histogenesis of lipomatous component in uterine lipoleiomyomas · menopausal, two were...

INTRODUCTION

Uterine lipoleiomyoma is a rare mesency-

ABSTRACT

Uterine neoplasms composed of an admixture of smoothmuscle and adipose tissue are rare and have been desig-nated as lipoleiomyomas. The origin of this tumor is stillcontroversial and it has not been sufficiently studied.The aim of our study was to investigate the immunohis-tochemical phenotype of fat cells in uterine lipoleiomyo-mas so as to clarify their origin. Archived tissue samp-les of 10 uterine lipoleiomyomas were selected andanalyzed immunohistochemically for vimentin, desmin,and HMB-45 expression. The patients ranged from 31to 63 years of age (mean age 53.5±9.9). Seven tumorswhich affected the uterine corpus, showed intramurallocation; while two cases were subserosal, and one wasin the cervix. All tumors were constituted by irregularbundles of smooth cells and mature large adipose cells.The amount of adipose component varied from 5 to95% of the tumor mass. Cytological atypia and necrosiswere not seen. Immunohistochemical investigations re-vealed obvious reactivity to vimentin and desmin in pe-rivascular immature mesencyhmal cells and tumoralsmooth muscle cells. Adipose cells in the tumors de-monstrated uniform vimentin expression and inconsis-tent desmin immunoreactivity. All adipose cells werenegative for HMB-45 antigen. However, HMB-45 anti-gen was weakly positive in spindle shaped tumor cells oftwo cases. In our study, the immunohistochemical fin-dings suggest a complex histogenesis for these tumors,which may arise from perivascular immature mesency-hmal cells or direct transformation of smooth musclecells into adipocytes by means of progressive intracellu-lar storage of lipids.

Key words: Female genital tract, histogenesis, lipole-iomyoma

ÖZET

Düz kas ve ya¤ dokusundan oluflan uterus tümörleri li-poleiomiyom olarak adland›r›l›r ve nadiren görülürler.Bu tümörlerin kökeni hala tam olarak anlafl›lama-m›flt›r. Bu konuda az say›da aç›klay›c› çal›flma vard›r.Bu çal›flman›n amac› uterus lipoleiomiyomlar›ndaki ya¤hücrelerinin fenotiplerini immünhistokimyasal olarakbelirlemek ve kökenlerini tan›mlamakt›r. Arflivimizdebulunan 10 uterus lipoleiomiyomuna ait doku örne¤içal›flmaya al›nd› ve vimentin, desmin ve HMB-45 eks-presyonu aç›s›ndan immünhistokimyasal olarak ince-lendi. Çal›flmaya al›nan hastalar›n yafllar› 31-63 yaflaras›nda idi (Yafl ortalamas›: 53,5±9,9 y›l). Tümörlerinyedisi uterus korpusunda ve intramural yerleflimli idi.‹ki olgu subserozal ve bir olgu servikal yerleflim göster-mekteydi. ‹ncelemeye al›nan tüm tümör örnekleri dü-zensiz düz kas lifleri ve büyük matür ya¤ hücreleri içer-mekteydi. Tümörlerdeki matür ya¤ dokusu oran› %5-95 aras›nda de¤iflmekteydi. Örneklerde sitolojik atipive nekroz izlenmedi. Çal›flmam›zda yapt›¤›m›z immün-histokimyasal incelemede; vimentin ve desmin ile tümördüz kas hücrelerinde ve damarlar çevresindeki imma-tür mezenkimal hücrelerde belirgin pozitif boyanmasaptand›. Tümör örneklerindeki ya¤ hücrelerinde ayn›düzeyde vimentin ekspresyonu, ve zay›f ve de¤iflenoranda desmin reaktivitesi saptand›. Tüm ya¤ dokuhücrelerinde HMB-45 antijeni negatif olarak bulundu.Bununla birlikte, iki olguda i¤si tümör hücreleri HMB-45 ile zay›f pozitif boyanma gösterdi. Damarlar çevresiimmatür mezenkimal hücrelerden köken alan ve/veyadüz kas hücrelerinin progressif intrasellüler lipid depo-lamas› sonucunda direkt matür ya¤ dokuya dönüflümüsonucu geliflebilen bu tümörlerin histogenezi immünhis-tokimyasal bulgulara göre de kompleks yap›dad›r.

Anahtar sözcükler: Kad›n genital sistemi, histogenez,lipoleiomiyom

Histogenesis of lipomatous component in uterine lipoleiomyomas

Uterus lipoleiomiyomlar›n›n lipomatöz içeri¤inin histogenezi

Filiz BOLAT1, Fazilet KAYASELÇUK1, Tuba CANPOLAT1, Serkan ERKANLI2, ‹lhan TUNCER1

Baskent University Faculty of Medicine, Department of Pathology1, Gynecology and Obstetrics2, ANKARA

Corresponding Author: Dr. Filiz Bolat, Baskent UniversityFaculty of Medicine, Department of Gynecology and Obstetrics,06490-Ankara

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Turkish Journal of Pathology 2007;23(2):82-86

hmal neoplasm and mostly described as a vari-ant of uterine leiomyoma. They constitute lessthan 0.2% of benign uterine tumors (1-6).

The other nomenculatures for this tumorare fibrolipoleiomyoma, benign mixed meso-dermal tumor, lipomatous tumor, and so on (3).Since most cases are not referred due to their be-nign behaviour and also in most circumstancesthe fat component represents a more or lessabundant cell population in the context of com-mon leiomyomas of the uterus their precise inci-dence is unknown (1,4). These tumors usuallyoccur in postmenopausal women between 50and 75 years of age. Many of these patients areasymptomatic, but in some patients symptomsare similar to those of uterine leiomyomas, suchas pelvic discomfort, heaviness, and pressure, orvaginal bleeding (1,4,7).

Lipoleiomyoma is composed of variablemixture of smooth muscle and mature adiposetissue. Sometimes this tumor is accompanied byanomalous blood vessels surrounded by smoothmuscle cells, and it is termed angiomyolipoma,eg. renal angiomyolipoma (RAML) (8). Altho-ugh the histogenesis of RAML is uncertain, it isbelieved to arise from a pluripotent cell that dif-ferentiates into adipocytes and smooth musclecells, as suggested for lipoleiomyoma (2,8). Se-veral reports in the literature have documentedpositive reactivity of HMB-45 for smooth-muscle cells in angiomyolipoma (8). Further-more, HMB-45 antigen positivity was describedin uterine lipoleiomyoma by Aung et al (2).

The origin of the lipomatous lesions of theuterus has been the subject of much speculation,including misplaced embryonic fat cells, metap-lasia of muscle or connective tissue cells into fatcells, lipocytic differentiation of a specific pri-mitive connective tissue cell, perivascular fatcells accompanying the blood vessels into theuterine wall during surgery, or fatty infiltrationor degeneration of connective tissue (9).

The aim of the study is to investigate pre-sumptive histogenesis of uterine lipomatous le-sions and to present their histological features,

and to discuss the possible origin of this lesion.

MATERIALS and METHODS

We reevaluated 10 cases diagnosed as ute-rine lipoleiomyomas in Department of Patho-logy, Adana Baskent University, between 1999and 2007. We recorded the following parame-ters: estimated percentage of tumor area invol-ved by adipocytes, presence and degree of aty-pia of smooth muscle and adipocytes, mitotic ra-te, and tumor borders (circumscribed versus in-filtrative).

The surgical specimens were fixed in 10%neutral-buffered formalin and paraffin embed-ded. For immunohistochemistry, serial sectionsof 5-µm-thickness were cut from the paraffinblocks. The sections were deparaffinized withxylene and rehydrated with etanol. Nonenzyma-tic antigen retrieval was performed on each sli-de and washed by phosphate-buffered saline.Immunohistochemical staining was performedmanually using the standard avitin-biotin-pero-xidase complex technique with DAKO (LSABkit; DAKO, Glostrup, Denmark). The slides we-re exposed to primary antibodies for vimentinAb-2 (cloned V9, NeoMarkers, Fremont CA,USA) desmin Ab-1 (Clone D33, dilution 1:50,NeoMarkers, Fremont CA, USA) and HMB-45(code N1545, LSAB kit; DAKO, Glostrup,Denmark).

Immunoperoxidase staining of smoothmuscle cells, adipocytes and perivascular me-sencyhmal cells are scored as negative and posi-tive.

RESULTS

During the study period, 707 patients withuterine leiomyomas were identified, and 10 li-poleiomyomas were found. Thus, lipoleiomyo-mas were found in 1.4% of pateints with uterineleiomyomas.

The patients ranged from 31 to 63 years ofage (mean age 53.5±9.9). Five cases were post-

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menopausal, two were perimenopausal and thre-e cases were in reproductive period. Nine pati-ents sought medical attention for symptomaticleiomyomas (pelvic pain, enlarged uterus,and/or dysmenorrhea). One patient presentedfor treatment of a gynecological malignancy(endometrial carcinoma).

Gross PathologyEight women underwent hysterectomy and

bilateral salphingoophorectomy, two myomec-tomy for a pre-operative diagnosis of leiomyo-ma. One patient underwent hysterectomy andbilateral salphingoopherectomy and pelvic para-aortic lymph node dissection for endometrialcarcinoma. The size of the lipoleiomyomas ran-ged from 1.5 cm to 19 cm, with a median of 4.75cm.

Seven tumors affected the uterine corpus,and they were located intramuraly; two caseswere subserosal, and one was in the cervix. Thegross appearance depended on the amount offatty component. With microscopic foci of adi-pose differentiation, the cut surface resembledthe usual leiomyoma. In cases with a large amo-unt of fat, the cut surface was yellow and occa-sionally lobulated (Figure 1).

Histopathological FindingsAll lipoleiomyoma cases consisted histo-

logically of smooth muscle tissue admixed witha varying amount of mature adipose tissue. Theamount of adipose component varied from 5%to 95% of the tumor mass. In two cases, the tu-mors consisted largely of mature adipose tissue(95%), and also islands composed of bundles ofsmooth muscle fibers and fibrous connective tis-sue were seen among the adipose tissue (Figure2). In three cases hyaline degeneration was de-tected. Blood vessels in the stroma were not pro-minent and showed the usual, thin walled appe-arance. Cytological atypia (in smooth musclecells or adipocytes), necrosis, and calcificationwere not seen. The mitotic rate was zero in allcases. In cases with malignancy no gross or mic-roscopic contiguity between the lipoleiomyomaand the malignancy was observed. None of thetumors had infiltrative margins.

ImmunohistochemistryVimentin and desmin were widely expres-

sed in smooth muscle cells, pericytes, and en-dothelial cells (Figure 3). Varying degrees ofimmunoreactivity for vimentin were uniformlydetected in fat cell components of all tumors(Figure 4).

Tumor cells with adipose feature also de-monstrated inconsistent desmin immunoreacti-vity. The number of desmin-positive tumor cellswas variable in various tumors and within diffe-rent areas of the same tumor.

Figure 1. Gross appearence of lipoleiomyoma with high adi-pocyte component, showing a yellowish lobulated cut surface.

Figure 2. Numerous mature lipocytes between smooth musclecells in a lipoleiomyoma (HE x100).

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All adipose cells were negative for HMB-45 antigen. However, HMB-45 antigen was we-akly positive in spindle shaped tumor cells oftwo cases.

DISCUSSION

Uterine lipoleiomyoma is a rare benignmesencyhmal neoplasm and mostly described asa variant of uterine leiomyoma (1-7). The repor-ted incidence varies from 0.03% to 0.2% (10).Lipoleiomyomas can occur anywhere in the ute-rus or the uterine cervix. They can be subsero-sal, intramural or submucosal (1,4). In our ca-ses, seven tumors were in the uterine corpus,and intramural; two cases were subserosal and

one of them was in the cervix.Histolopathologically, three types of uteri-

ne tumors with lipomatous component are seen(2,9): a) Pure lipoma consisting of adipocytesand very few scattered smooth musle cells, b)Lipoleiomyoma with a variable amount and dis-tribution of adipocytes and smooth muscle cells,c) Angiomyolipoma with prominent vascularstructures admixed with adipoytes and smoothmuscle cells.

The diagnosis of uterine lipomatous tu-mors is based on the recognition of mature adi-pocytes. Lipoblast (11) and atypical smoothmuscle cells (12) have been reported anecdo-tally in uterine lipoleiomyomas. The differentialdiagnosis of similar uterine tumors with adiposetissue and spindle cells include; spindle cell li-poma, angiolipoma, angiomyolipoma, myeloli-pomas, atypical lipoma, and well-differentiatedliposarcomas. In our cases, all lipoleiomyomaswere comprised of mature adipocytes and smo-oth muscle cells. There was neither lipoblasticcomponent, atypia nor necrosis and mitotic acti-vity in adipocytes or smooth muscle cells.

The origin of lipomatous tumors is contro-versial. Sieinski (5) summarized the differentproposed theories in: 1) Misplaced embryonalmesodermal rests with a potential for lipoblasticdifferentiation, 2) Lipoblast or pluripotentialcells migrating along uterine arteries and ner-ves, 3) Adipose metaplasia of stromal or smoothmuscle cells in a leiomyoma.

There are many controversies in the patho-genesis and origin of tumor cells in uterine lipo-leiomyoma and angiomyolipomas (5,6,9-11,13).

Our immunohistochemical studies haverevealed reactivity of adipocytes for vimentinand desmin confirming the hypothesis of theirdirect transformation from smooth muscle cellsinto adipose cells. Furthermore, in our series thepresence of vimentin positivity in mesencyhmalcells around the vessels strengthen the neome-taplasia of pericapillary pluripotential mesency-hmal cells as Seinski and Resta et al. have sug-

Figure 3. Smooth muscle cells in a lipoleiomyoma showingstrong vimentin immunoreactivity (x200).

Figure 4. Intense vimentin immunoreactivity in mature li-pocytes of lipoleiomyoma (x400).

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gested (4,5). In all cases, variable degrees of vi-mentin and desmin positivity in mature adipocy-tes might suggest a direct transformation ofmuscle cells into adipose cells.

Moreover, in our cases neither angimyoli-poma like vessels, nor HMB-45 antibody positi-vity was seen. Just in two cases weak HMB-45positivity in spindle cells was seen. Yaegashi etal. described a uterine angiomyolipoma, wheresmooth muscle cells from a tumor area werespindle shaped and negative for HMB-45 anti-gen (13). As in literature we found out that ute-rine and renal angiomyolipomas were differentclinical entities, having similarity only in histo-logic pattern (10).

In conclusion, our study revealed that thehistological and immunohistochemical findingssuggest a complex histogenesis for these tu-mors, in that they might arise from mesency-hmal immature cells or from direct transforma-tion of smooth muscle cells into adipocytes bymeans of progressive intracellular storage of li-pids.

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5. Sieinski W. Lipomatous neometaplasia of the uterus.Report of 11 cases with discussion of histogenesis andpathogenesis. Int J Gynecol Pathol 1989;8:357-363.

6. Yamadori I, Kobayashi S, Ogino T, Ohmori M, Tana-ka H, Jimbo T. Uterine leiomyoma with a focus of fattyand cartilaginous differentiation. Acta Obstet GynecolScand 1993;72:307-309.

7. Pham CA, Atri M, Senterman MK. Ultrasonographicappearance of uterine lipoleiomyoma. Can Assoc Ra-diol J 1993;44:463-465.

8. Hoon V, Thung SN, Kaneko M, Unger PD. HMB45 re-activity in renal angiomyolipoma and lymphangiole-iomyomatosis. Arch Pathol Lab Med 1994;118:732-734.

9. Willen R, Gad A, Willien H. Lipomatous lesions oftheuterus. Virchows Arch A Pathol Anat Histol 1978; 17;377:351-361.

10. Prieto A, Crespo C, Pardo A, Docal I, Calzada J, Alon-so P. Uterine lipoleiomyomas: US and CT findings.Abdom Imaging 2000;25:655-657.

11. Brooks JJ, Wells GB, Yeh IT, LiVolsi VA. Bizarreepitheloid lipoleiomyoma of the uterus. Int J GynecolPathol 1992;11:144-149.

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13. Yaegashi H, Moriya T, Soeda S, Yonemoto Y, NaguraH, Sasano H. Uterine angiomyolipoma: Case reportand review of the literature. Pathol Int 2001;51:896-901.

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histogenesis of lipomatous component in uterine lipoleiomyomas · menopausal, two were...

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