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Mucinous tumors of the ovary
Mutinous
tumors of the ovary
II. Ultrastructural
CECILIA
M.
ALEX
features
FENOGLIO,
FERENCZY,
of mutinous
cystadenocarcinomas
M.D. M.D.
RALPH
M.
RICHART.
New York,
New York, and
M.D. Montreal,
Quebec,
Canada
qf
On the basis light microscopic and scanning and transmission ultrastructural observations, ovarian mucinozls tumors of borderline malignancy contain two types of mutinous epithelium-an endocervical type and an intestinal type. The fully malignant tumors were composed solely of intestinal-type epithelium. These findings may have prognostic and therapeutic signz$cance.
THERE HAVE been numerous reports describing various clinical and histopathologic aspects of benign and malignant neoplasms of the ovary, but the ultrastructural features of these lesions have received little attention. To date, only two prior studies dealing with the ultrastructure of mutinous tumors have 3* 7; both dealt with the fine structure of the appeared benign mutinous epithelium. The present study was undertaken to examine the ultrastructural features of malignant mucin-producing neoplasms of the ovary and to compare them with their benign counterparts.
Material and methods The tissues used in this study were obtained fresh in the operating room from ten ovarian mutinous cystadenocarcinomas. Light microscopy. In addition to the routine histopathologic examination, histochemical stains for mutin (mucicarmine, azure A, Alcian blue, and periodic
e
From th.e Departmnt of Pathology, College of Physicians and Surgeons of Columbia Universitv. the Division of Obstet&al ani Gynecologic Patholoh and the Cytology Laboratory, Presbyterian Hospital, New York, the Department of Pathology, McGill Universit) the Gynecological Pathology and Cytology Laboratories of the Jewish General Hospital, Montreal. Received for publication Revised
November
Accepted December
August
18, 1975.
Fig. 1. Borderline malignancy. Portion of neoplasm illustrating an area of carcinoma in situ (top) in an ovarian mutinous tumor. The surrounding epithetium is of the intestinal type. Note the complex glandular structure of the area of carcinoma in situ (which resembles colonic neoplasms) and compare it to the single-cell lining of the benign portion of the cyst. (Alcian blue and periodic acid-Schiff. Original magnification X200.)
acid-Schiff were obtained.’ Only those carcinomas which stained positively for mucosubstances were included in this study. Autofluorescent studies were
24, 1975.
performed
1 I, 1975.
previously described.3 Scanning electron
microscopy
(SE&S).The tissues
for
in 5 per
acetic
Reprint requests: Dr. Ralph M. Richart, St., New York, New York 10032.
630 W. 168th
SEM
in each
were
washed
of the
cases
according
cent
to a method
acid
and
then
Volume
125
Number
7
Mutinous tumors of ovary.
II
991
Fig. 2. Moderately well-differentiated carcinoma. Mostly solid neoplasm composed of back-to-back proliferation of neoplastic epithelium in which the glandular pattern is readily apparent. Mucin-producing cells are present (arrow). (Mucicarmine. Original magnification x500.)
in phosphate-buffered saline (PBS). They were cut into 1 sq. cm. pieces and fixed in 2 per cent glutaraldehyde for 24 to 48 hours. The specimens were dehydrated, critical point dried as previously described,4 and examined in a JSM-US scanning electron microscope. Following SEM examination, the specimens were removed from their stubs and processed for routine histology according to methods described in a previous communication.3 Transmission electron microscopy (TEM). The fresh tissues were minced into 1 mm. cubes and fixed in 2 per cent glutaraldehyde. They were processed as previously described4 and examined in a JEM 7A transmission electron microscope. Results Light microscopy. The major clinical and pathologic features of the cases studied are summarized in Table I. The cytologic features directly correlated with the degree of differentiation and have been so tabulated. Borderline malignancy (Cases I and 2). Two of the ten neoplasms fulfilled the criteria for borderline malignancy.5 The majority of the epithelium was composed of endocervical-type mutinous cells and intestinal-type cells similar to those present in mutinous cystadenomas.3 This epithelium was arranged in papillary folds with extensive aborizations into the cyst lumina. The areas of borderline malignancy (carcinoma in situ) were confined to the intestinal-type epithelium (Fig. 1).
The areas of carcinoma in situ bore a striking histologic similarity to those of carcinoma in situ occurring in the colon. The glands were crowded together and had a branched appearance. The epithelium within this complex glandular pattern was composed of tall pencil-shaped, intermediate-type intestinal cells. Goblet cells were not present in these areas. Case 2 also contained areas of borderline serous cystadenocarcinema. The distinction between the mutinous and serous areas of this neoplasm was striking when the sections were stained for mucin. The epithelium in both of the cases was multilayered; the nuclei were cytologically atypical, and stromal or capsular invasion was absent. Well-differentiated carcinomas (Cases 3 to 5). All three neoplasms contained mature and immature intestinaltype epithetial cells as well as argentaffin and goblet cells. Endocervical cells were not identified. The epithelium had a stratified appearance, and many areas were histologically identical to those seen in welldifferentiated colonic carcinomas. In such areas, the stratified cells resembled the immature, pencil-shaped, colonic absorptive cells and intermediate cells, and well-developed goblet cells were scarce. Stromal invasion was present. There was a greater degree of pleomorphism than was noted in the borderline tumors, and the papillary, intracystic, glandular proliferations were slightly more complex. Case 5 was associated with a well-differentiated
992
Fenoglio,
Ferenczy,
and Richart
August I, 1976 Am. J. Obstet. Gynrcol.
Fig. 3. Scanning
electron micrograph. Borderline malignancy. The upper portion corresponds to the benign portion of the cyst which is lined by pentagonal ceils arrangement. In the lower portion of the picture, distortion of this pattern is produced of intracystic ridges corresponding to the areas of carcinoma in situ. The junction of malignant epithelium is indicated by the arrow and was verified by examination of SEM specimen. (X 700.)
serous
cystadenocarcinoma,
numerous
ciliated
Moderately These
and,
cells
were
well-dajjferentiated
neoplasms
were
in
the
serous
areas,
identified.
sheets
carcinomas
characterized
(Cases
by solid
6 to 8).
anaplastic
cellular proliferations in which complex gland-in-gland formations and sparse intervening connective tissue stroma were seen. Only rare mature goblet cells were identified. The lesions histologically bore a striking resemblance to moderately well-differentiated colonic carcinomas. Stains for mucosubstances highlighted the presence of some of the goblet cells within the glandular proliferations (Fig. 2). Many immature goblet cells with small apical mucin droplets were also encountered. In addition, argentaffin cells were identified in two of the three cases. Endocervical cells were not noted. Poorly
diffPrentiated
carcinomas
(Cases
specimens
9 and
IO).
These
were of
both
of the picture with a regular by formation the benign and the rehydrated
composed
anaplastic
cells.
predominantly A
glandular
of solid pattern
was
focally present but difficult to identify in most areas. It was not possible to identify the majority of cell types, but histochemical stains for mucin were focally positive. Occasional signet-ring cells were also identified. Endocervical in either
cells
and
argentaffin
cells were
not identified
neoplasm.
SEM. tumors. The cystic spaces of borderline tumors were lined by regular, pentagonally shaped epithelial cells which were thrown up into short Borderline
intracystic
ridges
(Fig.
3).
The
cells
were
of
uniform
size and pentagonal shape, and both endocervicat intestinal types of mutinous epithelial cells identified. They cystadenomas3
resembled those The intervening
seen
and were
in the mutinous non-mucin-pro-
Volume Number
Mutinous tumors of ovary. II 993
125
7
Fig. 4. Scanning electron micrograph. Moderately well-differentiated carcinoma. A population of pleomorphic cells is present. Note the irregular size and shape of these cells. A mucin-secreting cell is present. (X 1,400.)
ducing
cells
were
covered
with
a lush
microvillous
sur-
face. In the areas of Case 2 which corresponded to a borderline serous cystadenocarcinoma, numerous ciliated cells were identified. These were not present in other areas of this neoplasm, and they were not present in Case I. Well-differentiated carcinomas. The over-all architec-
ture of these lesions was that of a disorderly array of cells which were more stratified than those in the borderline tumors. The majority of the cells were covered with a well-developed microvillous surface, but mucin-secreting cells were interspersed among them. UnIike the cells present in the borderline tumors, the cells were no longer uniformly pentagonal, and their
994
Fenoglio,
Ferenczy,
and Richart
Fig. 5. Transmission Intestinal-type mucin-secr&g
electron micrograph. cells with an argentaffin cell. (X 174,000.) -
Borderline malignancy, cell Cz4), an intestinal
size was variable (Fig. 4). Ciliated cells were not noted in any of the neoplasms except in Case 5, in which they were confined te Ae areas of serous cystadenocarcinema. Moderately well-dz;fferentiated carcinomas. Only one of the neoplasms was satisfactory for SEM examination. In this case the cells were extremely variable in both size and shape with irregular cell borders. Some of the cells were 3 to 4 times normal size, and many were smaller than normal. Rare mucin-producing cells were identified, and, where present, the mucin droplets were always smaller than those seen in betterdifferentiated neoplasms. Poorly dzyferentiated carcinomas. It was not possible to study the surface of the poorly differentiated carcinomas because of the large amount of necrosis. hemorrhage, and surface debris. TEM. Borderline tumors. In the benign areas of these
area of carcinoma absorptive-type cell,
in situ and a
neoplasms, the papillary infoldings of the epithelium were lined by endocervical cells, rare mature absorptive cells, goblet cells, immature absorptive cells, immature goblet cells, intermediate cells, and argentaffin cells (Fig. 5). In both tumors, the cells in the areas of carcinoma in situ were stratified with loss of polarity. These areas were composed solely of immature colonic-type absorptive cells characterized by numerous supranuclear mitochondria, extensive Golgi zones and granular endoplasmic reticulum (GER), moderately complex interdigitating lateral margins, and long microvilli. The latter were anchored to the apical portions of the cells by long microfilamentous rootlets and were covered by a thick glycocalyx (Fig. 6). The area immediately below the apical surface was devoid of most cellular organelles except the microfilamento.us rootlets. The intercellular spaces were dilated at the basal ends of the cells, and the apical ends were closed by desmosomes and tight junctional complexes.
Volume Number
Mutinous tumors of ovary. II 995
125 7
6. Transmission electron micrograph. Borderline malignancy, area of carcinoma in situ. Portions of several immature absorptive-type cells with prominent mitochondria, long microvilli, and dense glycocalyx. (~4,200.)
Fig.
Ciliated cells corresponding
were only identified in those areas to the serous component in Case 2. Well-differentiated carcinomas. The frankly invasive carcinomas were composed exclusively of intestinal-type epithelium. Endocervical cells were absent. The immature epithelial cells focally maintained their polarity, and the majority of the mutinous
secretions were confined to apical droplets within immature goblet cells (Fig. 7). Ciliated cells were only present in Case 5 in areas with serous differentiation. The lateral cell margins were quite complex with extensive interdigitations, and the intercellular spaces were frequently dilated. The nuclei were elongated and contained rare cytoplasmic invaginations. The
996
Fenoglio, Ferenczy, and Richart
Fig. 7. Transmission which have maintained
electron their
August I. 1976 Am. J, Obstet. Gynecol.
micrograph. Well-differentiated carcinoma. Note polarity and contain apical cells of mucin secretion.
cells were covered with short, irregular microvilli. Moderately well-differentiated carcinomas. These neoplasms were composed almost exclusively of immature cells which no longer had a columnar shape but appeared rounded and broadened. (The only mature cell type identified was a rare argentaffin cell.) The cells were arranged in disorderly multilayers, with loss of
tall columnar (X 7,600.)
cells
polarity. The cells in the upper layers contained mutinous secretory vacuoles whereas the cells beneath them appeared totally undifferentiated without obvious secretory activity. These immature cells were round and contained abundant GER, free ribosomes, mitochondria, and Golgi zones. The mitochondria were pleomorphic. The cells had a wide range of sizes
Volume Number
125 7
Mutinous
Fig. 8. Transmission irregular microvillous (X 8,000.)
electron surface
micrograph. Poorly differentiated and small number of poorly formed
and shapes, and the nucleocytoplasmic ratio was increased. The nuclei were rounded with numerous cytoplasmic invaginations. Poorly differentiated carcinomas. The majority of these neoplasms were composed of immature cells of an indeterminate type. There was a wide range in cell size and shape, and the nuclei were enlarged with a high
tumors
of ovary.
II
9%’
carcinoma. Anaplastic cell with mucin droplets and lysozomes.
nucleocytoplasmic ratio. The nuclei had irregular complex shapes with numerous cytoplasmic invaginations. Extensive cytoplasmic accumulations of glycolipid droplets, and myelin gen, autophagosomes, figures were present. These cells were present in large cellular sheets with little intervening connective tissue stroma. An occasional anaplastic cell containing poorly
998
Fenoglio,
Ferenczy,
Table
I. Mutinous
CC&SC NO.
Age oJ. pat&l
1
2
3
and Richart
cystadenocarcinomas-pathologic
findings
side
Gross appearance
56
Right ovary
45
Right ovary
21 by I7 by 15 cm., 1,800 grams, multilocular 3 by 6 by 3 cm., unilocular with papillary projections
intestinal cells Borderline malignancy, mixed
Left ovary
Multilocular,
Well-differentiated
Right OWt-y
Multilocular, solid areas, 1,000 grams
17
600 grams
Light
Associated lesions in same ovary
microscopicfeatures
Borderline malignancy, endocervical and
mixed
None
5
6
7
61
41
56
62
Bilateral
Bilateral
Bilateral
Left4 by 12 by 15 cm., 470 grams; Right-3 by 8 by 12 cm., 260 grams Left-5 solid; Right-12 partly Solid
by 4 by 3.5 cm.,
carcinoma, intestinal cells including goblet cells Well differentiated
Mixed endwervicnl-,
None
tissue
Moderately
well-
carcinoma,
many signetring cells
51
9
51
10
47
Mature and immature intestinal, undifferentiated and ciliated ceils
None
Most+ immature type cells
differentiated carcinoma, intestinal cells
differentiated
8
None
carcinoma. and cells
Moderately well-
by 15 by 3 cm., solid
necrotic
Benign mutinous adenoma
mutinous and serous Goblet ciliated
Right ovary Right ovary
8.4 by 7.9 by 5.3 cm., solid Multilocular, partly solid, 750 grams
Moderately
well-
Right ovary
Large solid mass extending to adnexa, 6.5 by 3.5 by 3.0 cm.
Poor differentiated carcinoma
differentiated
Cortical Inclusion cysts
None
carcinoma
Poorly differentiated carcinoma,
None
mutinous lakes
formed mucin droplets was identified spaces were not identified.
(Fig. 8). Luminal
Comment The differentiation of the mutinous cystadenocarcinemas examined in this series ranged from borderline malignancy to so poorly differentiated that without the use of histochemical stains for mucin they would not have been classified as mutinous carcinomas. (The specific result of these histochemical studies is the subject of another article.‘) The benign areas of the borderline lesions resembled the mutinous cystadenomas of the mixed endocervical-intestinal type. 3 The carcinomatous areas were composed solely of intestinal epithelium. Like the mutinous cystadenomas,3 ciliated cells were absent in the mutinous carcinomas unless a serous component
and ype
intestinal-, and ciliated serous-typr cells Mature and immature intestinal-type cells Intestinal-type cells
carcinoma, Well-differentiated
Mixed intestinalendocervical-r cells
None
endocervical and intestinal cells. Serous component
intestinal cells only 4
7’I: M
None
intestinal-
Immature intestinaltype cells
Immature intestinal. type cells Verv immature cells with abortive mucin production Mostly immature cells. rate mucinproducing cells
was also present. The ultrastructural features of the serous component were similar to those of the pure ovarian serous cystadenomas.’ In all of the well-differentiated and moderately well-differentiated mutinous carcinomas, the various intestinal epithelial cell types which were noted in the mixed-type mutinous cystadenomas were present. With increasing histologic grade, the individual cells become increasingly immature, and the organization of these cells becomes increasingly chaotic. The ease with which mature intestinal cells could he identified was directly proportional to the differentiation of the neoplasm. The most significant finding was the apparent absence of endocervical-type mutinous cells in the frankly malignant tumors. Endocervical-type cells were present in both cases of borderline malignancy, but
Volume Number
125 7
Mutinous
A?-genSEM
4!@ cells
Other
Regular
Yes
Inactive endometrium
Regular with occasional ciliated cells
Yes
None
Irregular
Yes
None
Irregular
No
Omental metastases
Irregular
No
None
Irregular
-Yes
Specimen not adequate
Yes
Specimen not adequate Specimen not adequate
Yes
Endometrium retrogressive, cystic, glandular hyperplasia Omental metastases, endometrial polyp with cystic glandular hyperplasia None
No
None
Specimen not adequate
No
Omental metastases
they were relatively rare in comparison to the mixedtype mutinous cystadenomas. The majority of the cellular population was composed of immature absorptive cells. The lack of endocervical-type cells in the mutinous adenocarcinomas sharply contrasts with
REFERENCES
1. Fenoglio, C. M., Castadot, M-.J., Ferenczy, A., and Richart, R. M.: Ultrastructural features of serous tumors of the ovary. In preparation. 2. Fenoglio, C. M., Cottral, G. A., Richart, R. M., and Ferenczy, A.: Mutinous tumors of the ovary. III. Histochemical studies. Gvnecol. Oncol. In mess. 3. Fenoglio, C. M.,’ Ferenczy, A., and’ Richart, R. M.: Mutinous tumors of the ovarv. Ultrastructural studies of mutinous cystadenomas with ‘histogenetic considerations, Cancer 36: 1709, 1975.
tumors
of ovary.
II
999
findings in the mutinous cystadenomas, all of which contained endocervical-type cells either alone or in combination with intestinal-type epithelium. It is difficult to explain why all the carcinomas in this study were composed of intestinal-type epithelium when such epithelium is present in only 25 per cent of the mutinous cystadenomas and why there were no carcinomas with the endocervical type cells when that cell type is present in 100 per cent of the benign mutinous neoplasms. However, it may be important that the intestinal-type epithelium encountered in the mutinous cystadenomas is of the immature type generally found in colonic adenomas and known to be heir to a high rate of malignant transformation in its colonic location whereas the endocervical-type epithelium is of the mature type found in the adult endocervix and uncommonly becomes malignant. The colonic epithelium may also have a higher rate of proliferation than the endocervical component in the mixed-type tumors, and the former may gradually overgrow the latter and form a larger susceptible population. The relatively high proportion of mutinous cystadenomas which are composed solely of endocervical cells may account for the low incidence of malignancy in the mutinous neoplasms when compared to the serous tumors. Endocervical cells may normally have a low malignant potential (as in the normal endocervix), and this may also be true of endocervical cells in an ovarian site. If it were possible to distinguish prospectively the purely endocervical-type mutinous tumor from the mixed type which contains an intestinal component, the malignancy rate in the two would probably be strikingly different. In any case, the recognition that the mutinous carcinomas of the ovary are colonic cancers may be important clinically, and diagnostic and chemotherapeutic regimens which are effective in colon carcinomas should be evaluated in their ovarian counterparts.
4. Ferenczy, A., and Richart, R. M.: Female Reproductive System: Dynamics of Scanning and Transmission Electron Microscopy, New York, 1974, John Wiley & Sons. 5. Hart, W. R., and Norris, H. J.: Borderline and malignant mutinous tumors of the ovary: Histologic criteria and clinical behavior, Cancer 31: 1031, 1973. 6. Kawase, T., and Hashimoto, M.: Ultrastructural considerations on the histologic origin of ovarian mutinous cysts, J. Ian. Obstet. Gvnecol. Sot. 23: 77, 1971. 7. ‘bierbeck, L.:’ Die Ultrastructure der pseudomuzinosen Ovatialkystoma, Z. Geburtshiefe Gynaekol. 168: 1, 1967.
tumors of the ovary
II. Ultrastructural
CECILIA
M.
ALEX
features
FENOGLIO,
FERENCZY,
of mutinous
cystadenocarcinomas
M.D. M.D.
RALPH
M.
RICHART.
New York,
New York, and
M.D. Montreal,
Quebec,
Canada
qf
On the basis light microscopic and scanning and transmission ultrastructural observations, ovarian mucinozls tumors of borderline malignancy contain two types of mutinous epithelium-an endocervical type and an intestinal type. The fully malignant tumors were composed solely of intestinal-type epithelium. These findings may have prognostic and therapeutic signz$cance.
THERE HAVE been numerous reports describing various clinical and histopathologic aspects of benign and malignant neoplasms of the ovary, but the ultrastructural features of these lesions have received little attention. To date, only two prior studies dealing with the ultrastructure of mutinous tumors have 3* 7; both dealt with the fine structure of the appeared benign mutinous epithelium. The present study was undertaken to examine the ultrastructural features of malignant mucin-producing neoplasms of the ovary and to compare them with their benign counterparts.
Material and methods The tissues used in this study were obtained fresh in the operating room from ten ovarian mutinous cystadenocarcinomas. Light microscopy. In addition to the routine histopathologic examination, histochemical stains for mutin (mucicarmine, azure A, Alcian blue, and periodic
e
From th.e Departmnt of Pathology, College of Physicians and Surgeons of Columbia Universitv. the Division of Obstet&al ani Gynecologic Patholoh and the Cytology Laboratory, Presbyterian Hospital, New York, the Department of Pathology, McGill Universit) the Gynecological Pathology and Cytology Laboratories of the Jewish General Hospital, Montreal. Received for publication Revised
November
Accepted December
August
18, 1975.
Fig. 1. Borderline malignancy. Portion of neoplasm illustrating an area of carcinoma in situ (top) in an ovarian mutinous tumor. The surrounding epithetium is of the intestinal type. Note the complex glandular structure of the area of carcinoma in situ (which resembles colonic neoplasms) and compare it to the single-cell lining of the benign portion of the cyst. (Alcian blue and periodic acid-Schiff. Original magnification X200.)
acid-Schiff were obtained.’ Only those carcinomas which stained positively for mucosubstances were included in this study. Autofluorescent studies were
24, 1975.
performed
1 I, 1975.
previously described.3 Scanning electron
microscopy
(SE&S).The tissues
for
in 5 per
acetic
Reprint requests: Dr. Ralph M. Richart, St., New York, New York 10032.
630 W. 168th
SEM
in each
were
washed
of the
cases
according
cent
to a method
acid
and
then
Volume
125
Number
7
Mutinous tumors of ovary.
II
991
Fig. 2. Moderately well-differentiated carcinoma. Mostly solid neoplasm composed of back-to-back proliferation of neoplastic epithelium in which the glandular pattern is readily apparent. Mucin-producing cells are present (arrow). (Mucicarmine. Original magnification x500.)
in phosphate-buffered saline (PBS). They were cut into 1 sq. cm. pieces and fixed in 2 per cent glutaraldehyde for 24 to 48 hours. The specimens were dehydrated, critical point dried as previously described,4 and examined in a JSM-US scanning electron microscope. Following SEM examination, the specimens were removed from their stubs and processed for routine histology according to methods described in a previous communication.3 Transmission electron microscopy (TEM). The fresh tissues were minced into 1 mm. cubes and fixed in 2 per cent glutaraldehyde. They were processed as previously described4 and examined in a JEM 7A transmission electron microscope. Results Light microscopy. The major clinical and pathologic features of the cases studied are summarized in Table I. The cytologic features directly correlated with the degree of differentiation and have been so tabulated. Borderline malignancy (Cases I and 2). Two of the ten neoplasms fulfilled the criteria for borderline malignancy.5 The majority of the epithelium was composed of endocervical-type mutinous cells and intestinal-type cells similar to those present in mutinous cystadenomas.3 This epithelium was arranged in papillary folds with extensive aborizations into the cyst lumina. The areas of borderline malignancy (carcinoma in situ) were confined to the intestinal-type epithelium (Fig. 1).
The areas of carcinoma in situ bore a striking histologic similarity to those of carcinoma in situ occurring in the colon. The glands were crowded together and had a branched appearance. The epithelium within this complex glandular pattern was composed of tall pencil-shaped, intermediate-type intestinal cells. Goblet cells were not present in these areas. Case 2 also contained areas of borderline serous cystadenocarcinema. The distinction between the mutinous and serous areas of this neoplasm was striking when the sections were stained for mucin. The epithelium in both of the cases was multilayered; the nuclei were cytologically atypical, and stromal or capsular invasion was absent. Well-differentiated carcinomas (Cases 3 to 5). All three neoplasms contained mature and immature intestinaltype epithetial cells as well as argentaffin and goblet cells. Endocervical cells were not identified. The epithelium had a stratified appearance, and many areas were histologically identical to those seen in welldifferentiated colonic carcinomas. In such areas, the stratified cells resembled the immature, pencil-shaped, colonic absorptive cells and intermediate cells, and well-developed goblet cells were scarce. Stromal invasion was present. There was a greater degree of pleomorphism than was noted in the borderline tumors, and the papillary, intracystic, glandular proliferations were slightly more complex. Case 5 was associated with a well-differentiated
992
Fenoglio,
Ferenczy,
and Richart
August I, 1976 Am. J. Obstet. Gynrcol.
Fig. 3. Scanning
electron micrograph. Borderline malignancy. The upper portion corresponds to the benign portion of the cyst which is lined by pentagonal ceils arrangement. In the lower portion of the picture, distortion of this pattern is produced of intracystic ridges corresponding to the areas of carcinoma in situ. The junction of malignant epithelium is indicated by the arrow and was verified by examination of SEM specimen. (X 700.)
serous
cystadenocarcinoma,
numerous
ciliated
Moderately These
and,
cells
were
well-dajjferentiated
neoplasms
were
in
the
serous
areas,
identified.
sheets
carcinomas
characterized
(Cases
by solid
6 to 8).
anaplastic
cellular proliferations in which complex gland-in-gland formations and sparse intervening connective tissue stroma were seen. Only rare mature goblet cells were identified. The lesions histologically bore a striking resemblance to moderately well-differentiated colonic carcinomas. Stains for mucosubstances highlighted the presence of some of the goblet cells within the glandular proliferations (Fig. 2). Many immature goblet cells with small apical mucin droplets were also encountered. In addition, argentaffin cells were identified in two of the three cases. Endocervical cells were not noted. Poorly
diffPrentiated
carcinomas
(Cases
specimens
9 and
IO).
These
were of
both
of the picture with a regular by formation the benign and the rehydrated
composed
anaplastic
cells.
predominantly A
glandular
of solid pattern
was
focally present but difficult to identify in most areas. It was not possible to identify the majority of cell types, but histochemical stains for mucin were focally positive. Occasional signet-ring cells were also identified. Endocervical in either
cells
and
argentaffin
cells were
not identified
neoplasm.
SEM. tumors. The cystic spaces of borderline tumors were lined by regular, pentagonally shaped epithelial cells which were thrown up into short Borderline
intracystic
ridges
(Fig.
3).
The
cells
were
of
uniform
size and pentagonal shape, and both endocervicat intestinal types of mutinous epithelial cells identified. They cystadenomas3
resembled those The intervening
seen
and were
in the mutinous non-mucin-pro-
Volume Number
Mutinous tumors of ovary. II 993
125
7
Fig. 4. Scanning electron micrograph. Moderately well-differentiated carcinoma. A population of pleomorphic cells is present. Note the irregular size and shape of these cells. A mucin-secreting cell is present. (X 1,400.)
ducing
cells
were
covered
with
a lush
microvillous
sur-
face. In the areas of Case 2 which corresponded to a borderline serous cystadenocarcinoma, numerous ciliated cells were identified. These were not present in other areas of this neoplasm, and they were not present in Case I. Well-differentiated carcinomas. The over-all architec-
ture of these lesions was that of a disorderly array of cells which were more stratified than those in the borderline tumors. The majority of the cells were covered with a well-developed microvillous surface, but mucin-secreting cells were interspersed among them. UnIike the cells present in the borderline tumors, the cells were no longer uniformly pentagonal, and their
994
Fenoglio,
Ferenczy,
and Richart
Fig. 5. Transmission Intestinal-type mucin-secr&g
electron micrograph. cells with an argentaffin cell. (X 174,000.) -
Borderline malignancy, cell Cz4), an intestinal
size was variable (Fig. 4). Ciliated cells were not noted in any of the neoplasms except in Case 5, in which they were confined te Ae areas of serous cystadenocarcinema. Moderately well-dz;fferentiated carcinomas. Only one of the neoplasms was satisfactory for SEM examination. In this case the cells were extremely variable in both size and shape with irregular cell borders. Some of the cells were 3 to 4 times normal size, and many were smaller than normal. Rare mucin-producing cells were identified, and, where present, the mucin droplets were always smaller than those seen in betterdifferentiated neoplasms. Poorly dzyferentiated carcinomas. It was not possible to study the surface of the poorly differentiated carcinomas because of the large amount of necrosis. hemorrhage, and surface debris. TEM. Borderline tumors. In the benign areas of these
area of carcinoma absorptive-type cell,
in situ and a
neoplasms, the papillary infoldings of the epithelium were lined by endocervical cells, rare mature absorptive cells, goblet cells, immature absorptive cells, immature goblet cells, intermediate cells, and argentaffin cells (Fig. 5). In both tumors, the cells in the areas of carcinoma in situ were stratified with loss of polarity. These areas were composed solely of immature colonic-type absorptive cells characterized by numerous supranuclear mitochondria, extensive Golgi zones and granular endoplasmic reticulum (GER), moderately complex interdigitating lateral margins, and long microvilli. The latter were anchored to the apical portions of the cells by long microfilamentous rootlets and were covered by a thick glycocalyx (Fig. 6). The area immediately below the apical surface was devoid of most cellular organelles except the microfilamento.us rootlets. The intercellular spaces were dilated at the basal ends of the cells, and the apical ends were closed by desmosomes and tight junctional complexes.
Volume Number
Mutinous tumors of ovary. II 995
125 7
6. Transmission electron micrograph. Borderline malignancy, area of carcinoma in situ. Portions of several immature absorptive-type cells with prominent mitochondria, long microvilli, and dense glycocalyx. (~4,200.)
Fig.
Ciliated cells corresponding
were only identified in those areas to the serous component in Case 2. Well-differentiated carcinomas. The frankly invasive carcinomas were composed exclusively of intestinal-type epithelium. Endocervical cells were absent. The immature epithelial cells focally maintained their polarity, and the majority of the mutinous
secretions were confined to apical droplets within immature goblet cells (Fig. 7). Ciliated cells were only present in Case 5 in areas with serous differentiation. The lateral cell margins were quite complex with extensive interdigitations, and the intercellular spaces were frequently dilated. The nuclei were elongated and contained rare cytoplasmic invaginations. The
996
Fenoglio, Ferenczy, and Richart
Fig. 7. Transmission which have maintained
electron their
August I. 1976 Am. J, Obstet. Gynecol.
micrograph. Well-differentiated carcinoma. Note polarity and contain apical cells of mucin secretion.
cells were covered with short, irregular microvilli. Moderately well-differentiated carcinomas. These neoplasms were composed almost exclusively of immature cells which no longer had a columnar shape but appeared rounded and broadened. (The only mature cell type identified was a rare argentaffin cell.) The cells were arranged in disorderly multilayers, with loss of
tall columnar (X 7,600.)
cells
polarity. The cells in the upper layers contained mutinous secretory vacuoles whereas the cells beneath them appeared totally undifferentiated without obvious secretory activity. These immature cells were round and contained abundant GER, free ribosomes, mitochondria, and Golgi zones. The mitochondria were pleomorphic. The cells had a wide range of sizes
Volume Number
125 7
Mutinous
Fig. 8. Transmission irregular microvillous (X 8,000.)
electron surface
micrograph. Poorly differentiated and small number of poorly formed
and shapes, and the nucleocytoplasmic ratio was increased. The nuclei were rounded with numerous cytoplasmic invaginations. Poorly differentiated carcinomas. The majority of these neoplasms were composed of immature cells of an indeterminate type. There was a wide range in cell size and shape, and the nuclei were enlarged with a high
tumors
of ovary.
II
9%’
carcinoma. Anaplastic cell with mucin droplets and lysozomes.
nucleocytoplasmic ratio. The nuclei had irregular complex shapes with numerous cytoplasmic invaginations. Extensive cytoplasmic accumulations of glycolipid droplets, and myelin gen, autophagosomes, figures were present. These cells were present in large cellular sheets with little intervening connective tissue stroma. An occasional anaplastic cell containing poorly
998
Fenoglio,
Ferenczy,
Table
I. Mutinous
CC&SC NO.
Age oJ. pat&l
1
2
3
and Richart
cystadenocarcinomas-pathologic
findings
side
Gross appearance
56
Right ovary
45
Right ovary
21 by I7 by 15 cm., 1,800 grams, multilocular 3 by 6 by 3 cm., unilocular with papillary projections
intestinal cells Borderline malignancy, mixed
Left ovary
Multilocular,
Well-differentiated
Right OWt-y
Multilocular, solid areas, 1,000 grams
17
600 grams
Light
Associated lesions in same ovary
microscopicfeatures
Borderline malignancy, endocervical and
mixed
None
5
6
7
61
41
56
62
Bilateral
Bilateral
Bilateral
Left4 by 12 by 15 cm., 470 grams; Right-3 by 8 by 12 cm., 260 grams Left-5 solid; Right-12 partly Solid
by 4 by 3.5 cm.,
carcinoma, intestinal cells including goblet cells Well differentiated
Mixed endwervicnl-,
None
tissue
Moderately
well-
carcinoma,
many signetring cells
51
9
51
10
47
Mature and immature intestinal, undifferentiated and ciliated ceils
None
Most+ immature type cells
differentiated carcinoma, intestinal cells
differentiated
8
None
carcinoma. and cells
Moderately well-
by 15 by 3 cm., solid
necrotic
Benign mutinous adenoma
mutinous and serous Goblet ciliated
Right ovary Right ovary
8.4 by 7.9 by 5.3 cm., solid Multilocular, partly solid, 750 grams
Moderately
well-
Right ovary
Large solid mass extending to adnexa, 6.5 by 3.5 by 3.0 cm.
Poor differentiated carcinoma
differentiated
Cortical Inclusion cysts
None
carcinoma
Poorly differentiated carcinoma,
None
mutinous lakes
formed mucin droplets was identified spaces were not identified.
(Fig. 8). Luminal
Comment The differentiation of the mutinous cystadenocarcinemas examined in this series ranged from borderline malignancy to so poorly differentiated that without the use of histochemical stains for mucin they would not have been classified as mutinous carcinomas. (The specific result of these histochemical studies is the subject of another article.‘) The benign areas of the borderline lesions resembled the mutinous cystadenomas of the mixed endocervical-intestinal type. 3 The carcinomatous areas were composed solely of intestinal epithelium. Like the mutinous cystadenomas,3 ciliated cells were absent in the mutinous carcinomas unless a serous component
and ype
intestinal-, and ciliated serous-typr cells Mature and immature intestinal-type cells Intestinal-type cells
carcinoma, Well-differentiated
Mixed intestinalendocervical-r cells
None
endocervical and intestinal cells. Serous component
intestinal cells only 4
7’I: M
None
intestinal-
Immature intestinaltype cells
Immature intestinal. type cells Verv immature cells with abortive mucin production Mostly immature cells. rate mucinproducing cells
was also present. The ultrastructural features of the serous component were similar to those of the pure ovarian serous cystadenomas.’ In all of the well-differentiated and moderately well-differentiated mutinous carcinomas, the various intestinal epithelial cell types which were noted in the mixed-type mutinous cystadenomas were present. With increasing histologic grade, the individual cells become increasingly immature, and the organization of these cells becomes increasingly chaotic. The ease with which mature intestinal cells could he identified was directly proportional to the differentiation of the neoplasm. The most significant finding was the apparent absence of endocervical-type mutinous cells in the frankly malignant tumors. Endocervical-type cells were present in both cases of borderline malignancy, but
Volume Number
125 7
Mutinous
A?-genSEM
4!@ cells
Other
Regular
Yes
Inactive endometrium
Regular with occasional ciliated cells
Yes
None
Irregular
Yes
None
Irregular
No
Omental metastases
Irregular
No
None
Irregular
-Yes
Specimen not adequate
Yes
Specimen not adequate Specimen not adequate
Yes
Endometrium retrogressive, cystic, glandular hyperplasia Omental metastases, endometrial polyp with cystic glandular hyperplasia None
No
None
Specimen not adequate
No
Omental metastases
they were relatively rare in comparison to the mixedtype mutinous cystadenomas. The majority of the cellular population was composed of immature absorptive cells. The lack of endocervical-type cells in the mutinous adenocarcinomas sharply contrasts with
REFERENCES
1. Fenoglio, C. M., Castadot, M-.J., Ferenczy, A., and Richart, R. M.: Ultrastructural features of serous tumors of the ovary. In preparation. 2. Fenoglio, C. M., Cottral, G. A., Richart, R. M., and Ferenczy, A.: Mutinous tumors of the ovary. III. Histochemical studies. Gvnecol. Oncol. In mess. 3. Fenoglio, C. M.,’ Ferenczy, A., and’ Richart, R. M.: Mutinous tumors of the ovarv. Ultrastructural studies of mutinous cystadenomas with ‘histogenetic considerations, Cancer 36: 1709, 1975.
tumors
of ovary.
II
999
findings in the mutinous cystadenomas, all of which contained endocervical-type cells either alone or in combination with intestinal-type epithelium. It is difficult to explain why all the carcinomas in this study were composed of intestinal-type epithelium when such epithelium is present in only 25 per cent of the mutinous cystadenomas and why there were no carcinomas with the endocervical type cells when that cell type is present in 100 per cent of the benign mutinous neoplasms. However, it may be important that the intestinal-type epithelium encountered in the mutinous cystadenomas is of the immature type generally found in colonic adenomas and known to be heir to a high rate of malignant transformation in its colonic location whereas the endocervical-type epithelium is of the mature type found in the adult endocervix and uncommonly becomes malignant. The colonic epithelium may also have a higher rate of proliferation than the endocervical component in the mixed-type tumors, and the former may gradually overgrow the latter and form a larger susceptible population. The relatively high proportion of mutinous cystadenomas which are composed solely of endocervical cells may account for the low incidence of malignancy in the mutinous neoplasms when compared to the serous tumors. Endocervical cells may normally have a low malignant potential (as in the normal endocervix), and this may also be true of endocervical cells in an ovarian site. If it were possible to distinguish prospectively the purely endocervical-type mutinous tumor from the mixed type which contains an intestinal component, the malignancy rate in the two would probably be strikingly different. In any case, the recognition that the mutinous carcinomas of the ovary are colonic cancers may be important clinically, and diagnostic and chemotherapeutic regimens which are effective in colon carcinomas should be evaluated in their ovarian counterparts.
4. Ferenczy, A., and Richart, R. M.: Female Reproductive System: Dynamics of Scanning and Transmission Electron Microscopy, New York, 1974, John Wiley & Sons. 5. Hart, W. R., and Norris, H. J.: Borderline and malignant mutinous tumors of the ovary: Histologic criteria and clinical behavior, Cancer 31: 1031, 1973. 6. Kawase, T., and Hashimoto, M.: Ultrastructural considerations on the histologic origin of ovarian mutinous cysts, J. Ian. Obstet. Gvnecol. Sot. 23: 77, 1971. 7. ‘bierbeck, L.:’ Die Ultrastructure der pseudomuzinosen Ovatialkystoma, Z. Geburtshiefe Gynaekol. 168: 1, 1967.