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Background
Lobular carcinoma of the breast may have a very subtle presentation. There may be a mass or only a vague thickening of the breast. The diagnosis often rests with the pathologist to identify the subtly atypical cells that comprise the tumor.
OUTLINE
CHARACTERIZATION RADIOLOGIC-MAMMOGRAPHY
Invasive lobular carcinoma of the breast: mammographic characteristics and computer-aided detection.Evans WP, Warren Burhenne LJ, Laurie L, O'Shaughnessy KF, Castellino RA.
Susan G. Komen Breast Center, Baylor University Medical Center, Dallas, TX, USA.
Radiology 2002 Oct;225(1):182-9 Abstract quote PURPOSE: To characterize the mammographic appearance of invasive lobular carcinoma in a large series of screening-detected consecutive breast cancers and to evaluate the ability of a computer-aided detection system to mark these carcinomas.
MATERIALS AND METHODS: Investigators used the Breast Imaging Reporting and Data System lexicon to characterize lesions as part of a retrospective review of 90 screening mammographic examinations that led to biopsy-proved diagnosis of 94 invasive lobular carcinoma lesions. The 40 available prior mammographic examinations (obtained 9-24 months earlier) were also reviewed to characterize any visible findings. The results of a computer-aided detection analysis were compared with the images, and the sensitivity of the algorithm was calculated for correct detection of the lesions.
RESULTS: Fifty-six (60%) of 94 lesions manifested as masses, of which 40 (71%) were described as irregular and spiculated; 20 (21%) of 94, as architectural distortions; and the remainder, 18 (20%), as either asymmetric densities or calcifications. On the screening mammograms showing biopsy-proved cancers, the sensitivity of the computer-aided detection system was 86 (91%) of 94 lesions. Thirty-one of the 40 prior mammograms showed retrospectively visible findings, and 24 (77%) of 31 were marked by the computer-aided detection system.
CONCLUSION: Spiculated masses and architectural distortions are the predominant appearances of invasive lobular carcinoma, and a computer-aided detection system correctly marked a high percentage of invasive lobular carcinoma lesions.
RADIOLOGIC-MRI
Role of magnetic resonance imaging in the diagnosis and single-stage surgical resection of invasive lobular carcinoma of the breast.Munot K, Dall B, Achuthan R, Parkin G, Lane S, Horgan K.
Department of Surgery, The General Infirmary at Leeds, Great George Street, Leeds LS1 3EX, UK.
Br J Surg 2002 Oct;89(10):1296-301 Abstract quote BACKGROUND: Conventional imaging with mammography and ultrasonography has a low sensitivity for diagnosis and a tendency to underestimate the extent of invasive lobular carcinoma (ILC) of the breast. The aim was to determine whether magnetic resonance imaging (MRI) had any advantages for the characterization of ILC.
METHODS: Twenty patients with histologically proven ILC underwent preoperative imaging with MRI. MRI was performed to aid detection of malignancy in six patients with a clinically suspicious presentation but normal or indeterminate imaging on mammography and ultrasonography. In 14 patients MRI was performed to determine tumour extent.
RESULTS: MRI accurately identified malignancy in five of six patients with normal or indeterminate conventional imaging. In seven of 14 patients in whom MRI was performed to determine tumour extent, it provided significant additional information. These included four patients in whom conventional imaging grossly underestimated tumour size, two patients in whom MRI identified an unsuspected contralateral breast tumour and one patient in whom MRI predicted tumour invasion of the pectoral muscle. The correlation between tumour size on histological examination was better with MRI (r = 0.967) than with mammography (r = 0.663) and ultrasonography (r = 0.673).
CONCLUSION: MRI can provide considerable additional information in the detection and characterization of ILC.
GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION Prior and concurrent contralateral carcinomas 6-28% of cases Subsequent contralateral carcinomas 1-2.38 cases/100 women per year
HISTOLOGICAL TYPES CHARACTERIZATION CLASSIC Small to medium sized cells, occasionally with cytoplasmic mucin globules, infiltrating the breast in a linear fashion (Indian file pattern) and in a targetoid arrangement around pre-existing ducts and lobules VARIANTS ALVEOLAR Globular aggregate of 20 or more cells MYOSECRETORY
- Lobular Carcinoma of the Breast With Hybrid Myoepithelial and Secretory ("Myosecretory") Cell Differentiation.
Vecchio MD, Foschini MP, Peterse JL, Eusebi V.
From the *Section of Histopathology and Cytopathology, University of Bologna at Bellaria Hospital, Bologna, Italy; and the daggerDepartment of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Am J Surg Pathol. 2005 Nov;29(11):1530-1536. Abstract quote
Three cases of lobular carcinoma of the breast showing a complex morphology that included myoepithelial cell differentiation are reported.
One case was a pure in situ acinar lesion, while the other 2 cases were in situ and invasive carcinomas. Three different cell types were seen in these tumors: one was the phenotype commonly seen in the garden variety of in situ lobular carcinoma (LCIS) constituted by noncohesive round to ovoid cells with round nuclei and positivity for epithelial membrane antigen (EMA), estrogen receptor (ER), and progesteron receptor (PR). E-cadherin was negative in these cells. The second type was represented by cohesive elements with irregular nuclei. These cells were immunoreactive for smooth muscle actin, calponin, keratin 14, p63, and e-cadherin. EMA, ER, and PR were consistently negative. The third type, seen in a minority of cell population of case nos. 2 and 3, consisted of cells showing at the same time EMA and smooth muscle actin in their cytoplasm. This type was defined as "hybrid myosecretory cell" to highlight contractile and secretory properties present at the same time.
Cells with hybrid features probably indicate that myoepithelial and secretory cells are strictly related and the existence of a stem cell, at least for these cases, is not necessary.
PLEOMORPHIC Pleomorphic Lobular Carcinoma: Morphology, Immunohistochemistry, and Molecular Analysis
L. P. Middleton, M.D.; D. M. Palacios, M.D.; B. R. Bryant, M.T.; P. Krebs, M.D.; C. N. Otis, M.D.; M. J. Merino, M.D.
From the National Cancer Institute (L.P.M., D.M.P, B.R.B., M.J.M), Bethesda, Maryland; and Baystate Medical Center (P.K., C.N.O.), Tufts University School of Medicine, Springfield, Massachusetts, U.S.A.
Am J Surg Pathol 2000;24:1650-1656 Abstract quote
Infiltrating pleomorphic lobular carcinoma (PLC) is an aggressive variant of infiltrating lobular carcinoma. Recently, in situ changes identical to PLC (PLCIS) have been described. The role of prognostic markers and their correlation with therapeutics, clinical outcome, and genetic changes is not well established in PLC.
The authors examined 38 cases of this entity to understand better this tumor's biology.
Immunohistochemical (IHC) analysis was performed in 21 specimens for estrogen and progesterone steroid receptors, p53, Her 2 (p185), and GCDFP-15. Genomic deoxyribonucleic acid was obtained from microdissected tumor as well as normal control cells, and loss of heterozygosity was investigated at the ESR (16q24), p53 (TP53 17p), Her 2 (17q 11-12), and BRCA 1 (17q12-25) loci. In this series, the average patient age was 57.5 years (age range, 24–92 years). Twenty-seven women were postmenopausal. Tumor size ranged from 1.2 to 25 cm. Six patients were a pathologic stage I; 19, stage II; 12, stage III; and one, stage IV. Histologically, multifocal nodular aggregates of discohesive pleomorphic tumor cells were seen interspersed in dense and fibrotic breast parenchyma. Twenty-nine percent of the specimens demonstrated associated signet ring cells. The remainder had dishesive, globoid, plasmacytoid cells with high-grade nuclear features. PLCIS was identified in 17 of 38 patients (45%), and lobular carcinoma in situ (LCIS) was noted in 8 patients (21%). IHC analysis showed estrogen immunoreactivity in 81%, progesterone in 67%, GCDFP-15 in 71%, and Her 2 in 81% (2+ to 3+ membranous staining) of specimens. Antibodies to p53 stained the tumor cell nuclei in 48% of the tumors. Loss of heterozygosity was identified in 52% of the specimens at the p53 locus, 18% at the ESR locus, 19% to 24% at the Her 2 loci, and 27% to 32% at the BRCA 1 locus. Follow-up was available in 19 patients and ranged from 12 months to 15 years (mean, 73 months). Seven patients had no evidence of disease at last examination (range, 1–15 years), three patients were alive with disease (range, 2–14 years), and nine patients were dead of disease (range, 2 months–9 years). Six patients had subsequent diagnoses of tumor in the contralateral breast.
Analysis shows that PLC tends to appear in older postmenopausal women who present with locally advanced disease. PLCIS was found to be associated with PLC 45% of the time. The aggressive clinical course of patients with PLC is supported by tumor immunoreactivity with unfavorable markers Her 2 and p53. Overexpression of Her 2 in PLC may be therapeutically relevant, enabling the use of novel chemotherapeutic drugs like Herceptin. Interestingly, tumors that were Her 2 immunoreactive also maintained estrogen hormone immunoreactivity.
SOLID Solid nests with classic pattern TUBULOLOBULAR CARCINOMA Small tubules and cords of tumor cells in classic pattern
- Tubulolobular Carcinoma of the Breast: An Analysis of 27 Cases of a Tumor With a Hybrid Morphology and Immunoprofile.
Wheeler DT, Tai LH, Bratthauer GL, Waldner DL, Tavassoli FA.
From the *Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology, Washington, DC; daggerDepartment of Pathology, Potomac Hospital, Woodbridge, VA; double daggerDepartment of Pathology, Madigan Army Medical Center, Tacoma, WA; and section signDepartment of Pathology, Yale University School of Medicine, New Haven, CT.
Am J Surg Pathol. 2004 Dec;28(12):1587-1593. Abstract quote
Tubulolobular carcinoma (TLC) is a rare subtype of mammary carcinoma that has eluded precise classification, exhibiting features of both ductal and lobular differentiation.
The clinicopathologic features of 27 cases of TLC were analyzed by both hematoxylin and eosin and immunohistochemical stains for E-cadherin and 34betaE12 (high molecular weight cytokeratin). Five cases of both pure tubular and classic lobular carcinoma were included as controls. Patients with TLC ranged in age from 43 to 79 years (median, 60 years). Tumor characteristics were as follows: size, 0.5 cm to 2.5 cm (median, 1.4 cm); bilaterality, 1 of 27 (4%); and multifocality, 5 of 27 (19%). Twenty-two of the 27 cases (81%) contained an in situ component: 8 (36%) lobular (LIN); 4 (18%) ductal (DIN); and 10 (46%) mixed. All 27 cases were intensely positive (3+) for E-cadherin, a feature of ductal differentiation, while 25 of 27 (93%) cases showed variable positivity for 34betaE12 (1 to 3+), a feature far more common in tumors with lobular differentiation.
Clinical follow-up was available on 25 of 27 (93%) patients. Three of 24 (13%) patients developed axillary lymph node metastases and 1 of 25 (4%) patients developed a local recurrence over a follow-up period of 2 to 91 months (median, 39 months). In conclusion, TLCs are a distinct subtype of mammary carcinoma with overlapping morphologic features that are mirrored by a hybrid immunohistochemical profile. The uniform 3+ expression of E-cadherin in TLC supports the ductal differentiation of these tumors, despite a dominant lobular growth pattern.
The prognosis of these tumors appears to be excellent, especially in those cases that are unilateral and less than 2 cm in size.
SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION Special stains Immunoperoxidase Am J Clin Pathol 2001;115:85-98
Moderate to strong membrane expression found in all invasive (100/100) and in situ ductal carcinomas (131/131)
41/42 invasive and 50/53 in situ lobular carcinomas showed complete loss of expression
Invasive carcinomas with both features (41) showed three staining patterns:
Complete or almost complete lack of membrane staining similar to lobular CA
Uniform membrane expression througout the tumor similar to ductal CA
Focal loss of staining
*Molecular and Cellular Pathology, Mayne Medical School, University of Queensland †The Queensland Institute of Medical Research ‡The Royal Brisbane and Womenʼs Hospital, Brisbane, Australia.
Invasive lobular carcinoma (ILC) and lobular carcinoma in situ characteristically show loss of E-cadherin expression and so immunohistochemistry for E-cadherin is being increasingly used as a tool to differentiate between lobular and ductal lesions in challenging situations. However, misinterpretation of "aberrant" positive staining may lead some to exclude a diagnosis of lobular carcinoma.
E-cadherin and beta-catenin immunohistochemistry was analyzed in 25 ILCs. E-cadherin "positive" ILCs were subjected to molecular analysis including comparative genomic hybridization. Different morphologic components of case 25, showing heterogenous E-cadherin expression, were analyzed by E-cadherin gene sequencing, methylation, and DASL gene expression profiling. Four ILCs were positive for E-cadherin, but each also had neoplastic cells with aberrant staining. Two of these ILCs were positive for beta-catenin, again with some aberrantly stained neoplastic cells, and 2 were negative. The solid component of case 25 was positive for E-cadherin whereas the classic and alveolar areas were negative. All components harbored an in-frame deletion in exon 7 (867del24) of the E-cadherin gene and loss of the wild type allele. Comparative genomic hybridization demonstrated evidence of clonal evolution from E-cadherin-positive to E-cadherin-negative components. E-cadherin down-regulation seems to be through transcriptional repression via activation of transforming growth factor-beta/SMAD2 rather than methylation.
Positive staining for E-cadherin should not preclude a diagnosis of lobular in favor of ductal carcinoma. Molecular evidence suggests that even when E-cadherin is expressed, the cadherin-catenin complex maybe nonfunctional. Misclassification of tumors may lead to mismanagement of patients in clinical practice, particularly in the context of in situ disease at margins.E-Cadherin Reactivity of 95 Noninvasive Ductal and Lobular Lesions of the Breast Implications for the Interpretation of Problematic Lesions
Neal S. Goldstein, etal.
Am J Clin Pathol 2001;115:534-542 Abstract quote
Studies suggest that E-cadherin is useful to classify epithelial breast lesions as ductal or lobular, but extensive experience with this antibody is lacking.
We studied reactivity of lesions with classic and indeterminate morphologic features. We reviewed 95 lesions and divided them into unanimous and nonunanimous diagnosis groups; the unanimous group served as benchmark lesions to which E-cadherin reactivity could be standardized and compared.
All 37 ductal lesions in the unanimous group had strong, diffuse E-cadherin reactivity. Two of 22 classic lobular carcinoma in situ (LCIS) lesions had sparse E-cadherin–reactive lobular cells within a few terminal duct lobular units. Neither displayed transition from nonreactive to reactive cells.
Of 36 lesions in the nonunanimous group, 19 had insufficient morphologic features for definitive classification. Only 6 of 19 were E-cadherin reactive, including several minimally proliferative lesions. The other 17 lesions in the nonunanimous group had LCIS and ductal carcinoma in situ (DCIS) features. All had no E-cadherin, or strong membrane reactivity of constituent cells in varying proportions, without a transition between reactive and nonreactive cells.
Results suggest that the majority of morphologically nondiagnostic atypical lesions are lobular, including those associated with DCIS. E-cadherin seems to be absent in most lobular lesions.
E-cadherin expression in pleomorphic lobular carcinoma: An aid to differentiation from ductal carcinoma.Wahed A, Connelly J, Reese T.
Department of Pathology and Laboratory Medicine, University of Texas-Houston Medical School, Houston; the Department of Pathology, St Luke's Episcopal Hospital, Houston, TX.
Ann Diagn Pathol 2002 Dec;6(6):349-51 Abstract quote Pleomorphic lobular carcinoma is a recently described entity separated from classical lobular carcinoma by cytologic pleomorphism. It can have an aggressive clinical course with a higher frequency of recurrence. Histologic differentiation with ductal carcinoma may be difficult, but it is important for this differentiation to be made. E-cadherin is a transmembrane glycoprotein, and complete loss of E-cadherin expression has been observed in invasive lobular carcinoma and lobular carcinoma in situ. Ductal carcinoma retains at least some expression of E-cadherin.
We examined the pattern of E-cadherin expression in a series of 14 cases of pleomorphic lobular carcinoma by immunohistochemistry. Twelve of the 14 cases showed no staining (86%); the remaining two cases exhibited 10% to 25% positive cells.
In cases with histologic equivocal features, immunohistochemical detection of E-cadherin expression can be a useful diagnostic aid for the differentiation of pleomorphic lobular and ductal carcinoma.
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