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2020, Volume 36, Number 3, Page(s) 261-267
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DOI: 10.5146/tjpath.2020.01477 |
Small Cell Carcinoma of Ovary, Hypercalcemic Type (Malignant Rhabdoid Tumor of Ovary) with Loss of SMARCA4 (BRG1) Expression: Report of Two Cases |
Ayushi SAHAY1, Katha KANTE1, Santosh MENON1, Jaya GHOSH2, Rajendra A. KERKAR3, Kedar K. DEODHAR1 |
1Departments of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, MUMBAI, INDIA
2Departments of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, MUMBAI, INDIA
3Departments of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, MUMBAI, INDIA |
Keywords: Small cell carcinoma ovary, Rhabdoid tumor of ovary, BRG1, Ovarian tumor |
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Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) / malignant rhabdoid tumor of the ovary (MRTO) is a rare tumor affecting
young women. It is frequently misdiagnosed due to overlapping morphological and immunohistochemical features with many other ovarian
tumors. The prognosis of the tumors is very poor; hence an accurate diagnosis is of utmost importance. Recently, the loss of BRG1 protein by
immunohistochemistry has been shown to be a useful diagnostic marker. We present here two cases of SSCOHT/MRTO, in young women 22
and 32 years of age, where several differential diagnoses were considered on morphology and immunohistochemistry but were confirmed as
SCCOHT/MRTO by the demonstration of loss of BRG1. As the prognosis of SCCOHT is very dismal, and accurate diagnosis is of necessity,
we recommend the inclusion of BRG1 immunohistochemistry in the diagnostic armamentarium of poorly differentiated ovarian tumors,
particularly in young adults. |
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Ovarian small cell carcinoma of hypercalcemic type
(SCCOHT) is a rare and highly aggressive tumor of young
adults with uncertain histogenesis and very poor prognosis
1. Malignant rhabdoid tumors (MRT) have been rarely
reported in the ovaries. Recently, near-simultaneous
genomic studies demonstrated that SCCOHTs show
inactivating mutations in SMARCA4, accompanied by
loss of expression of its protein product BRG1, the same
mutation that has been described in a proportion of
atypical teratoid/rhabdoid tumors (ATRT) of the brain
as well as extracranial MRT 2-4. In addition, SCCOHTs
show histological similarity with MRT, with the presence of
small undifferentiated round cells, as well as large rhabdoid
looking cells in up to 40% of the cases (the so-called
“large cell variant”). Based on this histologic and genetic
similarity, it has been proposed to rename SCCOHT of
the ovary as MRT of the ovary (MRTO) 5. In most prior
studies, the primary diagnosis of SSCOHT was based on
morphology, which can mimic a large variety of other
ovarian tumors, and testing for SMARCA4 or BRG1 was
done only retrospectively in morphologically diagnosed
cases 5-7. There are very few cases of SCCOHT reported
prospectively based on loss of BRG1 8. We present here two cases of MRTO, which posed a diagnostic conundrum,
and were diagnosed by demonstration of loss of BRG1 on
immunohistochemistry. |
Top
Abstract
Introduction
Case Presentation
Disscussion
References
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Case 1
A 22-year-old unmarried female presented with lower
abdominal pain for two months associated with fever. On
per abdomen examination there was minimal hypogastric
tenderness and a large mobile pelvic mass in the left iliac
fossa extending to the umbilical region. Ultrasonography
revealed a large 18x17 cm cystic to solid mass lesion in the
lower abdominal and pelvic cavity, without calcification,
with ascites and minimal bilateral pleural effusion. On
investigation, her serum CA125 was 841 U/ml (range 0-35
U/ml), LDH was 361 U/L (range 100-190U/L), AFP was 1.3
ng/ml (0.89-8.78 ng/mL), CEA was 2.1 ng/ml (range 0-3
ng/ml), CA19-9 was 2 U/ml (range 0-37 U/ml), and Serum
B-HCG was 0.79 mIU/ml (range 0-5 mIU/ml). Clinically
germ cell tumor was strongly suspected. She underwent an
explorative laparotomy with left salphingoophorectomy
with omentectomy. In the intraoperative frozen section, a
poorly differentiated malignant tumor with the possibility
of dysgerminoma was suggested.
On gross examination, the left ovarian mass measured
17x16x9 cm with a bosselated external surface and
capsular breach. The cut surface was solid-cystic, with cysts
containing hemorrhagic fluid, and grey-white solid areas
with hemorrhage and necrosis. The omentum showed a
metastatic tumor deposit. On microscopic examination,
the tumor was composed of sheets of malignant small
round cells juxtaposed with areas showing islands and
nests of large cells with abundant eosinophilic cytoplasm,
and large vesicular nuclei with prominent nucleoli (Figure
1A,B). At places, mucinous degeneration with attempt at
follicle formation was noted. Focal areas of hyalinization
with tumor cells arranged in cords was seen. Frequent
mitoses and lymphovascular emboli were noted.
Click Here to Zoom |
Figure 1: Photomicrographs of case 1
showing
A) Sheets of large rhabdoid
cells with abundant
eosinophilic cytoplasm,
vesicular round nuclei
with prominent nucleoli,
and frequent mitosis
(H&E; x 400). B) Sheets
of malignant round cells
with scant cytoplasm and
hyperchromatic nuclei
(H&E; x 400).
C) Strong cytoplasmic and
nuclear immunopositivity
for calretinin (IHC; x200).
D) Strong nuclear
immunopositivity for p53
(mutant type) (IHC; x200).
E) Diffuse cytoplasmic
immunopositivity for
AE1/AE3 (IHC; x200).
F) Diffuse nuclear
immunopositivity for WT1
(IHC; x100). G) Patchy
membranous and dot-like
immunopositivity for MIC-
2 (CD99) (IHC; x200).
H) Diffuse moderate
immunopositivity for
synaptophysin (IHC; x200).
I) Immunostaining for
BRG1 demonstrating loss
of BRG1 in the tumor
cell nuclei, while normal
endothelial cell nuclei can
be seen as internal control
(IHC; x400). |
On morphology, differentials of a malignant sex cordstromal
tumor, poorly differentiated adenocarcinoma,
neuroendocrine tumor, and germ cell tumor were
entertained. Accordingly, immunohistochemistry was
performed, the results of which are summarized in Table
I (Figure 1C-H).
It can be seen from Table I that except for germ cell tumor
(for which all the markers were negative), the tumor was
polyphenotypic and showed a significantly overlapping
immunohistochemical profile for epithelial, neuroendocrine
as well as sex cord-stromal lineage. This, taken together
with the young age of the patient, was suggestive of small
cell carcinoma of the ovary, hypercalcemic type (SSCOHT),
now called malignant rhabdoid tumor of the ovary. The
patient’s preoperative serum calcium levels were not
available, and postoperative levels were found to be within
a normal range. We performed immunohistochemistry
for BRG1 protein which showed loss of the protein in the
tumor cells, confirming the diagnosis (Figure 1I).
Following the diagnosis, the patient was started on cisplatin
and etoposide based chemotherapy. However after 3 cycles,
a follow-up CT scan showed disease progression with an
increase in the size of the pelvic mass, retroperitoneal
nodes, and the hepatic and spleen metastatic deposits.
She was started on palliative chemotherapy with weekly
paclitaxel and supportive care. However, there was no
response and she succumbed to the disease within four
months of diagnosis.
Case 2
A 32-year-old female, presented with an abdominal mass
and underwent explorative laparotomy for a right ovarian
cyst. Preoperatively, CA125 was 36 U/ml (range 0-35 U/
ml), CA19-9 was 32 U/ml (range 0-37 U/ml), while CEA,
AFP, inhibin, and b-HCG were within normal limits.
Intraoperatively, the right ovary showed a cystic mass
measuring 25 cm in the largest dimension, and multiple
1-3 cm omental, peritoneal, bladder, mesenteric and
pouch of Douglas deposits. An intraoperative frozen
section confirmed malignancy and hence total abdominal
hysterectomy with bilateral salphingo-oophorectomy,
omentectomy and peritoneal deposit removal was carried
out. Subsequently, the patient presented to our hospital
for further management and we received the slides and
block of the ovarian tumor for review. On microscopic
examination, both the ovaries and all metastatic deposits
showed similar tumor morphology, composed of large
rhabdoid cells interspersed with sheets of malignant
round cell-like areas. Scattered follicle-like structures were
identified (Figure 2A,B). A spindle morphology was seen.
Frequent mitosis was observed. Foci of myxoid background
were noted. A differential of poorly differentiated sex cord-stromal tumor, high-grade neuroendocrine tumor,
and peripheral neuroectodermal tumor was entertained.
Immunohistochemical findings are summarized in Table
I (Figure 2C-F).
Click Here to Zoom |
Figure 2: Photomicrographs of case 2 showing A) Round cells with scant cytoplasm and hyperchromatic nuclei, showing mucinous
degeneration with formation of follicle-like structures (H&E; x 200). B) At other places, the tumor cells showed more abundant cytoplasm,
with vesicular nuclei and distinct to prominent nucleoli (H&E; x400). C) Moderate membranous immunopositivity for MIC-2 (IHC;
x400). D) Patchy cytoplasmic positivity for AE1/AE3 (IHC; x100). E) Diffuse cytoplasmic immunopositivity for CD56 (IHC; x200).
F) Diffuse nuclear immunopositivity for WT1 (IHC; x400). G) Loss of BRG1 protein in tumor cells with immunopositive internal control
(Blood vessels and inflammatory cells) (IHC; x400). |
The tumor, similar to the first case, showed polyphenotypic
expression of markers of epithelial, sex cord-stromal and
neuroendocrine lineage, and thus small cell carcinoma
of the ovary (malignant rhabdoid tumor) was suspected.
Immunohistochemistry for BRG1 showed a loss of BRG1
protein expression, confirming the diagnosis (Figure 2G). Pre-surgery, serum calcium levels were very mildly
elevated (11.4 mg/dl). Within three months of surgery,
the patient developed umbilical nodules and a CECT
scan showed multiple lesions in the hepatorenal space,
left hypochondrium, pelvis, anterior abdominal wall,
and enlarged nodes. On examination, multiple palpable
nodules were felt above the vault compressing the rectum.
The patient was started on etoposide and cisplatinum
based chemotherapy. There was a clinical response in the
first 2 weeks. However, by the end of the third cycle, there
was a rapid increase in pain and the size of the umbilical
nodule. The patient was sent for palliative care and was
subsequently lost to follow up.
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Top
Abstract
Introduction
Case Presentation
Disscussion
References
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SCCOHT was first described in 1979 by Robert Scully in
his first fascicle on ovarian tumors 9. Only about 350
cases have been reported, with nearly half of them in a
single large study by Young et al. 1. Although the tumor
is exceedingly rare, it is the most common undifferentiated
ovarian malignancy in women < 40 years of age. It is
seen mainly in the second and third decade (mean age
24 years). In the large series by Young et al., preoperative
hypercalcemia was seen in nearly two thirds (62%) of the
women. The tumor is almost always unilateral and shows
extra ovarian spread in nearly half the cases 1,10,11. There
are reports suggesting possible familial inheritance. On
gross examination, the tumors are large (mean diameter
15 cm) and predominantly solid. In both our cases, the
patients were young and showed large ovarian masses with
an extra ovarian spread. Preoperative calcium levels were
not measured in one case, while in the other, the level was
mildly elevated.
Microscopically, the tumor cells are arranged in diffuse
sheets, nests, cords, and trabeculae, with interspersed
variable follicle like spaces containing eosinophilic
fluid in nearly 80% of the cases. As per the name, the
tumor is mainly composed of small round cells with
hyperchromatic nuclei and brisk mitosis, but nearly half
the cases described also show a variable population of
cells with abundant eosinophilic cytoplasm, sometimes
containing hyaline globules, with vesicular nuclei and
prominent nucleoli 1,10,11. Some authors described cases
with a predominant large cell population as the “large cell
variant” of SCCOHT- an oxymoron 5. Other microscopic
morphological variations described include the presence
of a minor component of the mucinous epithelium,
sometimes forming glands or cysts, signet cells, spindle
cells and stromal edema, myxoid change or hyalinization.
Lymphovascular emboli are commonly seen 11. Because of these variability in features, the tumor can be confused
with many primary and secondary neoplasms of the ovary
such as sex cord-stromal tumor, including juvenile and
adult granulosa cell tumor, germ cell tumor, endometrial
stromal sarcoma, primitive neuroectodermal tumor
(PNET), neuroblastoma, intra-abdominal desmoplastic
small round cell tumor, undifferentiated carcinoma,
lymphoma, malignant melanoma, and metastatic small cell
neuroendocrine carcinoma. In both our cases, intermixed
areas of small cells and large rhabdoid looking cells were
encountered, with interspersed follicles in a variably
myxoid and hyalinized stroma.
The same capriciousness of morphology is also reflected in
the variable and non-specific immunohistochemical profile
of SCCOHT. The majority of the tumors are reactive for
p53, WT1, CD10 and one or more cytokeratins, about a
third for EMA. Over half are positive for vimentin, and
many for neuroendocrine markers, and calretinin. The
tumors are negative for TTF1, desmin, and alpha-inhibin,
and show retained expression of INI1 1,11-13. Due to the
morphological and immunohistochemical overlap, and its
rarity, the diagnosis of SCCOHT remained challenging,
even by expert pathologists, and many cases on review
were usually diagnosed as another entity initially 5,6.
Till recently, there was no specific confirmatory marker
for SCCOHT. In 2013, Kupryjańczyk et al. noticed the
clinical, histological and molecular similarities between
SCCOHT, atypical teratoid/rhabdoid tumor (AT/RT) of
the central nervous system, and malignant renal rhabdoid
tumor (MRT). All these tumors occurred at a young age,
showed rhabdoid large cells with admixed small cells and
a polyphenotypic immunohistochemical profile, were
genetically stable and had an exceedingly poor prognosis.
Based on this observation, Kupryjańczyk et al. first tested
two cases of SSCOHT for loss of INI-1 protein expression
(the protein product of SMARCB1 gene), which was the
known molecular diagnostic feature of MRT and AT/RT.
When INI1 was retained in both the tumors, they went ahead
and tested for loss of SMARCA4 immunohistochemical
expression, which was the other rarer mutation described
in a small percentage of AT/RT with retained INI1. INI-
1 protein is a core subunit, while SMARCA4 protein is a
catalytic ATPase subunit of the switching and sucrose nonfermenting
(SWI/SNF) chromatin-remodeling complex
critically involved in gene transcription. Both their cases
showed loss of SMARCA4 on immunohistochemistry, and
they confirmed the presence of SMARCA4 mutations in
both the tumors by DNA sequencing 14. Subsequently,
in 2014, three independent studies almost simultaneously carried out next-generation sequencing or whole-exome
sequencing and demonstrated that SCCOHT show
inactivating mutations in the SMARCA4 gene, accompanied
by loss of protein expression of its product BRG1 2-4. In
one study, inactivating bi-allelic SMARCA4 mutations were
seen in all 12/12 cases of SSCOHT (100%), accompanied
by clear loss of protein expression of BRG1 in seven out
of nine of these cases 2. Another study demonstrated
germline or somatic mutations in familial cases of SSCOHT
and showed loss of BRG1 immunohistochemistry in
38/40 familial and non-familial cases 4. The third study
demonstrated loss of SMARCA4 protein in 14/17 SSCOHT
and only 2/485 other primary ovarian tumors (0.4%). Both
of the non-SSCOHT tumors with loss of BRG1 were clear
cell carcinomas (CCC) 3. It was then that the Foulkes et
al. claimed, putting two and two together, that based on
the clinical, morphological, and now proved molecular
similarity, SCCOHT are in fact MRT of the ovary, and
should be renamed as such 5. Following these seminal
observations, a large retrospective study showed loss of
BRG1 with retained INI1 in 12/12 cases of SSCOHT and
retained BRG1 expression (some with variable staining
proportion and intensities) in 119 other tumors that can
mimic SSCOHT morphologically. They concluded that
immunohistochemical loss of BRG1 is a useful marker
for SSCOHT, but advised caution in the interpretation
of BRG1 on small biopsies due to the possibility of
variability in staining 7. Conlon et al. found BRG1 loss
in 16/17 (94%) SSCOHT and only 2/279 (0.7%) of other
poorly differentiated ovarian tumors (both primary and
metastatic). One of the non-SSCOHT cases which showed
BRG1 loss was a CCC, while the other was a melanoma.
Overall, they concluded that with a sensitivity of 94% and
specificity of 99.3%, loss of BRG1 immunohistochemical
expression is highly useful to distinguish SSCOHT from its
many morphological mimics 6. Still, very few cases have
been prospectively diagnosed based on BRG1 loss 8. The
only other primary ovarian tumor which has rarely shown
BRG1 loss in previous studies is CCC ovary, which is a tumor
of older patients and can be differentiated from SSCOHT
on morphology by the presence of clear cells, nuclear
hobnailing, and absence of small round cells. Also, CCC
does not show the polyphenotypic immunohistochemical
expression typical of SSCOHT, but is, instead, positive for
Napsin A. Among non-ovarian solid tumors, inactivating
mutations of SMARCA4 have been rarely described in
lung adenocarcinomas, and were associated with a poor
outcome 2.
Although the mutation can be detected and confirmed by
DNA sequencing methods, loss of protein expression of
BRG1 by immunohistochemistry is a relatively inexpensive
and more easily available technique. Due to the rarity of
this tumor, treatment guidelines are not well defined.
Thus, incorporation of BRG1 immunohistochemistry in
the diagnostic armamentarium will possibly increase the
number of accurately diagnosed cases, and may lead to
the formulation of more effective management guidelines.
Not only diagnostic, BRG1 loss carries implications for
classification of these tumors, for genetic counseling of the
patient’s family and in the future may be a candidate for
epigenetic therapies 2,8,10. The prognosis is generally
dismal, and despite multimodality treatment, median
survival is much less than two years 10. Thus, a precise
diagnosis is important, so aggressive multimodality
therapy can be instituted. In both of our cases, a variety of
differential diagnoses were considered on morphology. The
immunohistochemical results were highly confusing with
markers positive for epithelial, sex-cord stromal as well as
neuroendocrine lineage (Table I). Even though SCCOHT
was suspected based on the presence of polyphenotypic
ovarian tumors in young females, the diagnosis was
conclusively established by demonstration of loss of BRG1,
and chemotherapy was immediately initiated. However, in
keeping with the known prognosis of this tumor, both the
patients showed rapid disease progression.
To conclude, BRG1 is a novel immunohistochemical
diagnostic marker which can clinch the diagnosis in
suspected cases of SCCOHT, and should be included in
the immunohistochemical evaluation of polyphenotypic
ovarian tumors in young females. Accurate diagnosis
of this rare tumor is of paramount importance since the
tumor is resistant to all forms of therapy and has a dismal
prognosis.
ACKNOWLEDGEMENT
The authors would like to acknowledge Dr. Jay Mehta, for
his invaluable help in obtaining BRG1 immunohistochemistry
on our cases.
CONFLICT of INTEREST
The authors declare no conflict of interest.
FUNDING
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors. |
Top
Abstract
Introduction
Case Presentation
Discussion
References
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Top
Abstract
Introduction
Case Presentation
Discussion
References
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Copyright © 2020 The Author(s). This is an open-access article published by the Federation of Turkish Pathology Societies under the terms of the Creative Commons Attribution License that permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited. No use, distribution, or reproduction is permitted that does not comply with these terms. |
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