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Interpretation of 18F-FDG PET/CT studies in breast is challenging owing to nonspecific FDG uptake in various benign and malignant conditions. Benign conditions include breast changes in pregnancy and lactation, gynecomastia, mastitis, fat necrosis, fibroadenoma, intraductal papilloma, and atypical ductal hyperplasia. Among malignancies, invasive ductal carcinoma and invasive lobular carcinoma are common histological types of breast carcinoma. Rarely, other unusual histological types of breast carcinomas (eg, intraductal papillary carcinoma, invasive micropapillary carcinoma, medullary carcinoma, mucinous carcinoma, and metaplastic carcinoma), lymphoma, and metastasis can be the causes. Knowledge of a wide spectrum of hypermetabolic breast lesions on FDG PET/CT is essential in accurate reading of FDG PET/CT. The purpose of this atlas article is to demonstrate features of various breast lesions encountered at our institution, both benign and malignant, which can result in hypermetabolism on FDG PET/CT imaging.
Imaging diagnostic evaluation of the primary breast lesion itself is mainly determined from mammography, ultrasound, and MRI. In patients with known breast carcinoma, FDG PET/CT is performed for detection of unsuspected extra-axillary lymph nodes and distant metastases and evaluation of response to therapy. It is a problem-solving method when results of conventional imaging are equivocal.1 Breast incidental hypermetabolic lesions on FDG PET/CT are reported in 0.36% to 1.01% of female patients, and the prevalence rate of malignancies is approximately 27% to 38%.2–4 The false-positive interpretations may result from etiologies including benign hyperplasia, benign tumor, inflammation, and infection. Therefore, breast incidental hypermetabolic lesions need further workup, usually mammogram and/or ultrasound, and possible biopsy.2–4 At our institution, we encountered 18F-FDG PET/CT scans that demonstrated a variety of breast lesions with hypermetabolism. The purpose of this atlas article is to demonstrate a spectrum of breast lesions, both benign and malignant, which can show increased FDG uptake on PET/CT imaging. In addition, available radiological and pathological images are presented in this article because familiarity with the imaging features of different imaging modalities is helpful for making differential diagnosis and knowledge of the pathological characteristics of the breast lesions is helpful for understanding the mechanisms of FDG uptake.
The physical FDG uptake of normal breast tissues is generally homogeneous with SUVmax lower than 2.5.5–7 Factors that affect FDG uptake of normal breast tissue are mammographic density, age, and menstrual cycle. Breast FDG uptake significantly decreases as breast density decreases5–7 and age increases.7 In fertile female patients, FDG uptake of the normal breasts shows changes according to the menstrual cycle. The breast tends to show higher FDG uptake in the secretory, flow, and ovulatory phases than that in proliferative phase.8,9 Menopausal status has no significant effect on FDG uptake of normal breast.5,7 FDG uptake of the normal breast tissue has either no change or decrease on dual time point FDG PET.10 Therefore, dual time point FDG PET is helpful for detection of the breast malignancy by increasing the contrast between the lesion and the surrounding background. The FDG uptake of the bilateral beasts is usually symmetrical. Rarely, the bilateral beast FDG uptake may be asymmetrical which may be due to difference in response to hormonal stimulation (Fig. (Fig.11).
During pregnancy, the breast undergoes numerous changes in response to an increase in circulating hormones. These changes are characterized by marked ductular sprouting, increase in glandular vascularity, marked lobular growth with cellular proliferation, and involution of the fibrofatty stroma.11 These changes are more notable during lactation, the secretory state. Glucose plays a major role in mammary gland function during lactation as it is used both as a fuel and as a precursor of milk components.
Pregnant and postpartum women require FDG PET/CT examinations in very few cases, such as evaluation for malignant tumors. During pregnancy, the FDG uptake of the enlarged breast may, or may not, be similar to liver (Fig. (Fig.22).12 At CT, lactating breasts show enlargement with bilateral cord- and mass-like hyperattenuating tissue. Lactating breasts used for feeding can show diffuse and intense FDG uptake (Fig. (Fig.3),3), whereas lactating breasts unused for feeding only show little FDG uptake (Fig. (Fig.44).13,14 Therefore, suckling may be an important stimulus for FDG uptake in the lactating breasts by increasing expression of the insulin-independent glucose transporter (GLUT).15 The influence of breast-feeding on breast FDG uptake should be taken into consideration when interpreting FDG PET/CT findings in the postpartum women.
Mastitis is classified into 3 main types: infectious including simple mastitis (eg, lactational and nonlactational), complicated mastitis (eg, infected cysts, infected galactoceles, infected hamartoma, and infected hematoma), and specific mastitis (eg, tuberculosis); noninfectious (eg, periductal mastitis, plasma cell mastitis, granulomatous mastitis, and diabetic mastopathy); and malignant mastitis (eg, inflammatory breast carcinoma and malignant breast abscess).16 Infectious mastitis is more common during the child-bearing period especially during lactation. Noninfectious mastitis encompasses a group of aseptic or chemical inflammatory breast disorders. Malignant mastitis is the most serious form of mastitis, usually accompanying the inflammatory breast carcinoma. Clinically, inflammatory breast carcinoma is characterized by the rapid onset of swelling and enlargement of the breast. Differentiating this disease from acute mastitis may be difficult at presentation. Inflammatory breast carcinoma typically occurs in older women, whereas acute mastitis usually affects younger, lactating women.16
Increased FDG uptake in acute or chronic mastitis caused by bacteria, virus, parasite, tuberculosis, siliconoma, and surgery has been reported in the literature.17–24 Acute mastitis can show diffuse FDG uptake (Fig. (Fig.5).5). Chronic lesions usually show focal FDG uptake (Figs. (Figs.66 and and7).7). Inflammatory breast carcinomas demonstrate diffuse or focal FDG uptake in the enlarged breasts with increased skin FDG uptake.25
Fat necrosis is a sterile, inflammatory process which results from aseptic saponification of fat by means of blood and tissue lipase. It belongs to noninfectious mastitis. It varies in appearance depending on the stage of the process. Histologically, it is characterized as fat-filled macrophages and foreign body giant cells surrounded by interstitial infiltration of plasma cells.26 The common etiological factors of breast fat necrosis include trauma, biopsy, surgery, and radiotherapy.
On mammography, fat necrosis can present as lipid cysts, coarse calcifications, focal asymmetries, microcalcifications, or speculated masses. Fat necrosis can result in increased FDG uptake because of the presence of metabolically active inflammatory cells (Fig. (Fig.88).27–29
Atypical ductal hyperplasia is a neoplastic intraductal lesion characterized by proliferation of evenly distributed, monomorphic cells and associated with an elevated risk for progression to invasive breast carcinoma.30,31 It is more often found in older women and an unusual finding in the adolescent and young adult female patients. FDG PET/CT findings of atypical ductal hyperplasia have been rarely reported. We presented a case of atypical ductal hyperplasia showing focal FDG uptake with SUVmax of 6.3, which mimicked breast carcinoma (Fig. (Fig.9).9). On CT, the lesion could not be detected in the dense breast tissue.
Fibroadenoma is the most common benign breast tumor with admixture of stromal and epithelial proliferation, occurring most frequently in women of child-bearing age.31 Fibroadenoma usually presents as a painless, solitary, firm, slowly growing, mobile, well-defined nodule. It can be multiple in the same or in both breasts and may grow very large mainly when it occurs in adolescents.
At CT, fibroadenomas appear as well-circumscribed, round, or oval masses that may demonstrate coarse popcorn-like calcifications.32 FDG PET provides a high accuracy in the differentiation of fibroadenomas from malignant tumors because fibroadenomas usually show no or mild FDG uptake. Rarely, fibroadenomas may show significantly higher FDG uptake than the normal breast tissue and mimic malignancies (Fig. (Fig.1010).33,34
Papillary neoplasms are characterized by epithelial proliferations supported by fibrovascular stalks. They may occur anywhere within the ductal system from the nipple to the terminal ductal lobular unit and may be benign (intraductal papilloma), atypical, or malignant (intraductal papillary carcinoma).31 These neoplasms can be either solitary and central in location or multifocal within the terminal ductal lobular unit. The differentiation of benign from malignant papillary neoplasms on imaging is often difficult because of the wide spectrum of appearances of these lesions on MRI, ultrasound, and mammography.35
Overall, less than 10% of benign breast neoplasms correspond to intraductal papillomas.31 Intraductal papilloma can show slight (similar to the liver) or high FDG uptake.36–38 It is unclear whether the FDG uptake degree of intraductal papillomas is related to the GLUT subtypes or hexokinase II expression. Complex cyst with hypermetabolic mural nodule may suggest the diagnosis (Fig. (Fig.1111).
Less than 2% of breast carcinomas correspond to intraductal papillary carcinomas.31 Intraductal papillary carcinoma has a very favorable prognosis. Information is limited regarding the FDG PET/CT features of intraductal papillary carcinomas. We presented a case of intraductal papillary carcinoma located in the subareolar region, showing high FDG uptake (Fig. (Fig.1212).
Ductal carcinoma in situ (DCIS) is a neoplastic intraductal lesion characterized by increased epithelial proliferation, subtle to marked cellular atypia and an inherent but not necessarily obligate tendency for progression to invasive breast carcinoma.31 With improvements in imaging and increasing of screening, the detection of DCIS has been increasing. The most common mammographic finding in DCIS is microcalcifications (Fig. (Fig.13).13). A finding of segmental or ductal nonmass-like enhancement at contrast enhanced MRI is a hallmark of DCIS.39 Reports on FDG PET findings of DCIS are limited. The mean SUVmax of DCIS is approximately 2.0 to 2.4 (Fig. (Fig.1313).10,40 Avril et al found that the sensitivity of FDG PET in detecting DCIS is only 25%.41 Mavi et al suggested that dual time point FDG PET was helpful for improving the detection of DCIS with sensitivity of 76.9% because of increasing of the contrast between the lesion and the surrounding background.10 Compared with invasive carcinoma, DCIS shows lower intratumoral metabolic heterogeneity, which may be helpful for preoperative identification of invasive components in biopsy-confirmed DCIS.40
Invasive ductal carcinoma (IDC) is a heterogeneous group of tumors comprising the largest group (40%–70%) of invasive breast carcinomas.31 Invasive lobular carcinoma (ILC) is the second most common breast carcinoma, accounting for 10% to 15% of invasive breast carcinomas.31 The likelihood of bilaterality and multifocality of ILC is increased compared with IDCs. At CT, IDCs may be spiculated, rounded, occult, or other. They may show marked early and/or peripheral enhancement. Invasive lobular carcinoma spreads through the breast parenchyma by means of diffuse infiltration, which may cause little disruption of the underlying anatomical structures. CT findings of ILC may be nonspecific, showing an asymmetric soft-tissue density or a mass.32
Various cellular components and a variety of molecular mechanisms contribute to FDG uptake in breast carcinoma. The most important factors are expression of Glut-1 and hexokinase, number of viable tumor cells, histological subtype, microvessel density, tumor cell proliferation, and presence of inflammatory cells.42 Larger tumors, high-grade tumors, and tumors with the triple-negative profile tend to have higher FDG uptake.43,44 Estrogen receptor-negative tumors demonstrate a significantly higher SUVmax than do estrogen receptor-positive tumors.45 Invasive lobular carcinomas demonstrate lower SUVmax than IDCs. The lower FDG uptake in ILC may account for decreased detection rates on FDG PET.46 A lower tumor cell density, a diffuse infiltration of surrounding tissue, a low level of GLUT-1 expression, and a decreased proliferation rate in ILCs could explain this finding.47 Osseous metastases in patients with ILC also demonstrate lower FDG avidity than those in IDC patients. The non-FDG-avid sclerotic osseous metastases are significantly more common in untreated patients with ILC than with IDC.48 The impact of FDG PET/CT on systemic staging may be lower for ILC patients than for IDC patients.49
The specificity of PET for breast carcinoma detection is high, but sensitivity is relatively low. Avril et al showed that the specificity and sensitivity of single time point FDG PET in detecting invasive carcinoma is 94% and 62%, respectively.41 Dual time imaging can improve the sensitivity of FDG PET for detecting small breast carcinoma. Mavi et al reported that the sensitivity of dual time FDG PET for detecting breast carcinomas with size of 4 to 10 mm reached as high as 82.7%.10 Breast MRI has been increasingly adopted in clinical practice. It offers excellent sensitivity (90%) with relatively lower specificity (75%).50 The combined information of FDG PET and MRI increases user’s confidence in image interpretation in the specific case of patients with breast carcinoma (Fig. (Fig.1414).51
Invasive micropapillary carcinoma is composed of small clusters of tumor cells lying within clear stromal spaces resembling dilated vascular channels. Carcinomas with a dominant micropapillary growth pattern account for less than 2% of all invasive breast carcinomas.31 This unusual growth pattern is correlated with the presence of vascular invasion and axillary lymph node metastases.
There is limited information about the radiological features of invasive micropapillary carcinoma of the breast. On MRI, it commonly shows irregular shape, spiculated margin, and heterogeneous enhancement and frequently shows multiple lesions.52 We presented a case of invasive micropapillary carcinoma showing multiple lesions with inhomogeneous FDG uptake (Fig. (Fig.1515).
Medullary carcinoma is a well-circumscribed carcinoma composed of poorly differentiated cells arranged in large sheets, with no glandular structures, scant stroma, and a prominent lymphoplasmacytic infiltrate. It represents between 1% and 7% of all breast carcinomas.31 Medullary carcinoma has a better prognosis than the common invasive ductal carcinoma.
On MRI, the common features are an oval or lobular shape, a circumscribed margin, low apparent diffusion coefficient on diffusion-weighted imaging, rim enhancement, and washout or plateau pattern on kinetic curve.53 On PET/CT, it can show intense FDG uptake, which may be due to high cellular density and prominent lymphoplasmacytic infiltrate (Fig. (Fig.1616).54,55
Mucinous carcinoma is characterized by a proliferation of clusters of generally small and uniform cells floating in large amounts of extracellular mucus. Pure mucinous carcinoma accounts for approximately 2% of all breast carcinomas.31 In general, pure mucinous carcinomas have a favorable prognosis.
The imaging features of mucinous carcinoma differ from those of common breast carcinomas because of its high extracellular water component (mucin pool) and relatively low cell density. MRI features of pure mucinous carcinoma include lobular shape, homogeneous strongly high signal intensity on fat suppressed T2-weighted images, high apparent diffusion coefficient on diffusion-weighted imaging, rim or heterogeneous enhancement, and persistent pattern on kinetic curve.56,57 Mucinous carcinoma shows relatively lower FDG uptake, which may result from relatively low cellular density (Fig. (Fig.1717).10,55
Metaplastic carcinoma, a rare subtype accounting for less than 1% of invasive breast carcinomas, is characterized by high-grade carcinoma with heterogeneous metaplastic components.31 Metaplastic carcinomas include pure epithelial (squamous cell, adenocarcinoma with spindle cell differentiation, or adenosquamous including mucoepidermoid) and mixed epithelial-mesenchymal (carcinoma with chondroid or osseous metaplasia, and carcinosarcoma).31 They present with large tumors, aggressive pathological features, and frequent initial distant metastasis resulting in worse prognosis.58
At mammography, a metaplastic carcinoma typically is very dense and infrequently has calcifications. The MRI appearances of metaplastic carcinoma include a round or lobular mass with a relatively smooth margin, high signal intensity on T2-weighted images caused by the necrosis and cystic degeneration, rim-like enhancement, and washout pattern in the enhancing peripheral portion.59 FDG PET/CT findings of metaplastic carcinomas are rare. Groheux et al have reported 7 patients with metaplastic carcinomas showing high SUVmax, ranging from 6.2 to 18.9 (Fig. (Fig.1818).44 All the 7 tumors were grade 3, and 5 of them were triple negative. The status of p53 was found mutated in all cases. These factors may contribute to the high FDG uptake.
Malignant lymphoma of the breast may present as a primary or secondary tumor; both are rare. Most breast lymphomas are B-cell lymphoma and, rarely, T-cell lymphoma. They present unilateral or bilateral breast involvement. They can show unifocal, multifocal, or diffuse FDG uptake. High-grade tumors intend to show intense FDG uptake (Fig. (Fig.1919).60,61 Low-grade tumors, such as mucosa-associated lymphoid tissue lymphoma, show relatively lower activity.62 Occasionally, breast lymphoma only involves breast skin and superficial tissue with high FDG uptake (Fig. (Fig.2020).63
Male breast disease encompasses a variety of benign and malignant conditions. Almost all tumors that occur in the female breast can occur in the male breast, although much more rarely.
Gynecomastia is the most common breast disease in men. It is a non-neoplastic, often reversible, enlargement of the rudimentary duct system in male breast tissue with proliferation of epithelial and mesenchymal components in response to hormonal stimulation. It may be unilateral or bilateral and is usually subareolar in location. In male subjects, estrogenic effects increase in neonates, adolescents, and the elderly. Additional risk factors for development of gynecomastia include estrogen-producing tumors of the testis, such as Sertoli or Leydig cell tumors; feminizing adrenal cortical tumors; gonadotropin-secreting tumors, such as hepatoblastoma and fibrolamellar carcinoma or choriocarcinoma; prolactinoma; liver disease; obesity; Klinefelter syndrome; testicular feminization syndrome; neurofibromatosis type 1; and medication use.64,65
On PET/CT, gynecomastia is visualized as increased volume of breast tissue on the CT. It usually shows FDG uptake lower than or similar to the liver background (Fig. (Fig.2121).66–68 Unilateral nodular gynecomastia with increased FDG uptake may mimic a primary or secondary tumor.69 When interpreting FDG PET/CT as a staging tool in oncological male patients, one should consider gynecomastia as a possible cause for increased FDG uptake in the breast.
Carcinoma of the male breast is a rare malignant epithelial tumor histologically identical to that seen in the female breast. Male breast carcinoma is extremely rare, representing less than 1% of all breast carcinomas.31 The relative lack of glandular activity in the male breast potentially increases the sensitivity of FDG PET/CT for detection of male breast cancer.70,71 Groheux et al have reported that FDG PET/CT seems to be a powerful imaging method to perform staging, restaging, and treatment response assessment in male patients with breast carcinoma. They found that all the estrogen receptor positive breast carcinomas were FDG-avid (Fig. (Fig.22),22), and metastases could be detected with high sensitivity.72
It is difficult to distinguish true malignant breast lesions from benign ones on FDG PET/CT because there is significant overlap between the FDG-avidity of malignant and benign lesions on FDG PET, and CT is also poor for evaluation of lesions within the breast. In this atlas article, we demonstrate many representative lesions, which we have encountered, in an attempt to assist other interpreting physicians in expanding the differential diagnosis for hypermetabolic lesions in the breast.
Aisheng Dong and Yang Wang contributed equally to the article.
Conflicts of interest and sources of funding: none declared.