myometrium, as it oc-curred in one of our cases, and eventually tumor may bepresent in endometrial curettings (16).

The nodular appearance of ATs corresponds micro-scopically to well-outlined nodular proliferation ofsmooth muscle fascicles populated by a concentric,target-like or diffuse proliferation of adenomatoid tu-bules. It would seem that the mesothelial cells induce a

reactive proliferation of muscle. This biphasic appear-ance has even given rise to naming these tumors me-somyomas (17), a terminology that may be misleading,because the smooth muscle proliferation is only a reac-tive one. This fact is supported by the demonstration inthe present study of higher proliferation indices in thereactive muscle cells than in those in the surroundingnormal myometrium. In contrast, the neoplastic cells ofATs have a much lower proliferation index than normalmyometrium.

Identification of adenomatoid tubules is often difficultand may be overlooked, because they appear only asempty spaces within the myometrium. However, whenimmunohistochemistry is performed the lining of thesestructures becomes evident, especially when cytokeratinsor mesothelial markers are used. In this study we foundan invariably intense positivity to low molecular weightcytokeratins and two consistent mesothelial markers, cal-retinin and HMBE-1. Less intense coexpression of vi-mentin and only rare and occasional positivity to theepithelial antigen Ber-EP4 were found. EMA was con-sistently negative and thrombomodulin, a protein fre-

FIG. 7. Numerous cystically dilated spaces dissecting the myome-trium.

FIG. 8. Short coarse papillae are found in a labyrinthine space.

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quently positive in mesothelial tumors, was equallynegative in this study. This staining pattern points clearlytoward the mesothelial identity of the tumors. In a recentpaper studying these markers in mesothelial tumors (18),the combination of cytokeratins and calretinin proved tohave high sensitivity and specificity in identifying thetumors, including sarcomatoid mesothelioma.

The pathogenesis of these tumors is by no means cer-tain. Their usual subserosal position would suggest anorigin from the uterine peritoneum. Alternatively, it hasbeen speculated that the mesothelial component mayoriginate from muscle, because most tumors are intra-mural (9). Others have suggested that these cells mayoriginate from a precursor of both mesothelial andmuscle cells (19).

An interesting finding in ATs is the frequent presenceof inflammation. The report of Youngs and Taylor (6)documented it in 80% of cases. In our material, promi-nent chronic inflammation, even with lymphoid follicles,was present in more than 50% of cases and a lesserdegree of inflammation in a further 15%, consistent withthe fact that some lesions of mesothelial origin may havea reactive origin. Indeed, it has been proposed that somemulticystic mesotheliomas (20), an entity closely relatedto ATs, may have a posttraumatic or inflammatory originand thus, the designation multilocular peritoneal inclu-sion cyst has been proposed to stress their reactive ratherthan neoplastic character (21).

Large cystic ATs, like the four reported here, are ex-tremely rare (6,22,23) and have a substantially differentclinicopathologic profile from the usual, small ATs, be-cause they are detectable masses ranging from 7 to 11 cmin maximal dimension and are frequently confused withleiomyoma or adnexal masses due to their cystic ultra-sonographic appearance. They can be considered giantATs, because they usually have noncystic, typical ade-nomatoid areas. Different authors (8,22,24) have sug-gested their taxonomic kinship with multicystic meso-thelioma due to their close morphologic similarity. Theselarge cystic patterns may show further similarities withother abdominal mesothelial proliferative entities (mul-ticystic mesothelioma or multilocular peritoneal inclu-sion cysts), such as protrusion into the pelvic cavity asexternal multicystic grape-like lesions and formation ofpapillae. The latter, however, differ from those of meso-thelioma, because they are scarce and coarsely config-ured. Cystic ATs are invariably benign without any sub-sequent recurrences.

It could be said that there is a spectrum ranging fromsmall and solid to large and cystic ATs in the femalegenital tract, whereas outside the genital tract they aremorphologically similar to multicystic mesothelioma.

Although the presence of inflammatory features wouldfavor a reparative, reactive process, it would be difficultto exclude a neoplastic phenomenon.

The differential diagnosis is not usually complicatedbecause ATs are easily recognizable. However, macro-scopically large cystic tumors may resemble a lymphan-gioma (25) and occasionally a metastatic adenocarci-noma may be suspected on microscopic examination.The latter can be ruled out because the cells do not showany atypia and have an easily identifiable specializedapical brush border. It has been pointed out that Ber-EP4,an epithelial marker, can be occasionally positive in ATs(26), but this finding was exceedingly rare in the presentstudy.

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