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Uterine sarcomas
UTERINE SARCONIAS Classification, Diagnosis, and Prognosis Richard L. Kempson, J.H.D.,* and Wagili Bari, AI.D. t
Abstract Uterine sarcomas often present diagnostic problems. In addition, the plethora of names for the same tumor or groups of tumors makes it difficult to correlate diagnostic and therapeutic data. We have proposed a modification of the classification of Ober that we think offers a simple, straightforward, histogenetically accurate terminology for this group of tumors. It also permits as detailed a subclassification of each group of tumors as now seems warranted. To test this classification and the available diagnostic criteria, the uterine sarcomas at Barnes Hospital in St. Louis have been evaluated. Leiomyoma and leiomyosarcoma can be accurately separated in most instances. Smooth muscle tumors that have invaded contiguous organs or blood vessels are malignant. If invasion is not present the mitotic rate is evaluated. Tumors with less than 5 mitoses per 10 high power fields (HPF) are benign. Those with higher mitotic counts are malignant. The prognosis for leiomyosarcomas with greater than 10 mitoses per 10 HPF is poor and metastases are frequent. The behavior of smooth muscle tumors with mitotic counts between 4 and 9 per 10 HPF is less' certain, but some tumors with this level of mitotic activity will metastasize. Patients with malignant mixed Mullerian tumors of the homologous type that are small and not invasive or have invaded the myometrium only superficiallymay be cured by hysterectomy. If the tumors are large and highly invasive, the outlook is almost hopeless in spite of any form of therapy. Heterologous malignant mixed Mullerian tumors with chondrosarcoma as the heterologous element and without significant invasion may also be cured. In our series the presence of osteoid, bone, or rhabdornyoblasts indicated a highly malignant neoplasm with fatal outcome. All such tumors were large at the time of initial diagnosis. The infiltrating stromal tumors with mitotic counts of about 20 per 10 HPF all metastasized; those with 5 per 10 HPF or less have not metastasized or recurred after therapy. This provides a sharp dividing point between endolymphatic stromal myosis and endometrial stromal sarcoma. The behavior of tumors with mitotic counts of 6 to 20 per 10 HPF is unknown, but they may have a better prognosis than stromal tumors with higher counts.
*Associate Professor of Pathology, Stanford University School of Medicine. Surgical Pathologist. Stanford University Hospital, Stanford. California. tClinical Assistant Professor of Pathology, Washington University School of Medicine. Pathologist. St. John'S Mercy Hospital. St. Louis. Missouri.
331
HU~[AN PATHOLOGY-VOLUME 1, NUMBER 3
Accurate diagnosis and classification of any group of tumors is essential before effective therapy can be determined. If tumors with similar origin and behavior are classified separately, or if tumors of divergent origin and behavior are classified together, the results of therapy will not be valid. Establishing accurate diagnostic criteria for uterine sarcomas has been particularly difficult because of the large number of different histologic patterns that occur and because of the difficulty of separating benign from malignant mesenchymal neoplasms. This has resulted in a nomenclature that is confusing, complex, and often ambiguous. Recent publications have evaluated the diagnostic featur.es for the various types of sarcomas and have proposed definite criteria for the separation of malignant and benign tumors. Now a standard acceptable system of classification is needed. Only when this is accomplished will accurate studies on the effectiveness of treatment be possible. The purpose of this study is to review the uterine sarcomas from the Barnes Hospital in St. Louis, Missouri, in order to evaluate the diagnostic criteria previously published for uterine sarcomas and to propose a simplified practical classification of these tumors. The pathologic data are correlated with patient survival to determine the value of the proposed plan of classification and the validity of the diagnostic criteria.
NOMENCLATURE AND CLASSIFICATION
332
Several different classifications of uterine sarcomas have been proposed, but none of these has been universally accepted.v " In our experience the most useful and histogenetically correct classification is that proposed by Ober.' However, in attempting to utilize Ober's scheme for routine diagnosis and for the tumors in this study, we found the original classification more detailed than neces-: sary. As a result, we have developed a modification of the original abel' classification that we think is readily applicable to routine tissue diagnosis and provides an accurate nomenclature for the uterine sarcomas (Table I).
September 1970 TABLE 1.
CLASSIFICATlO1> OF
UTERII'\E SARCO~IAS
I. Pure sarcomas A. Pure homologous I. Leiomyosarcoma 2. Stromal sarcoma 3. Endolyrnphatic stromal myosis" 4. Angiosarcoma 5. Fibrosarcoma B. Pure heterologous I. Rhabdomyosarcoma (including sarcoma botryoides) 2. Chondrosarcoma 3. Osteosarcoma 4. Liposareo rna
I I. ;\Iixed sarcomas A. Mixed homologous B. Mixed heterologous Mixed heterologous sarcomas with or without homologous dements Ill. Malignant mixed ;\lUllerian tumors (mixed mesodermal tumors) A. ;\lalignant mixed ~Iiillerian tumor. homologous tH,e Carcinoma plus leiomyosarcoma. stromal sarcoma, Of fibrosarcoma, or mixtures of these sarcomas B. ;\lalignant mixed ~liillerian tumor, heterologous lype Carcinoma plus heterologous sarcoma with or withe OUt homologous S31'C01113 IV. Sarcoma, unclassified v, Malignant lymphoma *This tumor was benign in this series, but has been classified as sarcoma became of reponed recurrences and metastases.
This classification separates the sarcomas according to the number and types of recognizably differentiated tumor tissues present. Pure sarcomas contain only a single recognizable sarcomatous element, whereas mixed tumors contain two or more different malignant elements. The malignant cells in homologous tumors are morphologically recognizable as being derived from mesenchymal tissue normally present in the uterus. Heterologous tumors contain cells differentiated into mesenchymal structures not normal1y present in the uterus, such as bone, striated muscle, or cartilage. Therefore, a pure homologous sarcoma is composed of a single cell type resembling mesenchymal tissue found in the normal uterus, such as smooth muscle in a pure leiomyosarcoma. A pure heterologous tumor contains a single type of heterologous sarcoma. The mixed sarcomas contain tumor cells that have differentiated into at least two
UTERINE SARCO;\IAS-Knll'sox, different types of homologous or heterologous sarcoma without evidence of epithelial elements, Examples would be sarcomas containing mixtures of leiomyosarcoma and stromal sarcoma, or stromal sarcoma and rhabdomyosarcoma. The malignant mixed Miillerian tumors contain carcinoma and sarcoma mixed together. The carcinoma may be adenocarcinoma, squamous carcinoma, undifferentiated carcinoma, or any mixture of these, The sarcoma may be pure or mixed, homologous or heterologous. There is never evidence of the ectodermal or endodermal tissues found in teratomas. Although this group of tumors is often designated as mixed mesodermal tumors, the best histogenetic term is malignant mixed Mullerian tumor and we have used this terminology. . The pure sarcomas, whether homologous or heterologous, should be designated by their familiar names, such as leiomyosarcoma, stromal sarcoma, or rhabdomyosarcoma, The mixed sarcomas without carcinoma are designated as mixed sarcoma, homologous type, or mixed sarcoma, heterologous type: Neoplasms with carcinoma and sarcoma would be designated as malignant mixed Miillerian tumor, homologous type, or malignant mixed Mullerian tumor, heterologous type, depending on the differentiation of the sarcomatous tissue. Almost all of the classifiable sarcomas contain areas in which the malignant cells are undifferentiated, often with a "fibrosarcoma-like" pattern, These areas should not be interpreted as fibrosarcoma unless the diagnostic criteria for that tumor are present." Some sarcomas arc composed primarily of undifferentiated cells and many sections must be examined to find diagnostic areas. Histochemical stains are often needed to prove differentiation of malignant tissue. In spite of thorough sectioning and staining; some sarcomas of the uterus are composed entirely of tumor tissue so poorly differentiated as to defy classification. Forcing these tumors into the classification serves no useful purpose and they should be diagnosed as "sarcoma unclassified." The majority of uterine sarcomas will be leiomyosarcomas. malignant mixed Milllerian tumors, or stromal sarcomas. Other types are rarely encountered.
BAHI
We suggest . that all confusing and histogenetically meaningless terms, such as carcinosarcoma and sarcoma botr'yoides, be discarded. Although the term carcinosarcoma has been used to designate mixed mesodermal tumors of the homologous type, it has also been used to designate' mixed heterologous tumors, and its usefulness as a specific diagnostic term has been compromised. Sarcoma botryoides is a clinical term for grapelike tumors and should not be used morphologically. Most of the botryoid sarcomas in children arc embryonal rhabdomyosarcomas, and those in adults are usually malignant mixed Mullerian tumors. LEIOMYOSARCOMA The lack of uniformly accepted histologic criteria for the diagnosis of leiomyosarcoma of the uterus has made it almost impossible to determine the prognosis and to evaluate the results of therapy. This is clearly demonstrated by the discrepancy in the reponed incidence. which varies from 0.22 per cent" to as high as 6 per cent" of all uterine smooth muscle tumors, and by the disparity in the five year survival figures, which range from 3 per cent to as high as 75 per cent.5, 1-9 Taylor and Norris,'? and Aaro and his coworkers," II have reponed that the number of mitoses is a reliable basis for separating leiomyomas from leiomyosarcomas. Others have depended on pleomorphism, invasion, and the presence of giant cells as reliable criteria." 1, 12 At the far extreme, Corscaden and Stout 13 maintained that recurrence'or metastases, or both, are the only valid evidence of malignancy. Our purpose is to re-evaluate the accuracy of these criteria, especially the mitotic activity, in establishing the diagnosis of leiomyosarcoma of the uterus, If, as Taylor and Norris have reponed, there is a demarcation between benign and malignant tumors on the basis of the numbers of mitoses, accurate histologic diagnosis of leiomyosarcoma is possible. These authors state that tumors containing more than ] 0 mitoses per ]0 high power fields (H PF) arc leiomyosarcomas and that those with less than this number of mitoses arc benign cellular lciomyornas.!''
333
HUMAN PATHOLOGY-VOLU;"[E
1,
NUMBER
Material and Methods A total of 29 cases diagnosed during the past 30 years as cellular or atypical leiomyoma and leiomyosarcoma were found in the pathology and clinical files of Barnes Hospital, In each case histologic sections were reviewed and the most active areas of mitotic activity were evaluated by two independent counts of at least 40 high power fields. Three groups of tumors were defined on the basis of the number of mitoses per 10 HPF. All tumors with 10 or more mitoses per 10 HPF were placed" in the first group. The second group had 5 to 9 mitoses per 10 HPF, and the third had either no mitoses or less than 5 per 10 HPF. Also tabulated for each tumor were the location of the tumor in the uterus, the extent of growth outside the uterus at the time of surgery, the gross appearance of the tumor, the presence or absence of multinucleated giant cells, the presence or absence of vascular invasion, and the degree of cellular atypism in both the giant cells and the stromal cells. How-
TABLE 2.
3
September 1970
ever, the three groups just noted were defined only on the basis of the number of mitoses without regard to the other factors. The clinical records of the patients were then obtained, and the presenting symptoms, treatment, and post-therapy course were determined. Follow-up information was available for 27 of the 29 patients.
Results Twelve patients had tumors that contained more than 10 mitoses per 10 HPF; follow-up information was available for all 12 (Table 2). Nine of the patients have died as a result of the tumor, and two had metastases when last seen. Two of the remaining three patients have been followed for less than two years, and the third has survived for nine years without evidence of tumor. Seven patients were placed in the second group since their tumors contained 5 to 9 mitoses per 10 HPF (Table 3). Follow-up information was available for six of these patients, of whom five have
GROSS FI)\D1)\GS, CYTOLOGIC ATYPIS~I, A)\D SUBSEQ.UE)\T BEHAVIOR OF PURE 10 OR ;"[ORE ;"hTOSES "PER 10 HPF* (LEIO~IYOSARCmIA)
S~IOOTH ;"[USCLE TU~IORS WITH
Degree of AtJpism of Stromal Cells
Age
53
12
0
0
+
0
2
68
13
0
0
++
0
3
66
25
++
++
++
Patient
No. Giant
cai»
Extension of Tumor Outside Uterus
Rectum
4
43
24
++
+++
+++
Bladder, lateral pelvic wall, peritoneum
5
53
14
++
+++
+++
0
6
50
20
++
++
++
Parametrium
7
39
34
0
0
++
Parametrium
8
59
13
+++
+++
+++
0
9
56
2-1
+++
+++
++
0
10
-13
12
+++
+++
+++
II
51
15
0
0
+
0
12
72
17
+++
+++
++
0
'IIPF = high power fields
"0
334
Degree of At)pism of Giant Cells
No, Mitoses perIOHPF
= none
+= minimal ++= moderate +++= marked
Parametrium
Outcome
Died 3 years with metastases Living without metastases, 14 mo. Living without metastases, 3 mo. Died 5 years with metastases Died 15 months with metastases Died I week with metastases ~Ietastases when fast seen Died 3 years with metastases Metastases when last seen Died 7 years with metastases Died 12 years with metastases Living and well, 9 years
UTERINE
3.
TABLE
SARCOMAS-KDIPso~, BARI
GROSS FIXDlXGS, CYTOLOGIC ATYPJS~I, AXD SUBSEQ.UEXT BEHAVIOR OF S~IOOTII 5 TO 9 MITOSES PER 10 HI'F (LEJO~IYOSARCmIA)
~IUSCLE TU~IORS WITII
No. Giant Cells
Degree of At)'pism of Giani Cells
Degree of Atypism of Stromal Cells
Extension of Tumor 10 Contlg-
Age
No. Mitosis
-19
6
+++
++t-
++t-
O
2
-12
9
+++
++t-
+t-+
Vagina
3
60
5
+++
++t-
++t-
Pelvis
-1
-12
8
-t+
++t-
++t-
O
5
-13
9
0
0
+t-+
Patient
6
5i
7
+
-++
-++
7
-1-1
5
+
+
+
died. One patient was lost to follow-up after a three year tumor-free interval, and one patient died during hysterectomy. In 10 cases the tumors contained less than 5 mitoses per 10 HPF (Table 4). With one exception, all of these patients are alive and were well without evidence of metastases when last seen one to I I years after initial therapy. The exception is a patient who had a uterine smooth muscle tumor removed in 1958 with one mitosis per 10 HPF. In 1965 a metastasis, histologically the same as the original tumor, was re-
TABLE
4.
I-
Age
Parametrium
I'aramcuium Small intestine Pelvis
Outcome Lost to follow-up. 3 years Died 3 mo. with metastases Died -1 mo. with metastases Died I year with metastases Died 5 months wit~ metastases Died 15 months with metastases Died during hysterectomy
moved from the fifth lumbar vertebra, She has remained well without evidence of further metastases. The presence or absence of giant cells does not correlate with survival, and large numbers of giant cells may be found in tumors with few mitoses and a benign course. Although tumors with large numbers of mitoses have tended to contain more atypical stromal cells, the presence of atypical cells is not a reliable sign of rnalignancy.I'v ':' Those patients whose tumors contained large numbers of mi-
GROSS FIXDlXGS, CYTOLOGIC ATYI'IS~I, AXD SUBSEQ.UEXT BEHA\'IOR OF S~IOOTH
MUSCLE TU~IORS WITH LESS TIIAK
Patient
uous Structure
No. Mitosis
No. Giant Cells
33
Degree of AIJpism of Giani Cells
5
IO HI'F
Degree of AtJpism of Siromal Cells
Extension of Tumor 10 Conliguous Structure
0
0
+
0
2
50
-1
++t-
++t-
++t-
O
3
31
0
0
0
+
0
-1
-18
2
+
+
+
0
5
-12
2
+
+
-++
0
6
55
-t+
-++
-++
0
7
-19
0
+
+t-+
+
0
8
51
0
0
0
+
0
9
-13
0
0
0
+
0
10
58
0
0
0
+
0
-Benign metastasizing leiomyoma.
~retastasis removed
(LEIO~IYmIA)
MITOSES PER
from L5 vertebra,
Outcome Li\'ing and well, 8 years Lost to follow-up Died 10 years of unrelated disease Living and well. II years Living and well, 9 years Living and well, 1} years Living and \I'e1I, 3 years Living and well, 4 years Living' and well. i years Died -1 years of unrelated disease
335
HUMAN PATHOLOGY-VOLUME I, NU;\IBER 3
toses, but with minimal or moderate atypism, often lived for long periods of time before metastases appeared. Of the ten patients with extension of tumor outside the uterus, eight have died as a result of their tumor, one has been followed for only three months, and on e was lost to follow-up. The group of tumors with 5 to 9 mitoses per IO HPF all demonstrated either marked atypism of the stromal cells or extension of tumor outside the uterus. Tumors with 0 to 4 mitoses were all confined to the uterus and with one exception the tumor cells were only minimally or moderately atypical. The patient whose tumor contained markedly atypical cells was lost to follow-up. Vascular invasion was found infrequently and only in tumors with more than 10 mitoses per 10 HPF. The average age and clinical picture of this group of patients were the same as has been previously recorded, and there was no significant difference in symptoms or physical findings among the three groups. Total abdominal hysterectomy, with or without salpingo-oophorectorny, was the treatment for 19 patients. Six patients received radiotherapy before or after surgery, one patient received radiotherapy alone, two patients had supracervical hysterectomies, and one patient required local excision of the tumor. Although the groups of patients are small , there is no difference in 'survival between patients treated by surgery and radiotherapy and those treated by surgery alone.
Comment
336
The number of mitoses is the single most accurate criterion for the diagnosis of leiomyosarcoma. When there arc 10 or more mitoses per 10 HPF, the vast majority of uterine smooth muscle tumors will behave aggressively regardless of cellular atypism, presence of giant cells, or confinement of the tumor to the uterus at the time of surgery. Therefore, tumors with mitotic counts above 10 per HPF are classified as leiomyosarcomas. Our eX7 perience also indicates that tumors with 5 to 9 mitoses per 10 HPF usually behave aggressively and metastasize (Table 3). With less than 5 mitoses per 10 H PF, uterine smooth muscle tumors are almost always benign. The rare tumor that is
Septemb er 19iO
aggressive will fall into the categories of the so-called benign metastasizing leiomyoma and intravenous leiornyomatosis. IS. 16 As exemplified by our case, metastases usually appear at long intervals after the initial surgery, and often can be controlled by surgical excision. There is no way to separate these rare histologically benign but biologically malignant tumors from leiornyomas unless the tumor has invaded contiguous structures at the time of initial surgery (Fig. 1). It is obvious from these results and from previous reports that smooth muscle tumors at the extremes of the spectrum of mitotic activity can be accurately diagnosed by mitotic counts.'?: 11 However, the exact number of mitoses indicating malignancy has been arbitrarily set, and it is unknown whether individual tumors with borderline mitotic counts will be benign or malignant. Taylor and Norris consider tumors with less than 10 mitoses per 10 HPF as benign, while in this series tumors with 5 to 9 mitoses have- frequently behaved aggressively and metastasized. Are tumors with 4 mitoses per 10 HPF always benign and those with 5 to 6 mitoses per 10 HPF always malignant? This is unlikely, and the malignant potential of tumors with borderline mitotic counts between 3 and 9 per 10 HPF is still difficult to predict. . The degree of cellular atypism 'ap pears to be of limited value in determining the malignancy of smooth muscle tumors. Some leiomyosarcomas demonstrate minimal or no cellular pleomorphism while smooth muscle cells in leiornyomas may be markedly atypical (Fig. 2).~· 14 However, tumors with high mitotic counts most often contain a greater number of markedly atypical cells (Fig. 3). In addition, most of the leiomyosarcomas in this series with borderline mitotic counts of 5 to 9 per 10 HPF also contained large numbers of markedly atypical cells. We have no information concerning the behavior of tumors with mitotic counts between 5 and 9 per 10 HPF and minimal or no atypism of the stromal cells. Such tumors may be benign; this would explain the discrepancy between our findings and those of Taylor and Norris.!" The available evidence allows the following conclusions. True invasion of contiguous organs or blood vessels is indica-
UTERINE
SARCO~IAS-KDll' so;,\, BARI
Fig ure 1. Cellular leiom yom a with closely packed sm ooth mu scle nu clei but no a typism or m itoses. (Hematoxylin a nd eosi n slain. fl. x 80 . lt , X 350. )
337
HUMAN PATHOLOGY-VOLUME I, NU~IBER 3
September 1970
Figure 2. Atypical leiomyoma with giant cells and pleomorphism but no mitotic figures. Such tumors should not be diagnosed as sarcoma. (Hematoxylin and eosin stain. x 80.)
338
UTERINE SARCO;\IAS -KDII·SO)\. B.... Rl
Figure 3. Leiomyosarcoma showin g giallt cells. pleomorphism. and an exam plc of abnormal mitosi s. The increased numbers of mitos es in th is tumor allow a diagnosis of sarcoma. (Hematoxylin and eosin stain , x 350.)
339
HUMAN PATHOLOGY-VOLUl\IE 1, NUl\IBER 3
tive of malignancy regardless of mitotic counts or the prcscncc of atypical tumor ccIls. Invasive leiomyosarcoma must be carefully separated from parasitic leiomyomas, which may also grow onto other organs. If invasion is not demonstrated, the mitotic rate is evaluated. Tumors with o to 4 mitoses per 10 HPF arc bcnign reganlIcss of the degree of cellular atypism. Because of our experience we would consider a uterine smooth muscle tumor with 5 to 9 mitoses per 10 HPF and stromal ceIl pleomorphism as malignant. We would also consider the tumor to be malignant if atypism were minimal or absent, but we recognize that the exact behavior of this group of smooth muscle tumors is less certain. Tumors with more than 9 mitoses per '10 HPF must be regarded as being malignant regardless of whether atypism is present and should be diagnosed as leiomyosarcoma. By use of these criteria, the future behavior of almost all uterine smooth muscle tumors can be accurately predicted. If later reports of uterine smooth muscle tumors include tabulations as we have presented, it may be possible to assess more accurately those tumors whose histologic appearance is borderline between benign and .malignant, i.e., with mitotic counts of 5 to 9 per 10 HPF and no stromal ceIl atypism. MALIGNANT MIXED MULLERIAN TUMORS AND MIXED SARCOMAS The wide variety of histologic patterns encountered in malignant mixed Miillerian tumors has created problems in accurate diagnosis and classification." 18. 19 One problem is whether the presence or absence of a specifically differentiated tumor element is an important indication of future behavior. The answer to this question will determine the extent to which these tumors should be subclassified. Information is also needed concerning the response of specific homologous or heterologous elements to therapy. This study was carried out in an attempt to answer these problems and to determine whether other factors influence prognosis.
Material and Methods
340
Thirty-six uterine tumors contammg both carcinomatous and differentiated
Sell/ember 1970
sarcomatous elements, and two tumors containing mixed sarcomas without carcinoma, were found in the files of the Barnes Hospital. Tumors with only undifferentiated sarcomatous elements were excluded. The tumors were subdivided into homologous and heterologous types as previously described (Table 1). Tumors were not placed into the heterologous group unless there was definite histologic evidence of differentiation into tissue not normally found in the uterus, such as bone, cartilage, or skeletal muscle. The type of carcinoma present was also noted. The age of the patients, the presenting symptoms, the treatment, and survival were compared with the gross and microscopic findings. Follow-up information was available for 34 of the 38 patients.
Results The clinical presentation of this group of patients with mixed Mullerian tumors and mixed sarcomas was the same as that reported in previous series.3 • 17 - 19 Abnormal vaginal bleeding was the most common symptom, and some tumors protruded from the cervix. The majority of patients had an enlarged uterus at the time of pelvic examination. Grossly, the tumors were either polypoid or fungating with areas of hemorrhage and necrosis. The tumors invariably involved the endometrium and often exterided into the myometrium for variable distances. Microscopically these tumors demonstrated the wide variation in histologic patterns that has been well described (Tables 5 and 6). Although all tumors had foci where neoplastic cells had differentiated into recognizable epithelium or stromal elements, many had other areas that were bizarre and undifferentiated (Figs. 4 and 5). Large bizarre tumor ceIls with abundant eosinophilic cytoplasm but without cross striations were common and were not considered to be rhabdornyoblasts. A single tumor often showed wide variation in differentiation of tumor cells in different areas. Twenty-one tumors contained carcinoma and homologous sarcoma (Table 5). Adenocarcinoma was the epithelial element in 18 tumors and squamous carcinoma in five; two tumors contained both adenocarcinoma and squamous elements.
TABLES.
l'vIALIGNANT ]\!IXED MULLERIAN TU~IORS (HOMOLOGOUS TYPE)
lJistologic Components S(lrCOJ1lfl Carci1lo'!J(l Patient
~\'qll(/1Il0US
Stromal
l"domJo~
CarrilHlUIl(
Sllrcoma
,HlrW11Ifl
Agc
Treatment
Outcome
.'1d('1I0mvrinoma
IH
llied '2'/. ycars
+
Died I year
+
llicd 10 mouths
+
+
llied 5 mout lis
+
+
Living and well 2 years llied '2 weeks
+
+
l lalf-way through myomcrrium
+ +
Through serosa. Metastases in omenuun Extended !)O% through Protrusion through cervix, Hysterectomy not done Within inner half or
+
Through serosa
'2
77
11
!'H
.j
1i·1
:,
70
TAl I. & II.S.O.•* betatron liOOO R Radium !1ol00 1I1\(./hr.• T.A.II. &II.S.O. Radiatioll,** radium, TAIl. & B.S.O. Exp. lap., hctatron 5000 R T.A.II. & II.S.O.
Ii
(ill
TAIl. & II.S.O.
7
1i:1
llied :1.'1. years
+
+
Il
1l·1
Radium, T.A.II. & II.S.O. Radial ion ~!OOO R
Dicdli 1I10mhs
+
+
0
7R
Rudium 7000 lllA'./hr .• betatron !">CIOO R,
Living and well
+
+
Died 11 weeks
+
+
l" 0 [ollow-u p llied 5 months
+ +
Livinl( and well Il years Living' and well I!'> l1loll1!ls l"o follow-up llied " 1I10llths
+
]0
71i
II 12
!'if) 5,1
1:1
:15
]·1 15 ](j
:15 Il·l IH
TAIl. & II.S.O. TAIl. & II.s.O. Exp, lap .• radiation Radium li700 II1I(./hr., T.A.II. & II.S.O. Radium :,!150 1I1A'./h r., betatron 1l!)00 R Radiat ion 1500"R, T.A.II. & II.S.O. TAIL & II.S.O. T.A.II. & II.S.O.
+
+
+
Radiation fibrosis only. No 1111110r Through serosa
+
1\1JdOl1lillili metastases
myometrium
myomcrrium
·1 }'ea rs
+
+
+ +
+
Extent of tl/mor
+ +
+ +
+
+ +
Metastases, Uterus 1101 ,l\'ail"ble Extension over pelvis Ilair-wa)' through m}"ol1l ct ri 11 111 l lystercctomy not
III 10 '20 21
no !'H 50
,.
f\)
:,8
+
+
Radiation 2~()() R Exp, lap. T.A.II. & II.S.O.•
Living' and well 10ll1onths Died ·1 months Died Ii months Died 5 1I10nths
+ +
nitrogen mustard T.A.II. & II.S.O.
Died -l months
+
Radium :,0'2'2 1I1A'./h r., TAli. & II.S.O.
+
Il
~ .--
+
-
;;C
Z
en ;...
:;:
o
o :;..-
-
11I\',,;led the cervix, ~o myometrial invasion 'I'llrollgl1 scrosu Abdominal mcta!'>tascs
;;r:
l lall-wny through
I":
IItYOl1wtriUt1l
*'1'.1\.11. = Total abdominal hysterectomy '1'.1\.11. & n.s.o. = Total abdominal hysterectomy and bilateral salpill\(o-oophorecIOIllY **Radiatioll = External radiarion 2[,0 kv,
<.JO
+ + +
M
M
mVOl\wtril\lll
17
..,c
Uterus not available
::t-
en I
::::: ~
o
%
~
:::
~
~
~
:r: c ~
~
Z
>--;-
TABLE 6.
Al:e
~
711 !iH
:1
7'2
.-
·1
C"
:.
71!
n
(;·1
7
(;(
Il
Co,
!/
57
III II
(ill 7:'
I~
·10
1:1
[)·I
I-l
I,.
.-
Treatment
Cobah imp .• ex po 1,,1" Radium !i~7!i III)(./Iu'.. T .A.II..'\: II .S.0. T.A.II..'\: n.s.o. TA Il..'\: lI.s.a.. All 1!l1l-1511lllc. R:lClilClII !i1!'l/lIllJ.:./IIC·., Au ]!lH- I!iO me, Rudium, T.A.! I. I(: II .S.0. Rndium H700 IIIJ.:./hr.
o ro
---
Adrno-
~\' q ll tlmo IlJ
Ilisto logi« Components Sarcoma Stromal l~rimnJa. Ulwbtlo-
((/ f(;1I0 l1m
(;(l I'{;'IOIII 11
Smnlllm
Cnrriumna
Patient
:::
MAl.lGNANT MIXED MULLERIAN TUMORS (l-h:TEROI.OGOUS TYPE)
Dutconu:
Died n momhs Died H 1II11111hs
+ +
Died :1'12 yenrs
+
Lh·illJ.: a nd well 5 }'cars Dice! :. 1II00uhs
+
Died III 1II111ll hs
+
+
.~ (/ ,.(O ", ({
+ +
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o
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+
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+
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+
Eudllllleirial ill-
Died H 1II111llhs
+
+
+ +
IIle!" s. ill abd , !J IIII1111hs Died :1 months
+ +
+
+ +
+ + + +
(;Il
No 1"0111111""1' ~o 1i,!low'llp Died I month \.i ,-illl-: alld well J5 IUUI}(hs IIlel"sl"ses
"H
lIi0l'sy
Died I year
+
+ +
+
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+
+
T .A.II..'\: II.S.0.. Radi II III 'Ilillll IIIJ.:./h r, Radium !i!HlllIIJ.:./h r•• hcuuron :I!)!lll R T.A.II. I(: n.s.o, T.A .lI. I(: II .S.0. '1'.1\.11. I(: II.S.0. Rndiuru :1'2,,1l IIIJ.:./hr.. T .A.II. I(: II .S.0. TAIl. .'\: II .S.0.
+
+
+
I l yslen:Cllll1l r 1101 dlllle Ou tside uterus l lysrcrc cto m y 1101 dOlle OLlls ide u ter us
+
l lyst crc cromy L101
dun e
+
C
:::: trl
z
c
z
e::: trl
;>::l
+
+ +
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-:::
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myometrium VO h 'C lII l" U (111)'
+
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+ +
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No informuti on Outside uterus Outside uterus 1lal l"' lI'a y Ihr·CIIIJ.:h m yom etrium Uterus 1101 a vailable Metastas es
(,,);
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'" s ~ ..,
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UTERINE SARCOMAS-KDII'SOX,
llARI
Figurc 4. :'Ialignant mixcd ~Ilillerian tumor, homologous trpc, with leiomyosarcoma. ;\ote thc apparent differentiation of the mesodermal component into e pithelial islands. (Hematoxylin and eosin stain . x gO.)
Stromal sarcoma was identified in 15 tumors and leiomyosarcoma in nine. Three tumors contained both types of sarcoma. Ten homologous malignant mixed Mullerian tumors had extended beyond the uterus or had metastasized at the time of surgery, seven were limited to the uterus but had invaded the myometrium, and one tumor was confined to the endometrium. The uterus was not available for study in the remainder of the cases. Fourteen of the 21 patients have died , five are alive without tumor IS months to 8 years after primary therapy, and two patients have been lost to follow-up . All the survivors whose uteri were available for study had tumor originally confined to the uterus with invasion of the myometrium limited to the inner half of the wall or less. However, three patients with tumor confined to these areas have died as a result of the tumor. All patients with tumor extending to the serosa of the
uterus or beyond have died. A wide variety of therapies was utilized in these patients with no significant advantage noted for anyone method (Table 5). Fifteen malignant mixed Mtilleriau tumors contained recognizable heterologous elements (Table 6). Chondrosarcoma was the sole heterologous element in seven cases, six tumors contained rhabdomyosarcoma, and two tumors contained osteosarcoma with bone and osteo id formation. Eight tumors contained stromal sarcoma, and six contained leiomyosarcoma in addition to the heterologous elements. Adenocarcinoma was recognized in 14 of the heterologous tumors, squamous carcinoma in four, and mixtures of adenocarcinoma and squamous carcinoma in three tumors. Six tumors had extended through the serosa of the uterus at the time of initial therapy, and metastases were present in two additional patients at the time of diagnosis. Nin e of the 15 patients with malig-
343
HU~IAN
PATHOLOGY-VOLUME I. NUMBER 3
Sell/ember 1970
Figure 5. Malignant mixed ~liillerian rumor, heterologous type, with chondrosarcoma as thc heterologous clement. There is close intermingling of the epithelial and me sodermal clem ents. (Hematoxylin a nd eosin stain . x 90 .)
344
nant mixed Miillerian tumors of the heterologous type have died with persistent tumor and two had metastases when last seen. Two patients have been lost to follow-up. The two patients who are li\'ing and well without evidence of disease had tumor limited to the endometrium alone or involving only the inner half of the myometrium. The heterologous element was chondrosarcoma in both tumors. As with the homologous tumors a variety of different modes of therapy were used. including pre- and postoperative radiation and radiation alone (Table G). All three patients who received radiation as the sole method of treatment are dead, but all these patients were treated in this manner because they were deemed poor operative risks . Both the mixed sarcomas contained leiomyosarcoma (Table 7). One was a homologous tumor with leiomyosarcoma
and stromal sarcoma; the other contained rhabdomyosarcoma and leiomyosarcoma. The latter patient died six months after surgical therapy; the former' was lost to follow-up.
Comment 1n this series the survival rat e of the patients with homologous tumors is 27 per cent and that for the heterologous group is 15 per cent, an insignificant difference because of the small numbers of patients and the short follow-up period for some patients. If heterologous elements are present and these are rhabdomyoblasts or osteoblasts, the prognosis is extremely grave, All patients in this 'series whose tumor contained rhabdomyosarcoma or osteosarcoma have died. On the other hand, the 'o nly survivors are patients whose tumors contained chondrosarcoma
UTERINE SARCOMAS-KDIPSO:-:, BARI TABLE 7.
~hXED
SARcmlAS 1/istologic Components Stromal LeiomyoRhabdomyo-
Patient
2
Age
Treatment
48
T.A.H. & B.S.O., Crtexan, radiation Exp. lap.
57
Outcome
No follow-up Died 6 months
as the heterologous element. Similar findings were reported by Norris et aI.18 Equally as important to the prognosis as subdividing these tumors on the basis of differentiation of the tumor cell is the determination of the extent of myometrial invasion. The patients with homologous tumors who -have survived-In this series are those whose tumors had invaded no farther than half the distance through the myometrium at the time of hysterectomy. All II patients whose tumor extended beyond this point have died. However, superficial or no myometrial invasion does not necessarily mean that the patient will survive, since some deaths and metastases occurred in the absence of invasion. For the heterologous group of tumors the extent of the tumor at the time of therapy is also important. The only survivors in this series had small superficial tumors with chondrosarcoma as the only heterologous element. We do not know what the behavior of small superficially invasive tumors containing rhabdomyosarcoma or osteosarcoma would be, since all tumors with these elements extended outside the uterus and were over 4 em. in diameter at the time of diagnosis. Whether surgery, radiation, or a combination of both is the best treatment of malignant mixed Mullerian tumors cannot be determined from our data. One patient with a homologous tumor has survived eight years with only radiation therapy, and the other three survivors with homologous tumors had preoperative radiation. We have observed striking local regression of stromal sarcoma with radiation, but metastases often appear outside the pelvis even though the primary tumor has decreased in size. These findings suggest that preoperative radiation may be of value for tumors with significant stromal sarcomatous differentiation. If preoperative radiation is used, it would be most
Sarcoma
sarcoma
+
+ +
sarcoma
+
logical to utilize both radium implants and external therapy, since the goal is to control the tumor that has extended outside the uterus. Most malignant mixed Miillerian tumors do not regress completely after radiation and surgical extirpation must still be considered the primary therapy. In some poorly differentiated adenocarcinomas of the endometrium, the tumor cells do not form glands or glandlike spaces. Such tumors can be difficult to separate from homologous mixed Milllerian tumors in which the sarcomatous element is stromal sarcoma. In this circumstance reticulin stains are of value, since in stromal sarcoma the individual cell or at most small clumps of cells are surrounded by reticulin fibers. In some instances the differentiation between carcinoma and sarcoma may not be possible, and the approach to therapy should be the same as for poorly differentiated carcinoma. Diagnostic problems are also encountered when the amount of tissue removed at curettage or biopsy is so small that all the different types of tumor tissue are not present in the specimen. Mixed tumors may undergo extensive necrosis resulting in areas of differentiation being missed. Such sampling errors often lead to erroneous diagnoses. When hysterectomy is done, it is of great importance to sample the uterus extensively to avoid missing significant areas of tumor differentiation and to determine accurately the extent of myometrial invasion. Malignant mixed Mullerian tumors should be clearly separated from the purc embryonal rhabdomyosarcomas (sarcoma botryoides) usually encountered in childhood. This tumor most frequently involves the vagina, has morphologic features quite distinct from mixed tumors, and represents a pure heterologous sarcoma. Rarely two separate carcinomas will
345
HUMAN PATHOLOGY-VOLUME 1, NUMBER 3
arise within the uterus, most often mixed adenocarcinoma and squamous carcinoma. These should be distinguished from mixed Mullerian tumors. ENDOLYMPHATIC STROMAL MYOSIS AND ENDOMETRIAL STROMAL SARCOMA Infiltrating malignant tumors composed purely of cells resembling the endometrial stroma are rare. These tumors arc usually classified into two groups on the ba sis of morphology and behavior. Endolymphatic stromal myosis (stromal myosis) is an infiltrating stromal lesion with an indolent course that has been reported occasionally to recur or metastasize, usually after long periods of time. Endometrial stromal sarcoma infiltrates the myometrium more widely and has a more aggressive course, frequent metastases, and higher mortality. Both these tumors have many features in common, including the presence of tumor cells within lyrnphatic spaces, and there has been doubt as to whether they represent separate entities." However, Norris and Taylor'" have stated that the number of mitoses per 10 HPF is an accurate method for diagnosing these two neoplasms. This study was undertaken to evaluate the criteria for the diagnosis of endolymphatic stromal myosis and stromal sarcoma, and to determine the survival rates for each of these lesions. It must also be remembered that there is a benign endometrial stromal tumor, the so-called stromal nodule, which docs not infiltrate lymphatic spaces or myometrium and has a low mitotic counL. These benign tumors are not included in this study of malignant stromal tumors. Material and Methods
346
Seventeen infiltrating stromal lesions of the uterus were obtained from the pathology files of the Barnes Hospital. The clinical symptoms, gros s findings, location within the uterus, and treatment were reviewed. 1\1ultiple sections were available from each tumor, and the number of mitotic figures per 10 HPF in the most active areas of the tumor was determined. Follow-up information was available for 16 of the cases.
Sell/ember 1970
Results
The most common presenting complaint of patients with infiltrating stromal tumors was abnormal vaginal bleeding, which was massive in two patients. A polypoid ma ss presented from the cervix in one patient. The ages of the patients were similar to those in the leiomyosarcoma and malignant mixed Miillcrian tumor seri es except that one patient was 8 ycars of age and another 16. The youngest patient we hav e encountered with a malignant mixed Miillerian tumor was 35 years whereas the youngest with leiomyosarcoma was 39 years. The stromal tumors were yellow to gray-white and often contained areas of necrosis and hemorrhage. All the tumors bulged into the endometrial cavity and infiltrated the myometrium. They measured from 2 to 15 em. Histologically, both groups of infiltrating stromal tumors were composed of monotonous sheets of cells with basophilic nuclei and indistinct cytoplasm. In all tumors, strands of tumor cells infiltrated and separated the smooth muscle fibers of the myometrium, at least focally (Fig. 6). Some tumors contained predominantly round masses of tumor cells without infiltration at the points of contact with the myometrium. With silver stains fine strands of reticulin surrounded individual tumor cells or small clumps of tumor cells. In each case tumor could be demonstrated within lymphatics or lymphatic-like spaces. The stromal tumors were divided into two groups on the basis of the mitotic counts in the most active areas of the tumor (Tables 8 and 9). Ten tumors contained more than 20 mitoses per 10 HPF, and nine of the 10 patients with such tumors have died or had metastases when last seen. The other patient was lost to follow-up . Seven tumors contained 5 or fewer mitoses per 10 HPF, and all the patients from whom these tumors wer e removed are alive three to 15 years after treatment without recurrences or evidence of metastases, No tumors were found with mitotic counts between 6 and 20 per 10 HPF. Pleomorphism of the tumor cells was found in both groups and there was no correlation between malignancy and pleomorphism. The tumors with high mitotic counts usually infiltrated
UTERINE SARCOMAS-KDII'SO:\" BARI
Figure 6. Endometrial stromal sarcoma infiltrating the myometrium. The tumor is composed of nests of uniform cells with round nuclei. (Hematoxylin and eosin stain. A, x 45. B. x 350.)
347
HUMAN PATHOLOGY-VOLUME I, NUMBER 3
TABLE 8.
September 1970
"ENDo)IETRIAL STRO)IAL SARCO)IA
Age
Mitoses/IO HPF
Extension of tumor
Treatment
Outcome
73
35
47
·12
3 4
50 16
34 30
5 6 7
8 9
55 8 63 62 72
21 40 40 30 24
Through serosa Pelvic metastases Through serosa Extensive metastases Through serosa
10
67
29
Through serosa
T.A.H. & n.s.o.. radiation T.A.H. & n.s.o.• radiation T.A.I1. Wertheim without nodes AH* radiation Radiation 300 R T.A.H. & n.s.o, Exp. lap. Radium 9-10 mg.rhr., Au 198-150 me.• T.A.II. & s.s.o. T.A.H. & n.s.o.
Died 6 months
2
Half-way through myometrium Superficially invading myometrium Through serosa Through serosa
Patient
1'\0 follow-up
Died 4 months Died 9 months Died Died Died Died Died
21J2 years 3 months 1 month 2 months 4 months
Died 8 months
*AH = supracervical hysterectomy
the myometrium widely, whereas those with low counts often had pushing margins. However, this finding was inconstant and of little value in individual cases. Eight of the tumors with high mitotic counts had extended to the serosa or had metastasized at the time of surgery, whereas the other two were confined to the inner half of the uterus. None of the lesions with few mitoses had extended beyond the uterus, but all had extended into the myometrium. Comment
Our findings agree with those of Norris and Taylor that infiltrating stromal tumors with large numbers of mitoses are aggressive, metastasize frequently, and are therefore stromal sarcomas." The infiltrating stromal tumors with few mitoses have had a benign course and are designated as endolymphatic stromal myosis. Other authors have reported that these latter tumors may recur or metastasize but this did not occur in our series.": 22" TABLE 9.
348
Norris and Taylor set the dividing point of mitotic activity between stromal myosis and stromal sarcomas at 10 per HPF. Our series indicates an even more significant separation of the mitotic rate, since all the stromal sarcomas contained more than 20 mitoses per 10 HPF and the cndolymphatic stromal myosis cases 5 or fewer. \\l e did not encounter tumors with counts of 6 to 20 mitoses per 10 HPF. These differences in the level of mitotic activity are very interesting when compared to survival data. All our patients with stromal sarcoma have died. Norris and Taylor report a 26 per cent five year survival free of tumor for patients with stromal tumors with mitotic counts greater than 10 per 10 HPF. The survivors in their series had small tumors confined to the uterus, but it is not clear whether they also had mitotic counts below 20 per 10 HPF. It is possible that tumors with counts of 6 to 20 per 10 HPF may be of low grade malignancy as compared to tumors with mitotic counts greater than 20 per 10 HPF. Some of the aggressive and mctas-
ENDOLDII'HATIC STRO)IAL MYOSIS
Patient
Age
Mitosesl l O HPF
1 2 3 4 5 6 7
46 33 42 38 35 49 36
2 1 0 4 2 5 3
Treatment T.A.H. T.A.H. T.A.H. T.A.H. T.A.H. T.A.H. T.A.H.
& B.S.a. & n.s.o. & B.S.a. & n.s.o. & B.S.a.
s: a.s.o. n.s.o.
&
Outcome Living Living Living Living Living Living Living
and and and and and and and
well. well. well. well. well. well. well.
3 years 5 years 6 years 15 years 10 years 11 years 3 years
UTERINE
rasizing endolymphatic stromal tumors reported by Jensen et al. 22 may fall into this group with intermediate mitotic activity. Four of the patients with stromal sarcoma in this series were treated by both radiation therapy and surgery; one was treated with radiation alone and the remainder by surgery alone. Although there was usually an objective decrease in the size of the tumor mass after radiation, all the patients with follow-up died with metastases. In some instances no persistent tumor was found in the radiated areas. The patients with endolyrnphatic stromal myosis were treated by hysterectomy and bilateral salpingo-oophorectomy. Radiation therapy was not utilized. Histologically, endometrial stromal sarcoma and' occasionally endolymphatic stromal myosis may be confused with malignant lymphoma or undifferentiated small cell carcinoma of the cervix. Separation of the latter from stromal sarcoma may be a difficult problem because stromal sarcoma can invade the cervix. In our experience, the reticulin stain is the best method available to distinguish carcinoma from stromal sarcoma.
REFERENCES I. Ober, W. B.: Uterine sarcomas: Histogenesis and taxonomy. Ann. KY. Acad. Sci.. 75:568,1959. 2. Barstick, E. G., Bowl, E. T., and Morre, G. T.: Leiomyosarcoma of the uterus: A 50 year review of 42 cases. Obstet, Cynec., 32:101, 1968. 3. Aaro, L. A., Symmonds, R. E., and Dockerty, ~L B.: Sarcoma of the uterus. Amer, J. Obstet. Gynec., 94: 10 I, 1966. 4. Kraus, F. J.: Gynecologic Pathology. St. Louis, The C. V. Mosby Co., 1967. 5. Randall, C. L.: Sarcoma of the uterus. Amer. J. Obstet. Gynec., 45:445, 1943. 6. Proper, ~L S., and Simpson, B. T.: Malignant leiomyomata. Surg. Gynec, Ohstet., 29:39, 1919.
SARCO~IAS-KDll'so~, BARI
7. Corscaden, J. A., and Singh. B. P.: Leiomyosarcoma of the uterus, Amcr, J. Obstet. Gyncc., 75:149,1958. 8. Laberge, J.: Prognosis of uterine leiomyosarcomas based on histopathologic criteria. Arner, J.. Obstct. Gynec., 84: 1833, 1962. 9. Spiro, R. H., and Koss, L. G.: Myosarcoma of the uterus. Cancer, 18:571,1965. 10. Taylor, H. B., and Norris. H. J.: Mesenchymal tumors of the uterus. IV. Diagnosis and prognosis of leiomyosarcomas. Arch. Parh., 82:40, 1966. I I. Aaro, L. A., and Dockcrty, ~L B.: Leiomyosarcomas of the uterus. Amer. J. Obstet. Cyncc., 77:1187,1959. 12. Wheelock, ~L C., and Warren, S.: Leiomyosarcoma of the uterus. Ann.· Surg., 116:882, 1942. 13. Corscaden, J. A., and Stout, A. P.: Sarcoma of the uterus. Amer. J. Roentgenol., 21: 155, 1929. 14. Fechner, R. E.: Atypical leiomyornas and synthetic progestogen therapy. Arner. J. Clin. Path., 49:697, 1969. 15. Harper, R. S., and Scully, R. E.: Intravenous Ieiomyornatosis of the lIlerus. Obstet. Gynec., 18:519, 1961. 16. Steiner, 1'. E.: Metastasizing fibroleiomyoma of the uterus. Amer.J. Path., 15:89,1939. 17. Sternberg, W. H., Clark, W. H., and Smith, R. C.: Malignant mixed Mtillerian tumor (mixed mesodermal tumor of the uterus). Cancer, 7:704, 1954. 18. Norris, H. J., Roth, E., and Tar'lor, H. B.: Mesenchymal tumors of the uterus. II. A clinical and pathologic study of 31 mixed mesodermal tumors. Obstet. Cynec., 28:57, 1966. 19. Norris, H. J., and Taylor, H. B.: Mesenchymal tumors of the uterus. IlL A clinical and pathologic study of 31 carcinosarcomas. Cancer, 19:1459,1966. 20. Koss, L. G., Spiro, R. H., and Brunschwig, A.: Endometrial stromal sarcoma. Surg. Gynec. Obstet., 121 :531, 1965. 2 I. Norris, H. J., and Taylor, H. B.: Mesenchymal tumors of the uterus. I. A clinical and pathological study of 53 endometrial stromal tumors. Cancer, 19:755, 1966. 22. Jensen, P. A., Dockerty, M. B., Symmonds, R. E., and Wilson, R. B.: Endornetrioid sarcoma ("stromal endometriosis"). Amer. J. Obstet. Gynec., 95:79, 1966. Department of Pathology Stanford University School of Medicine Stanford, California 94304 (Dr. Kempson)
349
Abstract Uterine sarcomas often present diagnostic problems. In addition, the plethora of names for the same tumor or groups of tumors makes it difficult to correlate diagnostic and therapeutic data. We have proposed a modification of the classification of Ober that we think offers a simple, straightforward, histogenetically accurate terminology for this group of tumors. It also permits as detailed a subclassification of each group of tumors as now seems warranted. To test this classification and the available diagnostic criteria, the uterine sarcomas at Barnes Hospital in St. Louis have been evaluated. Leiomyoma and leiomyosarcoma can be accurately separated in most instances. Smooth muscle tumors that have invaded contiguous organs or blood vessels are malignant. If invasion is not present the mitotic rate is evaluated. Tumors with less than 5 mitoses per 10 high power fields (HPF) are benign. Those with higher mitotic counts are malignant. The prognosis for leiomyosarcomas with greater than 10 mitoses per 10 HPF is poor and metastases are frequent. The behavior of smooth muscle tumors with mitotic counts between 4 and 9 per 10 HPF is less' certain, but some tumors with this level of mitotic activity will metastasize. Patients with malignant mixed Mullerian tumors of the homologous type that are small and not invasive or have invaded the myometrium only superficiallymay be cured by hysterectomy. If the tumors are large and highly invasive, the outlook is almost hopeless in spite of any form of therapy. Heterologous malignant mixed Mullerian tumors with chondrosarcoma as the heterologous element and without significant invasion may also be cured. In our series the presence of osteoid, bone, or rhabdornyoblasts indicated a highly malignant neoplasm with fatal outcome. All such tumors were large at the time of initial diagnosis. The infiltrating stromal tumors with mitotic counts of about 20 per 10 HPF all metastasized; those with 5 per 10 HPF or less have not metastasized or recurred after therapy. This provides a sharp dividing point between endolymphatic stromal myosis and endometrial stromal sarcoma. The behavior of tumors with mitotic counts of 6 to 20 per 10 HPF is unknown, but they may have a better prognosis than stromal tumors with higher counts.
*Associate Professor of Pathology, Stanford University School of Medicine. Surgical Pathologist. Stanford University Hospital, Stanford. California. tClinical Assistant Professor of Pathology, Washington University School of Medicine. Pathologist. St. John'S Mercy Hospital. St. Louis. Missouri.
331
HU~[AN PATHOLOGY-VOLUME 1, NUMBER 3
Accurate diagnosis and classification of any group of tumors is essential before effective therapy can be determined. If tumors with similar origin and behavior are classified separately, or if tumors of divergent origin and behavior are classified together, the results of therapy will not be valid. Establishing accurate diagnostic criteria for uterine sarcomas has been particularly difficult because of the large number of different histologic patterns that occur and because of the difficulty of separating benign from malignant mesenchymal neoplasms. This has resulted in a nomenclature that is confusing, complex, and often ambiguous. Recent publications have evaluated the diagnostic featur.es for the various types of sarcomas and have proposed definite criteria for the separation of malignant and benign tumors. Now a standard acceptable system of classification is needed. Only when this is accomplished will accurate studies on the effectiveness of treatment be possible. The purpose of this study is to review the uterine sarcomas from the Barnes Hospital in St. Louis, Missouri, in order to evaluate the diagnostic criteria previously published for uterine sarcomas and to propose a simplified practical classification of these tumors. The pathologic data are correlated with patient survival to determine the value of the proposed plan of classification and the validity of the diagnostic criteria.
NOMENCLATURE AND CLASSIFICATION
332
Several different classifications of uterine sarcomas have been proposed, but none of these has been universally accepted.v " In our experience the most useful and histogenetically correct classification is that proposed by Ober.' However, in attempting to utilize Ober's scheme for routine diagnosis and for the tumors in this study, we found the original classification more detailed than neces-: sary. As a result, we have developed a modification of the original abel' classification that we think is readily applicable to routine tissue diagnosis and provides an accurate nomenclature for the uterine sarcomas (Table I).
September 1970 TABLE 1.
CLASSIFICATlO1> OF
UTERII'\E SARCO~IAS
I. Pure sarcomas A. Pure homologous I. Leiomyosarcoma 2. Stromal sarcoma 3. Endolyrnphatic stromal myosis" 4. Angiosarcoma 5. Fibrosarcoma B. Pure heterologous I. Rhabdomyosarcoma (including sarcoma botryoides) 2. Chondrosarcoma 3. Osteosarcoma 4. Liposareo rna
I I. ;\Iixed sarcomas A. Mixed homologous B. Mixed heterologous Mixed heterologous sarcomas with or without homologous dements Ill. Malignant mixed ;\lUllerian tumors (mixed mesodermal tumors) A. ;\lalignant mixed ~Iiillerian tumor. homologous tH,e Carcinoma plus leiomyosarcoma. stromal sarcoma, Of fibrosarcoma, or mixtures of these sarcomas B. ;\lalignant mixed ~liillerian tumor, heterologous lype Carcinoma plus heterologous sarcoma with or withe OUt homologous S31'C01113 IV. Sarcoma, unclassified v, Malignant lymphoma *This tumor was benign in this series, but has been classified as sarcoma became of reponed recurrences and metastases.
This classification separates the sarcomas according to the number and types of recognizably differentiated tumor tissues present. Pure sarcomas contain only a single recognizable sarcomatous element, whereas mixed tumors contain two or more different malignant elements. The malignant cells in homologous tumors are morphologically recognizable as being derived from mesenchymal tissue normally present in the uterus. Heterologous tumors contain cells differentiated into mesenchymal structures not normal1y present in the uterus, such as bone, striated muscle, or cartilage. Therefore, a pure homologous sarcoma is composed of a single cell type resembling mesenchymal tissue found in the normal uterus, such as smooth muscle in a pure leiomyosarcoma. A pure heterologous tumor contains a single type of heterologous sarcoma. The mixed sarcomas contain tumor cells that have differentiated into at least two
UTERINE SARCO;\IAS-Knll'sox, different types of homologous or heterologous sarcoma without evidence of epithelial elements, Examples would be sarcomas containing mixtures of leiomyosarcoma and stromal sarcoma, or stromal sarcoma and rhabdomyosarcoma. The malignant mixed Miillerian tumors contain carcinoma and sarcoma mixed together. The carcinoma may be adenocarcinoma, squamous carcinoma, undifferentiated carcinoma, or any mixture of these, The sarcoma may be pure or mixed, homologous or heterologous. There is never evidence of the ectodermal or endodermal tissues found in teratomas. Although this group of tumors is often designated as mixed mesodermal tumors, the best histogenetic term is malignant mixed Mullerian tumor and we have used this terminology. . The pure sarcomas, whether homologous or heterologous, should be designated by their familiar names, such as leiomyosarcoma, stromal sarcoma, or rhabdomyosarcoma, The mixed sarcomas without carcinoma are designated as mixed sarcoma, homologous type, or mixed sarcoma, heterologous type: Neoplasms with carcinoma and sarcoma would be designated as malignant mixed Miillerian tumor, homologous type, or malignant mixed Mullerian tumor, heterologous type, depending on the differentiation of the sarcomatous tissue. Almost all of the classifiable sarcomas contain areas in which the malignant cells are undifferentiated, often with a "fibrosarcoma-like" pattern, These areas should not be interpreted as fibrosarcoma unless the diagnostic criteria for that tumor are present." Some sarcomas arc composed primarily of undifferentiated cells and many sections must be examined to find diagnostic areas. Histochemical stains are often needed to prove differentiation of malignant tissue. In spite of thorough sectioning and staining; some sarcomas of the uterus are composed entirely of tumor tissue so poorly differentiated as to defy classification. Forcing these tumors into the classification serves no useful purpose and they should be diagnosed as "sarcoma unclassified." The majority of uterine sarcomas will be leiomyosarcomas. malignant mixed Milllerian tumors, or stromal sarcomas. Other types are rarely encountered.
BAHI
We suggest . that all confusing and histogenetically meaningless terms, such as carcinosarcoma and sarcoma botr'yoides, be discarded. Although the term carcinosarcoma has been used to designate mixed mesodermal tumors of the homologous type, it has also been used to designate' mixed heterologous tumors, and its usefulness as a specific diagnostic term has been compromised. Sarcoma botryoides is a clinical term for grapelike tumors and should not be used morphologically. Most of the botryoid sarcomas in children arc embryonal rhabdomyosarcomas, and those in adults are usually malignant mixed Mullerian tumors. LEIOMYOSARCOMA The lack of uniformly accepted histologic criteria for the diagnosis of leiomyosarcoma of the uterus has made it almost impossible to determine the prognosis and to evaluate the results of therapy. This is clearly demonstrated by the discrepancy in the reponed incidence. which varies from 0.22 per cent" to as high as 6 per cent" of all uterine smooth muscle tumors, and by the disparity in the five year survival figures, which range from 3 per cent to as high as 75 per cent.5, 1-9 Taylor and Norris,'? and Aaro and his coworkers," II have reponed that the number of mitoses is a reliable basis for separating leiomyomas from leiomyosarcomas. Others have depended on pleomorphism, invasion, and the presence of giant cells as reliable criteria." 1, 12 At the far extreme, Corscaden and Stout 13 maintained that recurrence'or metastases, or both, are the only valid evidence of malignancy. Our purpose is to re-evaluate the accuracy of these criteria, especially the mitotic activity, in establishing the diagnosis of leiomyosarcoma of the uterus, If, as Taylor and Norris have reponed, there is a demarcation between benign and malignant tumors on the basis of the numbers of mitoses, accurate histologic diagnosis of leiomyosarcoma is possible. These authors state that tumors containing more than ] 0 mitoses per ]0 high power fields (H PF) arc leiomyosarcomas and that those with less than this number of mitoses arc benign cellular lciomyornas.!''
333
HUMAN PATHOLOGY-VOLU;"[E
1,
NUMBER
Material and Methods A total of 29 cases diagnosed during the past 30 years as cellular or atypical leiomyoma and leiomyosarcoma were found in the pathology and clinical files of Barnes Hospital, In each case histologic sections were reviewed and the most active areas of mitotic activity were evaluated by two independent counts of at least 40 high power fields. Three groups of tumors were defined on the basis of the number of mitoses per 10 HPF. All tumors with 10 or more mitoses per 10 HPF were placed" in the first group. The second group had 5 to 9 mitoses per 10 HPF, and the third had either no mitoses or less than 5 per 10 HPF. Also tabulated for each tumor were the location of the tumor in the uterus, the extent of growth outside the uterus at the time of surgery, the gross appearance of the tumor, the presence or absence of multinucleated giant cells, the presence or absence of vascular invasion, and the degree of cellular atypism in both the giant cells and the stromal cells. How-
TABLE 2.
3
September 1970
ever, the three groups just noted were defined only on the basis of the number of mitoses without regard to the other factors. The clinical records of the patients were then obtained, and the presenting symptoms, treatment, and post-therapy course were determined. Follow-up information was available for 27 of the 29 patients.
Results Twelve patients had tumors that contained more than 10 mitoses per 10 HPF; follow-up information was available for all 12 (Table 2). Nine of the patients have died as a result of the tumor, and two had metastases when last seen. Two of the remaining three patients have been followed for less than two years, and the third has survived for nine years without evidence of tumor. Seven patients were placed in the second group since their tumors contained 5 to 9 mitoses per 10 HPF (Table 3). Follow-up information was available for six of these patients, of whom five have
GROSS FI)\D1)\GS, CYTOLOGIC ATYPIS~I, A)\D SUBSEQ.UE)\T BEHAVIOR OF PURE 10 OR ;"[ORE ;"hTOSES "PER 10 HPF* (LEIO~IYOSARCmIA)
S~IOOTH ;"[USCLE TU~IORS WITH
Degree of AtJpism of Stromal Cells
Age
53
12
0
0
+
0
2
68
13
0
0
++
0
3
66
25
++
++
++
Patient
No. Giant
cai»
Extension of Tumor Outside Uterus
Rectum
4
43
24
++
+++
+++
Bladder, lateral pelvic wall, peritoneum
5
53
14
++
+++
+++
0
6
50
20
++
++
++
Parametrium
7
39
34
0
0
++
Parametrium
8
59
13
+++
+++
+++
0
9
56
2-1
+++
+++
++
0
10
-13
12
+++
+++
+++
II
51
15
0
0
+
0
12
72
17
+++
+++
++
0
'IIPF = high power fields
"0
334
Degree of At)pism of Giant Cells
No, Mitoses perIOHPF
= none
+= minimal ++= moderate +++= marked
Parametrium
Outcome
Died 3 years with metastases Living without metastases, 14 mo. Living without metastases, 3 mo. Died 5 years with metastases Died 15 months with metastases Died I week with metastases ~Ietastases when fast seen Died 3 years with metastases Metastases when last seen Died 7 years with metastases Died 12 years with metastases Living and well, 9 years
UTERINE
3.
TABLE
SARCOMAS-KDIPso~, BARI
GROSS FIXDlXGS, CYTOLOGIC ATYPJS~I, AXD SUBSEQ.UEXT BEHAVIOR OF S~IOOTII 5 TO 9 MITOSES PER 10 HI'F (LEJO~IYOSARCmIA)
~IUSCLE TU~IORS WITII
No. Giant Cells
Degree of At)'pism of Giani Cells
Degree of Atypism of Stromal Cells
Extension of Tumor 10 Contlg-
Age
No. Mitosis
-19
6
+++
++t-
++t-
O
2
-12
9
+++
++t-
+t-+
Vagina
3
60
5
+++
++t-
++t-
Pelvis
-1
-12
8
-t+
++t-
++t-
O
5
-13
9
0
0
+t-+
Patient
6
5i
7
+
-++
-++
7
-1-1
5
+
+
+
died. One patient was lost to follow-up after a three year tumor-free interval, and one patient died during hysterectomy. In 10 cases the tumors contained less than 5 mitoses per 10 HPF (Table 4). With one exception, all of these patients are alive and were well without evidence of metastases when last seen one to I I years after initial therapy. The exception is a patient who had a uterine smooth muscle tumor removed in 1958 with one mitosis per 10 HPF. In 1965 a metastasis, histologically the same as the original tumor, was re-
TABLE
4.
I-
Age
Parametrium
I'aramcuium Small intestine Pelvis
Outcome Lost to follow-up. 3 years Died 3 mo. with metastases Died -1 mo. with metastases Died I year with metastases Died 5 months wit~ metastases Died 15 months with metastases Died during hysterectomy
moved from the fifth lumbar vertebra, She has remained well without evidence of further metastases. The presence or absence of giant cells does not correlate with survival, and large numbers of giant cells may be found in tumors with few mitoses and a benign course. Although tumors with large numbers of mitoses have tended to contain more atypical stromal cells, the presence of atypical cells is not a reliable sign of rnalignancy.I'v ':' Those patients whose tumors contained large numbers of mi-
GROSS FIXDlXGS, CYTOLOGIC ATYI'IS~I, AXD SUBSEQ.UEXT BEHA\'IOR OF S~IOOTH
MUSCLE TU~IORS WITH LESS TIIAK
Patient
uous Structure
No. Mitosis
No. Giant Cells
33
Degree of AIJpism of Giani Cells
5
IO HI'F
Degree of AtJpism of Siromal Cells
Extension of Tumor 10 Conliguous Structure
0
0
+
0
2
50
-1
++t-
++t-
++t-
O
3
31
0
0
0
+
0
-1
-18
2
+
+
+
0
5
-12
2
+
+
-++
0
6
55
-t+
-++
-++
0
7
-19
0
+
+t-+
+
0
8
51
0
0
0
+
0
9
-13
0
0
0
+
0
10
58
0
0
0
+
0
-Benign metastasizing leiomyoma.
~retastasis removed
(LEIO~IYmIA)
MITOSES PER
from L5 vertebra,
Outcome Li\'ing and well, 8 years Lost to follow-up Died 10 years of unrelated disease Living and well. II years Living and well, 9 years Living and well, 1} years Living and \I'e1I, 3 years Living and well, 4 years Living' and well. i years Died -1 years of unrelated disease
335
HUMAN PATHOLOGY-VOLUME I, NU;\IBER 3
toses, but with minimal or moderate atypism, often lived for long periods of time before metastases appeared. Of the ten patients with extension of tumor outside the uterus, eight have died as a result of their tumor, one has been followed for only three months, and on e was lost to follow-up. The group of tumors with 5 to 9 mitoses per IO HPF all demonstrated either marked atypism of the stromal cells or extension of tumor outside the uterus. Tumors with 0 to 4 mitoses were all confined to the uterus and with one exception the tumor cells were only minimally or moderately atypical. The patient whose tumor contained markedly atypical cells was lost to follow-up. Vascular invasion was found infrequently and only in tumors with more than 10 mitoses per 10 HPF. The average age and clinical picture of this group of patients were the same as has been previously recorded, and there was no significant difference in symptoms or physical findings among the three groups. Total abdominal hysterectomy, with or without salpingo-oophorectorny, was the treatment for 19 patients. Six patients received radiotherapy before or after surgery, one patient received radiotherapy alone, two patients had supracervical hysterectomies, and one patient required local excision of the tumor. Although the groups of patients are small , there is no difference in 'survival between patients treated by surgery and radiotherapy and those treated by surgery alone.
Comment
336
The number of mitoses is the single most accurate criterion for the diagnosis of leiomyosarcoma. When there arc 10 or more mitoses per 10 HPF, the vast majority of uterine smooth muscle tumors will behave aggressively regardless of cellular atypism, presence of giant cells, or confinement of the tumor to the uterus at the time of surgery. Therefore, tumors with mitotic counts above 10 per HPF are classified as leiomyosarcomas. Our eX7 perience also indicates that tumors with 5 to 9 mitoses per 10 HPF usually behave aggressively and metastasize (Table 3). With less than 5 mitoses per 10 H PF, uterine smooth muscle tumors are almost always benign. The rare tumor that is
Septemb er 19iO
aggressive will fall into the categories of the so-called benign metastasizing leiomyoma and intravenous leiornyomatosis. IS. 16 As exemplified by our case, metastases usually appear at long intervals after the initial surgery, and often can be controlled by surgical excision. There is no way to separate these rare histologically benign but biologically malignant tumors from leiornyomas unless the tumor has invaded contiguous structures at the time of initial surgery (Fig. 1). It is obvious from these results and from previous reports that smooth muscle tumors at the extremes of the spectrum of mitotic activity can be accurately diagnosed by mitotic counts.'?: 11 However, the exact number of mitoses indicating malignancy has been arbitrarily set, and it is unknown whether individual tumors with borderline mitotic counts will be benign or malignant. Taylor and Norris consider tumors with less than 10 mitoses per 10 HPF as benign, while in this series tumors with 5 to 9 mitoses have- frequently behaved aggressively and metastasized. Are tumors with 4 mitoses per 10 HPF always benign and those with 5 to 6 mitoses per 10 HPF always malignant? This is unlikely, and the malignant potential of tumors with borderline mitotic counts between 3 and 9 per 10 HPF is still difficult to predict. . The degree of cellular atypism 'ap pears to be of limited value in determining the malignancy of smooth muscle tumors. Some leiomyosarcomas demonstrate minimal or no cellular pleomorphism while smooth muscle cells in leiornyomas may be markedly atypical (Fig. 2).~· 14 However, tumors with high mitotic counts most often contain a greater number of markedly atypical cells (Fig. 3). In addition, most of the leiomyosarcomas in this series with borderline mitotic counts of 5 to 9 per 10 HPF also contained large numbers of markedly atypical cells. We have no information concerning the behavior of tumors with mitotic counts between 5 and 9 per 10 HPF and minimal or no atypism of the stromal cells. Such tumors may be benign; this would explain the discrepancy between our findings and those of Taylor and Norris.!" The available evidence allows the following conclusions. True invasion of contiguous organs or blood vessels is indica-
UTERINE
SARCO~IAS-KDll' so;,\, BARI
Fig ure 1. Cellular leiom yom a with closely packed sm ooth mu scle nu clei but no a typism or m itoses. (Hematoxylin a nd eosi n slain. fl. x 80 . lt , X 350. )
337
HUMAN PATHOLOGY-VOLUME I, NU~IBER 3
September 1970
Figure 2. Atypical leiomyoma with giant cells and pleomorphism but no mitotic figures. Such tumors should not be diagnosed as sarcoma. (Hematoxylin and eosin stain. x 80.)
338
UTERINE SARCO;\IAS -KDII·SO)\. B.... Rl
Figure 3. Leiomyosarcoma showin g giallt cells. pleomorphism. and an exam plc of abnormal mitosi s. The increased numbers of mitos es in th is tumor allow a diagnosis of sarcoma. (Hematoxylin and eosin stain , x 350.)
339
HUMAN PATHOLOGY-VOLUl\IE 1, NUl\IBER 3
tive of malignancy regardless of mitotic counts or the prcscncc of atypical tumor ccIls. Invasive leiomyosarcoma must be carefully separated from parasitic leiomyomas, which may also grow onto other organs. If invasion is not demonstrated, the mitotic rate is evaluated. Tumors with o to 4 mitoses per 10 HPF arc bcnign reganlIcss of the degree of cellular atypism. Because of our experience we would consider a uterine smooth muscle tumor with 5 to 9 mitoses per 10 HPF and stromal ceIl pleomorphism as malignant. We would also consider the tumor to be malignant if atypism were minimal or absent, but we recognize that the exact behavior of this group of smooth muscle tumors is less certain. Tumors with more than 9 mitoses per '10 HPF must be regarded as being malignant regardless of whether atypism is present and should be diagnosed as leiomyosarcoma. By use of these criteria, the future behavior of almost all uterine smooth muscle tumors can be accurately predicted. If later reports of uterine smooth muscle tumors include tabulations as we have presented, it may be possible to assess more accurately those tumors whose histologic appearance is borderline between benign and .malignant, i.e., with mitotic counts of 5 to 9 per 10 HPF and no stromal ceIl atypism. MALIGNANT MIXED MULLERIAN TUMORS AND MIXED SARCOMAS The wide variety of histologic patterns encountered in malignant mixed Miillerian tumors has created problems in accurate diagnosis and classification." 18. 19 One problem is whether the presence or absence of a specifically differentiated tumor element is an important indication of future behavior. The answer to this question will determine the extent to which these tumors should be subclassified. Information is also needed concerning the response of specific homologous or heterologous elements to therapy. This study was carried out in an attempt to answer these problems and to determine whether other factors influence prognosis.
Material and Methods
340
Thirty-six uterine tumors contammg both carcinomatous and differentiated
Sell/ember 1970
sarcomatous elements, and two tumors containing mixed sarcomas without carcinoma, were found in the files of the Barnes Hospital. Tumors with only undifferentiated sarcomatous elements were excluded. The tumors were subdivided into homologous and heterologous types as previously described (Table 1). Tumors were not placed into the heterologous group unless there was definite histologic evidence of differentiation into tissue not normally found in the uterus, such as bone, cartilage, or skeletal muscle. The type of carcinoma present was also noted. The age of the patients, the presenting symptoms, the treatment, and survival were compared with the gross and microscopic findings. Follow-up information was available for 34 of the 38 patients.
Results The clinical presentation of this group of patients with mixed Mullerian tumors and mixed sarcomas was the same as that reported in previous series.3 • 17 - 19 Abnormal vaginal bleeding was the most common symptom, and some tumors protruded from the cervix. The majority of patients had an enlarged uterus at the time of pelvic examination. Grossly, the tumors were either polypoid or fungating with areas of hemorrhage and necrosis. The tumors invariably involved the endometrium and often exterided into the myometrium for variable distances. Microscopically these tumors demonstrated the wide variation in histologic patterns that has been well described (Tables 5 and 6). Although all tumors had foci where neoplastic cells had differentiated into recognizable epithelium or stromal elements, many had other areas that were bizarre and undifferentiated (Figs. 4 and 5). Large bizarre tumor ceIls with abundant eosinophilic cytoplasm but without cross striations were common and were not considered to be rhabdornyoblasts. A single tumor often showed wide variation in differentiation of tumor cells in different areas. Twenty-one tumors contained carcinoma and homologous sarcoma (Table 5). Adenocarcinoma was the epithelial element in 18 tumors and squamous carcinoma in five; two tumors contained both adenocarcinoma and squamous elements.
TABLES.
l'vIALIGNANT ]\!IXED MULLERIAN TU~IORS (HOMOLOGOUS TYPE)
lJistologic Components S(lrCOJ1lfl Carci1lo'!J(l Patient
~\'qll(/1Il0US
Stromal
l"domJo~
CarrilHlUIl(
Sllrcoma
,HlrW11Ifl
Agc
Treatment
Outcome
.'1d('1I0mvrinoma
IH
llied '2'/. ycars
+
Died I year
+
llicd 10 mouths
+
+
llied 5 mout lis
+
+
Living and well 2 years llied '2 weeks
+
+
l lalf-way through myomcrrium
+ +
Through serosa. Metastases in omenuun Extended !)O% through Protrusion through cervix, Hysterectomy not done Within inner half or
+
Through serosa
'2
77
11
!'H
.j
1i·1
:,
70
TAl I. & II.S.O.•* betatron liOOO R Radium !1ol00 1I1\(./hr.• T.A.II. &II.S.O. Radiatioll,** radium, TAIl. & B.S.O. Exp. lap., hctatron 5000 R T.A.II. & II.S.O.
Ii
(ill
TAIl. & II.S.O.
7
1i:1
llied :1.'1. years
+
+
Il
1l·1
Radium, T.A.II. & II.S.O. Radial ion ~!OOO R
Dicdli 1I10mhs
+
+
0
7R
Rudium 7000 lllA'./hr .• betatron !">CIOO R,
Living and well
+
+
Died 11 weeks
+
+
l" 0 [ollow-u p llied 5 months
+ +
Livinl( and well Il years Living' and well I!'> l1loll1!ls l"o follow-up llied " 1I10llths
+
]0
71i
II 12
!'if) 5,1
1:1
:15
]·1 15 ](j
:15 Il·l IH
TAIl. & II.S.O. TAIl. & II.s.O. Exp, lap .• radiation Radium li700 II1I(./hr., T.A.II. & II.S.O. Radium :,!150 1I1A'./h r., betatron 1l!)00 R Radiat ion 1500"R, T.A.II. & II.S.O. TAIL & II.S.O. T.A.II. & II.S.O.
+
+
+
Radiation fibrosis only. No 1111110r Through serosa
+
1\1JdOl1lillili metastases
myometrium
myomcrrium
·1 }'ea rs
+
+
+ +
+
Extent of tl/mor
+ +
+ +
+
+ +
Metastases, Uterus 1101 ,l\'ail"ble Extension over pelvis Ilair-wa)' through m}"ol1l ct ri 11 111 l lystercctomy not
III 10 '20 21
no !'H 50
,.
f\)
:,8
+
+
Radiation 2~()() R Exp, lap. T.A.II. & II.S.O.•
Living' and well 10ll1onths Died ·1 months Died Ii months Died 5 1I10nths
+ +
nitrogen mustard T.A.II. & II.S.O.
Died -l months
+
Radium :,0'2'2 1I1A'./h r., TAli. & II.S.O.
+
Il
~ .--
+
-
;;C
Z
en ;...
:;:
o
o :;..-
-
11I\',,;led the cervix, ~o myometrial invasion 'I'llrollgl1 scrosu Abdominal mcta!'>tascs
;;r:
l lall-wny through
I":
IItYOl1wtriUt1l
*'1'.1\.11. = Total abdominal hysterectomy '1'.1\.11. & n.s.o. = Total abdominal hysterectomy and bilateral salpill\(o-oophorecIOIllY **Radiatioll = External radiarion 2[,0 kv,
<.JO
+ + +
M
M
mVOl\wtril\lll
17
..,c
Uterus not available
::t-
en I
::::: ~
o
%
~
:::
~
~
~
:r: c ~
~
Z
>--;-
TABLE 6.
Al:e
~
711 !iH
:1
7'2
.-
·1
C"
:.
71!
n
(;·1
7
(;(
Il
Co,
!/
57
III II
(ill 7:'
I~
·10
1:1
[)·I
I-l
I,.
.-
Treatment
Cobah imp .• ex po 1,,1" Radium !i~7!i III)(./Iu'.. T .A.II..'\: II .S.0. T.A.II..'\: n.s.o. TA Il..'\: lI.s.a.. All 1!l1l-1511lllc. R:lClilClII !i1!'l/lIllJ.:./IIC·., Au ]!lH- I!iO me, Rudium, T.A.! I. I(: II .S.0. Rndium H700 IIIJ.:./hr.
o ro
---
Adrno-
~\' q ll tlmo IlJ
Ilisto logi« Components Sarcoma Stromal l~rimnJa. Ulwbtlo-
((/ f(;1I0 l1m
(;(l I'{;'IOIII 11
Smnlllm
Cnrriumna
Patient
:::
MAl.lGNANT MIXED MULLERIAN TUMORS (l-h:TEROI.OGOUS TYPE)
Dutconu:
Died n momhs Died H 1II11111hs
+ +
Died :1'12 yenrs
+
Lh·illJ.: a nd well 5 }'cars Dice! :. 1II00uhs
+
Died III 1II111ll hs
+
+
.~ (/ ,.(O ", ({
+ +
Jill" "'''''
o
Chumlr,,-
OM /'/I-
.w rn JIIUl
,\O ,.( 0 11la
+
+
+
Extension of tum or Ihrolll:" uterus Outside ute rus Outside ut erus
+
Half-way IhroU!;h
+
Eudllllleirial ill-
Died H 1II111llhs
+
+
+ +
IIle!" s. ill abd , !J IIII1111hs Died :1 months
+ +
+
+ +
+ + + +
(;Il
No 1"0111111""1' ~o 1i,!low'llp Died I month \.i ,-illl-: alld well J5 IUUI}(hs IIlel"sl"ses
"H
lIi0l'sy
Died I year
+
+ +
+
+
+
+
+
T .A.II..'\: II.S.0.. Radi II III 'Ilillll IIIJ.:./h r, Radium !i!HlllIIJ.:./h r•• hcuuron :I!)!lll R T.A.II. I(: n.s.o, T.A .lI. I(: II .S.0. '1'.1\.11. I(: II.S.0. Rndiuru :1'2,,1l IIIJ.:./hr.. T .A.II. I(: II .S.0. TAIl. .'\: II .S.0.
+
+
+
I l yslen:Cllll1l r 1101 dlllle Ou tside uterus l lysrcrc cto m y 1101 dOlle OLlls ide u ter us
+
l lyst crc cromy L101
dun e
+
C
:::: trl
z
c
z
e::: trl
;>::l
+
+ +
I
-:::
o r-
myometrium VO h 'C lII l" U (111)'
+
..-::
+ +
+ +
No informuti on Outside uterus Outside uterus 1lal l"' lI'a y Ihr·CIIIJ.:h m yom etrium Uterus 1101 a vailable Metastas es
(,,);
c",
'" ~
'" s ~ ..,
...
'0
-,
C
UTERINE SARCOMAS-KDII'SOX,
llARI
Figurc 4. :'Ialignant mixcd ~Ilillerian tumor, homologous trpc, with leiomyosarcoma. ;\ote thc apparent differentiation of the mesodermal component into e pithelial islands. (Hematoxylin and eosin stain . x gO.)
Stromal sarcoma was identified in 15 tumors and leiomyosarcoma in nine. Three tumors contained both types of sarcoma. Ten homologous malignant mixed Mullerian tumors had extended beyond the uterus or had metastasized at the time of surgery, seven were limited to the uterus but had invaded the myometrium, and one tumor was confined to the endometrium. The uterus was not available for study in the remainder of the cases. Fourteen of the 21 patients have died , five are alive without tumor IS months to 8 years after primary therapy, and two patients have been lost to follow-up . All the survivors whose uteri were available for study had tumor originally confined to the uterus with invasion of the myometrium limited to the inner half of the wall or less. However, three patients with tumor confined to these areas have died as a result of the tumor. All patients with tumor extending to the serosa of the
uterus or beyond have died. A wide variety of therapies was utilized in these patients with no significant advantage noted for anyone method (Table 5). Fifteen malignant mixed Mtilleriau tumors contained recognizable heterologous elements (Table 6). Chondrosarcoma was the sole heterologous element in seven cases, six tumors contained rhabdomyosarcoma, and two tumors contained osteosarcoma with bone and osteo id formation. Eight tumors contained stromal sarcoma, and six contained leiomyosarcoma in addition to the heterologous elements. Adenocarcinoma was recognized in 14 of the heterologous tumors, squamous carcinoma in four, and mixtures of adenocarcinoma and squamous carcinoma in three tumors. Six tumors had extended through the serosa of the uterus at the time of initial therapy, and metastases were present in two additional patients at the time of diagnosis. Nin e of the 15 patients with malig-
343
HU~IAN
PATHOLOGY-VOLUME I. NUMBER 3
Sell/ember 1970
Figure 5. Malignant mixed ~liillerian rumor, heterologous type, with chondrosarcoma as thc heterologous clement. There is close intermingling of the epithelial and me sodermal clem ents. (Hematoxylin a nd eosin stain . x 90 .)
344
nant mixed Miillerian tumors of the heterologous type have died with persistent tumor and two had metastases when last seen. Two patients have been lost to follow-up. The two patients who are li\'ing and well without evidence of disease had tumor limited to the endometrium alone or involving only the inner half of the myometrium. The heterologous element was chondrosarcoma in both tumors. As with the homologous tumors a variety of different modes of therapy were used. including pre- and postoperative radiation and radiation alone (Table G). All three patients who received radiation as the sole method of treatment are dead, but all these patients were treated in this manner because they were deemed poor operative risks . Both the mixed sarcomas contained leiomyosarcoma (Table 7). One was a homologous tumor with leiomyosarcoma
and stromal sarcoma; the other contained rhabdomyosarcoma and leiomyosarcoma. The latter patient died six months after surgical therapy; the former' was lost to follow-up.
Comment 1n this series the survival rat e of the patients with homologous tumors is 27 per cent and that for the heterologous group is 15 per cent, an insignificant difference because of the small numbers of patients and the short follow-up period for some patients. If heterologous elements are present and these are rhabdomyoblasts or osteoblasts, the prognosis is extremely grave, All patients in this 'series whose tumor contained rhabdomyosarcoma or osteosarcoma have died. On the other hand, the 'o nly survivors are patients whose tumors contained chondrosarcoma
UTERINE SARCOMAS-KDIPSO:-:, BARI TABLE 7.
~hXED
SARcmlAS 1/istologic Components Stromal LeiomyoRhabdomyo-
Patient
2
Age
Treatment
48
T.A.H. & B.S.O., Crtexan, radiation Exp. lap.
57
Outcome
No follow-up Died 6 months
as the heterologous element. Similar findings were reported by Norris et aI.18 Equally as important to the prognosis as subdividing these tumors on the basis of differentiation of the tumor cell is the determination of the extent of myometrial invasion. The patients with homologous tumors who -have survived-In this series are those whose tumors had invaded no farther than half the distance through the myometrium at the time of hysterectomy. All II patients whose tumor extended beyond this point have died. However, superficial or no myometrial invasion does not necessarily mean that the patient will survive, since some deaths and metastases occurred in the absence of invasion. For the heterologous group of tumors the extent of the tumor at the time of therapy is also important. The only survivors in this series had small superficial tumors with chondrosarcoma as the only heterologous element. We do not know what the behavior of small superficially invasive tumors containing rhabdomyosarcoma or osteosarcoma would be, since all tumors with these elements extended outside the uterus and were over 4 em. in diameter at the time of diagnosis. Whether surgery, radiation, or a combination of both is the best treatment of malignant mixed Mullerian tumors cannot be determined from our data. One patient with a homologous tumor has survived eight years with only radiation therapy, and the other three survivors with homologous tumors had preoperative radiation. We have observed striking local regression of stromal sarcoma with radiation, but metastases often appear outside the pelvis even though the primary tumor has decreased in size. These findings suggest that preoperative radiation may be of value for tumors with significant stromal sarcomatous differentiation. If preoperative radiation is used, it would be most
Sarcoma
sarcoma
+
+ +
sarcoma
+
logical to utilize both radium implants and external therapy, since the goal is to control the tumor that has extended outside the uterus. Most malignant mixed Miillerian tumors do not regress completely after radiation and surgical extirpation must still be considered the primary therapy. In some poorly differentiated adenocarcinomas of the endometrium, the tumor cells do not form glands or glandlike spaces. Such tumors can be difficult to separate from homologous mixed Milllerian tumors in which the sarcomatous element is stromal sarcoma. In this circumstance reticulin stains are of value, since in stromal sarcoma the individual cell or at most small clumps of cells are surrounded by reticulin fibers. In some instances the differentiation between carcinoma and sarcoma may not be possible, and the approach to therapy should be the same as for poorly differentiated carcinoma. Diagnostic problems are also encountered when the amount of tissue removed at curettage or biopsy is so small that all the different types of tumor tissue are not present in the specimen. Mixed tumors may undergo extensive necrosis resulting in areas of differentiation being missed. Such sampling errors often lead to erroneous diagnoses. When hysterectomy is done, it is of great importance to sample the uterus extensively to avoid missing significant areas of tumor differentiation and to determine accurately the extent of myometrial invasion. Malignant mixed Mullerian tumors should be clearly separated from the purc embryonal rhabdomyosarcomas (sarcoma botryoides) usually encountered in childhood. This tumor most frequently involves the vagina, has morphologic features quite distinct from mixed tumors, and represents a pure heterologous sarcoma. Rarely two separate carcinomas will
345
HUMAN PATHOLOGY-VOLUME 1, NUMBER 3
arise within the uterus, most often mixed adenocarcinoma and squamous carcinoma. These should be distinguished from mixed Mullerian tumors. ENDOLYMPHATIC STROMAL MYOSIS AND ENDOMETRIAL STROMAL SARCOMA Infiltrating malignant tumors composed purely of cells resembling the endometrial stroma are rare. These tumors arc usually classified into two groups on the ba sis of morphology and behavior. Endolymphatic stromal myosis (stromal myosis) is an infiltrating stromal lesion with an indolent course that has been reported occasionally to recur or metastasize, usually after long periods of time. Endometrial stromal sarcoma infiltrates the myometrium more widely and has a more aggressive course, frequent metastases, and higher mortality. Both these tumors have many features in common, including the presence of tumor cells within lyrnphatic spaces, and there has been doubt as to whether they represent separate entities." However, Norris and Taylor'" have stated that the number of mitoses per 10 HPF is an accurate method for diagnosing these two neoplasms. This study was undertaken to evaluate the criteria for the diagnosis of endolymphatic stromal myosis and stromal sarcoma, and to determine the survival rates for each of these lesions. It must also be remembered that there is a benign endometrial stromal tumor, the so-called stromal nodule, which docs not infiltrate lymphatic spaces or myometrium and has a low mitotic counL. These benign tumors are not included in this study of malignant stromal tumors. Material and Methods
346
Seventeen infiltrating stromal lesions of the uterus were obtained from the pathology files of the Barnes Hospital. The clinical symptoms, gros s findings, location within the uterus, and treatment were reviewed. 1\1ultiple sections were available from each tumor, and the number of mitotic figures per 10 HPF in the most active areas of the tumor was determined. Follow-up information was available for 16 of the cases.
Sell/ember 1970
Results
The most common presenting complaint of patients with infiltrating stromal tumors was abnormal vaginal bleeding, which was massive in two patients. A polypoid ma ss presented from the cervix in one patient. The ages of the patients were similar to those in the leiomyosarcoma and malignant mixed Miillcrian tumor seri es except that one patient was 8 ycars of age and another 16. The youngest patient we hav e encountered with a malignant mixed Miillerian tumor was 35 years whereas the youngest with leiomyosarcoma was 39 years. The stromal tumors were yellow to gray-white and often contained areas of necrosis and hemorrhage. All the tumors bulged into the endometrial cavity and infiltrated the myometrium. They measured from 2 to 15 em. Histologically, both groups of infiltrating stromal tumors were composed of monotonous sheets of cells with basophilic nuclei and indistinct cytoplasm. In all tumors, strands of tumor cells infiltrated and separated the smooth muscle fibers of the myometrium, at least focally (Fig. 6). Some tumors contained predominantly round masses of tumor cells without infiltration at the points of contact with the myometrium. With silver stains fine strands of reticulin surrounded individual tumor cells or small clumps of tumor cells. In each case tumor could be demonstrated within lymphatics or lymphatic-like spaces. The stromal tumors were divided into two groups on the basis of the mitotic counts in the most active areas of the tumor (Tables 8 and 9). Ten tumors contained more than 20 mitoses per 10 HPF, and nine of the 10 patients with such tumors have died or had metastases when last seen. The other patient was lost to follow-up . Seven tumors contained 5 or fewer mitoses per 10 HPF, and all the patients from whom these tumors wer e removed are alive three to 15 years after treatment without recurrences or evidence of metastases, No tumors were found with mitotic counts between 6 and 20 per 10 HPF. Pleomorphism of the tumor cells was found in both groups and there was no correlation between malignancy and pleomorphism. The tumors with high mitotic counts usually infiltrated
UTERINE SARCOMAS-KDII'SO:\" BARI
Figure 6. Endometrial stromal sarcoma infiltrating the myometrium. The tumor is composed of nests of uniform cells with round nuclei. (Hematoxylin and eosin stain. A, x 45. B. x 350.)
347
HUMAN PATHOLOGY-VOLUME I, NUMBER 3
TABLE 8.
September 1970
"ENDo)IETRIAL STRO)IAL SARCO)IA
Age
Mitoses/IO HPF
Extension of tumor
Treatment
Outcome
73
35
47
·12
3 4
50 16
34 30
5 6 7
8 9
55 8 63 62 72
21 40 40 30 24
Through serosa Pelvic metastases Through serosa Extensive metastases Through serosa
10
67
29
Through serosa
T.A.H. & n.s.o.. radiation T.A.H. & n.s.o.• radiation T.A.I1. Wertheim without nodes AH* radiation Radiation 300 R T.A.H. & n.s.o, Exp. lap. Radium 9-10 mg.rhr., Au 198-150 me.• T.A.II. & s.s.o. T.A.H. & n.s.o.
Died 6 months
2
Half-way through myometrium Superficially invading myometrium Through serosa Through serosa
Patient
1'\0 follow-up
Died 4 months Died 9 months Died Died Died Died Died
21J2 years 3 months 1 month 2 months 4 months
Died 8 months
*AH = supracervical hysterectomy
the myometrium widely, whereas those with low counts often had pushing margins. However, this finding was inconstant and of little value in individual cases. Eight of the tumors with high mitotic counts had extended to the serosa or had metastasized at the time of surgery, whereas the other two were confined to the inner half of the uterus. None of the lesions with few mitoses had extended beyond the uterus, but all had extended into the myometrium. Comment
Our findings agree with those of Norris and Taylor that infiltrating stromal tumors with large numbers of mitoses are aggressive, metastasize frequently, and are therefore stromal sarcomas." The infiltrating stromal tumors with few mitoses have had a benign course and are designated as endolymphatic stromal myosis. Other authors have reported that these latter tumors may recur or metastasize but this did not occur in our series.": 22" TABLE 9.
348
Norris and Taylor set the dividing point of mitotic activity between stromal myosis and stromal sarcomas at 10 per HPF. Our series indicates an even more significant separation of the mitotic rate, since all the stromal sarcomas contained more than 20 mitoses per 10 HPF and the cndolymphatic stromal myosis cases 5 or fewer. \\l e did not encounter tumors with counts of 6 to 20 mitoses per 10 HPF. These differences in the level of mitotic activity are very interesting when compared to survival data. All our patients with stromal sarcoma have died. Norris and Taylor report a 26 per cent five year survival free of tumor for patients with stromal tumors with mitotic counts greater than 10 per 10 HPF. The survivors in their series had small tumors confined to the uterus, but it is not clear whether they also had mitotic counts below 20 per 10 HPF. It is possible that tumors with counts of 6 to 20 per 10 HPF may be of low grade malignancy as compared to tumors with mitotic counts greater than 20 per 10 HPF. Some of the aggressive and mctas-
ENDOLDII'HATIC STRO)IAL MYOSIS
Patient
Age
Mitosesl l O HPF
1 2 3 4 5 6 7
46 33 42 38 35 49 36
2 1 0 4 2 5 3
Treatment T.A.H. T.A.H. T.A.H. T.A.H. T.A.H. T.A.H. T.A.H.
& B.S.a. & n.s.o. & B.S.a. & n.s.o. & B.S.a.
s: a.s.o. n.s.o.
&
Outcome Living Living Living Living Living Living Living
and and and and and and and
well. well. well. well. well. well. well.
3 years 5 years 6 years 15 years 10 years 11 years 3 years
UTERINE
rasizing endolymphatic stromal tumors reported by Jensen et al. 22 may fall into this group with intermediate mitotic activity. Four of the patients with stromal sarcoma in this series were treated by both radiation therapy and surgery; one was treated with radiation alone and the remainder by surgery alone. Although there was usually an objective decrease in the size of the tumor mass after radiation, all the patients with follow-up died with metastases. In some instances no persistent tumor was found in the radiated areas. The patients with endolyrnphatic stromal myosis were treated by hysterectomy and bilateral salpingo-oophorectomy. Radiation therapy was not utilized. Histologically, endometrial stromal sarcoma and' occasionally endolymphatic stromal myosis may be confused with malignant lymphoma or undifferentiated small cell carcinoma of the cervix. Separation of the latter from stromal sarcoma may be a difficult problem because stromal sarcoma can invade the cervix. In our experience, the reticulin stain is the best method available to distinguish carcinoma from stromal sarcoma.
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SARCO~IAS-KDll'so~, BARI
7. Corscaden, J. A., and Singh. B. P.: Leiomyosarcoma of the uterus, Amcr, J. Obstet. Gyncc., 75:149,1958. 8. Laberge, J.: Prognosis of uterine leiomyosarcomas based on histopathologic criteria. Arner, J.. Obstct. Gynec., 84: 1833, 1962. 9. Spiro, R. H., and Koss, L. G.: Myosarcoma of the uterus. Cancer, 18:571,1965. 10. Taylor, H. B., and Norris. H. J.: Mesenchymal tumors of the uterus. IV. Diagnosis and prognosis of leiomyosarcomas. Arch. Parh., 82:40, 1966. I I. Aaro, L. A., and Dockcrty, ~L B.: Leiomyosarcomas of the uterus. Amer. J. Obstet. Cyncc., 77:1187,1959. 12. Wheelock, ~L C., and Warren, S.: Leiomyosarcoma of the uterus. Ann.· Surg., 116:882, 1942. 13. Corscaden, J. A., and Stout, A. P.: Sarcoma of the uterus. Amer. J. Roentgenol., 21: 155, 1929. 14. Fechner, R. E.: Atypical leiomyornas and synthetic progestogen therapy. Arner. J. Clin. Path., 49:697, 1969. 15. Harper, R. S., and Scully, R. E.: Intravenous Ieiomyornatosis of the lIlerus. Obstet. Gynec., 18:519, 1961. 16. Steiner, 1'. E.: Metastasizing fibroleiomyoma of the uterus. Amer.J. Path., 15:89,1939. 17. Sternberg, W. H., Clark, W. H., and Smith, R. C.: Malignant mixed Mtillerian tumor (mixed mesodermal tumor of the uterus). Cancer, 7:704, 1954. 18. Norris, H. J., Roth, E., and Tar'lor, H. B.: Mesenchymal tumors of the uterus. II. A clinical and pathologic study of 31 mixed mesodermal tumors. Obstet. Cynec., 28:57, 1966. 19. Norris, H. J., and Taylor, H. B.: Mesenchymal tumors of the uterus. IlL A clinical and pathologic study of 31 carcinosarcomas. Cancer, 19:1459,1966. 20. Koss, L. G., Spiro, R. H., and Brunschwig, A.: Endometrial stromal sarcoma. Surg. Gynec. Obstet., 121 :531, 1965. 2 I. Norris, H. J., and Taylor, H. B.: Mesenchymal tumors of the uterus. I. A clinical and pathological study of 53 endometrial stromal tumors. Cancer, 19:755, 1966. 22. Jensen, P. A., Dockerty, M. B., Symmonds, R. E., and Wilson, R. B.: Endornetrioid sarcoma ("stromal endometriosis"). Amer. J. Obstet. Gynec., 95:79, 1966. Department of Pathology Stanford University School of Medicine Stanford, California 94304 (Dr. Kempson)
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