Hannah Marie Garmino1 and Arnold John B. Uson1,2
1 Department of Internal Medicine, Section of Medical Oncology, Chong Hua Hospital, Cebu City, Philippines, 2 Department of Internal Medicine, Perpetual Succour Hospital, Gorordo, Cebu City, Philippines
Corresponding author: Hannah Marie Garmino; hannah.garmino@gmail.com
ABSTRACT
Background: Breast cancer is known to metastasize to many sites. Orbital metastasis is a rare occurrence, along with rectal metastasis. Currently, there are no published case reports of primary breast cancer with synchronous orbital and rectal metastasis.
Case Description: We report a 58-year-old menopausal female who presented a right orbital mass, causing eventual blindness of the affected eye. A biopsy of the orbital mass showed a poorly differentiated carcinoma. Further work-up revealed a right breast mass with a biopsy consistent with invasive ductal carcinoma, with estrogen-receptor and progesterone-receptor being positive. The metastatic evaluation showed multiple lung and bone metastasis and a rectal mass with histopathology consistent with metastatic carcinoma. Immunohistochemical staining showed substantial estrogen and progesterone receptor positivity for both rectal and orbital masses consistent with primary breast carcinoma. The patient underwent palliative chemotherapy with six cycles of Docetaxel and Cyclophosphamide followed by CDK4/6 inhibitor with Aromatase inhibitor. The patient has been well on follow-up with good clinical and radiologic response and stable disease as of this reporting.
Conclusion: Our case demonstrates an exceptional presentation of a primary breast malignancy with synchronous orbital and rectal metastasis. This case report attests to the broad clinical presentation of breast carcinoma and the need for extensive work-up via imaging and pathological review in its recognition and eventual diagnosis of a once thought to be double primary that will undergo further investigation as a single entity.
Keywords: Breast cancer, orbital metastasis, rectal metastasis, case report
INTRODUCTION
Breast cancer is one of the most common malignancies worldwide. Common sites of metastasis involve the bones, liver, and lungs.1 Orbital metastases, in general, are relatively uncommon, representing 1-13 % of reported orbital tumors, and are seen in 2-5 % of patients with systemic malignancies. These metastasize via the hematogenous route, with the most significant portion coming from breast and lung carcinoma. 2 Common presenting symptoms include diplopia, ocular pain, visual impairment, and eventual vision loss, which may significantly impact the functional status of the oncological patient. 3 More so, gastrointestinal tract involvement from primary breast cancer is an even rarer phenomenon, with one study showing the rates of metastasis to be 4.5 and 0.2 percent for invasive lobular carcinoma and invasive ductal carcinoma, respectively. 4 The finding further underscores the unusual metastatic presentation of breast carcinoma.
CASE PRESENTATION
A 58-year-old menopausal Filipino female with controlled essential hypertension presented, five months before consultation, with a right orbital mass causing pain, amaurosis (blindness), and proptosis (eye bulging). This presentation ultimately led to blindness in her right eye. The patient also complained of occasional dyspnea at rest. A computed tomography (CT) scan of the orbit with contrast revealed a lobulated enhancing mass along the superior aspect of the right orbit. The mass compressed the ocular globe, obscuring the fascial plane. The right ocular lobe showed thickening. The mass measured approximately 3.4 x 1.9 x 2.9 cm with erosion and mild remodeling at the roof of the right orbit (Figure 1).
FIGURE 1 CT scan of the orbits with contrast, lobulated enhancing mass 3.4 x 1.9 x 2.9 cm of the right orbit with thickening obscuring the fascial plane.
A core needle biopsy of the orbital mass showed a Poorly differentiated Adenosquamous carcinoma. Further physical examination showed a 10 cm fixed right breast mass on the right upper quadrant at the ten-clock position, which the patient did not disclose at the time. Metastatic work- up with computed tomography scan of the chest and whole abdomen with contrast showed an irregular right breast mass measuring 10.1 x 4 x 8.9 cm with suspicious infiltration to the right pectoralis muscle. (Figure 2). There was a suspicious mass lesion in the dextrolateral aspect of the distal rectum extending to the anorectal junction, measuring approximately 3.1 x 1.3 x 3.6 cm with enlarged para-aortic and inter-aortocaval lymph nodes. These findings were suspicious for a Primary breast malignancy with a possible second primary rectal carcinoma with lymph node metastasis. However, the patient currently does not have any gastrointestinal-related complaints. Whole body PET (Positron Emission Tomography) CT scan confirmed the presence of a hypermetabolic stable enhancing lobulated right breast mass infiltrating the pectoralis muscle with thickening of the overlying skin and nipple retraction findings consistent with breast carcinoma. There were findings of hypermetabolic mediastinal, bilateral axillary, and abdominal lymph nodes consistent with metastases and multiple hypermetabolic varisized solid pulmonary nodules scattered in both lung fields compatible with pulmonary metastases. PET CT scan showed hypermetabolic eccentric wall thickening in the distal rectum with prominent mildly FDG avid mesorectal lymph node suspicious with a primary malignancy. (Figure 6, B). FDG avid lesions in the parietal bone, left scapula, right 7th,8th, and left 4th, 7th ribs, C3, C6, T4, T8, and L3 vertebrae consistent with bone metastasis.
Figure 2 CT scan of the chest with contrast shows an irregular enhancing mass (arrow) in the right breast with distortion of the breast architecture.
FIGURE 3 CT scan of the whole abdomen with contrast showing a suspicious mass (cross) at the distal rectum extending to the anorectal region.
The patient underwent a core needle biopsy of the right breast mass. Biopsy showed Invasive ductal Carcinoma, Grade 1-2. The Breast Panel showed estrogen receptor-positive 100 %, progesterone receptor-positive 90%, and human epidermal growth factor receptor (Her 2) negative. (Figure 4 and 4.1). Colonoscopy showed a rectal mass 5cm from the anal verge. A biopsy was then performed. Histopathologic examination showed small round cells. Initially, a neuroendocrine tumor was considered. Immunohistochemical staining showed that chromogranin and synaptophysin were negative but showed both Estrogen 100% and Progesterone 100% receptor- positive, with a low Ki67 of 10% (Figure 6). CEA was expected at 35 ng/ml (Normal value: 0.14- 6.5 ng/ml), and CA 15-3 elevated at 204 U/ml (Normal value: 32 U/ml). Consequently, the right orbital mass showed intense nuclear staining for estrogen receptors at 90% and progesterone at 80%. (Figure 5). Comparing the biopsy specimens, the poorly differentiated areas of the orbital and rectal biopsy showed a similar morphology to the tumor in the breast.
FIGURE 4 Hematoxylin and eosin stain of the right breast mass reveals infiltrating cords and nests of ductal cells within a desmoplastic stroma. Increased mitotic activity is also present.
FIGURE 4.1 Breast Panel: Estrogen receptor showing intense positive staining of 100%, B. Progesterone receptor staining showing 90% positivity C. Her 2-receptor staining negative.
FIGURE 5 Immunohistochemical staining of Right orbital mass, A. Estrogen receptor showing intense positive staining of 90%, B. Progesterone receptor staining showing 80% positivity.
FIGURE 6 A. Hematoxylin and eosin stain of the rectal mass show sheets and prominent nests of small round tumor cells with fine nuclear chromatin and inconspicuous nucleoli. B Estrogen receptor showing intense positive staining of 100%, C. Progesterone receptor staining showing 100% positivity.
These findings were consistent with a Primary Right Breast carcinoma stage IV (c T4aN1M1) with orbital, rectal, bone, and lung metastasis, ER and PR positive, HER two negative. Initial work-up showed 2D echo results of concentric left ventricular hypertrophy with segmental wall motion abnormality, normal global systolic function, and an Ejection fraction of 63%. 12-lead ECG showed paroxysmal Atrial fibrillation. Due to the high burden of the disease and symptomatic lung metastasis, the patient was started with palliative chemotherapy with Docetaxel at 75 mg/m2 and Cyclophosphamide at 600 mg/m2 every 21 days for six cycles with monthly zoledronic infusion and showed overall good clinical response. The right orbital mass decreased in size; however, her vision did not recover. After six chemotherapy cycles, a whole-body PET CT scan revealed a significant decrease in size and metabolic activity in the right orbital and breast mass, lymph nodes, bone, and multiple pulmonary nodules. (Figure 7).
Further testing for germline BRCA1/2 mutation results showed to have no mutations present. The patient received palliative radiotherapy to the right breast, right supraclavicular area, posterior axilla, and T1-T8 region. The patient was then started on CDK4/6 (Cyclin-dependent kinase 4 and 6 inhibitor) using Abemaciclib with Aromatase inhibitor- Anastrozole in the background of the patient’s cardiac status. The patient shows remarkable improvement in exertional dyspnea with a resolution of bone pain and overall improvement in her functional status. She is currently continuing her Abemaciclib with Anastrozole with no adverse effects and is continuing follow-up.
There is a significant decrease in the size of the right Orbital mass lesion, from 3.1 × 1.6 x 2.3 cm to 1.8 x 0.8 x 1.2 cm (previously). This mass lesion is no longer FDG-avid. (RECIST v1.1 -84% Partial response with complete metabolic response)
.
Ophel Gantuangco-Baliuag 1 and Chita Nazal-Matunog 1
1 Section of Medical Oncology, Department of Internal Medicine, Southern Philippines Medical Center, Davao City, Philippines
Corresponding author: Ophel Gantuangco-Baliuag; osgantuangco@gmail.com
ABSTRACT
Background: Beta-human chorionic gonadotropin (ß-hCG) is produced by the placenta syncytiotrophoblasts and some nonseminomatous germ cell tumors (GCT). In this paper, we report a rare case of retroperitoneal soft tissue sarcoma in a young male with elevated serum ß-hCG, which presents a diagnostic dilemma for clinicians.
Case Discussion: A 33-year-old male presented with a 4-year history of right lower quadrant abdominal mass. A computed tomography (CT) scan revealed bilateral iliopsoas masses with enhancing ileocolic lymph nodes. Tumor markers showed a 131x elevated ß-hCG. Based on these findings, the patient was diagnosed with extragonadal GCT and referred to medical oncology for chemotherapy. He has no history of cryptorchidism; testicular physical examination and ultrasound were unremarkable. CT scan-guided biopsy of the mass was pursued, which revealed a high-grade sarcoma. After work-up, the patient already had liver metastasis and subsequently underwent palliative chemotherapy. There was an improvement in symptoms during chemotherapy with decreasing ß-hCG trends. However, the patient contracted a coronavirus disease 2019 infection, which delayed his treatment. On follow-up, he presented with progressive disease, and ß-hCG was also further elevated at >1,361 mIU/mL.
Conclusion: Young adult male patients presenting with a retroperitoneal mass and elevated serum ß-hCG should also be differentially diagnosed with soft tissue sarcomas. This will help avoid delays in the initiation of treatment, as these have different management and prognosis.
Keywords: Beta-hCG, soft tissue sarcoma, retroperitoneal mass
INTRODUCTION
The placenta’s syncytiotrophoblasts and some germ cell tumors produce beta-human chorionic gonadotropin (ß-hCG). However, it can also be secreted ectopically by some epithelial tumors, such as bladder, colorectal, and lung cancers, and is associated with a poor prognosis.1 Interestingly, only a few cases report sarcomas to be secreting ß-hCG, and even in sarcomas, most of them are found in leiomyosarcomas and osteosarcomas.2 We report a rare case of ß-hCG- secreting soft tissue sarcoma, which presented as a diagnostic dilemma among clinicians.
In a young male presenting with a retroperitoneal tumor, one of the differential diagnoses would be germ cell tumors (GCT). Tumor markers, including alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and ß-hCG, play a valuable role in diagnosing, treating, and following GCTs. Elevated levels of these markers can often help identify the histological type of the tumor.3 The markedly elevated ß-hCG level in the patient’s blood tests led medical oncologists to suspect
an extragonadal germ cell tumor. GCT predominantly arises from the testis, but a subset may be extragonadal. 5 to 10% of these arise in nongonadal sites, especially in the mediastinum and retroperitoneum. The initial hypothesis on the tumorigenesis of GCT is that these tumors represent metastasis from an occult gonadal primary.4 However, the patient’s history and physical examination do not align with a typical presentation of extragonadal GCT. Therefore, medical oncologists sought a definitive diagnosis through histological examination.
METHODS
A 33-year-old male presented with a tumor located in the lower right region of his abdomen. The patient initially had right lower quadrant abdominal pain in 2018, which gradually increased in intensity over time. In January 2022, the patient noticed a mass in the exact location, about 5 inches in diameter. He then consulted a gastroenterologist, and a whole abdominal CT scan revealed a mass in the right iliopsoas muscle measuring 13.35 x 12.48 x 13.46 cm and another mass in the left iliopsoas measuring 3.78 x 3.21 x 2.77 cm. There were also enhancing nodes in the ileocolic region. The patient was then referred to surgical oncology for further management. The differential diagnoses at this time were extragonadal soft tissue tumor, gastrointestinal stromal tumor, or soft tissue sarcomas. Tumor markers were requested, and they showed an elevated ß- hCG at 350.91 mIU/ml, normal CEA of 1.220 ng/ml, and normal AFP at 1.920 ng/ml. The markedly elevated ß-hCG level and a retroperitoneal mass in a young adult male suggested an extragonadal germ cell tumor. Based on these findings, doctors referred the patient to medical oncology for chemotherapy. He has no comorbidities, no cryptorchidism history, and unremarkable family history. On physical examination, he has a performance status of Eastern Cooperative Oncology Group (ECOG) 1, with a palpable mass in the right hemiabdomen measuring approximately 17 x 16 cm, fixed, solid, and non-tender on palpation. The testicular examination and scrotal ultrasound requested were unremarkable.
CT scan-guided biopsy of the right iliopsoas mass revealed a spindle cell neoplasm with the following immunohistochemical staining results:
25% of the cells were partially positive for cytokeratin, while vimentin showed diffuse strong positivity. The tests were negative for smooth muscle actin (SMA), Desmin, S100, and CD-45. The pathologist identified the tumor as unusual due to its expression of both vimentin and cytokeratin and, therefore, recommended a repeat biopsy. The patient was referred back to surgical oncology for surgery. However, it was deemed unresectable at that time. The patient’s complex diagnosis and treatment plan were presented at a multidisciplinary team (MDT) conference. To obtain a larger tissue sample and expedite treatment, the team decided to perform an open tumor biopsy. Chemotherapy for the spindle cell neoplasm would begin while awaiting the final pathology report. The patient’s serum ß-hCG level increased to 468.54 mIU/ml. In September 2022, he underwent a cranial, chest, and repeat whole abdominal CT scan. This scan revealed an increase in the size of the large, hypodense, heterogeneously enhancing lobulated masses in the right and left iliopsoas muscles. The right mass now measured 17.8 x 16.7 x 21.5 cm, and the left mass measured 4.4 x 4.7 x 4.1 cm. Recent fairly-defined hypodense masses are seen in segments 8 and 7 of the liver, measuring 3.1 x 2.5 x 3.5 cm and 1.8 x 1.4 x 1.7 cm, respectively, suspicious for metastasis (Figure 1). The cranial and chest CT scans were unremarkable.
FIGURE 1 CT scan of the patient showing the patient’s tumor. (A) Right iliopsoas muscle mass.
(B) Left iliopsoas muscle mass. (C) Hypodense mass in the liver is suggestive of metastasis.
The final histopathology report of the repeat biopsy of the iliopsoas mass revealed atypical spindle- shaped cells interlacing fascicles with areas in a storiform pattern. Cells showed nuclear pleomorphism and hyperchromatism, giving the impression of high-grade sarcoma. Consider undifferentiated pleomorphic sarcoma (Figure 2).
FIGURE 2 The patient’s histopathology report shows (A) atypical spindle cells in interlacing fascicles with areas in a storiform pattern and cells showing (B and C) nuclear pleomorphism and hyperchromatism.
The patient was given palliative chemotherapy composed of ifosfamide at 1,500 mg/m2 on days 1-4 and doxorubicin at 25 mg/m2 on days 1-3. MESNA was given with ifosfamide to reduce the risk of hemorrhagic cystitis. ß-hCG was monitored on each cycle and was noted with a decreasing trend, with the lowest ß-hCG of 181.39 mIU/mL (Figure 3), with improvement of symptoms as manifested by a decrease in abdominal pain and feeling of fullness. The medical oncologists planned a repeat imaging study after the third cycle of chemotherapy.
FIGURE 3 ß-hCG trend of the patient during chemotherapy and upon follow-up.
However, after three cycles of chemotherapy, the patient contracted a coronavirus disease 2019 (COVID-19) infection, which resulted in the delay of his treatment. Two months later, he was now presenting with severe abdominal pain, with elevated ß-hCG to >1,361 mIU/mL (Figure 3). Whole abdomen ultrasound showed massive ascites, with an increase in the size of the right iliopsoas mass to 25.9 x15.8 x 9.5 cm, with marked kidney compression by the mass. The patient also suffered acute kidney injury secondary to the mass effect. Due to his poor performance status and elevated creatinine, he was ineligible for chemotherapy. The patient received supportive care, including paracentesis, for fluid drainage. He was also referred to palliative care for pain management and psychosocial support. Ultimately, he chose to return home and discontinued further follow-up appointments.
CASE DISCUSSION
Soft tissue sarcomas are a heterogeneous collection of rare, solid tumors of mesenchymal origin. Each subtype is categorized depending on clinical imaging, histopathologic morphology, special stains, and evaluation of translocations. These tumors so rarely secrete ß-hCG that medical oncologists do not routinely check for this marker in patients with them. However, if they do secrete ß-hCG, they are associated with poorer outcomes, and some authors have published ß-hCG as a marker of soft tissue tumor response.2 They can occur at almost any anatomical site and
account for 1% of all malignant tumors in adults and 15% of all malignant tumors in children. The incidence varies in different countries and regions, with a crude incidence of 2.91 per 100,000 population in China and a 1.05% overall cancer incidence.5 It has a poor prognosis with a 5-year disease-specific survival rate of 50-70%.6 In the Philippines, there is no published data regarding ß-hCG-secreting sarcomas.
ß-hCG is a quaternary structure with a “cysteine knot” in its X-ray crystallography. It is structurally similar to transforming growth factor beta (TGFß), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and bone morphogenic proteins. This finding aligns with observations linking high serum hCG levels with tumor neovascularization. Studies also show that hCG can counteract the cell death effects of TGFß, thereby promoting tumor growth. These findings suggest that ß-hCG might play a role in resistance to VEGF inhibition.7
The first case reported on ß-hCG-secreting sarcomas is that of Meredith et al., where a 22-year- old female diagnosed with primary leiomyosarcoma presented with nausea and vomiting that could easily be associated with hyperemesis gravidarum in a pregnant female.8 She showed high levels of serum ß-hCG, which were eventually localized to the leiomyosarcoma cells using the immunoperoxidase staining technique. This led to the thought that ß-hCG may be used as a tumor marker in some sarcoma patients.8 Another case report in 2002 was in a 57-year-old man presenting with a one-month history of abdominal pain and a palpable abdominal mass in the xiphisternum down to the pelvis. This case is similar to our patient’s case. The examination included a testicular exam and ultrasound, which were both normal. A CT scan revealed a retroperitoneal mass measuring 30 x 21 x 13 cm. Serum ß-hCG levels were serially measured and increased to 19.71-22.71 mIU/mL. Histopathology showed leiomyosarcoma. After chemotherapy, the level of serum ß-hCG decreased to <0.2 mIU/mL.9
Below are the cases found in the literature of elevated serum ß-hCG in soft tissue sarcomas using keywords “Beta-hCG” and “sarcoma” on PubMed and Google Scholar. The most common soft tissue sarcomas associated with ectopic ß-hCG production was leiomyosarcoma. Similar to our case, there have been two reported cases of retroperitoneal tumors in males with elevated serum ß-hCG that were initially suspected to have germ cell tumors, which presented a diagnostic dilemma as well. Treatment varied from surgery to chemotherapy and radiotherapy. Four of the cases found in the literature died from the disease.
TABLE 1 Cases of soft tissue sarcomas in the literature presenting with elevated serum ß-hCG.
No.
First Author
Age
Sex
Diagnosis
Baseline ß-hCG
Post- treatment
ß-hCG
Management
Outcome
1
Krishnan
V10
33
F
Uterine leiomyosarcoma
49.7 U/L
0.7 U/L
Surgery
Alive
2
Inoue N11
3
mos
M
Back nonrhabdomyosarcoma
soft tissue sarcoma
17,528
mU/ml
3.4
mU/ml
Surgery and Chemotherapy
Died after 19
months
3
Tsakos E12
54
F
Uterine leiomyosarcoma
383.3
IU/L
2.2
IU/L
Surgery and Chemotherapy
Died
after six months
4
Froehner M13
65
M
Retroperitoneal pleomorphic leiomyosarcoma
48
U/l
0.5
U/l
Chemotherapy
Died after two months
5
Stevens
E14
45
F
Synovial sarcoma of the hip
Unavailable
6
Mansi
I9
57
M
Retroperitoneal leiomyosarcoma
22.71
mIU/mL
<0.2
mIU/mL
Chemotherapy
Alive
7
Seidl C15
51
M
Spermatic cord
pleomorphic leiomyosarcoma
35
IU/l
<0.15
IU/l
Surgery
Unknown
8
Meredith R8
22
F
Small bowel leiomyosarcoma
2900
mIU/ml
7,550
mIU/ml
Surgery
Died after six weeks
9
Blank A2
55
F
Posterior thigh unclassified pleomorphic sarcoma
1122
IU/L
Negative
Surgery and Radiotherapy
Alive
10
Index Case
33
M
Retroperitoneal
undifferentiated pleomorphic sarcoma
468.54
mIU/mL
181.39
mIU/mL
Chemotherapy
Alive
In the case of a young male patient (like our 33-year-old example) presenting with a retroperitoneal mass and elevated ß-hCG, the initial impression typically leans towards germ cell tumors. This is because nonseminomatous germ cell tumors, particularly choriocarcinomas, are known to be associated with elevated ß-hCG levels.16 In cancers of unknown primary, it is essential to identify favorable features as they often have a higher response to locoregional or systemic therapy, such as that of GCT.17 Given the unresectable nature of the lesion and established knowledge of high chemosensitivity in nonseminomatous GCTs18 initiating chemotherapy might seem like a straightforward course of action. However, the patient’s medical history – lacking cryptorchidism and showing a normal testicular ultrasound – argued against this approach. Therefore, we opted to proceed with a biopsy of the retroperitoneal mass for a more definitive diagnosis.
The initial biopsy then only involved spindle cell neoplasm. Indeed, the mass was not an extragonadal germ cell tumor. The unusual presentation of the case led to a delay in the treatment initiation, and eventually, the patient’s lesion became unresectable and metastasized before we were able to initiate treatment.
CONCLUSION
Young adult male patients presenting with a retroperitoneal mass and elevated serum ß-hCG should include the differential diagnosis of soft tissue sarcomas as well, in addition to the more common extragonadal germ cell tumors. Clinicians should be aware that these cases exist to avoid delays in initiating treatment as they have different management and prognosis. In the case presented, the serum ß-hCG levels seem to coincide with the improvement and worsening of the patient’s symptoms, suggesting that this could be used not only as a marker of tumor response but also of relapse and poor prognosis. This report recommends further investigation into the characteristics of these patients. It also suggests exploring the usefulness of ß-hCG as a marker for predicting prognosis and tumor response.
REFERENCES
Iles RK, Delves PJ, Butler SA. Does hCG or hCGβ play a role in cancer cell biology? Mol Cell Endocrinol. 2010;329(1-2):62-70.
Blank AT, Khalighi M, Randall RL, et al. Don’t cancel the surgery just yet! A case report of positive preoperative pregnancy test due to a soft tissue sarcoma production of ectopic human chorionic gonadotropin. Rare Tumors. 2018;10:2036361318789727.
Niwakawa M, Tobisu K. [The role of tumor markers in the treatment of germ cell tumor]. Gan To Kagaku Ryoho. 2001 Aug;28(8):1159-65. Japanese.
Luna M, Valenzuela-Tamariz J. Germ cell tumors of the mediastinum, post mortem findings. Am J Clin Pathol. 1976;65:450-4.
Yang Z, Zheng R, Zhang S, Zeng H, Li H, Chen W. Incidence, Distribution of Histological Subtypes and Primary Sites of Soft Tissue Sarcoma in China. Cancer Biol Med. 2019;16(3):565-74.
Youn P, Milano MT, Constine LS, Travis LB. Long-Term Cause-Specific Mortality in Survivors of Adolescent and Young Adult Bone and Soft Tissue Sarcoma: A Population-Based Study of 28,844 Patients. Cancer. 2014;120(15):2334-42.
Glass R, Asirvatham JR, Kahn L, Aziz M. Beta-Human Chorionic Gonadotropin Producing Osteosarcoma of the Sacrum in a 26-Year-Old Woman: A Case Report and Review of the Literature. Case Rep Pathol. 2015;2015:897230.
Meredith RF, Wagman LD, Piper LA, et al. Beta-chain human chorionic gonadotropin- producing leiomyosarcoma of the small intestine. Cancer. 1986;58(1):131-5.
Mansi IA, Ashley I, Glezerov V. Retroperitoneal leiomyosarcoma and enlarged epididymis associated with a positive pregnancy test. Am J Med Sci. 2002;324(2):104-5.
Krishnan V, Sauthier P, Provencher D, Rahimi K. Pleomorphic Undifferentiated Uterine Sarcoma in a Young Patient Presenting With Elevated Beta-hCG and Rare Variants of Benign Leiomyoma: A Case Report and Review of the Literature. Int J Gynecol Pathol. 2020 Jul;39(4):362-6.
Inoue N, Watanabe H, Takehara H, et al. Refractory pediatric nonrhabdomyosarcoma soft tissue sarcoma associated with ectopic production of beta hCG and hypercalcemia induced by PTHrP. Pediatr Blood Cancer. 2011 Dec 15;57(7):1244-6.
Tsakos E, Xydias EM, Ziogas AC, et al. Uterine malignant leiomyosarcoma associated with high levels of serum beta-human chorionic gonadotropin: A case report. Clin Case Rep. 2022 Sep 19;10(9):e6322.
Froehner M, Gaertner HJ, Manseck A, et al. Retroperitoneal Leiomyosarcoma Associated with an Elevated beta-HCG Serum Level Mimicking Extragonadal Germ Cell Tumor. Sarcoma. 2000;4(4):179-81.
Stevens EE, Aquino J, Barrow N, Lee YC. Ectopic production of human chorionic gonadotropin by synovial sarcoma of the hip. Obstet Gynecol. 2013 Feb;121(2 Pt 2 Suppl 1):468-71.
Seidl C, Lippert C, Grouls V, Jellinghaus W. Leiomyosarkom des Samenstranges mit paraneoplastischer beta-hCG Produktion [Leiomyosarcoma of the spermatic cord with paraneoplastic beta-hCG production]. Pathologe. 1998 Feb;19(2):146-50. German.
Busch J, Seidel C, Zengerling F. Male Extragonadal Germ Cell Tumors of the Adult. Oncol Res Treat. 2016;39(3):140-4.
DeVita Jr VT, Lawrence TS, Rosenberg SA. Devita, Hellman and Rosenberg’s Cancer Principles and Practice of Oncology. 12th ed. Wolters Kluwer; 2022.
Kondagunta GV, Motzer RJ. Chemotherapy for advanced germ cell tumors. J Clin Oncol. 2006;24(35):5493-502.
DATA AVAILABILITY STATEMENTS
The authors will make the raw data underpinning this article’s conclusions accessible upon request without unnecessary restriction. To protect ethical considerations and participant privacy, the
authors cannot publicly share the data. However, they can make it available upon reasonable request with approval from the institutional ethics committee.
ETHICS STATEMENT
Informed consent was secured from the patient and his identity was kept confidential. The paper did not include any data that could identify the patient, such as address and patient initials pertaining to his name.
AUTHORS CONTRIBUTION
OGB, investigation, methodology, writing original draft, review, and editing; CNM, supervision, review and editing
FUNDING
This research received no external funding.
CONFLICT OF INTEREST
The authors declare no conflicts of interest related to commercial or financial relationships.
PUBLISHER’S NOTE
This article reflects the views and findings of the authors alone and does not necessarily represent the official position of the author’s affiliated organizations, the publisher, editors, or reviewers. We encourage readers to remember that the content presented here does not constitute endorsement or approval by any of the entities above.
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Joanne Abigail R. Pamin1 and Elizabeth P. Prieto,1
1 Department of Dermatology, East Avenue Medical Center, Metro Manila
Corresponding author: Joanne Abigail R. Pamin; paminjoanne@gmail.com
ABSTRACT
Background: Breast cancer is the most diagnosed cancer worldwide and has the most significant cancer burden for women. As much as 70% of female breast cancer patients will develop cutaneous metastasis. Despite the myriad of therapeutic options, few have demonstrated the synergistic effect imiquimod 5% cream has on cutaneous metastatic prognosis in addition to chemotherapy.
Case Discussion: Herein is a case of an ER/PR negative and HER2NEU positive patient who presented with cutaneous invasive breast carcinoma metastasis to the right chest wall. The patient developed cutaneous papules and patches despite already having undergone multi-modal treatment. The patient first underwent a modified radical mastectomy. Next, the patient received chemotherapy with fluorouracil, epirubicin hydrochloride, and cyclophosphamide (FEC-D), followed by docetaxel. The patient also received radiation therapy alongside a trastuzumab regimen. After cutaneous lesions developed, the doctor referred the patient to dermatology. There, a histological evaluation revealed findings consistent with cutaneous metastasis. The medical oncologists then added topical 5% imiquimod cream to the ongoing trastuzumab and capecitabine therapy, which the patient tolerated well. In just three months, the patient, demonstrating remarkable resilience, experienced tumor regression, improved quality of life, and even survived beyond the typical prognosis for this condition.
Conclusion: This case highlights the potential of topical 5% imiquimod cream as a minimally invasive and effective local therapy for cutaneous breast carcinoma metastasis.
KEYWORDS: Imiquimod; Capecitabine; breast carcinoma; cutaneous metastasis
INTRODUCTION
Cutaneous metastasis accounts for two percent of skin tumors, with an overall incidence of 5.
3% in cancer patients. In females with breast cancer, cutaneous metastasis develops in up to 70% of cases.1 Since 2013, cutaneous metastasis has risen by 45% from 0.9%. This trend is expected to continue.2 Thus, clinicians need a high index of suspicion for recognition, a low threshold for biopsy, and the capability to optimize cutaneous metastasis management.
Metastatic dissemination may be the first sign of underlying malignancy. Notably, when the primary is of the breast, the most common location for metastasis is the anterior chest. It may present as patches, papules, ulcers, nodules, induration of the skin, or even hair loss. Of those cases,0.6% arise from the mastectomy scar. Other concurrent metastases develop in the lungs, liver, and lymph nodes.3 Thus, a complete body evaluation is prudent. Though rare, cutaneous metastasis usually presents in the later stages of cancer. Its development heralds a poor prognosis as patients tend to die from the malignancy in six months or within the first two years. The treatment objective is palliative, expressly to relieve symptoms, improve quality of life, slow cancer growth, and prolong life.
Topical imiquimod 5% cream, a well-documented effective treatment for actinic keratosis and superficial basal cell carcinoma, holds promising potential as a specific treatment for cutaneous metastasis. This case demonstrates the treatment of an ER/PR negative and HER2NEU positive patient with cutaneous invasive breast metastasis using imiquimod adjunctively, sparking further interest in its potential applications.
CASE DESCRIPTION
S/P Mastectomy, Right
Imiquimod 5% BID on
Imiquimod 5% BID on
Imiquimod 5% BID on
Breast,
weekdays,
weekdays,
weekdays for 3 months
S/P FEC 100,
Mupirocin ointment BID
Mupirocin ointment BID
(last application July 25,
S/P Radiation Therapy,
x 7 days,
x 7 days,
2023)
NSS compress BID for 20
NSS compress BID for 20
mins,
mins,
Ongoing Trastuzumab 600 mg SQ
Ongoing Trastuzumab 600 mg SQ
Capecitabine 500 mg 2 tabs AM, 1 tab PM + Trastuzumab 600 mg SQ
Ongoing Capecitabine 500 mg 2 tabs AM, 1 tab PM + Trastuzumab 600 mg SQ
FIGURE 1 Clinical progression. (circles = topical treatment area)
The patient is a 63-year-old Filipino female with invasive breast carcinoma of the right breast, stage IIIC. Co-morbidities include hypertension and diabetes. Unfortunately, the patient’s mother died before medical oncologists could diagnose her breast mass. She mothered and breastfed one son. Otherwise, the patient’s medical history is unremarkable. Two months following diagnosis, the patient underwent a modified radical mastectomy, and all twelve of the dissected lymph nodes were positive. Immunohistochemical stain revealed ER/PR negative HER2NEU strongly positive. The patient received six cycles of FEC-D chemotherapy followed by 34 sessions of radiation therapy.
Doctors started additional immune-targeted therapy of trastuzumab 600mg subcutaneously every 21 days to treat HER2NEU overproduction.
After her fourth trastuzumab session, the patient developed multiple papules and plaques associated with mild pruritus over her right chest. In the interim, the plaques spread to the right shoulder and back. A solitary lymph node over the right clavicle became palpable.
Nine months since cutaneous lesion onset in March 2023, referral to Dermatology service for suspected locoregional recurrence prompted skin punch biopsy. Baseline bloodwork showed anemia, leukopenia, and marginally elevated total bilirubin. Breast and liver ultrasound and chest
x-ray were unremarkable. Chest computed tomography (CT) scan detected mildly nodular thickening of the mastectomy bed. The presence of solitary pre-sternal nodules and enlargement of a few axillary and mediastinal lymph nodes at the right paratracheal region was detected.
FIGURE 2 Histological evaluation (H and E). A. Scanning view: nests of large atypical pleomorphic cells in the papillary dermis. B. HPO: Nests of large atypical pleomorphic cells with mitotic figures with attempts at ductal formation. C. CK7 + stain. D. CEA + stain.
Histopathologic evaluation revealed nests of pleomorphic atypical cells, consistent with cutaneous metastasis, probably secondary to invasive ductal carcinoma. Subsequent CK7 staining revealed robust cytoplasmic staining in neoplastic cells, while CEA indicated moderate to intense cytoplasmic staining. Adjuvant imiquimod 5% cream was initiated. Initially, this was applied twice daily on weekdays over the papules on the right chest (encircled in Figure 1).
After two weeks of applying topical imiquimod cream, the medical oncologist added oral capecitabine 1500mg daily in three doses to the patient’s ongoing trastuzumab therapy. There was marked improvement, as physical examination showed papular regression with erosion and crusting. Imiquimod application was thus expanded beyond papules to all affected areas of the trunk and back. Imiquimod was well tolerated; the patient only reported mild stinging, which went away independently.
After three months of adding imiquimod treatment, the patient’s condition resolved. However, there was post-inflammatory hypo-to hyperpigmentation (skin discoloration) where the papules used to be. Plaques had resolved as hyperpigmented patches. Repeat chest CT revealed no sign of tumor recurrence, and abdominal CT was unremarkable. Ideally, histopathologic examination with staining is done to document regression on top of imaging, but priority is placed on affording chemotherapy treatment.
DISCUSSION
Herein, we present a case of ER/PR negative HER2 strongly positive cutaneous metastatic breast cancer treated successfully using topical immunotherapy. Our patient underwent three months of topical imiquimod 5% therapy twice daily on weekdays. As an adjunct to trastuzumab and capecitabine, the regimen was well-tolerated. This case demonstrates the efficacy of topical imiquimod immunotherapy as an adjunct to conventional chemotherapy in the treatment of cutaneous invasive breast cancer metastasis.
Immunotherapy in breast cancer is an actively evolving field. Localized imiquimod, along with 5- fluorouracil and the newer interleukin therapies, are among the options demonstrated to be effective adjuncts to chemotherapy. Imiquimod is of interest due to its efficacy, ease of access, and local availability. It is an immune response modifier with potent anti-tumor activity via toll-
like receptors, resulting in apoptosis. Primarily, imiquimod activates the intrinsic pathway of the caspases to create an apoptosome, which destroys malignant cells. Topical application leads to localized increased expression of proapoptotic proteins of the Bcl-2 family.4 It also directly stimulates Langerhans cells to activate the adaptive immune response, aside from increasing cytokines, IL-12, TNF-alpha INF-gamma, and IL-10, which stimulates anti-tumor T cells and natural killer cells.
Imiquimod emerges as a promising alternative to surgery for treating pre-cancerous and cancerous skin lesions. Studies have documented its effectiveness as monotherapy for squamous and basal cell carcinoma, achieving cure rates between 42% and 100%. Depending on the frequency and the six or 12-week duration of application, 80%-93% of patients were in remission with high tolerability.5,6 It is commonly combined with five fluorouracil, gentian violet, chemotherapy, and physical therapy like cryotherapy for advanced primary cancers or metastasis. Literature has various examples of efficacy studies on metastasis from primary colon cancer, malignant melanoma, Merkel cell carcinoma, metastatic renal cell carcinoma, and more.7
Specifically for breast carcinoma, imiquimod stimulates dendritic cells and macrophages, releasing inflammatory cytokines and enabling apoptosis. Various studies have demonstrated the effectiveness of imiquimod. Application three times a week as an adjunct to chemotherapy resulted in decreased lesion thickness and pain score.4,8 Nguyen et al. reported using topical imiquimod to successfully shorten the ductal carcinoma in situ (DCIS) duration. In their study, patients with painful, hardened, and ulcerated plaques experienced resolution within four months, suggesting imiquimod’s potential as a needed topical treatment for such cases. Regression of the cutaneous metastasis was documented to regress as early as 3 weeks.8 Drohan et al. demonstrated cutaneous regression in three months with intralesional IL-2 injections biweekly in combination with imiquimod treatment over 32 weeks.9 Krishnasamy et al. conducted a case series investigating a synergistic response to systemic therapy. The case series showed that combining cryotherapy with imiquimod and 5-fluorouracil improved cutaneous lesions in three women within four months, with sustained improvement lasting up to six months.10 Our case demonstrated increased efficacy of topical imiquimod added to chemotherapy, resulting in tumor regression compared to untreated areas with no regression, only hyperpigmentation. It was well tolerated, with only localized irritation and erosions and clinical regression of erythema, induration, and papules in the applied area.
This case’s oncologic management also demonstrates optimized management to delay cancer progression and further metastasis. The National Comprehensive Cancer Network (NCCN) Panel recommends post-mastectomy radiation to the chest wall in all surgical breast carcinomas. Radiation therapy after mastectomy and axillary node dissection reduced both recurrence and breast cancer mortality in patients with positive lymph nodes.11 According to Dr. Coudert and his colleagues, FEC-D in HER2NEU(+) and node-positive patients results in a 15% relative risk reduction of relapse and a 25% relative risk reduction in the relative risk of death at year eight.12 The patient’s aggressive cancer prompted the addition of trastuzumab to her treatment regimen.
Trastuzumab, a drug used to improve survival since the 1990s13, has shown positive outcomes in similar cases involving HER2NEU overexpression. Studies reveal that patients treated with trastuzumab experience delayed disease progression, longer response durations, higher overall response rates, lower death rates at one year, and a reduced risk of death compared to those receiving standard chemotherapy alone.14,21
The confirmation of metastasis coincided with the initiation of trastuzumab therapy combined with capecitabine. Capecitabine is an oral prodrug of fluorouracil, which is FDA-approved for the
treatment of metastatic breast cancer. It is effective after anthracycline- or taxane-based regimens, as in our patients. Musada and colleagues have demonstrated that those treated with capecitabine compared to anthracycline and taxanes achieved longer disease-free survival times. In the capecitabine group, a higher percentage were alive without recurrence or secondary cancer at five years compared to the control (74.1% vs. 67.6%). Similarly, the overall survival rate was 78.8% versus 70.3%.15 Overall response rate for continuous capecitabine was 20% and 18% for a cyclophosphamide, methotrexate, and 5-fluorouracil regimen. Treatment duration was more likely to continue beyond six months in monotherapy capecitabine-treated patients versus combination therapy, but the former has a shorter median time to progression (TTP) of >4 months or even as early as 3.1 months and lower overall response rates.16 As for the combination of trastuzumab and capecitabine, there is an expected 23% tumor shrinkage and 27% increase in the two-year survival rate for HER2NEU-positive patients. This combination effectively increases survival in patients who have already received multi-modal treatment.13 The combination of trastuzumab and capecitabine had a median TTP of 8 months but no significant difference in overall survival for combination treatment with a standard taxane-containing regimen.17 This is similar to the duration of trastuzumab therapy, where the times to progression were 7.25 and 5.25 months for the first and second lines of trastuzumab therapy.18
Generally speaking, the prognosis of cutaneous metastasis is poor. Mortality is >70% in the first year after diagnosis, and as much as 50% of patients expire within the first six months, with an average survival time of 7.5 months. Treating the primary tumor is essential for any chance of curing cutaneous metastasis.19 The response to combination chemotherapy varies significantly between patients. Therefore, standardized criteria for evaluating response in cutaneous metastasis and treatment algorithms specifically designed to optimize skin-directed therapies are urgently needed.
As seen in our patient, for the goal of prolonging patient survival and a disease-free state, topical therapy to conventional systemic chemotherapy has been demonstrated to improve the disease prognosis rapidly. Combination treatment is generally well tolerated, and imiquimod 5% cream treatment improved quality of life. This case demonstrates that adjunct imiquimod 5% cream applied twice daily on weekdays with systemic chemotherapy can achieve disease regression in three months, more rapidly than previously documented.
CONCLUSION
Imiquimod therapy proves to be an effective complementary treatment for cutaneous metastasis from invasive breast carcinoma. In this case, combination treatment resulted in tumor regression, improved quality of life, and even survival beyond the typical prognosis for this condition. This finding highlights imiquimod cream as a practical option for minimally invasive and effective local therapy in such cases.
However, due to the observation of tumor recurrence six months onwards (TTP noted), long-term follow-up every two years (bi-annually) is warranted. Further research is also needed to investigate the effectiveness of imiquimod as a standalone treatment (monotherapy) and its potential application in treating cutaneous metastases originating from other primary tumors.
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DATA AVAILABILITY STATEMENTS
All data underlying the results are available as part of the article, and no additional source data are required.
ETHICS STATEMENT
Written informed consent was obtained from the patient for their anonymized information to be published in this article.
AUTHORS CONTRIBUTION
JAP, writing – original draft, review and editing, resources; Elizabeth P. Prieto, writing – review and editing
FUNDING
This research received no external funding.
CONFLICT OF INTEREST
The authors declare no conflicts of interest related to commercial or financial relationships.
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