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Distinguishing lymph node metastases from benign glandular inclusions in low-grade ovarian carcinoma
Distinguishing lymph node metastases from benign glandular inclusions in low-grade ovarian carcinoma R. L.
EHRMANN,
J.
FEDERSCHNEIDER,
M.
R. C.
M.D.
KNAPP,
Brookline,
M.D.
M.D.
Massachusetts
In order to properly stage patients with ovarian carcinoma, we are routinely removing and microscopically examining sample aortic lymph nodes in these patients, since aortic lymph node metastases may affect long-term survival. Inasmuch as benign glandular inclusions can be found in pelvic and aortic lymph nodes, we have run into difficulty distinguishing such inclusions from genuine me&Stases in cases of low-grade or borderline serous ovarian carcinomas. Atypical epithelium in these tumors may closely resemble the lining of benign glandular lymph node inclusions. Moreover, like metastases benign glandular inclusions may grow in the peripheral sinusoid, show epithelial papillae and psammoma bodies, and may even proliferate as small sheets of cells. Just how crucial it is to recognize aortic lymph node metastases in these low-grade tumors will be clarified when the prognostic importance of aortic node metastases becomes understood. (AM. J. OBSTET. GYNECOL. 136:737, 1960.)
EARLY Stage I undifferentiated and embryonal ovarian carcinomas have been shown to be associated with a poor prognosis when microscopic aortic lymph node metastases are present.’ In order to more accurately stage ovarian carcinoma, we are examining aortic lymph nodes in all patients to determine whether the nodes contain metastases and to see whether the metastases correlate with histologic type and grade of the primary ovarian tumor. During the course of this investigation, four cases of low-grade or borderline ovarian carcinoma were found associated with glandular structures in aortic lymph nodes. Benign glandular inclusions within pelvic and aortic lymph nodes are a well-known entity.* However, in three of the four cases, the ovarian tumors were so well differentiated that there was great difficulty in deciding whether the epithelial structures within aortic nodes were metastases From the Departments Gynecologic Oncology Gynecology, Harvard Hospital for Women.
of Pathology and Division oj of the Department of Obstetrics and Medical School, and the Boston
Received for publication Revised April Accepted April
February
8, 1979.
2, i979. 10, 1979.
Rep&t requests: Dr. Robert L. Ehrmann, Parkway Division, Boston Hospital for Women, 245 Pond Ave., Brookline, Massachusetts 02146. 000%9378/80/060737+10$01.00/0~
1980 The C.
V. MO&y co.
or benign glandular inclusions. Aortic metastases indicate Stage III carcinoma, which requires chemotherapy and/or whole abdominal irradiation with its inherent risks. Determining whether aortic metastases are present or not may be crucial to the life of the patient. The purpose of this paper is to deal with identification of metastases in aortic lymph nodes and to then comment on their implications.
Clinical data and pathology The essential clinical data are given in Table I. In Case 2, the uterus was adherent to the peritoneum posteriorly, and it was necessary to do a modified radical hysterectomy to release the ureters and free up the uterus. At laparoscopy prior to surgery in Case 3, a biopsy of the right ovarian mass was interpreted as a papillary fibroma. In Case 4, the supracervical hysterectomy and bilateral salpingo-oophorectomy were performed at an outside hospital. The patient was then referred to our hospital where a staging laparotomy was performed together with multiple biopsies of tumor implants. In all of the cases, removed pelvic and aortic lymph nodes appeared grossly normal. Using recently published criteria,3 the ovarian tumors in Cases 1 and 2 would probably be reclassified as borderline malignancy. In any event, the important point is that all the tumors were low grade. 737
738
Table
Ehrmann.
I. C%nical
Federschneider,
data,
March Am. J Ohstrr.
and Knapp
diagnoses,
and
treatment Findings at operation
Warging mass
pelvic
Heavy bleeding, large pelvic mass Bilateral hard adnexal masses found on physical examination Pelvic-
pain
15. 1980 Cknecd
Bilateral papillary ovarian tumors
Operution
cystic
TAH and BSO: removal of an aortic lymph node; remo\al of Meckel diverticulum.
Bilateral multicystic ovarian tumors with external papillary growth and extension to right broad ligament Bilateral nodular cystic ovarian tumors with external excrescenses and peritoneal seedings, including diaphragm
Modified radical hysterectomy with BSO: removal of representative pelvic and aorticlymph nodes Laparoscopy subsequendy followed by TAH and BSO; excision of involved peritoneum; removal of four aortic lymph nodes
Bilateral papillary cystic ovarian tumors and widespread peritoneal implants including omentum
Supracervical hysterectomy and BSO, followed later by sraging laparotomy, partial omentectomy. multiple biopsies of implants, and removal of representative pelvic and anrtir lymph nodes
M’ithin the fibrous srrmm of’ the tumor uerr man) small cvsts. some lined hv slightly pleomor-phic lo\%- columnar cells. others lined by benign-appearing ciliated tubal-typr epithelium. I’sammom;t bodies WPI-c f’requent. The ovarian tumors were diagnosed as welldif’ferentiated papillar) serous c\staderlocarcinorna. grade 1. The endometrium showed hyperplasia. Much to everyone’s surprise, 19 of 44 pelvic and -4 of 4 aortic lymph nodes were fi)und to contain glandutat structures. interpreted as metastases. ?-hew structllres wxe very numerous in the aortic lymph nodes, as illustrated in a low-power view (Fig. 4). ‘I‘hey consisted of small cystically dilated irregular glands, most frequent ar the node periphery. but none identiticd within the peripheral sinusoid. Similar to Case I. the cpithelium lining these glands \vas simple cuboidal to low columnar, and focally ciliated. There was slight variation in nuclear size, with central micronucleolIls and no mitoses. The glandular epithelium in the nodes closeI) resembled the more benign-appearing components of’ the ovarian tumors, nameI), the crevices between papitlae and the small cysts within fibrous stroma. X supraclavicular nodal biopsy was found to be normal. Case 3. Both ovaries were surrounded and almost replaced by broad dense fibrous papillac containing small gland spares. The papillae were covered in most places I,\ a single layer of tubal-t! pe (uhoidal to loJ\ cotumna~- epithelium with varying f’wal stratification ~tp to ten cells deep. The epithelial nuclei showed minor rounding
atypia.
i.e.,
n;trrow
prominent
clwr
micronucleoli
with
;t sur-
Ionc ;IIIC~ sli,qhr 11~1c1rar plt~~-
Volume Number
Tumor
136 6
diagnosis
and clinical stage
Distinguishing
Original aortic lymph node diagnosis
Subsequent treatment
Papillary serous cystadenoca, grade 1, stage Ib
Benign glandular inclusions
None
Papillary serous cystadenoca, grade 1, stage III Papillary serous cystadenofibroma of borderline malignancy, Stage III Papillary serous cystadenoma of borderline malignancy, Stage III
Metastases
X-ray treatment of pelvis; chlorambucil
Metastases
None; follow-up laparoscopy after three months
Metastases
Intraperitoneal P-32 radioisotope
morphism. Mitoses were rare. In many small foci there were surface micropapillae from which cell clusters exfoliated. The micropapillae contained large numbers of psammoma bodies (Fig. 5). It was the overall massive replacement of the ovaries by tumor together with the slight nuclear pleomorphism and minimal cell exfoliation that led to a diagnosis of papillary serous adenofibroma of borderline malignancy. The biopsied small peritoneal lesion closely resembled the ovarian primary. The peritoneal lesion showed connective tissue with psammoma bodies and a few micropapillae with exfoliating cell clusters. One of four aortic lymph nodes showed in its periphery small ciliated glands and epithelial papillae undergoing degeneration and replacement by psammoma bodies (Fig. 6). These epithelial changes closely resembled that of the ovarian tumor. In one focus, epithelial papillae and cell clusters were seen within the peripheral sinusoid (Fig. 7). This will be commented upon shortly. The aortic node lesion was diagnosed as metastatic papillary serous adenofibroma of borderline malignancy. Case 4. The ovarian tumors showed cysts and surface growth with connective tissue papillae covered by low columnar epithelium one to six cells deep. Single cells and clusters exfoliated from the papillae (Fig. 8). Abundant cilia were noted in some areas, and there were occasional psammoma bodies. The tumor cell nuclei showed a fine, even granularity and slight pleomorphism. Cytoplasm was scant and mitoses were rare. Because of the marked cellular differentiation and exfoliation, and absence of capsular invasion, we
lymph
node
metastases
from
glandular
inclusions
739
diagnosed the tumor as papillary serous cystadenoma of borderline malignancy. Papillary tumor was growing on the serosal surface of the uterus and superficially invading the underlying myometrium. A tumor implant was also present in a uterosacral ligament biopsy. The peritoneal metastases varied from papillary tumor with psammoma bodies to small benign-appearing glands lined by tubal-type cuboidal epithelium. The involved aortic lymph nodes contained irregular, variably dilated glandular spaces, mostly in the node periphery, but none identified in the peripheral sinusoid. These glands were lined by tubal-type ciliated cuboidal to columnar cells, with occasional focal stratification up to three cells deep. The nuclei were generally bland, with a prominent central micronucleolus. Mitoses were rare. There were several papillary glands with psammoma bodies (Fig. 9). The cell nuclei in the papillary epithelium were somewhat disoriented and granular. In addition to the glandular structures, the lymph node tissue near one of the papillary glands contained isolated rosettes and sheets of epithelial cells, and a psammoma body (Fig. 10). These loose structures intermingling with the lymphocytes strongly suggested metastatic tumor and will be commented upon shortly.
Comment The structures within aortic lymph nodes of the patients just described should be reconsidered in the light of what is already known about glandular inclusions within lymph nodes in general.’ These structures have been recognized since 1897 and have been variously interpreted as lymphatic transport of endometrial glands from the uterus, fragments constricted off lymph vessels as a result of chronic inflammation or carcinoma, Wolffian remnants, Miillerian metaplasia of coelomic epithelium, and mesothelial inclusions from the overlying peritoneum.“ According to the latter theory, glandular inclusions in lymph nodes illustrate the multicentricity of peritoneal proliferations which can occur with serous ovarian tumors, and which can be misinterpreted as metastases5 Decidual changes in lymph nodes have also been interpreted as metastatic cancer.6 To date, the exact origin of these structures remains unknown. The glandular inclusions are found exclusively in females2 They are often cystically dilated and are usually lined by simple benign-appearing cuboidal epithelium that is often ciliated. However, the lining epithelium may be simple columnar or pseudostratified columnar. Occasionally, the epithelium forms papillary infoldings into the gland lumens. Cytoplasmic or intraluminal secretion may be present, and periglandular calcifications resembling psammoma bodies may occur, some of which distort the glandular
740
Ehrmann. Federschneider,
and Knapp
Fig. 1. Case 1. Left ovary with grade 1 papillary serous cystadenocarcinoma. x 319.) Table
II. Gross features
Care
No.
Maximum diameter
of ovarian tumor (cm)
1.5 (left) 7 (right) 20 (left) 12 (right) IO (left) 9 (right)
1
8 (left) IO (right)
(Hemataxylin
and eosin.
tumors 7-U
uvzght
Internal
VLW
(g-m)
I .42.5 (left)
87 (left) 84 (right)
General appearance Unilocular
Extfnal growth
papillary
growth
Yes
No
Multicystic mass
Yes
Yes
Hard, white nodular mass with interspersed small cysts Multicystic mass (left), unilocular cyst (right)
NO
Yes
shape h111osc~ al-c exr~cmel~ rare. In most ~ase5. the glands arc peripherally located Lvit bin I he fibrous capstric or wrtitxl portion of the hmph nodes. E;arp and C;/.ex-nobilsk\” found seven cases in their $rries of 50 autoap) c.ISC’S ot- an incidence ot’ l-45: , that showed glandular inc.lusions within lymph nodes (pelvic or aortic). N~nt: of the seven cases had malignant tumors, None ot’tht. glandular structures ohset-vccl bv Karp and (Sizer-nobilsk~ wart’ found tvithin the peripheral sinusoid. in I otrtrast to ‘raussqi and J,~ver.t~ isho often tound such >rructurcs. which the\ hcli~ved to be enrlomctriosis. \
cyst
papillary
Yes (left only)
Yes (left and right)
of the cervix. ‘There is no satisfactor) explanation for this, although Huhn I” felt that groll th of the carcinoma was accompanied bv a nonspecific factor which favored developmenr of the glandular inclusions. One wonders if an increased incidence also occurs in ovarian c-arcinoma. Of all the many authors, Schnurr and associatesl’ are the only ones \~ho warn that a false diagnosis of metastatic adenocarcinoma in aortic lymph nodes can occur if the pathologist is unaware of benign glandular inclusions. Having briefly reviewed the concept of glandular in&sions. we can now re-evaluate these structures in the fbur patients already presented. In Case I. the aor-tic lymph node inclusions were benign appearing (Fig. Z), in contrast to the malignant
Volume 136 Number 6
Distinguishing
Fig, 2. Case 1. Aortic lymph node with benign glandular
lymph
node
me&stases
inclusions. (Hematoxylin
Fig. 3. Case 2. Right ovary with grade 1 papillary serous cystadenocarcinoma. eosin. X319.) featul -es of the ovarian carcinoma (Fig. 1). We therefore f eel confident that the aortic node structures were not m IetastCtses. On our review of the outside slides on Case 2, the gland inclusions within aortic nodes (Fig. 5) appeared relatil Jely benign, as did the crypt epithelium and small gland spaces within the ovarian tumor. In this case, the ‘YmPt I node structures could be either benign inclu-
from
glandular
inclusions
741
and eosin. X319.)
(Hematoxylin
and
sions or metastatic carcinoma. Since the glal ndular structures were so numerous in the aortic lymph nodes without any destruction of nodal architecture I, and since no papillae were found in any of the lymph nodes, in constrast with the ovarian tumor where papillae were numerous, we concluded that the nodal inclusions in Case 2 were benign, rather than met :astalic carcinoma originally diagnosed.
742
Ehrmann, Federschneider,
and Knapp
March
Am. J. Obstet
Fig. 4. Case and eosin.
2. Aortic x
lymph node with glandular
inclusions interpreted
1.5, 1980 Cwzcol.
as metastases. (Hematoxylin
19.)
Fig. 5. Case 3. Right ovar! with papillary serous adenofibroma of’ borderline malignancy. showing wrfacc mitropapillae and psammoma bodies. (Hematoxylin and e&n. X 319.) Kn t&e 3. \\e originall!~ thought that epithelial papiland ps;tmmoma bodies within the aortic node inclusions (big. 6) indicated metastases, since thesr f’eatuws werr c haractcristic of the oval-ian tumor (Fig. 3. kit-p and 1.,xrnobilsk! however, described these samt f eaturrs u ithin lynph node inclusions in autopsied t.ascs7itl~c~1~~ c~arcinoma. One might then argue that epithelial papillae in (;a~: 3 within the peripheral sinusoid /Fig, 71 indicated malignalIt v. hwauw Karp and C7v1 ix
nobilsky had never seen such structures within nodal Iymphatics of their benign cases. f~cJwevcr, other authors, as already mentioned, described these structures ,uufiwl~ in peripheral sinusoids.‘, h \Ve finally concluded that the aortic node inclusions were benign. and not metastatic tumor. Case 4 is the most controversial of. all since there were widespread definite pelvic and cment;d mrtastases 8s well as invasion ot the utcl-[Is. making the pos-
Volume Number
136 6
Distinguishing
lymph
node
metastases
from
glandular
Fig. 6. Case 3. Aortic lymph node showing gland with papilla and psammoma body, interpreted metastatic tumor. (Hematoxylin and eosin. x 3 19.)
Fig. 7. Case 3. Same lymph node showing epithelial inclusions within the peripheral matoxylin and eosin. x 3 19.) sibility of aortic lymph node metastasis in this case quite plausible. Highly suggestive were papillary glands and psammoma bodies within aortic nodes (Fig. 9) that histologically resembled the peritoneal and uterine metastases in this patient. Karp and Czernobilsky,2 however, showed that papillae and psammoma-like calcifications can occur in benign inclusions. Even more suggestive of metastasis were the loose rosettes and sheets of cells lying among the lymphocytes (Fig. 10). Huhn,t” how-
inclusions
743
as
sinusoid. (He-
ever, described similar, yet benign structures in lymph nodes from patients with cervical squamous cell carcinoma. Despite these diagnostic pitfalls, the papillary appearance in the aortic node glandular inclusions was so striking that we sustained the diagnosis of metastatic tumor. It must be evident to the reader that the diagnosis of lymph node metastases is so difficult in the absence of clearcut malignant features, it becomes almost an arbi-
744
Ehrmann,
Federschneider,
and Knapp
Fig. 8. Case 4. Left ovary and rosin. ~319.)
Fig, 9. Case 4. Aortic the ovarian primary.
with papillary
March 15, 1980 Am. J. Ohstet. Gynecol.
serous
cvstadrnoma
of borderline
lymph node with papillary glandular structure Note psammoma bodies and cilia. (Hematoavlin
malignancy.
interpreted as metastatic and eosin. ~319.)
ing to Bergman. rinal,
(Hematoxylin
These included
supraclavicular.
axillary,
from
pelvic, aortic., mediasand
inguinal
+ph
nodes. With rhe subject ol' our own paper in mind, we must quesGon Bergman’s identification of lymph node metastdses in borderline ovarian tumors. It is quite possible that he was observing benign glandular inclusions.
l’aticnts
with borderline
or low-grade
ovarian
carc-i-
Volume Number
136 6
Distinguishing
lymph
Fip.. 10. Case 4. Same aortic lvmnh node with epithelial (Hematoxylin and eosin x319:) ’ nomas live for many years, even with pelvic spread,‘“-‘6 and most recurrences are intra-abdominal. As reported by Aure and colleagues,13 after 20 years there was a 76% survival rate of 74 patients with borderline serous tumors compared with only an 18% 20 year survival rate of 283 patients with invasive serous carcinoma. On the other hand, between 15% and 25% of patients with borderline malignant tumors will eventually die from a recurrence,‘” and patients with initial pelvic spread from their borderline tumor have a shorter survival than those patients without such spread.r3’ r4, r6 Although aortic lymph nodes were not examined in these reported studies, the presence or absence of aortic .node metastases in cases of borderline tumors may significantly influence the prognosis. Aortic node metastases might remain dormant for a long time before they disseminate, but there is evidence that late distant metastases do occur in borderline serous carcinoma. Munnell and associatesI cite the case of a patient operated upon in 1935, who 20 years later died with pulmonary metastases that microscopically looked like borderline serous carcinoma. It is possible that most deaths from low-grade or borderline carcinomas occur before the aortic node metastases have disseminated, but there is no documentation of this. In any
REFERENCES
1. Knapp, R. C., and Friedman, E. A.:Aortic lymph node metastases in early ovarian cancer, AM. J. OBSTET. GYNECOL. 119:1013, 1974.
node
metastases
from
glandular
inclusions
745
rosettes, sheets, and a psammoma body.
event, since most women with borderline ovarian tumors are young, with a long life expectancy,” we must evaluate all areas of tumor dissemination including aortic lymph nodes. Then consideration can be given to proper treatment plans. If pathologic features are insufficient to distinguish benign glandular inclusions from metastatic tumor in aortic lymph nodes, it may be best not to treat for aortic nodal disease. In summary, as the clinician develops better surgical techniques in staging patients with ovarian carcinoma and in performing aortic lymph node dissections, the pathologist is called upon to make every effort to determine whether or not metastases exist in the removed aortic nodes. The prognosis of the patient and decision on therapy may in fact depend on the accuracy of this interpretation. It would appear that the borderline or well-differentiated lesions may have a low propensity to metastasize to the aortic nodes and that epithelial structures resembling metastases are, in fact, benign. If, on the other hand, true aortic node metastases do exist, these may affect long-term survival. The authors wish to thank the following consultants for their valued opinions on the cases described in this paper: Dr. Arthur T. Hertig, Dr. Robert E. Scully, and Dr. J. Donald Woodruff.
2. Karp, L. A., and Czernobilsky, B.: Glandular inclusions in pelvic and abdominal para-aortic lymph nodes, Am. J. Clin. Pathol. 52:212, 1969. 3. Katzenstein, A. A., Mazur, M. T., Morgan, T. E.. and
746
4 5. 6.
7.
8.
9.
IO.
Ehrmann,
federschneider,
and Knapp
Kao. M.: Proliferative serous tumors of the ovarv. Am. J, Surg. Pathol. 2:339. 1978. Fvoodruff, J. I).: Personal communication, 1978. Parmley, ‘I’. I-I., and Woodruff, J. D.: The ovarian mesothelioma, AM, J, OBSTET. GYNECOL. 120:234, 1974. Covell, I.. M.. DiSciulIo, A. J., and Knapp, R. C.: Decidual change in pelvic lymph nodes in the presence of cervical squamous cell carcinoma during pregnancy. AM. J. OBSTEI. GYXECC)L. 127:674, 1977. Taussig, F. ,J.: A study of the lymph glands in cancer of the cervix and cancel of the vulva, AM. J. OBSTET. GYSKOL. 36:819. 1938. Javert, C. ‘I’.: The spread of benign and malignant endomctrium in the lymphatic system with a note on coexisting vascular involvement, AM. J. OBSTET. GYNECOL. 64:780, 1952. Wertheim, E.: The extended abdominal operation for carcinoma uteri. Based on 500 operative cases, A&t. J. OBs-I El. GYNLCOL. 66: 169, 1912. Huhn, F. 0.: Driiseneinschliisse in Beckenlymphknoten drt- Frau. Vitx,hows Arch. Pathol. Anat. 335:84, 1962.
March Am. J. Obstet.
Il.
15, 1980 chmecd
Schnurr, R. C., Delgado, G., and Chun, B.: Benign glandular inclusions in para-aortic lymph nodes in women undergoing lymphadenectomies, AM. J. ORSTET. GYNECOL.
130~813,
1978.
12. Bergman, F.: Carcinoma of the ovary, a chnicopathological study of 86 autopsy cases with special reference to mode of spread, Acta Ohstet. Gynecol. Stand. 45:211. 1966. IS. Aure, J. C., Hoeg, K., and Kolstad, P.: Clinical and histologic studies of ovarian carcinoma. Long-term followup
of 990
cases,
AM.
J. OBSTET.
GYNECOL.
37: 1, 1971.
14. Julian, C. G., and Woodruff, J. D.: The biologic behavior of low-grade papillary serous carcinoma of the ovary, Obstet. Gynecol. 40~860, 1972. 15. Munnell. E. W., Jacox, H. W., and Taylor, H. C.: Treatment and prognosis in cancer of the ovary, with a review of a new series of 143 cases treated in the years 1944 1951, Am. J. Obstet. Gynecol. 74: 1187, 1957. 16. Santesson, I.., and Kottmeier. H. L.: General classification of ovarian tumors. Ovarian Cancer, UICC Monograph series, vol. 1 1, New York, 1968, Springer Verlag, p. I.
EHRMANN,
J.
FEDERSCHNEIDER,
M.
R. C.
M.D.
KNAPP,
Brookline,
M.D.
M.D.
Massachusetts
In order to properly stage patients with ovarian carcinoma, we are routinely removing and microscopically examining sample aortic lymph nodes in these patients, since aortic lymph node metastases may affect long-term survival. Inasmuch as benign glandular inclusions can be found in pelvic and aortic lymph nodes, we have run into difficulty distinguishing such inclusions from genuine me&Stases in cases of low-grade or borderline serous ovarian carcinomas. Atypical epithelium in these tumors may closely resemble the lining of benign glandular lymph node inclusions. Moreover, like metastases benign glandular inclusions may grow in the peripheral sinusoid, show epithelial papillae and psammoma bodies, and may even proliferate as small sheets of cells. Just how crucial it is to recognize aortic lymph node metastases in these low-grade tumors will be clarified when the prognostic importance of aortic node metastases becomes understood. (AM. J. OBSTET. GYNECOL. 136:737, 1960.)
EARLY Stage I undifferentiated and embryonal ovarian carcinomas have been shown to be associated with a poor prognosis when microscopic aortic lymph node metastases are present.’ In order to more accurately stage ovarian carcinoma, we are examining aortic lymph nodes in all patients to determine whether the nodes contain metastases and to see whether the metastases correlate with histologic type and grade of the primary ovarian tumor. During the course of this investigation, four cases of low-grade or borderline ovarian carcinoma were found associated with glandular structures in aortic lymph nodes. Benign glandular inclusions within pelvic and aortic lymph nodes are a well-known entity.* However, in three of the four cases, the ovarian tumors were so well differentiated that there was great difficulty in deciding whether the epithelial structures within aortic nodes were metastases From the Departments Gynecologic Oncology Gynecology, Harvard Hospital for Women.
of Pathology and Division oj of the Department of Obstetrics and Medical School, and the Boston
Received for publication Revised April Accepted April
February
8, 1979.
2, i979. 10, 1979.
Rep&t requests: Dr. Robert L. Ehrmann, Parkway Division, Boston Hospital for Women, 245 Pond Ave., Brookline, Massachusetts 02146. 000%9378/80/060737+10$01.00/0~
1980 The C.
V. MO&y co.
or benign glandular inclusions. Aortic metastases indicate Stage III carcinoma, which requires chemotherapy and/or whole abdominal irradiation with its inherent risks. Determining whether aortic metastases are present or not may be crucial to the life of the patient. The purpose of this paper is to deal with identification of metastases in aortic lymph nodes and to then comment on their implications.
Clinical data and pathology The essential clinical data are given in Table I. In Case 2, the uterus was adherent to the peritoneum posteriorly, and it was necessary to do a modified radical hysterectomy to release the ureters and free up the uterus. At laparoscopy prior to surgery in Case 3, a biopsy of the right ovarian mass was interpreted as a papillary fibroma. In Case 4, the supracervical hysterectomy and bilateral salpingo-oophorectomy were performed at an outside hospital. The patient was then referred to our hospital where a staging laparotomy was performed together with multiple biopsies of tumor implants. In all of the cases, removed pelvic and aortic lymph nodes appeared grossly normal. Using recently published criteria,3 the ovarian tumors in Cases 1 and 2 would probably be reclassified as borderline malignancy. In any event, the important point is that all the tumors were low grade. 737
738
Table
Ehrmann.
I. C%nical
Federschneider,
data,
March Am. J Ohstrr.
and Knapp
diagnoses,
and
treatment Findings at operation
Warging mass
pelvic
Heavy bleeding, large pelvic mass Bilateral hard adnexal masses found on physical examination Pelvic-
pain
15. 1980 Cknecd
Bilateral papillary ovarian tumors
Operution
cystic
TAH and BSO: removal of an aortic lymph node; remo\al of Meckel diverticulum.
Bilateral multicystic ovarian tumors with external papillary growth and extension to right broad ligament Bilateral nodular cystic ovarian tumors with external excrescenses and peritoneal seedings, including diaphragm
Modified radical hysterectomy with BSO: removal of representative pelvic and aorticlymph nodes Laparoscopy subsequendy followed by TAH and BSO; excision of involved peritoneum; removal of four aortic lymph nodes
Bilateral papillary cystic ovarian tumors and widespread peritoneal implants including omentum
Supracervical hysterectomy and BSO, followed later by sraging laparotomy, partial omentectomy. multiple biopsies of implants, and removal of representative pelvic and anrtir lymph nodes
M’ithin the fibrous srrmm of’ the tumor uerr man) small cvsts. some lined hv slightly pleomor-phic lo\%- columnar cells. others lined by benign-appearing ciliated tubal-typr epithelium. I’sammom;t bodies WPI-c f’requent. The ovarian tumors were diagnosed as welldif’ferentiated papillar) serous c\staderlocarcinorna. grade 1. The endometrium showed hyperplasia. Much to everyone’s surprise, 19 of 44 pelvic and -4 of 4 aortic lymph nodes were fi)und to contain glandutat structures. interpreted as metastases. ?-hew structllres wxe very numerous in the aortic lymph nodes, as illustrated in a low-power view (Fig. 4). ‘I‘hey consisted of small cystically dilated irregular glands, most frequent ar the node periphery. but none identiticd within the peripheral sinusoid. Similar to Case I. the cpithelium lining these glands \vas simple cuboidal to low columnar, and focally ciliated. There was slight variation in nuclear size, with central micronucleolIls and no mitoses. The glandular epithelium in the nodes closeI) resembled the more benign-appearing components of’ the ovarian tumors, nameI), the crevices between papitlae and the small cysts within fibrous stroma. X supraclavicular nodal biopsy was found to be normal. Case 3. Both ovaries were surrounded and almost replaced by broad dense fibrous papillac containing small gland spares. The papillae were covered in most places I,\ a single layer of tubal-t! pe (uhoidal to loJ\ cotumna~- epithelium with varying f’wal stratification ~tp to ten cells deep. The epithelial nuclei showed minor rounding
atypia.
i.e.,
n;trrow
prominent
clwr
micronucleoli
with
;t sur-
Ionc ;IIIC~ sli,qhr 11~1c1rar plt~~-
Volume Number
Tumor
136 6
diagnosis
and clinical stage
Distinguishing
Original aortic lymph node diagnosis
Subsequent treatment
Papillary serous cystadenoca, grade 1, stage Ib
Benign glandular inclusions
None
Papillary serous cystadenoca, grade 1, stage III Papillary serous cystadenofibroma of borderline malignancy, Stage III Papillary serous cystadenoma of borderline malignancy, Stage III
Metastases
X-ray treatment of pelvis; chlorambucil
Metastases
None; follow-up laparoscopy after three months
Metastases
Intraperitoneal P-32 radioisotope
morphism. Mitoses were rare. In many small foci there were surface micropapillae from which cell clusters exfoliated. The micropapillae contained large numbers of psammoma bodies (Fig. 5). It was the overall massive replacement of the ovaries by tumor together with the slight nuclear pleomorphism and minimal cell exfoliation that led to a diagnosis of papillary serous adenofibroma of borderline malignancy. The biopsied small peritoneal lesion closely resembled the ovarian primary. The peritoneal lesion showed connective tissue with psammoma bodies and a few micropapillae with exfoliating cell clusters. One of four aortic lymph nodes showed in its periphery small ciliated glands and epithelial papillae undergoing degeneration and replacement by psammoma bodies (Fig. 6). These epithelial changes closely resembled that of the ovarian tumor. In one focus, epithelial papillae and cell clusters were seen within the peripheral sinusoid (Fig. 7). This will be commented upon shortly. The aortic node lesion was diagnosed as metastatic papillary serous adenofibroma of borderline malignancy. Case 4. The ovarian tumors showed cysts and surface growth with connective tissue papillae covered by low columnar epithelium one to six cells deep. Single cells and clusters exfoliated from the papillae (Fig. 8). Abundant cilia were noted in some areas, and there were occasional psammoma bodies. The tumor cell nuclei showed a fine, even granularity and slight pleomorphism. Cytoplasm was scant and mitoses were rare. Because of the marked cellular differentiation and exfoliation, and absence of capsular invasion, we
lymph
node
metastases
from
glandular
inclusions
739
diagnosed the tumor as papillary serous cystadenoma of borderline malignancy. Papillary tumor was growing on the serosal surface of the uterus and superficially invading the underlying myometrium. A tumor implant was also present in a uterosacral ligament biopsy. The peritoneal metastases varied from papillary tumor with psammoma bodies to small benign-appearing glands lined by tubal-type cuboidal epithelium. The involved aortic lymph nodes contained irregular, variably dilated glandular spaces, mostly in the node periphery, but none identified in the peripheral sinusoid. These glands were lined by tubal-type ciliated cuboidal to columnar cells, with occasional focal stratification up to three cells deep. The nuclei were generally bland, with a prominent central micronucleolus. Mitoses were rare. There were several papillary glands with psammoma bodies (Fig. 9). The cell nuclei in the papillary epithelium were somewhat disoriented and granular. In addition to the glandular structures, the lymph node tissue near one of the papillary glands contained isolated rosettes and sheets of epithelial cells, and a psammoma body (Fig. 10). These loose structures intermingling with the lymphocytes strongly suggested metastatic tumor and will be commented upon shortly.
Comment The structures within aortic lymph nodes of the patients just described should be reconsidered in the light of what is already known about glandular inclusions within lymph nodes in general.’ These structures have been recognized since 1897 and have been variously interpreted as lymphatic transport of endometrial glands from the uterus, fragments constricted off lymph vessels as a result of chronic inflammation or carcinoma, Wolffian remnants, Miillerian metaplasia of coelomic epithelium, and mesothelial inclusions from the overlying peritoneum.“ According to the latter theory, glandular inclusions in lymph nodes illustrate the multicentricity of peritoneal proliferations which can occur with serous ovarian tumors, and which can be misinterpreted as metastases5 Decidual changes in lymph nodes have also been interpreted as metastatic cancer.6 To date, the exact origin of these structures remains unknown. The glandular inclusions are found exclusively in females2 They are often cystically dilated and are usually lined by simple benign-appearing cuboidal epithelium that is often ciliated. However, the lining epithelium may be simple columnar or pseudostratified columnar. Occasionally, the epithelium forms papillary infoldings into the gland lumens. Cytoplasmic or intraluminal secretion may be present, and periglandular calcifications resembling psammoma bodies may occur, some of which distort the glandular
740
Ehrmann. Federschneider,
and Knapp
Fig. 1. Case 1. Left ovary with grade 1 papillary serous cystadenocarcinoma. x 319.) Table
II. Gross features
Care
No.
Maximum diameter
of ovarian tumor (cm)
1.5 (left) 7 (right) 20 (left) 12 (right) IO (left) 9 (right)
1
8 (left) IO (right)
(Hemataxylin
and eosin.
tumors 7-U
uvzght
Internal
VLW
(g-m)
I .42.5 (left)
87 (left) 84 (right)
General appearance Unilocular
Extfnal growth
papillary
growth
Yes
No
Multicystic mass
Yes
Yes
Hard, white nodular mass with interspersed small cysts Multicystic mass (left), unilocular cyst (right)
NO
Yes
shape h111osc~ al-c exr~cmel~ rare. In most ~ase5. the glands arc peripherally located Lvit bin I he fibrous capstric or wrtitxl portion of the hmph nodes. E;arp and C;/.ex-nobilsk\” found seven cases in their $rries of 50 autoap) c.ISC’S ot- an incidence ot’ l-45: , that showed glandular inc.lusions within lymph nodes (pelvic or aortic). N~nt: of the seven cases had malignant tumors, None ot’tht. glandular structures ohset-vccl bv Karp and (Sizer-nobilsk~ wart’ found tvithin the peripheral sinusoid. in I otrtrast to ‘raussqi and J,~ver.t~ isho often tound such >rructurcs. which the\ hcli~ved to be enrlomctriosis. \
cyst
papillary
Yes (left only)
Yes (left and right)
of the cervix. ‘There is no satisfactor) explanation for this, although Huhn I” felt that groll th of the carcinoma was accompanied bv a nonspecific factor which favored developmenr of the glandular inclusions. One wonders if an increased incidence also occurs in ovarian c-arcinoma. Of all the many authors, Schnurr and associatesl’ are the only ones \~ho warn that a false diagnosis of metastatic adenocarcinoma in aortic lymph nodes can occur if the pathologist is unaware of benign glandular inclusions. Having briefly reviewed the concept of glandular in&sions. we can now re-evaluate these structures in the fbur patients already presented. In Case I. the aor-tic lymph node inclusions were benign appearing (Fig. Z), in contrast to the malignant
Volume 136 Number 6
Distinguishing
Fig, 2. Case 1. Aortic lymph node with benign glandular
lymph
node
me&stases
inclusions. (Hematoxylin
Fig. 3. Case 2. Right ovary with grade 1 papillary serous cystadenocarcinoma. eosin. X319.) featul -es of the ovarian carcinoma (Fig. 1). We therefore f eel confident that the aortic node structures were not m IetastCtses. On our review of the outside slides on Case 2, the gland inclusions within aortic nodes (Fig. 5) appeared relatil Jely benign, as did the crypt epithelium and small gland spaces within the ovarian tumor. In this case, the ‘YmPt I node structures could be either benign inclu-
from
glandular
inclusions
741
and eosin. X319.)
(Hematoxylin
and
sions or metastatic carcinoma. Since the glal ndular structures were so numerous in the aortic lymph nodes without any destruction of nodal architecture I, and since no papillae were found in any of the lymph nodes, in constrast with the ovarian tumor where papillae were numerous, we concluded that the nodal inclusions in Case 2 were benign, rather than met :astalic carcinoma originally diagnosed.
742
Ehrmann, Federschneider,
and Knapp
March
Am. J. Obstet
Fig. 4. Case and eosin.
2. Aortic x
lymph node with glandular
inclusions interpreted
1.5, 1980 Cwzcol.
as metastases. (Hematoxylin
19.)
Fig. 5. Case 3. Right ovar! with papillary serous adenofibroma of’ borderline malignancy. showing wrfacc mitropapillae and psammoma bodies. (Hematoxylin and e&n. X 319.) Kn t&e 3. \\e originall!~ thought that epithelial papiland ps;tmmoma bodies within the aortic node inclusions (big. 6) indicated metastases, since thesr f’eatuws werr c haractcristic of the oval-ian tumor (Fig. 3. kit-p and 1.,xrnobilsk! however, described these samt f eaturrs u ithin lynph node inclusions in autopsied t.ascs7itl~c~1~~ c~arcinoma. One might then argue that epithelial papillae in (;a~: 3 within the peripheral sinusoid /Fig, 71 indicated malignalIt v. hwauw Karp and C7v1 ix
nobilsky had never seen such structures within nodal Iymphatics of their benign cases. f~cJwevcr, other authors, as already mentioned, described these structures ,uufiwl~ in peripheral sinusoids.‘, h \Ve finally concluded that the aortic node inclusions were benign. and not metastatic tumor. Case 4 is the most controversial of. all since there were widespread definite pelvic and cment;d mrtastases 8s well as invasion ot the utcl-[Is. making the pos-
Volume Number
136 6
Distinguishing
lymph
node
metastases
from
glandular
Fig. 6. Case 3. Aortic lymph node showing gland with papilla and psammoma body, interpreted metastatic tumor. (Hematoxylin and eosin. x 3 19.)
Fig. 7. Case 3. Same lymph node showing epithelial inclusions within the peripheral matoxylin and eosin. x 3 19.) sibility of aortic lymph node metastasis in this case quite plausible. Highly suggestive were papillary glands and psammoma bodies within aortic nodes (Fig. 9) that histologically resembled the peritoneal and uterine metastases in this patient. Karp and Czernobilsky,2 however, showed that papillae and psammoma-like calcifications can occur in benign inclusions. Even more suggestive of metastasis were the loose rosettes and sheets of cells lying among the lymphocytes (Fig. 10). Huhn,t” how-
inclusions
743
as
sinusoid. (He-
ever, described similar, yet benign structures in lymph nodes from patients with cervical squamous cell carcinoma. Despite these diagnostic pitfalls, the papillary appearance in the aortic node glandular inclusions was so striking that we sustained the diagnosis of metastatic tumor. It must be evident to the reader that the diagnosis of lymph node metastases is so difficult in the absence of clearcut malignant features, it becomes almost an arbi-
744
Ehrmann,
Federschneider,
and Knapp
Fig. 8. Case 4. Left ovary and rosin. ~319.)
Fig, 9. Case 4. Aortic the ovarian primary.
with papillary
March 15, 1980 Am. J. Ohstet. Gynecol.
serous
cvstadrnoma
of borderline
lymph node with papillary glandular structure Note psammoma bodies and cilia. (Hematoavlin
malignancy.
interpreted as metastatic and eosin. ~319.)
ing to Bergman. rinal,
(Hematoxylin
These included
supraclavicular.
axillary,
from
pelvic, aortic., mediasand
inguinal
+ph
nodes. With rhe subject ol' our own paper in mind, we must quesGon Bergman’s identification of lymph node metastdses in borderline ovarian tumors. It is quite possible that he was observing benign glandular inclusions.
l’aticnts
with borderline
or low-grade
ovarian
carc-i-
Volume Number
136 6
Distinguishing
lymph
Fip.. 10. Case 4. Same aortic lvmnh node with epithelial (Hematoxylin and eosin x319:) ’ nomas live for many years, even with pelvic spread,‘“-‘6 and most recurrences are intra-abdominal. As reported by Aure and colleagues,13 after 20 years there was a 76% survival rate of 74 patients with borderline serous tumors compared with only an 18% 20 year survival rate of 283 patients with invasive serous carcinoma. On the other hand, between 15% and 25% of patients with borderline malignant tumors will eventually die from a recurrence,‘” and patients with initial pelvic spread from their borderline tumor have a shorter survival than those patients without such spread.r3’ r4, r6 Although aortic lymph nodes were not examined in these reported studies, the presence or absence of aortic .node metastases in cases of borderline tumors may significantly influence the prognosis. Aortic node metastases might remain dormant for a long time before they disseminate, but there is evidence that late distant metastases do occur in borderline serous carcinoma. Munnell and associatesI cite the case of a patient operated upon in 1935, who 20 years later died with pulmonary metastases that microscopically looked like borderline serous carcinoma. It is possible that most deaths from low-grade or borderline carcinomas occur before the aortic node metastases have disseminated, but there is no documentation of this. In any
REFERENCES
1. Knapp, R. C., and Friedman, E. A.:Aortic lymph node metastases in early ovarian cancer, AM. J. OBSTET. GYNECOL. 119:1013, 1974.
node
metastases
from
glandular
inclusions
745
rosettes, sheets, and a psammoma body.
event, since most women with borderline ovarian tumors are young, with a long life expectancy,” we must evaluate all areas of tumor dissemination including aortic lymph nodes. Then consideration can be given to proper treatment plans. If pathologic features are insufficient to distinguish benign glandular inclusions from metastatic tumor in aortic lymph nodes, it may be best not to treat for aortic nodal disease. In summary, as the clinician develops better surgical techniques in staging patients with ovarian carcinoma and in performing aortic lymph node dissections, the pathologist is called upon to make every effort to determine whether or not metastases exist in the removed aortic nodes. The prognosis of the patient and decision on therapy may in fact depend on the accuracy of this interpretation. It would appear that the borderline or well-differentiated lesions may have a low propensity to metastasize to the aortic nodes and that epithelial structures resembling metastases are, in fact, benign. If, on the other hand, true aortic node metastases do exist, these may affect long-term survival. The authors wish to thank the following consultants for their valued opinions on the cases described in this paper: Dr. Arthur T. Hertig, Dr. Robert E. Scully, and Dr. J. Donald Woodruff.
2. Karp, L. A., and Czernobilsky, B.: Glandular inclusions in pelvic and abdominal para-aortic lymph nodes, Am. J. Clin. Pathol. 52:212, 1969. 3. Katzenstein, A. A., Mazur, M. T., Morgan, T. E.. and
746
4 5. 6.
7.
8.
9.
IO.
Ehrmann,
federschneider,
and Knapp
Kao. M.: Proliferative serous tumors of the ovarv. Am. J, Surg. Pathol. 2:339. 1978. Fvoodruff, J. I).: Personal communication, 1978. Parmley, ‘I’. I-I., and Woodruff, J. D.: The ovarian mesothelioma, AM, J, OBSTET. GYNECOL. 120:234, 1974. Covell, I.. M.. DiSciulIo, A. J., and Knapp, R. C.: Decidual change in pelvic lymph nodes in the presence of cervical squamous cell carcinoma during pregnancy. AM. J. OBSTEI. GYXECC)L. 127:674, 1977. Taussig, F. ,J.: A study of the lymph glands in cancer of the cervix and cancel of the vulva, AM. J. OBSTET. GYSKOL. 36:819. 1938. Javert, C. ‘I’.: The spread of benign and malignant endomctrium in the lymphatic system with a note on coexisting vascular involvement, AM. J. OBSTET. GYNECOL. 64:780, 1952. Wertheim, E.: The extended abdominal operation for carcinoma uteri. Based on 500 operative cases, A&t. J. OBs-I El. GYNLCOL. 66: 169, 1912. Huhn, F. 0.: Driiseneinschliisse in Beckenlymphknoten drt- Frau. Vitx,hows Arch. Pathol. Anat. 335:84, 1962.
March Am. J. Obstet.
Il.
15, 1980 chmecd
Schnurr, R. C., Delgado, G., and Chun, B.: Benign glandular inclusions in para-aortic lymph nodes in women undergoing lymphadenectomies, AM. J. ORSTET. GYNECOL.
130~813,
1978.
12. Bergman, F.: Carcinoma of the ovary, a chnicopathological study of 86 autopsy cases with special reference to mode of spread, Acta Ohstet. Gynecol. Stand. 45:211. 1966. IS. Aure, J. C., Hoeg, K., and Kolstad, P.: Clinical and histologic studies of ovarian carcinoma. Long-term followup
of 990
cases,
AM.
J. OBSTET.
GYNECOL.
37: 1, 1971.
14. Julian, C. G., and Woodruff, J. D.: The biologic behavior of low-grade papillary serous carcinoma of the ovary, Obstet. Gynecol. 40~860, 1972. 15. Munnell. E. W., Jacox, H. W., and Taylor, H. C.: Treatment and prognosis in cancer of the ovary, with a review of a new series of 143 cases treated in the years 1944 1951, Am. J. Obstet. Gynecol. 74: 1187, 1957. 16. Santesson, I.., and Kottmeier. H. L.: General classification of ovarian tumors. Ovarian Cancer, UICC Monograph series, vol. 1 1, New York, 1968, Springer Verlag, p. I.