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Asia-Pacific Journal of Clinical Oncology 2015
doi: 10.1111/ajco.12353
CASE REPORT
Solitary pituitary metastasis from HER2-positive breast cancer Jeremy KAM,1 Jeffrey KAM,2 G. Bruce MANN,2 Claire PHILLIPS,3 John M WENTWORTH,4,5 James KING1 and Geoffrey J LINDEMAN6,7,8 Departments of 1Neurosurgery, 4Diabetes and Endocrinology and 6Medical Oncology, Royal Melbourne Hospital, 2Breast Service, Royal Melbourne Hospital and Royal Women’s Hospital, 3Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, 5Molecular Medicine and 7Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, and 8Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
Abstract The introduction of anti-HER2 therapy with trastuzumab has seen an increase in frequency of central nervous system metastasis as the site of first recurrence. Here, we present a rare case of a 63-year-old woman who presented with an isolated breast carcinoma pituitary metastasis 5 years following treatment for a high-risk breast cancer. This report underscores the changing nature of HER2-positive disease in the post-trastuzumab era.
INTRODUCTION Approximately one-third of patients with HER2positive breast cancer who develop metastatic disease will experience central nervous system (CNS) involvement.1 Following the introduction of adjuvant therapy with the anti-HER2 therapy trastuzumab (Herceptin), an increase in the frequency of CNS metastasis as the site of first recurrence has been observed.2 Here, we report a 63-year-old woman with a solitary pituitary metastasis 5 years following treatment for a high-risk (T2N3M0) HER2-amplified breast carcinoma.
CASE REPORT A postmenopausal 63-year-old woman presented with diabetes insipidus, giving a 6-month history of symptomatic polyuria and polydipsia. Biochemical studies confirmed diabetes insipidus and also revealed concomi-
Correspondence: Professor Geoffrey Lindeman FRACP PhD, Department of Medical Oncology, The Royal Melbourne Hospital, Grattan Street, Parkville, Vic. 3050, Australia. Email: [email protected] Conflict of interest: none Accepted for publication 30 December 2014.
© 2015 Wiley Publishing Asia Pty Ltd
tant panhypopituitarism. The patient was otherwise well, with no headache or visual disturbance. Visual acuity and eye movement were normal and visual fields were intact. Contrast magnetic resonance imaging (MRI) revealed an enhancing sellar and suprasellar mass, which included enhancement of the thickened pituitary infundibulum (Fig. 1a–d). The patient had undergone a left mastectomy and axillary clearance 5 years earlier for breast cancer. Her tumor had been a 40 mm Grade 3 invasive ductal carcinoma with lymphovascular invasion, with involvement of all 49 resected axillary lymph nodes. The tumor exhibited estrogen receptor (ER) expression (90%, moderate intensity), but lacked progesterone receptor (PR) expression. Strong HER2 immunostaining was noted, with HER2 amplification confirmed by chromogenic in situ hybridization (CISH, 11.9 copies). Staging investigations, which included bone scan and computerized tomography (CT) of the chest, abdomen and pelvis, had not revealed any signs of metastatic disease. The patient was treated with adjuvant chemotherapy comprising adriamycin, cyclophosphamide (AC × 3) and docetaxel (D × 3), followed by radiotherapy to the left chest wall, axilla and supraclavicular fossa (50 Gy delivered over 25 cycles). Trastuzumab was commenced with the docetaxel and administered for 1 year. Following radiotherapy, the patient was commenced on anastrozole,
2
J Kam et al.
Figure 1 Magnetic resonance imaging (MRI) brain images showing the lesion (arrow heads). (a) Sagittal T1 contrast-enhanced MRI brain demonstrating two principal components, first sellar (straight arrowhead, white) measuring 14 × 9 × 10 mm, inseparable from the pituitary gland, and second suprasellar (straight arrowhead, black) measuring 11 × 8 × 8 mm, rounded and arising from the superior infundibulum/hypothalamus with no other brain lesions. (b) Coronal T1 contrast-enhanced MRI demonstrating enhancement of the infundibulum (curved arrowhead) and lack of cavernous sinus invasion. (c) Sagittal T1 MRI reveals isointensity of the lesion on T1-weighted imaging as well as mass effect compressing the optic chiasm (*). (d) Coronal T1 MRI showing thickened infundibulum (curved arrowhead) with deviation to the left. (e) Sagittal T1 MRI, 3 months post-radiotherapy demonstrating marked improvement in appearance of the sellar and suprasellar region with a mass no longer present. The chiasm (*) has near normal appearance with slight thickening. (f) Coronal T1 MRI post-biopsy and radiotherapy showing marked reduction in size of pituitary and pituitary stalk appearances. (g–i) Histological sections of the metastatic tumor obtained following transsphenoidal biopsy. (g) H&E section (original magnification ×400), (h) Immunostaining for HER2 showing strong complete membrane staining (original magnification ×400), and (i) gross cystic disease fluid protein-15, suggestive of primary tumor origin in breast (original magnification ×400).
which she was taking at the time of presentation. Her past history included a right mastectomy 16 years earlier for a phyllodes tumor. She also had a long-standing history of osteoporosis (which preceded aromatase inhibitor therapy), managed with alendronate. The patient was initially treated with desmopressin, thyroxine and hydrocortisone. A staging CT of the chest, abdomen and pelvis, abdominal ultrasound and bone scan did not reveal any other lesions, suggestive of metastasis. She subsequently underwent an endoscopic transsphenoidal biopsy of the pituitary lesion, which was noted to be firm, gritty and highly vascularized at surgery. Histopathologic examination revealed an undifferentiated carcinoma, consistent with origin in breast (Fig. 1g–i). Tumor cells were weakly ER-positive, PR-negative, with strong HER2 staining in >90% of tumor cells. HER2 amplification was con-
© 2015 Wiley Publishing Asia Pty Ltd
firmed by CISH (12 copies). Tumor cells also stained strongly for gross cystic disease fluid protein-15 (GCDFP) and cytokeratin CK5/6, with weak staining for E-cadherin. The patient was treated with stereotactic radiotherapy to the metastasis (40 Gy in 15 fractions over 3 weeks), which was well tolerated, with no change in vision. Three months later, she remained asymptomatic on medical therapy, with an MRI scan demonstrating complete resolution of the sella and suprasellar tumor mass (Fig. 1e–f). The optic chiasm, pituitary stalk and pituitary gland had near normal appearance. Six months following radiotherapy, a repeat CT scan with contrast and restaging investigations were also unremarkable. The patient remains on medical therapy with desmopressin, thyroxine and hydrocortisone, together with anastrozole and alendronate.
Asia-Pac J Clin Oncol 2015
Pituitary metastasis in HER2+ breast cancer
DISCUSSION To our knowledge, this is the first report of a histologically proven solitary HER2-positive breast carcinoma metastasis to the pituitary gland. There have been three other reports of isolated pituitary metastasis of breast cancer. In those cases, HER2 status was unknown and there was no history of treatment with trastuzumab. Azambuja et al. reported an isolated pituitary metastasis in a patient treated 2 years earlier for a T2N0M0 breast cancer that had been initially managed with surgery and radiotherapy. The lesion was treated by surgical resection and chemotherapy and the patient remained alive 9 years following therapy.3 A second report described a pituitary mass that was presumed to be metastatic breast cancer, as post-contrast T1-weighted MRI revealed a tiny nodular enhancing lesion in the infundibulum consistent with metastases. However, in this case, biopsy was not performed, and investigations into other sites of metastases were not reported.4 The third and most recent report describes an ER-negative and PR-negative isolated pituitary metastasis developing 7 years postmastectomy, radiotherapy and chemotherapy for breast cancer. This patient was treated with transcranial surgery due to tumor extension out of the sellar region followed by radiosurgery.5 Pituitary metastasis in breast cancer is a rare event and almost always occurs in the setting of widespread metastatic disease, most commonly involving bone, lung, liver and other CNS sites. For breast cancer patients who develop a solitary pituitary lesion, there is a reasonable likelihood (∼15%) that it will prove to be an adenoma or another incidental pituitary lesion, making it important to consider the differential diagnosis.6 For metastatic breast cancer, the clinical presentation can include diabetes insipidus, panhypopituitarism, headache and/or visual disturbance. By contrast, pituitary adenomas rarely present with diabetes insipidus. The pituitary recurrence in our patient likely reflects occult micrometastasis to a sanctuary site that remained dormant from the time of her original diagnosis with a poor prognosis breast cancer, which appears to have been otherwise effectively treated by systemic chemotherapy, trastuzumab and endocrine therapy. Trastuzumab, a humanized monoclonal immunoglobulin G antibody, would not be expected to cross an intact blood–brain barrier. The pituitary gland is situated outside the blood–brain barrier, whereas the hypothalamus and pituitary stalk lie within the blood–brain barrier. We therefore speculate that a micrometastasis seeded within the patient’s hypothalamus or pituitary
Asia-Pac J Clin Oncol 2015
3
stalk, and subsequently spread to the pituitary by direct extension and/or via the hypophyseal portal system. This case underscores the important changes in the natural history of HER2-positive breast cancer in the post-trastuzumab era, where the incidence of CNSassociated metastases has increased.1 This is likely to be due to reduced tumor recurrence rates coupled with longer patient survival and the inability of trastuzumab to cross the blood–brain barrier. As a result, CNS progression now represents a major clinical challenge. Confirming tissue diagnosis via endoscopic transsphenoidal biopsy is not without risk. Major complications can include cerebrospinal fluid leak (7.0%), diabetes insipidus either temporary (9%) or permanent (2%), and hypopituitarism (8.5%).7 Other complications (
Asia-Pacific Journal of Clinical Oncology 2015
doi: 10.1111/ajco.12353
CASE REPORT
Solitary pituitary metastasis from HER2-positive breast cancer Jeremy KAM,1 Jeffrey KAM,2 G. Bruce MANN,2 Claire PHILLIPS,3 John M WENTWORTH,4,5 James KING1 and Geoffrey J LINDEMAN6,7,8 Departments of 1Neurosurgery, 4Diabetes and Endocrinology and 6Medical Oncology, Royal Melbourne Hospital, 2Breast Service, Royal Melbourne Hospital and Royal Women’s Hospital, 3Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, 5Molecular Medicine and 7Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, and 8Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
Abstract The introduction of anti-HER2 therapy with trastuzumab has seen an increase in frequency of central nervous system metastasis as the site of first recurrence. Here, we present a rare case of a 63-year-old woman who presented with an isolated breast carcinoma pituitary metastasis 5 years following treatment for a high-risk breast cancer. This report underscores the changing nature of HER2-positive disease in the post-trastuzumab era.
INTRODUCTION Approximately one-third of patients with HER2positive breast cancer who develop metastatic disease will experience central nervous system (CNS) involvement.1 Following the introduction of adjuvant therapy with the anti-HER2 therapy trastuzumab (Herceptin), an increase in the frequency of CNS metastasis as the site of first recurrence has been observed.2 Here, we report a 63-year-old woman with a solitary pituitary metastasis 5 years following treatment for a high-risk (T2N3M0) HER2-amplified breast carcinoma.
CASE REPORT A postmenopausal 63-year-old woman presented with diabetes insipidus, giving a 6-month history of symptomatic polyuria and polydipsia. Biochemical studies confirmed diabetes insipidus and also revealed concomi-
Correspondence: Professor Geoffrey Lindeman FRACP PhD, Department of Medical Oncology, The Royal Melbourne Hospital, Grattan Street, Parkville, Vic. 3050, Australia. Email: [email protected] Conflict of interest: none Accepted for publication 30 December 2014.
© 2015 Wiley Publishing Asia Pty Ltd
tant panhypopituitarism. The patient was otherwise well, with no headache or visual disturbance. Visual acuity and eye movement were normal and visual fields were intact. Contrast magnetic resonance imaging (MRI) revealed an enhancing sellar and suprasellar mass, which included enhancement of the thickened pituitary infundibulum (Fig. 1a–d). The patient had undergone a left mastectomy and axillary clearance 5 years earlier for breast cancer. Her tumor had been a 40 mm Grade 3 invasive ductal carcinoma with lymphovascular invasion, with involvement of all 49 resected axillary lymph nodes. The tumor exhibited estrogen receptor (ER) expression (90%, moderate intensity), but lacked progesterone receptor (PR) expression. Strong HER2 immunostaining was noted, with HER2 amplification confirmed by chromogenic in situ hybridization (CISH, 11.9 copies). Staging investigations, which included bone scan and computerized tomography (CT) of the chest, abdomen and pelvis, had not revealed any signs of metastatic disease. The patient was treated with adjuvant chemotherapy comprising adriamycin, cyclophosphamide (AC × 3) and docetaxel (D × 3), followed by radiotherapy to the left chest wall, axilla and supraclavicular fossa (50 Gy delivered over 25 cycles). Trastuzumab was commenced with the docetaxel and administered for 1 year. Following radiotherapy, the patient was commenced on anastrozole,
2
J Kam et al.
Figure 1 Magnetic resonance imaging (MRI) brain images showing the lesion (arrow heads). (a) Sagittal T1 contrast-enhanced MRI brain demonstrating two principal components, first sellar (straight arrowhead, white) measuring 14 × 9 × 10 mm, inseparable from the pituitary gland, and second suprasellar (straight arrowhead, black) measuring 11 × 8 × 8 mm, rounded and arising from the superior infundibulum/hypothalamus with no other brain lesions. (b) Coronal T1 contrast-enhanced MRI demonstrating enhancement of the infundibulum (curved arrowhead) and lack of cavernous sinus invasion. (c) Sagittal T1 MRI reveals isointensity of the lesion on T1-weighted imaging as well as mass effect compressing the optic chiasm (*). (d) Coronal T1 MRI showing thickened infundibulum (curved arrowhead) with deviation to the left. (e) Sagittal T1 MRI, 3 months post-radiotherapy demonstrating marked improvement in appearance of the sellar and suprasellar region with a mass no longer present. The chiasm (*) has near normal appearance with slight thickening. (f) Coronal T1 MRI post-biopsy and radiotherapy showing marked reduction in size of pituitary and pituitary stalk appearances. (g–i) Histological sections of the metastatic tumor obtained following transsphenoidal biopsy. (g) H&E section (original magnification ×400), (h) Immunostaining for HER2 showing strong complete membrane staining (original magnification ×400), and (i) gross cystic disease fluid protein-15, suggestive of primary tumor origin in breast (original magnification ×400).
which she was taking at the time of presentation. Her past history included a right mastectomy 16 years earlier for a phyllodes tumor. She also had a long-standing history of osteoporosis (which preceded aromatase inhibitor therapy), managed with alendronate. The patient was initially treated with desmopressin, thyroxine and hydrocortisone. A staging CT of the chest, abdomen and pelvis, abdominal ultrasound and bone scan did not reveal any other lesions, suggestive of metastasis. She subsequently underwent an endoscopic transsphenoidal biopsy of the pituitary lesion, which was noted to be firm, gritty and highly vascularized at surgery. Histopathologic examination revealed an undifferentiated carcinoma, consistent with origin in breast (Fig. 1g–i). Tumor cells were weakly ER-positive, PR-negative, with strong HER2 staining in >90% of tumor cells. HER2 amplification was con-
© 2015 Wiley Publishing Asia Pty Ltd
firmed by CISH (12 copies). Tumor cells also stained strongly for gross cystic disease fluid protein-15 (GCDFP) and cytokeratin CK5/6, with weak staining for E-cadherin. The patient was treated with stereotactic radiotherapy to the metastasis (40 Gy in 15 fractions over 3 weeks), which was well tolerated, with no change in vision. Three months later, she remained asymptomatic on medical therapy, with an MRI scan demonstrating complete resolution of the sella and suprasellar tumor mass (Fig. 1e–f). The optic chiasm, pituitary stalk and pituitary gland had near normal appearance. Six months following radiotherapy, a repeat CT scan with contrast and restaging investigations were also unremarkable. The patient remains on medical therapy with desmopressin, thyroxine and hydrocortisone, together with anastrozole and alendronate.
Asia-Pac J Clin Oncol 2015
Pituitary metastasis in HER2+ breast cancer
DISCUSSION To our knowledge, this is the first report of a histologically proven solitary HER2-positive breast carcinoma metastasis to the pituitary gland. There have been three other reports of isolated pituitary metastasis of breast cancer. In those cases, HER2 status was unknown and there was no history of treatment with trastuzumab. Azambuja et al. reported an isolated pituitary metastasis in a patient treated 2 years earlier for a T2N0M0 breast cancer that had been initially managed with surgery and radiotherapy. The lesion was treated by surgical resection and chemotherapy and the patient remained alive 9 years following therapy.3 A second report described a pituitary mass that was presumed to be metastatic breast cancer, as post-contrast T1-weighted MRI revealed a tiny nodular enhancing lesion in the infundibulum consistent with metastases. However, in this case, biopsy was not performed, and investigations into other sites of metastases were not reported.4 The third and most recent report describes an ER-negative and PR-negative isolated pituitary metastasis developing 7 years postmastectomy, radiotherapy and chemotherapy for breast cancer. This patient was treated with transcranial surgery due to tumor extension out of the sellar region followed by radiosurgery.5 Pituitary metastasis in breast cancer is a rare event and almost always occurs in the setting of widespread metastatic disease, most commonly involving bone, lung, liver and other CNS sites. For breast cancer patients who develop a solitary pituitary lesion, there is a reasonable likelihood (∼15%) that it will prove to be an adenoma or another incidental pituitary lesion, making it important to consider the differential diagnosis.6 For metastatic breast cancer, the clinical presentation can include diabetes insipidus, panhypopituitarism, headache and/or visual disturbance. By contrast, pituitary adenomas rarely present with diabetes insipidus. The pituitary recurrence in our patient likely reflects occult micrometastasis to a sanctuary site that remained dormant from the time of her original diagnosis with a poor prognosis breast cancer, which appears to have been otherwise effectively treated by systemic chemotherapy, trastuzumab and endocrine therapy. Trastuzumab, a humanized monoclonal immunoglobulin G antibody, would not be expected to cross an intact blood–brain barrier. The pituitary gland is situated outside the blood–brain barrier, whereas the hypothalamus and pituitary stalk lie within the blood–brain barrier. We therefore speculate that a micrometastasis seeded within the patient’s hypothalamus or pituitary
Asia-Pac J Clin Oncol 2015
3
stalk, and subsequently spread to the pituitary by direct extension and/or via the hypophyseal portal system. This case underscores the important changes in the natural history of HER2-positive breast cancer in the post-trastuzumab era, where the incidence of CNSassociated metastases has increased.1 This is likely to be due to reduced tumor recurrence rates coupled with longer patient survival and the inability of trastuzumab to cross the blood–brain barrier. As a result, CNS progression now represents a major clinical challenge. Confirming tissue diagnosis via endoscopic transsphenoidal biopsy is not without risk. Major complications can include cerebrospinal fluid leak (7.0%), diabetes insipidus either temporary (9%) or permanent (2%), and hypopituitarism (8.5%).7 Other complications (
