BENIGN METASTASIZING U T E R I N E LEIOMYOMA Multiple Lymph Nodal Metastases M. R. ABELL,MD, PHD," AND E. R. LITTLER,MD+

A case of histologically benign lymph nodal metastases from a uterine Ieiomyoma in a 27-year-old woman is reported. It is postulated that fragments of a leiomyoma, detached a t the time of endometrial curettage, entered dilated lymphatic channels in or adjacent to a large projecting submucous leiomyoma, and seeded several pelvic and para-aortic lymph nodes. During an interval of 8 years, these grew slowly and did not infiltrate the perinodal tissues or give rise to secondary metastases. Cancer 36:2206-2213, 1975.

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uncommon conditions in which histo. logically benign leiomyomas of the uterus extend beyond their usual confines or are associated with independent extrauterine leiomyomas. These syndromes may evolve by parasitization, direct infiltration, implantation, embolization, or by proliferation and differentiation of autochthonous cellular foci. Parasitic leiomyomas probably represent the best known form of extension. They are believed to arise by adhesions of subserous leiomyomas to peritoneal structures, with subsequent separation from the uterus. A few examples of direct infiltration and surgical implantation of uterine leiomyomas into adjacent adnexal and retroperitoneal tissues have (been reported.4.13 Intravenous leiomyomatosis consists of proliferating cores of benign smooth muscle that permeate uterine and adnexal veins but rarely extend beyond the pelvis.".7.8~11JS Although peritoneal leiomyomatosis occurs in association with multiple uterine leiomyomas, it probably r e p resents many autochthonous lesions arising from the submesothelial mesenchyme of the peritoneum rather than peritoneal seeding from a uterine leiomyoma.6.18.20 From the Departments of Pathology, Wayne County General Hospital, Eloise, MI, and The University of Michigan hfedical Center, Ann Arbor, MI. * Professor of Pathology, The University of Michigan. t Associate Professor of Pathology, The University of Michigan, and Pathologist at Wayne County General Hospital. Address for reprints: M. R. Abell, MD, Department of Pathology, The University of Michigan, 1335 E. Catherine St., Ann Arbor, MI 48104. Received for publication August 26, 1974.

Reported examples of embolic metastases from benign uterine leiomyomas by way of blood or lymphatic vessels are rare to the point of being curiosities; skepticism is justifiably expressed in regard to some of the reports because of poor documentation or illustrations that suggest borderline or low-grade sarcomas. There are, however, a few reports of acceptable examples by all histologic criteria of benign metastases occurring in lungs and/or lymph nodes.1JJ)J6J7 The case reported herein represents metastases from a benign uterine leiomyoma to pelvic and para-aortic lymph nodes. It was observed over a period of 8 years. CASEREPORT History and Clinical Findings A 27-year-old black woman, gravida V, Para 2, abortus 3, was admitted to Wayne County General Hospital in January of 1965 for a hysterectomy. At the time of pelvic examination and uterine curettage for the investigation of hypermenorrhea 1 year previously, the uterus was considered to be twice the normal size and irregular in configuration due to leiomyomas. Six months and 1 month prior to admission, incomplete abortions of 3-month pregnancies occurred and were followed by uterine curettages. At the time of the last curettage it was thought that a large submucous leiomyoma occluded most of the endometrial cavity and was the probable cause of the repeated abortions. A pelvic examination prior to hysterectomy revealed a uterus the size of a 10-12-week pregnancy, with nodular irregularities on the left. There were no other significant physical findings, and no abnormal laboratory findings other than a slight microcytic anemia. At celiotomy the uterus was en-

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A~ETASTATIC UTERINE LEIOMYOMA AOell and Littler

FIG. 1 . Metastatic leiomyoma in lymph node. T h e smaller foci appear to be related to sinuses ( H 8: E, xG6, wlucctl from i s ) .

Fic:. 2. Metastatic Icioin~otna in I!mph node consisting of interlacing bundles of smooth . from 190). Inusclc cells w i t l i small uiiifot-rn nuclei (H 8: E, ~ 1 3 4 reduced

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FK;. 3. This reprcscnts the most cellular aIea of any of the utcl-inc 1ciom)otn;is. So histologic cvitlcncc of malignancy (H & E, xlS0).

larged and distorted by leiomyomatous tumors; there were several hard pelvic a n d para-aortic nodules, which were interpreted as lymph nodes replaced by metastatic cancer. T h e uterus a n d three of the nodules were excised.

Pathologic Findings T h e three “lymph nodes,” the largest measuring 1.2 cm in diameter, were largely replaced by whorled, firm, tan-white tissue. Rlicroscopically, these areas consisted of interlacing bundles of pale eosinophilic muscle cells, with uniform, elongated a n d oval nuclei (Figs. 1 a n d 2). Rlasson’s trichrome stain confirmed that the tumors were composed of smooth muscle. Residual areas of lymphoreticular cells in the nodules indicated that they were indeed replaced lymph nodes. I n areas where normal lymph nodal structure remained, several plugs of muscle cells appeared to be within endothelial sinuses. T h e r e was n o extension of muscle proliferation I)eyond the capsules of the lymph nodes. hlitotic figures antl nuclear hyperchromatism a n d pleomorphism were not present in any of the 14 blocks of tissue that were sectioned.

T h e uterus measured 1G x 13 x 8 cm and weighed 482 g. T h e endometrial cavity w;is tlistortetl b y a whorled leiomyomatous siibmucosal mass 9 x 5 x 1 cm. T h e r e were also a noncontiguous subserosal tumor 1.5 cni in diameter and a number of smaller leiomyomas. All tumors were well circumscribed, antl there was n o gross evidence of vascular invasion. A total of 4 G blocks of tissue w;is taken from the uterus; sections from these were stained routinely with hematoxylin antl cosin, a n d in selected instances with Rr;tsson’s trichrome antl silver reticulin stains. hlicroscopically, a11 of the leiomyomas were histologically benign and consisted of intcrlacing bundles of uniform smooth muscle cells (Fig. 3). T h e 1 cry occasional normal-appearing mitotic figure W;IS found after prolonged search, but nuclear crowding, pleomorphism, and hyperchromatism were absent. Areas of hyalinization occiipied areas of the two largest leiomyomas. Dilated entlothelial c1i;innels of various sizes were particularly prominent i n several of the leiomyomas, including the largest, i n the myometrium, and in the I)as;il cntlometi-ium overlying the submucosal leio-

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~IETASTATIC UTICRINE LEIOMYOMA - Abell rind Littler

2209

4. hlarkcdly tlilatctl enia-litic(l slxiccs ;it junction rloiiicti ium ant1 m)omcovc~-lyi~ig t l w IaIgc subs Icionl)otn;i (Masson’s tric , xM. rctlucetl froin 75).

niyoma (Fig. 1). Some of these were obviously veins; otlicrs were lympliatic cliaiinels, b u t in many irist;inces it was n o t p o s s i l h to say what type of vessel tliey rcprcseiited. N o v;iscul;ir irivasion was fountl. ;I rwicw of the materi;il from the first curettage taken I year prior to hysterectomy reve;ilcd f r q inelits of sniootli muscle ;idmixed with hypersecrctory endometrium ; i n d tlecitlu;i. These fr:igments Ii;itl ; i n intcrtligit;iting f;iscicul;ir arrangement intlic;itive of ;I leioniyom;i rather than normal myometrium (Fig. 5 ) .

Subsequent Course

:I “second-look” ccliotomy was done in July, 1!)66. T h e r e was 110 -gross evidence of neopl;istic involvemeiit of the pelvic soft tissues, peritoneum, o r ;il)tlomin;il viscera. Firm lymph nodes in the p;ir:i-:iortic a t i d pelvic ;ireas were noted. O n e paraaortic riotle. 1.3 cni in diameter, was excised. Its cut surface Ii;itl ;I whorlctl yellow-white appearxiice; Iiistologic:illy, i t was almost completely re-

placed by interlacing I)untllcs of benign smooth inuscle cells, representing mct;istatic leiomyoma. After recovery from this procedure the patient w a s not secii ng;iiii until September, 1073. rZ r o w tine pelvic examination a t this time revealed a lower mid:il)domiiial m;iss and a right ;itlnexal m x s . I’licre were no other abnormal findings. T h e patient denied any symptoms referable to these lesions. T h e r e was no suggestion of any metastatic disease on chest roentgenograms. :It celiotomy the left ovary was fountl to be repl:icctl l)y ;I 12-cm cystic tumor: there were bilateral enlarged hard iliac lymph nodes, 6 x 5 x 3 a n d 8 x 3 x 1 cm, a n d one pcriaortic node, 4 cm i n greatcst diameter, j u s t below its bifurcation. These were excised, and a bilateral snlpingo-oophorectomy was done. T h e r e was no other evidence of neoplasm. T h e cut surfaces of the three excised tumors had a typical leiomyomatous appearance. hlicroscopically, many sections revealed bcnign:ippearing leiomyomas similar to the previously examined lymph nodes and uterus (Figs. G and 7).

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FK;.5. Benign Iriomyomatous tissue i n c ~ t r c t t n g cspecimen t;~hen 1 yrar p i o r to 1i)stctectomy (H & E, ~ 1 4 3 retlucctl , from 160). I n two of the Icsions there were small residual areas, :rind i n the other ;I pcripher;rl rim of nornial lymph notla1 tissue. Thc ovarian lesion was a benign mucinous cyst;rtlcnoma.

DISCUSSION Considerable controversy has surrounded the pathogenesis of the various syndromes comprised of uterine leiom yomas and related extrauterine leiomyomatous tumors. It is theoretically possible for fragments of a uterine myoma released into the peritoneal cavity by surgical incision or rupture to implant and grow. Several examples of normal tissue such a s spleen have been reported to implatlt and grow on the pelvic peritoneum following rupture." Renign neoplasms of the ovary may on occasion do likewise. A somewhat similar evolution is accepted for parasitic or migratory subserous uterine leiomyomas. However, it would appear that such a mechanism cannot be evoked for peritoneal leiomyomatosis. T h e most likely explanation for this condition is a prosoplasia of the submesothelial mesenchyme drie to some combination of hormonal

stimulation. It is interesting to note that the case reported by Willson and PealezO occurred in association with a granulosa cell tumor of ovary, and that several of the other cases occurred in association with pregnancies,6918 a known stimulus to smooth muscle prolifera tion. T h e r e is also uncertainty as to the p a t h e genesis of intravenous leiomyomatosis. Marshall ;ind Norris" and Borland and Wotring* concluded that these lesions arose either from muscle cells or uncommitted mesenchymal cells in the walls of veins, and were indepentlent of any extravascular component, whereas others supported the supposition of origin from either myometrial or leiomyomatous cells.**'~ Idelson and D a v i d ~ ,i ~ n a review of the world's literature in 1962, accepted only four reported cxamples of benign metastasizing uterine leiomyomas. However, they included the case of peritoneal leiomyomatosis reported by Willson and Peale,?O and one of direct extension into the spinal canal and dura.I3 T h e case reported by Steiner" is accepted and

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1 - i ~ 6. . Ititeilacing buritllcs of I)iolifcrating smooth mrisclc cells, which represent inetastatic 1ciotn)onia i n Iyinpli node. 7 his specimen was excised 8 years after hysteicctom) (H k E,

xi't9, te~iucetiriot11 160).

cited as tlie classic csample of benign venous invasion by ;I utei iiie leiomyoma antl benign;ippc;iring mct;istases in the lungs. Spiro and RIcPe;ikI" reportcd a case of benign-apparing leiomyoma in lung that was presumed to be ;I metastasis from ;I similar uterine tumor. Hy a11 of the histologic criteria that are usctl lor diagnosing leiomyosarcoma, borderline sarcoma, antl atypical leiomyomas, the tiiiiiors iii the uteriis arid 1)nipli nodes of the ciise reportctl here were histologically benign. S i t i i i 1;ir benign 1y in pli notla 1 metastases from uterine leiomyomas have been reported by Idel>on and Davitls!' and Boyce and Buddhcle\,.:' 111 ;itltlition, Boyce and Ruddhdev's case Iiad pulmonary metastases in the absence of ititraveiiotis leiomyoniatosis. In neither of the above tivo c;ises w a s ' iiitralymphatic or intravenous extension observed in the uterus. T h e possibility that the lymph node lesions in the above two cases and our case were multiple primary lesions independent of the uteriis must be considered, but seems highly

unlikely. I n oEering an explanation for the metastatic theory, tlie following observations in our case would appear to be of importance: the patient liatl three previous uterine dilatations and curettages; fragmented leiomyomatous tissue was present i n the curettage specimen taken 1 year prior t o hysterectomy; there was a large submucous leiomyoma protruding into the uterine cavity; antl venous and lymphatic vessels within the leiomyoma, the adjacent myometrium, and the overlying basal endometrium were markedly dilated and possibly increased in number. It is postulated that at the time of the first of the three curettages, lymphatic channels in the subserous leiomyoma o r adjacent myometriuml* were opened, and fragments of the leiomyoma entered these antl were transported to the lymph nodes, where they became implanted and grew slowly. There is some support for such a possibility. Sanipson16 found fragments of endometrium in atlnexal veins following endometrial curettage. It has also been postulated

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FIG. i . Higher magnification of section depicted in Fig. 6 . ;\lthougli this metastasis is more cellular than tlie initial metastases, i t is histologically I)eiiigii ( H R: E, x212, ~-educetlfrom 240).

that some examples of lymph nodal endometriosis result from lymphatic embolization.10.1* I n our case, no attempt was made to excise all of the involved lymph nodes at the time of the initial ccliotomy antl hysterectomy in 1965 or at the “second-look” celiotomy in 1966, as they were thought to represent metastatic cancer. During the intcrval of 7 years, the metastases in the lymph nodes that were left Ixhind grew slowly antl remained confined within the nodes. T h e r e was no evidence of local perinoclal invasion. T h i s course further sulistantiates the liiological benignity of these lesions.

It is well rccognizctl that the ovarian hormoncs, particrilarly estrogens, play an important role in the pathogcnesis of uterine leiomyomas, and that with tlie cessation of ovarian function, Iciomyomas usually cease to develop. I t is interesting to speculate whether the lynipli nodal lcsions woultl have ceased to grow if the ovaries hat1 Iieen removed at the time of liystercctomy. At the last surgical procedure (19’i3), all grossly involved lymph nodes were excised, but in the event that others might contain small metastases, the removal of the ovaries prcsuinalily will have reduced the s ti mu1us for con ti nued growth.

R EFE 11E S CES 1. I%ariics, H. hl.. and Richartlson, 1’. J.: Beiiigii metastasizing fil)i-olcioniyomn. J . 0 6 s k t . Gynatcol. Ilr. C o m ~ t i o n r 80:569-5i3, ~~. 1W 3 . 2. Borlaiid, L). S . , a i i t l \l’oti.iiig, J . \V.: Iiitravcnous leiomyomatosis of the I I I C ~ I I S and I)roatl liganieiitReport o f ;I C;ISC. A?tt. 1. C l i n . Pat/loi. 423182-188, 1964. 3. Doycc. C. I