Introduction
Malignant peripheral nerve sheath tumor (MPNST) is a spindle cell sarcoma that originates
from the peripheral nerves or shows differentiation of various components of the nerve
sheath, formerly known as neurogenic sarcoma, neurofibrosarcoma or malignant schwannoma.
MPNST is a relatively rare spindle cell sarcoma that accounts for approximately 3%
to 10% of soft tissue sarcomas. Nearly half of the cases are due to neurofibromatosis
type 1 (NF 1), less than 10% are radiation-induced (post-radiotherapy sarcomas), and
the remainder are sporadic cases of unknown etiology. Malignant schwannomas in parenchymal
organs are very rare.
A recent case in our hospital with schwannoma of the cervix uteri prompted us to conduct
an extensive literature search. The case reported here is the 18th to be definitively
confirmed worldwide. In the past, neither chemotherapy nor radiotherapy has been effective
for malignant schwannomas. This is the first case in which advanced (next-generation)
gene sequencing (NGS) has been used to better understand the biology of the tumor
and identify potential treatment options in the event of recurrence. According to
the literature, approximately half of these cases will experience recurrence, even
when the tumor is removed with extensive resection in health tissue. The aim of this
article is to report a significant clinical case and add to the available literature
on cervical schwannoma.
Case Report with Next-generation Sequencing
We report a case of malignant nerve sheath tumor of the cervix (MPNST). The patient,
29 years old, gravida 3 and para 1, presented with vaginal spotting for 2 months.
She had a history of spontaneous vaginal delivery and no hereditary disease or other
complaints. Her mother had a history of rectal cancer and her aunt had endometrial
cancer.
Physical examination with speculum revealed no normal anatomy of the cervical os,
which was occupied by a lesion about 6 cm in diameter with an ulcerated cauliflower-like
surface and contact bleeding. It looked like cervical cancer. The mass on the cervix
protruded through the entire cervical stroma into the vaginal cavity without invading
the vaginal fornices or rectum. The abdomen was soft to palpation and there was no
lump in the adenoids. Total body examination was unremarkable. Laboratory tests including
complete blood count, liver function tests, coagulation parameters and tumor markers
(including AFP, CEA, CA 125, CA 153, CA 199, CA 724, HE4, SCCA, HCG) were within reference
ranges. Human papillomavirus (HPV) testing was reported as negative for a high-risk
strain. Colposcopy was performed ([Fig. 1 ] and [Fig. 2 ]), as was cervical biopsy and endocervical curettage.
Fig. 1
No normal anatomy of the cervical os, which is occupied by a reddish-yellow lesion
with a diameter of about 6 cm.
Fig. 2
On colposcopy, the tumor shows numerous atypical vessels.
Histopathological examination combined with immunohistochemical results revealed a
malignant peripheral nerve sheath tumor (MPNST). The initial microscopic differential
diagnosis was cervical melanoma, but immunohistochemical analysis excluded this tumor
(see Discussion). The final pathological diagnosis was malignant peripheral nerve
sheath tumor, also known as malignant schwannoma.
For preoperative evaluation, the patient was referred to the radiology department
for pelvic magnetic resonance imaging (MRI) and abdominal computed tomography (CT).
MRI showed a cervical tumor of approximately 7.0 × 5.8 × 5.4 cm invading the parametrium
and upper segment of the vagina, but no invasion of the rectum. T2-weighted image
sagittal scan showed no normal cervical morphology, with irregular high-signal masses
and total stromal invasion of the cervix. T1-weighted image showed an equal signal,
and the T2-weighted image and T2 lipid-suppressing sequence showed an uneven high
signal, with small cystic changes within; the enhanced scan showed significantly heterogeneous
enhancement ([Fig. 3 ] and [Fig. 4 ]). There was no evidence of lymphadenectasis or distant metastasis on CT scan.
Fig. 3
T2-weighted image sagittal scan showed no normal cervical morphology, with irregular
high-signal masses and whole stromal invasion of the cervix.
Fig. 4
Cervical irregular soft tissue mass involving the whole cervix. T1-weighted image
scan showed an equal signal, and T2-weighted image and T2 lipid-suppressing sequence
showed an uneven high signal, with small cystic change inside. The enhanced scan showed
significantly heterogeneous enhancement.
After a meeting of the MDT, we made a clinical diagnosis of cervical malignant schwannoma
stage IIb, analogous to cervical cancer staging [1 ]. Radical resection of the tumor with wide free margins was essential to optimize
the patient’s prognosis, given that other therapeutic strategies (radiotherapy, chemotherapy)
will not be effective against this tumor biology [2 ]. To achieve free margins, a wide vaginal cuff was excised. A type C hysterectomy
according to the classification of Querleu & Morrow [3 ] was planned to preserve the bladder and ureters. The patient was prepared for surgery
according to our routine preoperative procedures.
The cervical tumor was completely removed circumferentially together with the uterus
and a vaginal cuff, leaving a margin of at least 2.5 cm of healthy tissue in the deep
vaginal mucosa. On gross examination, the tumor had a yellowish-red appearance without
necrosis, with an irregular surface measuring 6 × 4 × 3 cm ([Fig. 5 ]). The patient’s postoperative course was uneventful and there were no perioperative
complications.
Fig. 5
Gross pathological specimen of the uterus and vaginal excision. Incised anterior vaginal
wall.
The case was discussed in detail at the tumor conference. It was agreed that neither
radiotherapy nor chemotherapy could be considered based on the available data. Based
on the sparse but still available data (see below), the patient’s prognosis was not
so unfavorable that experimental adjuvant therapy would be considered at this time,
especially since it would have to be paid for by the patient herself. However, next-generation
gene sequencing, immunotherapy and other antineoplastic options were explored in case
of recurrence.
Paraffin sections and an oral mucosal swab were subjected to next-generation sequencing
of 270 genes specifically selected for sarcoma at the Changke Laboratory, Beijing
(https://www.ck-dx.com/ ).
This test revealed 5 gene mutations or gene deletions:
HER2 mutation
CDKN2A deletion
CDKN2B deletion
TP53 mutation
TSC2 deletion
The tumor did not show microsatellite instability, mismatch repair genes were normal,
and no mutations in hyperprogression-related genes were detected.
The patient presented for a first follow-up two months after surgery. All findings
were unremarkable. After half a year of follow-up, the patient had pelvic and vaginal
recurrence, with a palpable lump in the vaginal stump and pelvic cavity, approximately
5 cm in diameter, with an unclear border to the bladder. The biopsy showed a malignant
tumor, as in the previous pathology. We discussed the treatment options and reviewed
the specimens from the primary surgery. The tumor was definitively resected with at
least 1.5 cm of healthy tissue on all sides. Repeat surgery without residual tumor
would have meant total exenteration for the young patient, with no likelihood of a
definitive cure. The patient then transferred to another university hospital and is
being treated with dacarbazine 360 mg d1–5 q4w, cisplatin 40 mg d1–3 q4w and bevacizumab
400 mg d1 q4w. Response results are not yet available.
Pathological findings of the primary tumor
Macroscopically
Gross findings: The resected uterus and bilateral adnexa measured 11.8 × 10.5 × 2.7 cm.
There was a large mass of 6.5 × 4.5 × 3.9 cm in the cervix from 12 o’clock to 8 o’clock
and the tumor had infiltrated the outer third. There was no invasion of the corpus
uteri, vaginal fornices, bilateral fallopian tubes. The vaginal margins were clear.
Parametrial infiltration was confirmed. No lymphovascular invasion was present but
neural invasion was. There were no lymphatic metastases. The tumor was categorized
as pTN stage pT2bN0 according to cervical cancer classification.
Microscopic
Microscopic examination revealed densely cellular compact bundles of spindle cells
arranged in a fascicular pattern with perivascular condensation and focally myxoid
stroma. The nuclei were elongated with tapered ends and there was little eosinophilic
cytoplasm, with highly atypical hyperchromatic nuclei and sparse cytoplasm. Mitosis
was active at a rate of 5–8 per high-power field ([Fig. 6 ]).
Fig. 6
Photomicrograph shows a spindle cell tumor arranged in a fascicular pattern (a H & E 40×), focally myxoid stroma (b H & E 100×), some highly pleiomorphic nuclei (c H & E 200×), and atypical mitosis (d H & E 200×).
Immunohistochemistry
Immunohistochemical staining showed that tumor cells were positive for S-100 and SOX10,
with the majority of tumor areas showing loss of H3 lysine 27 trimethylation (H3K27Me3)
and mutant P53 expression. The cells were negative for Desmin, SMA, HMB-45, Melan-A,
CD10. The expression of BRG1 and INI-1 was positive with a Ki67 labeling index of
approximately 30% ([Fig. 7 ]).
Fig. 7
Immunohistochemical analysis of MPNST showed loss of expression of H3K27Me3 (a ). SOX10 (b ) and S100 (c ) were positive bit negative for Melan-A (d ), HMB-45 (e ), and Desmin (f ). BRG1 (g ) was not absent. Mutant P53 (h ) expression, and elevated Ki67 (i ) labeling are also features of MPNST.
Differential diagnosis
The differential diagnosis of large cervical masses includes endometrioid stromal
sarcoma, leiomyosarcoma, and especially spindle cell melanoma. Melanoma can be excluded
in cases without expression of HMB-45 and Melan-A. Lack of expression of supportive
stromal and myogenic cell markers (i.e., Desmin, SMA, CD10) excluded endometrioid
stromal sarcoma and leiomyosarcoma. Tumor-positive expression of Schwann cell markers
(i.e., S-100 and SOX10) and loss of H3K27me3 expression, a highly specific marker
for MPNST, were included in the diagnosis.
Discussion
In addition to the hereditary form of nerve tumors (neurofibromatosis type 1 [NF1]),
there are solitary nerve tumors, often referred to as schwannomas or Schwann cell
tumors. Most Schwann cell tumors are benign and only a rare minority have malignant
criteria. When a tumor is found around a peripheral nerve or within the brachial or
pelvic plexus, the diagnosis is obvious and only differentiation between malignancy
and non-malignancy is required. Even under benign conditions, complete removal of
the tumor may be difficult.
Malignant peripheral nerve sheath tumors (MPNSTs) are malignancies that arise from
the cells that sheath the nerve fibers of peripheral nerves (Schwann cells) [4 ]. They infiltrate peripheral nerves and account for approximately 10% of soft tissue
malignancies. The estimated incidence of MPNST is 1.46 per 1000000 [5 ]. They develop in approximately 8–13% of people with neurofibromatosis type 1. Neurofibromatosis
type 1 (NF1) is an inherited disorder. MPNSTs are associated with a poor prognosis
and are the leading cause of death in NF1 patients [2 ]. The 8–13% of individuals with NF1 mutations who develop MPNSTs account for nearly
50% of all MPNST cases. Of the remaining cases, 45% of MPNSTs occur sporadically with
unidentified genetic abnormalities and the remainder are associated with radiation
therapy. MPNST are most
common in adults aged 30–60 years, with a median age of 37 years and an age range
of 7–94 years. Children and adolescents are also at risk of developing MPNST, but
it is relatively rare [6 ], about 13%, and less common in children under six years of age, although slightly
more common in males. MPNSTs occur primarily in the trunk, the proximal extremities,
and neck [7 ]. The occurrence of most tumors is closely associated with the peripheral nerve trunks
(e.g. sciatic, sacral and brachial plexus). Therefore, these tumors are most commonly
found in the buttocks, thighs, upper arm and the paraspinal area, but rarely in the
head and neck (mostly in the trigeminal and auditory nerves). In organ structures,
MPNSTs are rare and the differential diagnosis is difficult. In the past, misdiagnosis
was possible without immunohistochemistry. Clinically, MPNSTs may be associated with
pain, especially in patients with NF 1, and are usually located in deep soft tissues,
with occasional superficial involvement [8 ].
Nowadays the diagnosis of malignant peripheral schwannoma is based on histomorphological
and finally immunohistochemical diagnosis. The main microscopic differential diagnosis
is melanoma. Melanoma can be excluded in cases without expression of HMB-45 and Melan-A.
Positive expression of Schwann cell markers (i.e., S-100 and SOX10) and loss of H3K27me3
expression, which is a highly specific marker for MPNST, make the diagnosis certain.
The histologic cell types of malignant schwannomas include glandular, melanocytic,
malignant triton and epithelioid types [9 ]. 50–70% of tumors express S-100 at variable levels and, in general, the higher the
malignancy, the lower the expression of S-100. In addition to S-100, they may also
express SOX10 at variable levels and occasionally express focal CK8 and CK18, but
without expression of CK7 and CK19 [10 ].
It is possible that Sloan [11 ] reported the first case of a schwannoma in 1988, which was described as a melanocytic
schwannoma and did not include determination of HMB-45, so that the differential diagnosis
between melanoma and schwannoma is uncertain from today’s perspective. This patient
was still free of recurrence after 10 years. The publication by Junge et al. dates
from 1989 [12 ] and the authors are believed to be the first to report a malignant schwannoma. They
reported on a 45-year-old patient who also underwent hysterectomy with pelvic lymphadenectomy.
The histopathological examination described the typical picture of a malignant schwannoma
(MPNST). The tumor was S-100 and vimetin positive, but Desmin and cytokeratin negative.
No follow-up information is available.
Bernstein et al. [13 ] published a case of epithelioid malignant schwannoma of the cervix uteri in 1999.
The patient was a 65-year-old Caucasian woman. She underwent radical hysterectomy
with bilateral adnexectomy and pelvic and para-aortic lymphadenectomy. The tumor was
histomorphologically negative for the melanoma-associated antigen HMB-45 and strongly
positive for S-100 antigen. They compared their case with the publication by Junge
et al., which was a spindle cell schwannoma (S-100 positive), and with the publication
by Terzakis et al. [14 ], which was classified as a melanocytic schwannoma (S-100 positive, HMB-45 positive,
keratin negative, GFAP negative). In the latter case, the diagnosis of schwannoma
is questionable because of the HMB-45 positivity.
Later publications [15 ] (with three cases), [16 ]
[17 ]
[18 ] followed. Kim et al. [19 ] treated a 50-year-old woman with this condition. She underwent hysterectomy and
bilateral salpingo-oophorectomy (BSO). Lymph node dissection was also performed. The
patient received chemotherapy with cyclophosphamide and cisplatin. Despite this intensive
primary therapy, the patient relapsed after six months. This case showed an atypical
immunohistochemistry, the marker HBM-45 was positive. They compared this case with
a single other MPNST case with positive HBM-45, a malignant schwannoma of the skin
[20 ].
Mills et al. [21 ] reported three cases of malignant schwannoma. The patients were aged 25, 32 and
60 years. The 32-year-old man was free of recurrence for 33 months after tracheal
resection and brachytherapy. The 60-year-old woman underwent hysterectomy. She had
a recurrence at 30 months. A 25-year-old woman underwent local excision only. This
patient developed a recurrence after six months and died rapidly. In the 53-year-old
patient reported by Akhavan et al. [22 ], complete resection of the malignant schwannoma was not possible. The patient received
radiochemotherapy, which did not result in tumor control.
Dong et al. [23 ] reported mainly on CT and PET/CT imaging in a 45-year-old female patient. The imaging
is almost identical to the case reported here. The patient underwent laparoscopic
radical hysterectomy with bilateral adnexectomy and lymph node dissection. No information
is available on the patient’s outcome in this primarily image-guided procedure. Sangiorgio
et al. [25 ] reported the case of a 45-year-old woman with an MPNST of the cervix uteri. They
point out that the differential diagnosis of melanoma, leiomyosarcoma, endometrial
stromal sarcoma, synovial sarcoma and other spindle cell neoplasms must be carefully
considered.
Zhang et al. [25 ] reported on a 46-year-old woman who was diagnosed after radical hysterectomy with
the final specimen investigated by histology and immunohistochemistry. One year later,
the patient relapsed and developed pulmonary metastases. She received combination
chemotherapy with epirubicin/ifosfamide, dacarbazine and etoposide/cisplatin. Median
survival was 44 months. In a very recent paper, Nair et al. [26 ] reported a case in which preoperative radiotherapy was followed by radical hysterectomy
with bilateral adnexectomy.
When the 18 confirmed cases of MPNST, including our case, are combined, the prognosis
is unfavorable ([Table 1 ]). Of the 12 cases that could be followed, six had recurrence or primary progression.
Six cases have survived (50%). In some cases, follow-up is too short to make a definitive
assessment. The mortality rate is also very high, at least 50%. Primary surgery with
secure tumor-free margins is required. Whether hysterectomy or even radical hysterectomy
is necessary to achieve this cannot be definitively assessed in these cases. In any
case, accurate imaging with MRI should be performed to prove or exclude parametrial
invasion. Our case shows that the preoperative imaging suggested a parametrial lesion,
which was then confirmed on the surgical specimen. The case of Rodriguez et al. [18 ], a 22-year-old woman who remained free of recurrence after trachelectomy, shows
that
organ-sparing resection must be discussed on a case-by-case basis and may be justified
in women who wish to have children. Our case confirms that even resection far into
healthy tissue is no guarantee that local recurrence will not occur.
Table 1
Published cases of MSRNT.
No
Author
Year
Age at diagnosis
Subtype
Therapy
Follow-up
IHC
1
Sloan [11 ]
1988
47
Melanocytic schwannoma
Hysterectomy and BSO
Tumor free at 10 years
S-100 pos
2
Junge et al. [12 ]
1989
45
Spindle cell schwannoma
Hysterectomy and pelvic lymphadenectomy
No data
S100 pos
Vimentin pos
Desmin neg
Cytokeratin neg
3?
Terzakis et al. [14 ]
1990
47
Melanocytic schwannoma
No data
No data
S-100 pos
HMB-45 pos
4
Lallas et al. [16 ]
1997
52
Hysterectomy and BSO
Tumor free at 10 years
S-100 neg
Vimentin pos
5
Keel et al. [15 ]
1998
25
Cone resection and hysterectomy
Too short
S-100 pos
Vimentin pos
Cytokeratin neg
Desmin neg
HMB-45 neg
6
65
Hysterectomy
Too short
S-100 pos
Vimentin pos
Cytokeratin neg
HMB-45 neg
7
73
Hysterectomy and pelvic lymphadenectomy
Metastasis after 20 months
S-100 pos
Vimentin pos
Cytokeratin neg
HMB-45 neg
8
Bernstein et al. [13 ]
1999
65
Radical hysterectomy and BSO & pelvic and para-aortic lymphadenectomy
No data
S-100 pos
HMB-45 neg
Cytokeratin neg
9
Di Giovannantonio et al. [17 ]
2005
27
No data
Disease free at 34 months
S-100 pos
Vimentin pos
Keratin neg
Desmin neg
Actin neg
HMB-45 neg
10
Rodriguez et al. [18 ]
2006
22
Trachelectomy
Disease free at 20 months
S-100 pos
HMB-45 neg
CD-10 neg
11?
Kim et al. [19 ]
2009
50
Radical hysterectomy and BSO and lymphadenectomy
Chemotherapy (cyclophosphamide and cisplatin 6 cycles)
Progression after 6 months
S-100 pos
HMB-45 pos
Melan-A neg
Desmin neg
SMA neg
NSE neg
12
Mills et al. [21 ]
2011
32
Trachelectomy and brachytherapy
Disease free at 33 months
S-100 pos
CD-34 pos
Vimentin pos
Glial fibrillary acid neg
NF-1 neg
SOX-10 neg
EMA neg
CD-56 neg
HMB-45 neg
13
60
Associated with other nerve sheath tumors
Hysterectomy
Local recurrence after 13 months
S-100 pos
CD-34 pos
Vimentin pos
Glial fibrillary acid neg
NF-1 neg
SOX-10 neg
EMA neg
CD-56 neg
HMB-45 neg
14
25
Local excision
Tumor recurrence after 6 months and rapid death
S-100 pos
CD-34 pos
Vimentin pos
Glial fibrillary acid neg
NF-1 neg
SOX-10 neg
EMA neg
CD-56 neg
HMB-45 neg
15
Akhavan et al. [22 ]
2012
53
Surgery impossible
Radiochemotherapy
Progression
S-100 pos
Vimentin pos
Desmin focally pos
Cytokeratin neg
HMB-45 neg
16
Dong et al. [23 ]
2014
45
Laparoscopic radical hysterectomy & BSO & pelvic lymphadenectomy
No data
S-100 pos
KI-67 40%
17
Sangiorgio et al. [25 ]
2018
45
Radical hysterectomy
Tumor free at 12 months
S-100 pos
HMB-45 neg
p16 neg
CD10 neg
E2 neg
SOX10 neg
GFAP neg
CD56 neg
Cytokeratin neg
AE1/AE3 neg
Desmin neg
h-Caldesmon neg
SMA neg
ALK neg
EMA neg
Bcl2 neg
CD99 neg
18
Zhang et al. [25 ]
2022
46
Radical hysterectomy
Died after 44 months
?
19
Nair et al. [26 ]
2023
44
Radical hysterectomy and BSO
Too short
S-100 pos
HMB-45 neg
Melan-A neg
20
Present case
2023
29
Radical hysterectomy and BSO and pelvic lymphadenectomy
Local recurrence after half a year
2 cases uncertain due to HMB-45 positivity
Remaining 18 cases
Lost to follow-up: 3 cases
Too short for follow-up: 3 cases
Cases with follow-up: 12 cases
Lymph node metastases are not described in any of the studies, and even in our own
case the pelvic and para-aortic lymph nodes were tumor-free despite the diagnosis
of parametrial involvement. The question of lymphadenectomy should also be decided
on a case-by-case basis but may be unnecessary.
Data from MPNSTs of other localizations also show that the tumor is not sensitive
to either radiotherapy or chemotherapy. The prognosis for malignant schwannomas is
poor. Surgery is the first line of treatment and complete excision with free margins
is essential [2 ].
The most important prognostic factors in MPNST were the presence of neurofibromatosis,
tumor size > 5 cm, and extent of resection. Complete resection improved survival,
but adjuvant radiation or chemotherapy did not. Five- and ten-year overall survival
rates were 34% and 22%, respectively [29 ]
[28 ]. In sporadic MPNST, the radicality of the resection with tumor-free margins seems
to be the only prognostic factor. Perhaps the localization of the tumor in the cervix
uteri also favors prognosis, as the disease can be detected relatively early on and
is easily accessible for radical resection. The patient in our case apparently had
no signs of neurofibromatosis (no café-au-lait plaques or neurofibromas) and must
be classified as a sporadic malignancy. Of the 18 confirmed cases of cervical schwannoma
seen today, only one patient had evidence of neurofibromatosis. All other
patients appeared to be sporadically affected.
The next-generation sequencing results were interpreted in two ways. First, they were
used to perform a differentiated genetic analysis of the tumor, as this had not been
done in any of the other case reports. The second use was to determine possible therapeutic
approaches in the event of recurrence, as it is known that recurrence can occur at
a very early stage.
The protein encoded by the TSC2 gene is a tumor suppressor in the mTOR signaling pathway
that is inactivated by mutations or deletions in a variety of cancers. TSC2 is a key
negative regulator of the proto-oncogenic mTOR pathway [29 ]. The mTOR signaling pathway plays an important role in promoting cell growth and
regulating protein synthesis. Somatic mutations in TSC2 have been found in several
cancers, including liver cancer and endometrial cancer, and are mainly truncated loss-of-function
mutations. Loss-of-function mutations of TSC2 cause constitutive activation of the
mTORC1 complex, leading to the opposite effect of mTOR inhibitors. The FDA has approved
everolimus for the treatment of CNS cancers with mutations in the TSC2 gene. Clinical
trials of targeted drugs for solid tumors with the TSC2 gene mutation are underway
abroad, and the test drugs are sapanisertib and samotolisib. On this basis, everolimus
would be a
current treatment option.
In carcinomas, CDKN2A is altered by mutation and/or deletion. The CDKN2A gene encodes
two unique proteins, p16 (Ink4a) and p14 (ARF), which are important in regulating
cell cycle progression [30 ]. The p16 (Ink4a) is a cyclin-dependent kinase (CDK) inhibitor that represses CDK
4 and CDK 6 by preventing CDK 4 and CDK 6 from binding to cyclin. Loss of CDKN2A in
the mouse model leads to spontaneous carcinogenesis, consistent with its role as a
tumor suppressor [31 ]. To date, no targeted drugs based on the CDKN2A deletion mutation have been approved
for this type of cancer.
If ERBB2 (HER2) (p.Val777Leu) mutation is detected, FDA approval and NCCN guidelines
recommend using trastuzumab and other drugs to treat NSCLC with this gene mutation
[32 ]. Whether cross-cancer drugs should be chosen must be determined by clinicians.
As a result of gene sequencing, the mTOR inhibitor everolimus would initially be administered
as an off-label use in the event of a relapse. Another treatment option is the use
of trastuzumab, which is also off-label. The colleagues at the other hospital did
not base their treatment protocol on the gene sequencing done with their results.
We had an NGS result in this patient that showed us a possible benefit of two drugs,
trastuzumab and everolimus, and we did not have the opportunity to use and test these
drugs because the patient changed hospital, which is unfortunate.
