CASE 1 Stage IV presentation of breast cancer with bone metastases

A 60-year-old woman presented with a large, palpable right breast mass (same patient as in Case 19 in Chapter 4). Imaging workup, including mammography, ultrasound, breast MRI, and ultrasound-guided core needle biopsy and axillary lymph node aspiration, confirmed node-positive multifocal infiltrating ductal carcinoma (IDC). Based on physical examination, the patient was thought to have an advanced breast cancer, at least T3 by size, and she was started on neoadjuvant chemotherapy while her staging workup was completed. The staging evaluation included a bone scan and positron emission tomography (PET)/CT. The bone scan, obtained before starting chemotherapy, showed several foci of increased activity, including in the left anterior third rib, one focus each in the cervical and thoracic spine, and a focus at the left upper sacroiliac joint region (Figure 1). A breast MRI, obtained a few days after the first round of chemotherapy, included a coronal short tau inversion recovery (STIR) series of the thorax, obtained with the body coil. This showed evidence of widespread bone metastases, with hyperintense foci in the right medial clavicle and in a lower thoracic vertebral body (Figure 2). A PET/CT scan was performed about 1 week after the first cycle of chemotherapy. In addition to showing hypermetabolism of the multifocal breast carcinoma, hypermetabolic foci were identified in multiple bony sites, including the right clavicular head, right upper cervical spine, two adjacent lower thoracic vertebrae, the left medial iliac crest, and a left anterior rib (Figure 3). These sites of abnormal activity overlapped in distribution with the abnormalities noted previously on limited chest MRI and the prechemotherapy bone scan. No definite correlates were found at these sites on CT. Thus, as the staging was completed in this patient, it became apparent that what was initially thought to be T3N1 disease (stage IIIA) was actually stage IV disease.

FIGURE 1 A, Anterior image from a prechemotherapy bone scan shows a focus of increased activity at the left anterior third rib level. The focus is less punctate than usually seen with trauma, although fracture is in the differential diagnosis. Note the slight asymmetry in sternoclavicular activity, with the right-sided activity slightly proximal to the joint compared with the left. B, Posterior view from the same prechemotherapy bone scan shows an intense focus of activity at the right upper cervical spine, with smaller foci of activity on the right at the lower thoracic spine level and a small focus at the left upper sacroiliac joint level. Degenerative changes, metastases, or some combination are in the scintigraphic differential diagnosis.

FIGURE 2 Coronal STIR image of the thorax, obtained with the body coil as part of the breast MRI, shows a hyperintense focus in a lower thoracic vertebral body. Similar findings were seen elsewhere, including the right clavicular head (not shown), suggesting bone metastases.

FIGURE 3 A to D, Sagittal images through the spine from PET/CT, performed 1 week after one round of chemotherapy. Two adjacent foci of hypermetabolism are seen in the lower thoracic spine, at T11 and T12. The corresponding CT bone window showed no definite lesions. A smaller hypermetabolic metastasis is seen in C2, above a prior surgical level.

After one cycle of chemotherapy, CT scanning was repeated. The large breast mass and axillary adenopathy showed improvement, and new sclerosis was now evident at several levels in the spine (Figure 4).

FIGURE 4 A, Detail of T11 vertebral body from staging CT, obtained before neoadjuvant chemotherapy. No definite osseous abnormality is seen to correlate with the hypermetabolism subsequently demonstrated at this level 1 week later on PET/CT. B, Detail of the same level, 3 weeks later, after one cycle of chemotherapy, shows new sclerosis (arrows), at the level where PET/CT had shown hypermetabolism.

Before undergoing repeat bone scanning and spine MRI, a second cycle of chemotherapy was given. The repeat bone scan, obtained 1 month after the prechemotherapy study, showed an increase in number of foci of increased activity (Figure 5). Several preexisting foci of activity appeared larger and more intensely active. MRI of the lumbar spine showed multiple areas of abnormal signal intensity, at levels corresponding to the prior bone and PET scans (Figure 6).

FIGURE 5 Repeat bone scan, 1 month after the prechemotherapy study, after two cycles of chemotherapy. A, Anterior planar view shows increased activity of the right clavicular head. The activity is now seen more clearly to be bone centered (versus joint centered). Intense shine-through activity of a larger right upper cervical spine lesion is seen, with less intense shine-through noted of adjacent right lower thoracic foci. The left anterior rib activity persists without clear change from before. B, Posterior planar bone scintigraphy shows more numerous and intense foci of activity compared with the prior study, including multiple spinal foci, correlating with hypermetabolism on PET/CT.

FIGURE 6 Sagittal lumbar spine MRIs, obtained after two cycles of chemotherapy. A, Sagittal, T1-weighted image shows hypointense foci of altered marrow signal, contrasting with the normal bright signal of fatty marrow. Lesions are seen at T11, T12, and the inferior-anterior L4 level. The larger lesions at T11 and T12 correlate with bone and PET scan findings. B, Sagittal STIR image through the same level shows corresponding peripheral hyperintensity of the metastases.

After completion of three cycles of neoadjuvant chemotherapy, the breast mass and axillary adenopathy had shrunk. Three months after diagno-sis, the patient underwent bilateral mastectomies, right axillary dissection, left sentinel lymph node sampling, and removal of breast implants. The right mastectomy specimen contained a 3.5-cm IDC, with multiple satellite nodules and clear margins. Six of 16 axillary lymph nodes showed metastases.

Two weeks after surgery, CT-guided sampling of the sclerotic T11 lesion was performed and did not confirm metastatic disease. The needle biopsy was repeated 2 months later, confirming metastasis. A nearly concurrent repeat PET/CT for restaging had normalized (Figure 7).

FIGURE 7 A to D, Sagittal images through the spine on follow-up PET/CT, 5 months after the initial staging PET/CT scan. The PET activity has resolved. The lesions can now be seen on the CT bone windows as sclerotic foci. The focus at T11 was biopsied 2 days before this study, confirming metastatic carcinoma.

TEACHING POINTS

This case represents stage IV disease at presentation, with a locally advanced breast cancer, metastatic to bone. It provides an excellent take-off point for discussion of some of the imaging issues raised on initial identification of bone metastases, as well as the assessment of treatment responses.

Bone scanning is not routinely obtained in the initial staging of all newly diagnosed breast cancer patients, as it once was. The yield in early-stage disease is low. In general, bone scanning performed during initial staging is reserved for patients with stage III or greater disease, unless there is a symptom, physical examination finding, tumor marker, or other abnormal laboratory value to suggest advanced disease.

Bone metastases can have a variety of appearances on bone scintigraphy, from a solitary active lesion, to multiple focal areas of increased activity, to diffuse involvement. Whether a bone metastasis is visualized on a bone scan depends on the size of the lesion, the location, and the type of bone reaction elicited. Because breast cancer metastases can be lytic, sclerotic, and frequently are mixed, a variety of manifestations are possible. Adding to the difficulty is the potential for conversion of successfully treated lytic metastases to blastic lesions. In general, bone scans most reliably depict osteoblastic metastases and can miss purely lytic disease. The converse is true of PET, which is highly sensitive for lytic bone lesions, but less sensitive for blastic metastases.

How then to resolve and explain the apparently conflicting imaging study results obtained in this patient?

The initial bone scan, obtained before starting chemotherapy, was abnormal, although not definitively diagnostic of bone involvement. Without imaging correlation, provided subsequently by a limited chest MRI, a number of the bone scan findings could have been accounted for by other explanations. The rib lesion, for example, could have been post-traumatic, and a possible trauma history was elicited from the patient. The activity is less punctate than generally seen with fractures, but a long segment of involvement, which would more compellingly suggest neoplasia, is not seen either. The patient had had prior cervical spine surgery, raising the possibility of accelerated de-generative change at an adjacent level. At the same time, the activity in both the cervical and thoracic levels is disturbingly focal and relatively intense. Degenerative findings frequently involve multiple adjacent levels and, unless actively degenerating, are often less intense in activity than the findings seen here.

The correlation provided subsequently by the limited chest MRI and PET/CT resolves the questions and provides compelling evidence of bony metastatic disease.

What is the significance of the apparent increase in disease seen on the second bone scan, performed 1 month later, after two cycles of chemotherapy? Does this mean the metastases are progressing? Not necessarily. In fact, the changes we see between these two bone scans are an excellent example of the flare phenomenon, whereby a patient responding to hormonal therapy or chemotherapy may actually appear worse on bone scanning. Increased activity of previously identified lesions and even new lesions may be seen (as in this case). Recall that it is the osteoblastic response to a bone abnormality (neoplastic, infectious, or traumatic) that we see as an increase in activity on a bone scan. Metastases that are initially lytic may become sclerotic in response to treatment, and this is demonstrated in this case on the PET/CT. The hypermetabolic bone foci that were seen on the initial PET/CT were without a clear CT correlate (indicating they were lytic) but became sclerotic (within 3 weeks, after one cycle of chemotherapy!) and readily visible on the CT portion of the follow-up PET/CT, at which time the PET activity had resolved. This does not mean the patient is cured or that the disease is not active. This patient had biopsy confirmation of metastatic involvement of T11, concurrent with normalization of PET scan activity. This constellation of findings reflects the reality that initially lytic bone metastases, best seen on PET imaging, responded to treatment by developing sclerosis. In the process, the bone metastases became increasingly visible on CT and bone scan, and inactive on PET.

CASE 2 Stage IV presentation with bone metastases (breast cancer presenting with back pain)

A 35-year-old obese woman presented with severe low back, knee, and hip pain and 5 days of intermittent fever up to 102 degrees. She was evaluated with abdominal, pelvic, and lumbar spine CT scans for suspicion of a spinal infection. These studies showed multiple lytic lesions in bone, including the L5 vertebral body, and left sacrum, ilium, and proximal femur (Figures 1, 2, 3, and 4). Bony metastatic disease was suspected, and a lung primary was sought with a chest CT. This showed a 2-cm spiculated right breast mass, suspicious for a breast cancer primary (Figure 5).

FIGURE 1 Axial CT scan (bone window) through the sacrum shows lytic destruction of the left posterior sacrum, extending to the sacral foramina.

FIGURE 2 More inferior axial CT image (bone window) through the sacroiliac (SI) joints shows another lytic lesion in the left medial ilium, adjacent to the SI joint.

FIGURE 3 Sagittal lumbar spine reconstruction (bone window) shows another lytic lesion in L5, extending to the superior end plate.

FIGURE 4 Coronal reconstruction (bone window) shows the lytic change in L5 and another small lytic lesion in the left intertrochanteric proximal femur.

FIGURE 5 Axial unenhanced chest CT image shows a central right breast mass in largely fatty breasts.

Bone scan showed corresponding, highly suspicious, multifocal findings suggesting bone metastases (Figure 6).

FIGURE 6 Bone scan images (A, anterior and posterior whole-body; B, spot views of the ribs [oblique], knees [lateral], and pelvis [anterior and posterior]) show multiple foci of abnormally increased activity in a highly suspicious pattern for bony metastatic disease. In addition to activity that corresponds to the known lytic foci in spine and pelvis on CT, sites are seen in the right clavicular head, ribs, and left proximal tibia, among others. The long segments of rib activity (left posterior, right anterior) are a pattern of activity that is highly suspect for neoplasia.

Breast imaging workup with diagnostic mammography, breast ultrasound, and ultrasound-guided core needle biopsy confirmed right breast cancer. The mammogram showed a dominant, central, 5-cm spiculated mass (Figure 7). Ultrasound showed a corresponding irregular hypoechoic mass in the retroareolar region, with a separate 1.7-cm suspicious shadowing focus in the upper outer quadrant (UOQ) (Figures 8 and 9). A suspicious axillary lymph node was also noted, with mild cortical mantle thickening (Figure 10).

FIGURE 7 MLO (A) and CC (B) mammograms show a dominant central, spiculated right breast mass behind the nipple, with stranding extending anteriorly toward the nipple. This mass corresponds to the mass identified on CT. The breasts are predominantly fatty.

FIGURE 8 Ultrasound of the right central breast shows a large area of ill-defined hypoechoic shadowing, which corresponds in location with the dominant mass on CT and mammography.

FIGURE 9 Ultrasound of the right UOQ shows a separate hypoechoic shadowing mass at 10 o’clock.

FIGURE 10 Right axillary ultrasound shows two lymph nodes with hypoechoic, thickened cortices. Fine-needle aspiration confirmed metastatic tumor.

Histologic sampling of the breast masses confirmed infiltrating ductal carcinoma (IDC) from both sites, estrogen receptor and progesterone receptor positive, and HER-2/neu positive. Fine-needle aspiration of the axillary lymph node demonstrated metastatic carcinoma.

CT-guided sampling of a lucent sacral lesion showed metastatic adenocarcinoma, consistent with breast primary (Figure 11).

FIGURE 11 Sampling of the sacral lucent lesion was performed with CT guidance. Axial image with the patient in prone position shows the needle in the lesion. Histology confirmed metastatic adenocarcinoma, consistent with a breast primary.

Palliative radiation therapy to the lumbar spine (L5 and sacroiliac region) and left knee were given for pain relief, and the patient was started on tamoxifen and zoledronic acid (Zometa). Repeat CT images, 7 months later, show a variety of bone responses to these interventions (Figure 12).

FIGURE 12 Coronal CT reconstructions (A anterior to B), 7 months after initial CT in Figure 4, after lumbar spine radiation, and treatment with tamoxifen and Zometa. In A, the left intertrochanteric metastasis has grown. It now displays a dominant central sclerotic component, with a lucent rim. In B, the lytic focus at the superior end plate of L5 remains visible, but now shows a thick surrounding blastic response. At the superior end plate of L3, a blastic lesion is now seen. This may reflect healing of a subradiographic lytic metastasis.

TEACHING POINTS

This is a distinctly unusual presentation of breast cancer, with symptomatic bone metastases bringing this pre-screening-age patient with no notable family history to attention. Less than 10% of breast cancer patients present with stage IV disease. This patient’s primary tumor was also identified through an unusual route, being first seen on a chest CT. Breast cancers can certainly be picked up initially on chest CT, which usually is performed for other reasons. (See Case 15 in Chapter 1 for another example.) For this reason, CT interpreters should always scrutinize chest wall soft tissues and breasts as part of their routine search pattern.

The initial presentation of these bone metastases was lytic, manifested on CT as soft tissue replacement of bone. The lumbar spine was locally treated with radiation therapy for pain palliation. The follow-up study shows a new sclerotic metastasis at L3, which was not previously known. Sclerosis can be a manifestation of healing of a subradiographic lytic lesion. Sclerosis is now also seen surrounding the lytic end-plate change at L5. At the left hip level, the lytic lesion with central sclerosis grew between studies. On the later study, the lesion displays a larger and more sclerotic central component. Is this growth and progression of a mixed lytic and sclerotic metastasis, or growth despite a partial healing response manifested by the larger and more sclerotic central component? Unfortunately, this illustrates the difficulty of assessing by imaging the response of bone metastases to therapy.

CASE 3 Relapse with bone metastases

A 36-year-old woman sought orthopedic advice for low back and right leg pain that developed while training for a half marathon. She had been treated 4 years before for an estrogen receptor and progesterone receptor positive, T1cN1b(4) infiltrating ductal carcinoma with breast conservation and axillary dissection, with 4 of 20 lymph nodes positive with microscopic extracapsular extension. Additional treatment was with chemotherapy (four cycles of doxorubicin [Adriamycin] plus cyclophosphamide [Cytoxan] [AC] and four cycles of paclitaxel [Taxol]); right breast, supraclavicular, and axillary radiation therapy; and tamoxifen.

A pelvis x-ray was abnormal, with a moth-eaten appearance of the right ischium (Figure 1). Subsequent evaluations with pelvis and lumbar spine MRI, body CT scans, positron emission tomography (PET), and bone scan suggested extensive bony metastases (Figures 2, 3, 4, and 5). A bone marrow aspirate confirmed metastatic breast cancer. The patient was placed on goserelin acetate (Zoladex), zoledronic acid (Zometa), and anastrozole (Arimidex).

FIGURE 1 Anteroposterior view of the pelvis (cropped) shows expansion and abnormal bone mineral texture, with coarsened trabecula and mixed lucency and sclerosis, in the right ischium.

FIGURE 2 Sagittal MRIs of the lumbar spine show diffusely abnormal bone marrow signal. A, T1-weighted imaging shows complete loss of normal bright fatty marrow signal. B, T2-weighted, fat-saturated sequence shows heterogeneous patchy abnormal increased signal, involving portions of L1, L5, and S1 particularly. C, STIR sagittal view shows increased abnormal signal involving much of L1 and L2, and portions of L4, L5, and S1.

FIGURE 3 Axial pelvis CT image shows diffuse markedly abnormal bone mineral texture, with mixed lucency and osteosclerosis.

FIGURE 4 Bone scan is abnormal but under-represents the extent of the abnormalities apparent from MRI and CT. There are subtle abnormalities that correspond to known abnormalities (increased activity of the radiographically abnormal right ischium compared with the left), but overall the extent of disease suggested by bone scan is discrepant with other imaging studies. The most clear-cut evidence of bone metastases based on this study includes the patchy foci of increased activity in the shafts of both femurs and the increased activity in the right lower sternum. Activity is asymmetrically increased in the right proximal humerus, but also abnormal on the left. In fact, there is an overall “metabolic bone disease” pattern for much of the activity on this bone scan, with prominent periarticular activity of large joints.

FIGURE 5 A to D, Sagittal PET/CT images of the spine show diffusely abnormal bone mineral texture on the CT portion (left), with some areas predominantly lytic and others mostly sclerotic. Diffuse, but markedly inhomogeneous increased PET scan activity is seen in the sternum and spine. In a general way, the sites of greatest PET scan activity appear to correlate with levels with more lytic than blastic change.

A year later, while on Zoladex, Zometa, and exemestane (Aromasin), the patient was restaged with PET/CT for symptoms of increased aching, weight loss, depressed appetite, and rising tumor markers. PET/CT showed new liver metastases. Chemotherapy was recommended, but declined. The patient was started on fulvestrant (Faslodex). Restaging after 2 months, at which time the patient had fatigue, shortness of breath, and rising tumor markers, showed progression of liver metastases as well as evidence of lung involvement (see Case 13 in Chapter 10

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