—  INTERNATIONAL SOCIETY OF BREAST PATHOLOGY   —

Pertinent Issues Related to In Situ and Invasive Lobular Carcinoma
in Contemporary Breast Carcinoma Patients


Neal Goldstein
William Beaumont Hospital
Royal Oak, MI


Large bore needle core biopsies have become the standard method of initial diagnosis for most patients. These specimens engender a novel set of issues that were not operative in open biopsy and mastectomy specimens. This presentation will address the issues that pertain to lobular neoplasia.

For many years lobular carcinoma in situ (LCIS) has been considered and treated as a prognostic marker of increased risk of bilateral carcinoma rather than a direct precursor lesion [1, 2, 3] . Recent studies have that treatment other than tamoxifen for usual-type low-grade LCIS is probably not indicated since the long-term risk of subsequent invasive carcinoma or DCIS is sufficiently low [4, 5] . These observations and outcomes were based on open biopsy specimens/ partial mastectomy specimens in which ALH or LCIS was the only lesion present in the specimen.

Question 1: Is a subsequent excisional biopsy warranted if (only) atypical lobular hyperplasia (ALH) or LCIS is found in a needle core biopsy?

The long-term outcome risks of isolated ALH/ LCIS found in an open (excisional) biopsy specimen is unrelated to the issue of using ALH/ LCIS as a tissue marker of neoplastic processes in the adjacent, unsampled, breast parenchyma.

Retrospective needle core-excisional biopsy correlation studies have produced generally affirmative results. A few authors concluded that subsequent excisional biopsy is not warranted when ALH/LCIS is the only finding [6, 7, 9] , whereas most have concluded that follow-up excisional biopsy around the needle core biopsy tract or marker clips is appropriate [10, 11, 12, 13, 14, 15, 16, 17] . Some authors included additional decision factors such as whether the needle core biopsy was performed for a mass lesion or whether there were residual microcalcifications in the adjacent parenchyma. Given the limitations of small numbers of studied cases and variations in institutional practice parameters, widespread implementation of these factors is dubious. The association of a significant lesion in the adjacent parenchyma when only ALH or LCIS is found in a needle core biopsy appears to be similar to the rate when only ADH is present in the needle core biopsy. Approximately 10% - 20% of subsequent excisional biopsy specimens will have DCIS or invasive carcinoma when only ALH or LCIS is present in the needle core biopsy. The rate of coexistent, adjacent tissue malignancy is increased when additional lesions, such as ADH are present with the ALH/ LCIS in the same needle core biopsy specimen.

In the context of a marker for adjacent tissue malignancy, a new question is raised, whether ALH/ LCIS can be a direct precursor lesion? Almost all evidence supports an affirmative response. Morphologically, microinvasive lobular carcinoma in association with LCIS has been reported [18, 19, 20] . Genetic studies have found similar or identical mutations in LCIS and the corresponding invasive lobular carcinoma supporting that LCIS can be a direct precursor lesion to invasive carcinoma [21, 22, 23] . On a side note: that LCIS is a precursor lesion yet is treated as a prognostic risk marker is best explained by the comments of Dr Fisher based on NSABP data; that LCIS was a direct precursor lesion, similar to, but more indolent than grade 1 DCIS [4].

Conclusion: ALH/ LCIS alone on a needle core biopsy should be followed by an excisional biopsy of the target area.



Question 2: How does E-cadherin immunohistochemistry help establish distinguish between LCIS and DCIS and what does focal or inconclusive staining mean?

E-cadherin is a calcium-dependent, transmembrane protein responsible for the majority of intercellular adhesion and cell-polarity by binding to E-cadherin molecules of adjacent epithelial cells. The cytoplasmic region of E-cadherin is bound to the actin cytoskeleton by binding to β- or γ-catenin, which are bound α-catenin that is attached to actin filaments.

The E-cadherin gene, named CDH1 consists of 16 exons (a large gene) on 16q22.1. Lobular neoplasia (LCIS and invasive lobular carcinoma) are genetically characterized by a unique set of CDH1 biallelic mutations which distinguish it from ductal and other types of carcinoma. Most commonly in LCIS, one CDH1 gene is inactivated by a frameshift insertion, deletion or nonsense mutation that produces a truncation mutation of the E-cadherin protein and the second allele is inactivated by either a large pan-gene deletion [termed loss of heterozygosity (LOH)] or CDH1 promoter gene inactivation due to hypermethylation. Approximately 80% of the second CDH1 gene inactivations are due to LOH and 20% are caused by promoter gene hypermethylation.

The truncated, mutant E-cadherin protein is no longer able function appropriately and bind to the E-cadherin molecules of other cells, resulting in the complete absence of functional E-cadherin and complete cellular dyshesion. Depending where the mutation occurs in the CDH1 gene alters the immunohistochemical staining pattern in lobular carcinoma. Truncation mutations of the transmembrane or extracellular segments of E-cadherin leads to the inability of E-cadherin to localize to the membrane and the truncated protein becomes soluble. This results absent membrane immunohistochemical staining and sometimes diffuse faint cytoplasmic reactivity, depending where the truncation mutation occurred. Truncation mutations within the proximal cytoplasmic segment of E-cadherin results is a nonfunctional protein due to interruption of the binding of β- or γ-catenin. In some of these cases, a shortened, but intact transmembrane E-cadherin protein is produced which results in focal, punctate membrane staining. Truncation mutations that occur in the C-terminal 72 AA conserved region of E-cadherin directly impact the binding site of β- or γ-catenin. Since E-cadherin is bound to β- or γ-catenin within endoplasmic reticulum before it migrates to the membrane, there is strong staining of the perinuclear region of cells and absent membrane immunoreactivity [21, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71] .

Importantly, ductal carcinomas can also show no or decreased E-cadherin immunoreactivity. I have encountered rare grade 1 ductal carcinomas (almost all have been tubular) with intact, well-formed ducts with no E-cadherin. This phenomenon has been noted by several authors and is used as evidence that loss or decreased E-cadherin expression is an epiphenomenon in ductal carcinomas whereas it is an early and necessary molecular event in most, if not all lobular carcinomas. Decreased and absent E-cadherin immunoreactivity results from a different series of molecular events in ductal carcinomas than in lobular carcinomas. The CDH1 gene is prone to large deletions which can be identified by the LOH assay. As mentioned previously, large LOH-level deletions of one CDH1 gene occurs in most lobular carcinomas (>90%). Similar, large deletions of the CDH1 gene also occur in ductal carcinomas. In the William Beaumont Hospital molecular laboratory, approximately 50% of grade 2 ductal carcinomas and 80% of grade 3 carcinomas have a LOH deletion mutation of one CDH1 gene (making it a useful marker to include in molecular clonality assays). Unlike lobular carcinomas, ductal carcinomas do not incur point mutations of the second CDH1 gene that produce truncated E-cadherin proteins. Higher grade ductal carcinomas also have numerous somatic mutations that occur throughout the genome, of which deletion mutations in β-catenin are especially common. Mutations in any of the catenin genes alters or prevents normal E-cadherin function, leading to decreased immunoreactivity and usually a focal dyshesive infiltrative growth pattern. Usually, the altered E-cadherin staining in ductal carcinomas is decreased intensity or retained partial membrane reactivity. It is rare to see a complete absence of E-cadherin staining in ductal carcinoma. Lastly, E-cadherin antibody is prone to produce focal membranous staining in poorly fixed tissues, possibly due to retained, agglutinated antibody within the clefts of cell stromal interfaces.

Conclusion: Only the complete absence of E-cadherin membrane staining is supportive of lobular carcinoma. Because punctate membrane immunoreactivity can occur in a small minority of lobular and many ductal carcinomas, this pattern should be interpreted as noncontributory. Focal membrane reactivity is characteristic of many ductal carcinomas and is not a pattern seen in lobular carcinoma.



Question 3: What is the morphologic definition of lobular carcinoma and why is this important?

It may seem strange to include this question at the end of a discussion pertaining to the lesion. However, as molecular events become better characterized, immunohistochemical staining patterns become dogma, it is worthwhile in my opinion to ask this question in order to improve the accuracy and consistency of contemporary surgical pathology. A poll of practicing surgical pathologists would probably find that most are of the opinion that they can clearly define the entity and that their criteria are within the range of standard practice parameters. In this context, a recent SEER analysis reported the incidence of lobular carcinoma increased 1.65x from 1987 to 1999 [72, 73] . Lobular carcinomas constituted 9.5% of all carcinomas in 1987 compared to a 15.6% proportion in 1999. It is doubtful that this increase can be attributed to simply to biology. I propose that the major factor behind this increase is the imprecise application of lobular carcinoma by pathologists. It is my anecdotal experience that lobular carcinoma is used by some for carcinomas with even a focal area of dyshesive growth pattern. In support if this opinion is data showing that the reproducibility of the diagnosis of invasive lobular carcinoma is poor with kappa values between general surgical pathologists for pure invasive lobular carcinoma and for the presence of an invasive lobular carcinoma component of 0.31 and 0.32, respectively which was only marginally better among pathologists experienced in breast pathology (0.43 and 0.46) [83]. The importance of lobular carcinoma as a morphologic subtype of carcinoma is increasing, not decreasing. It is one of the principle indications for a preoperative breast MRI. Many surgeons consider it a more difficult lesion to adequately treat with breast conserving therapy. A recent study concluded that lobular carcinoma responds less favorably to neoadjuvant chemotherapy than ductal carcinoma [26]. There is increasing pressure for pathologists not to miss lobular carcinoma and it is therefore used more indiscriminately for all tumors with a dyshesive growth pattern. An extreme example of this is the entity of pleomorphic lobular carcinoma. Initially coined to distinguish it from classical-type lobular carcinoma [74], numerous studies have seemingly merged it back with classical lobular carcinoma, despite sharing no histological, clinical, mammographic, prognostic, or genetic similarities with classical lobular carcinoma [75, 76, 77, 78, 79, 80, 81, 82] .

Higher grade ductal carcinoma often have a dyshesive, single cell infiltrative pattern of growth around its periphery. As mentioned previously, a dyshesive growth pattern in ductal carcinoma is usually due to somatic mutations in one of the catenin genes. The catenins, especially β-catenin act as 'nuts' and cement to anchor the transmembranous E-cadherin molecule in place. Somatic mutations typically accrue during mitoses, so it is not surprising to see dyshesive infiltrative pattern at the peripheral, infiltrating edge of higher grade ductal carcinomas. Since needle core biopsies most commonly sample the periphery of carcinomas (especially large neoplasms), the dyshesive growth pattern is disproportionately represented, possibly facilitating the opportunity for pathologists to diagnose these areas as invasive lobular carcinoma. Being cognizant of this phenomenon and the morphologic identification of higher grade nuclei and or abortive ducts should allow pathologists to classify these lesions as ductal carcinoma in my opinion.

Conclusions: Lobular carcinoma, as a diagnostic entity should be restricted to a completely dyshesive, grade 1 nuclear invasive carcinoma. Although mixed lobular-ductal carcinoma occur, they are extremely rare. Higher grade carcinomas or those with focal abortive duct formation that is admixed with dyshesive, similar nuclear grade carcinoma should be classified as ductal carcinoma in my opinion.

References

  1. Wheeler JE, Enterline HT, Roseman JM et al. Lobular carcinoma in situ of the breast. Long-term followup. Cancer. 1974;34:554-563.

  2. Rosen PP, Kosloff C, Lieberman PH et al. Lobular carcinoma in situ of the breast. Detailed analysis of 99 Patients with average follow-up of 24 years. Am J Surg Pathol. 1978;2:225-251.

  3. Page DL, Kidd TE, Jr., Dupont WD et al. Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease. Hum Pathol. 1991;22:1232-1239.

  4. Fisher ER, Land SR, Fisher B et al. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: twelve-year observations concerning lobular carcinoma in situ. Cancer. 2004;100:238-244.

  5. Goldstein NS, Kestin LL, Vicini FA. Clinicopathologic implications of E-cadherin reactivity in patients with lobular carcinoma in situ of the breast. Cancer. 2001;92:738-747.

  6. Middleton LP, Grant S, Stephens T et al. Lobular carcinoma in situ diagnosed by core needle biopsy: when should it be excised? Mod Pathol. 2003;16:120-129.

  7. Berg WA, Mrose HE, Ioffe OB. Atypical lobular hyperplasia or lobular carcinoma in situ at core-needle breast biopsy. Radiology. 2001;218:503-509.

  8. Renshaw AA, Cartagena N, Derhagopian RP et al. Lobular neoplasia in breast core needle biopsy specimens is not associated with an increased risk of ductal carcinoma in situ or invasive carcinoma. Am J Clin Pathol. 2002;117:797-799.

  9. Bauer VP, Ditkoff BA, Schnabel F et al. The management of lobular neoplasia identified on percutaneous core breast biopsy. Breast J. 2003;9:4-9.

  10. O'Driscoll D, Britton P, Bobrow L et al. Lobular carcinoma in situ on core biopsy-what is the clinical significance? Clin Radiol. 2001;56:216-220.

  11. Shin SJ, Rosen PP. Excisional biopsy should be performed if lobular carcinoma in situ is seen on needle core biopsy. Arch Pathol Lab Med. 2002;126:697-701.

  12. Foster MC, Helvie MA, Gregory NE et al. Lobular carcinoma in situ or atypical lobular hyperplasia at core-needle biopsy: is excisional biopsy necessary? Radiology. 2004;231:813-819.

  13. Arpino G, Allred DC, Mohsin SK et al. Lobular neoplasia on core-needle biopsy-Clinical significance. Cancer. 2004;101:242-250.

  14. Irfan K, Brem RF. Surgical and mammographic follow-up of papillary lesions and atypical lobular hyperplasia diagnosed with stereotactic vacuum-assisted biopsy. Breast J. 2002;8:230-233.

  15. Crisi GM, Mandavilli S, Cronin E et al. Invasive mammary carcinoma after immediate and short-term follow-up for lobular neoplasia on core biopsy. Am J Surg Pathol. 2003;27:325-333.

  16. Dmytrasz K, Tartter PI, Mizrachy H et al. The significance of atypical lobular hyperplasia at percutaneous breast biopsy. Breast J. 2003;9:10-12.

  17. Lee AH, Denley HE, Pinder SE et al. Excision biopsy findings of patients with breast needle core biopsies reported as suspicious of malignancy (B4) or lesion of uncertain malignant potential (B3). Histopathology. 2003;42:331-336.

  18. Nemoto T, Castillo N, Tsukada Y et al. Lobular carcinoma in situ with microinvasion. J Surg Oncol. 1998;67:41-46.

  19. Howat AJ, Armour A, Ellis IO. Microinvasive lobular carcinoma of the breast. Histopathology. 2000;37:477-478.

  20. Prasad ML, Osborne MP, Giri DD et al. Microinvasive carcinoma (T1mic) of the breast: clinicopathologic profile of 21 cases. Am J Surg Pathol. 2000;24:422-428.

  21. Nyante SJ, DeVries S, Chen YY et al. Array-based comparative genomic hybridization of ductal carcinoma in situ and synchronous invasive lobular cancer. Hum Pathol. 2004;35:759-763.

  22. Shelley HE, Nyante SJ, Yi CY et al. Clonality of lobular carcinoma in situ and synchronous invasive lobular carcinoma. Cancer. 2004;100:2562-2572.

  23. Etzell JE, DeVries S, Chew K et al. Loss of chromosome 16q in lobular carcinoma in situ. Hum Pathol. 2001;32:292-296.

  24. Brinck U, Jacobs S, Neuss M et al. Diffuse growth pattern affects E-cadherin expression in invasive breast cancer. Anticancer Res. 2004;24:2237-2242.

  25. Foty RA, Steinberg MS. Cadherin-mediated cell-cell adhesion and tissue segregation in relation to malignancy. Int J Dev Biol. 2004;48:397-409.

  26. Fricke E, Hermannstadter C, Keller G et al. Effect of wild-type and mutant E-cadherin on cell proliferation and responsiveness to the chemotherapeutic agents cisplatin, etoposide, and 5-fluorouracil. Oncology. 2004;66:150-159.

  27. Hazan RB, Qiao R, Keren R et al. Cadherin switch in tumor progression. Ann N Y Acad Sci. 2004;1014:155-163.

  28. Kobielak A, Fuchs E. Alpha-catenin: at the junction of intercellular adhesion and actin dynamics. Nat Rev Mol Cell Biol. 2004;5:614-625.

  29. Laux H, Tomer R, Mader MT et al. Tumor-associated E-cadherin mutations do not induce Wnt target gene expression, but affect E-cadherin repressors. Lab Invest. 2004;84:1372-1386.

  30. Marques FR, Fonsechi-Carvasan GA, De Angelo Andrade LA et al. Immunohistochemical patterns for alpha- and beta-catenin, E- and N-cadherin expression in ovarian epithelial tumors. Gynecol Oncol. 2004;94:16-24.

  31. Qian X, Karpova T, Sheppard AM et al. E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases. EMBO J. 2004;23:1739-1784.

  32. Takeno S, Noguchi T, Fumoto S et al. E-cadherin expression in patients with esophageal squamous cell carcinoma: promoter hypermethylation, Snail overexpression, and clinicopathologic implications. Am J Clin Pathol. 2004;122:78-84.

  33. Fedor-Chaiken M, Meigs TE, Kaplan DD et al. Two regions of cadherin cytoplasmic domains are involved in suppressing motility of a mammary carcinoma cell line. J Biol Chem. 2003;278:52371-52378.

  34. Graziano F, Ruzzo AM, Bearzi I et al. Screening E-cadherin germline mutations in Italian patients with familial diffuse gastric cancer: an analysis in the District of Urbino, Region Marche, Central Italy. Tumori. 2003;89:255-258.

  35. Graziano F, Humar B, Guilford P. The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice. Ann Oncol. 2003;14:1705-1713.

  36. Gulmann C, Grace A, Leader M et al. Adenomatous polyposis coli gene, beta-catenin, and E-cadherin expression in proximal and distal gastric cancers and precursor lesions: an immunohistochemical study using tissue microarrays. Appl Immunohistochem Mol Morphol. 2003;11:230-237.

  37. Hofler H, Specht K, Becker KF. Molecular analysis of gene expression in tumor pathology. Adv Exp Med Biol. 2003;532:19-26.

  38. Hu XC, Wong IH, Chow LW. Tumor-derived aberrant methylation in plasma of invasive ductal breast cancer patients: clinical implications. Oncol Rep. 2003;10:1811-1815.

  39. Kim H, Kim YH, Kim SE et al. Concerted promoter hypermethylation of hMLH1, p16INK4A, and E-cadherin in gastric carcinomas with microsatellite instability. J Pathol. 2003;200:23-31.

  40. Klingelhofer J, Troyanovsky RB, Laur OY et al. Exchange of catenins in cadherin-catenin complex. Oncogene. 2003;22:1181-1188.

  41. Kovacs A, Dhillon J, Walker RA. Expression of P-cadherin, but not E-cadherin or N-cadherin, relates to pathological and functional differentiation of breast carcinomas. Mol Pathol. 2003;56:318-322.

  42. Kren L, Hermanova M, Goncharuk VN et al. Downregulation of plasma membrane expression/cytoplasmic accumulation of beta-catenin predicts shortened survival in non-small cell lung cancer. A clinicopathologic study of 100 cases. Cesk Patol. 2003;39:17-20.

  43. Ozawa M. p120-independent modulation of E-cadherin adhesion activity by the membrane-proximal region of the cytoplasmic domain. J Biol Chem. 2003;278:46014-46020.

  44. Roylance R, Droufakou S, Gorman P et al. The role of E-cadherin in low-grade ductal breast tumourigenesis. J Pathol. 2003;200:53-58.

  45. Sarrio D, Moreno-Bueno G, Hardisson D et al. Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: relationships with abnormal E-cadherin and catenin expression and microsatellite instability. Int J Cancer. 2003;106:208-215.

  46. Suriano G, Oliveira MJ, Huntsman D et al. E-cadherin germline missense mutations and cell phenotype: evidence for the independence of cell invasion on the motile capabilities of the cells. Hum Mol Genet. 2003;12:3007-3016.

  47. Suriano G, Mulholland D, de WO et al. The intracellular E-cadherin germline mutation V832 M lacks the ability to mediate cell-cell adhesion and to suppress invasion. Oncogene. 2003;22:5716-5719.

  48. Wong AS, Gumbiner BM. Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J Cell Biol. 2003;161:1191-1203.

  49. Becker KF, Kremmer E, Eulitz M et al. Functional allelic loss detected at the protein level in archival human tumours using allele-specific E-cadherin monoclonal antibodies. J Pathol. 2002;197:567-574.

  50. Bremnes RM, Veve R, Hirsch FR et al. The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cancer. 2002;36:115-124.

  51. Carpenter PM, Al-Kuran RA, Theuer CP. Paranuaclear E-cadherin in gastric adenocarcinoma. Am J Clin Pathol. 2002;118:887-894.

  52. Castano J, Raurell I, Piedra JA et al. Beta-catenin N- and C-terminal tails modulate the coordinated binding of adherens junction proteins to beta-catenin. J Biol Chem. 2002;277:31541-31550.

  53. Cleton-Jansen AM. E-cadherin and loss of heterozygosity at chromosome 16 in breast carcinogenesis: different genetic pathways in ductal and lobular breast cancer? Breast Cancer Res. 2002;4:5-8.

  54. Feltes CM, Kudo A, Blaschuk O et al. An alternatively spliced cadherin-11 enhances human breast cancer cell invasion. Cancer Res. 2002;62:6688-6697.

  55. Hajra KM, Fearon ER. Cadherin and catenin alterations in human cancer. Genes Chromosomes Cancer. 2002;34:255-268.

  56. Joo YE, Rew JS, Choi SK et al. Expression of e-cadherin and catenins in early gastric cancer. J Clin Gastroenterol. 2002;35:35-42.

  57. Lee YC, Wu CT, Chen CS et al. The significance of E-cadherin and alpha-, beta-, and gamma-catenin expression in surgically treated non-small cell lung cancers of 3 cm or less in size. J Thorac Cardiovasc Surg. 2002;123:502-507.

  58. Lehmann U, Celikkaya G, Hasemeier B et al. Promoter hypermethylation of the death-associated protein kinase gene in breast cancer is associated with the invasive lobular subtype. Cancer Res. 2002;62:6634-6638.

  59. Lei H, Sjoberg-Margolin S, Salahshor S et al. CDH1 mutations are present in both ductal and lobular breast cancer, but promoter allelic variants show no detectable breast cancer risk. Int J Cancer. 2002;98:199-204.

  60. Lim SC, Lee MS. Significance of E-cadherin/beta-catenin complex and cyclin D1 in breast cancer. Oncol Rep. 2002;9:915-928.

  61. Lowy AM, Knight J, Groden J. Restoration of E-cadherin/beta-catenin expression in pancreatic cancer cells inhibits growth by induction of apoptosis. Surgery. 2002;132:141-148.

  62. Malaguti C, Rossini GP. Recovery of cellular E-cadherin precedes replenishment of estrogen receptor and estrogen-dependent proliferation of breast cancer cells rescued from a death stimulus. J Cell Physiol. 2002;192:171-181.

  63. Nagae Y, Kameyama K, Yokoyama M et al. Expression of E-cadherin catenin and C-erbB-2 gene products in invasive ductal-type breast carcinomas. J Nippon Med Sch. 2002;69:165-171.

  64. Toyooka KO, Toyooka S, Maitra A et al. Establishment and validation of real-time polymerase chain reaction method for CDH1 promoter methylation. Am J Pathol. 2002;161:629-634.

  65. Vizirianakis IS, Chen YQ, Kantak SS et al. Dominant-negative E-cadherin alters adhesion and reverses contact inhibition of growth in breast carcinoma cells. Int J Oncol. 2002;21:135-144.

  66. Chalmers IJ, Aubele M, Hartmann E et al. Mapping the chromosome 16 cadherin gene cluster to a minimal deleted region in ductal breast cancer. Cancer Genet Cytogenet. 2001;126:39-44.

  67. Chan JK, Wong CS. Loss of E-cadherin is the fundamental defect in diffuse-type gastric carcinoma and infiltrating lobular carcinoma of the breast. Adv Anat Pathol. 2001;8:165-172.

  68. Cheng CW, Wu PE, Yu JC et al. Mechanisms of inactivation of E-cadherin in breast carcinoma: modification of the two-hit hypothesis of tumor suppressor gene. Oncogene. 2001;20:3814-3823.

  69. Droufakou S, Deshmane V, Roylance R et al. Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast. Int J Cancer. 2001;92:404-408.

  70. Gamallo C, Moreno-Bueno G, Sarrio D et al. The prognostic significance of P-cadherin in infiltrating ductal breast carcinoma. Mod Pathol. 2001;14:650-654.

  71. Huber AH, Stewart DB, Laurents DV et al. The cadherin cytoplasmic domain is unstructured in the absence of beta-catenin. A possible mechanism for regulating cadherin turnover. J Biol Chem. 2001;276:12301-12309.

  72. Li CI, Anderson BO, Daling JR et al. Changing incidence of lobular carcinoma in situ of the breast. Breast Cancer Res Treat. 2002;75:259-268.

  73. Li CI, Anderson BO, Daling JR et al. Trends in incidence rates of invasive lobular and ductal breast carcinoma. JAMA. 2003;289:1421-1424.

  74. Weidner N, Semple JP. Pleomorphic variant of invasive lobular carcinoma of the breast. Hum Pathol. 1992;23:1167-1171.

  75. Bassler R, Kronsbein H. Disseminated lobular carcinoma- A predominantly pleomorphic lobular carcinoma of the whole breast. Pathol Res Pract. 1980;166:456-470.

  76. Eusebi V, Magalhaes F, Azzopardi JG. Pleomorphic lobular carcinoma of the breast: an aggressive tumor showing apocrine differentiation. Hum Pathol. 1992;23:655-662.

  77. Frolik D, Caduff R, Varga Z. Pleomorphic lobular carcinoma of the breast: its cell kinetics, expression of oncogenes and tumour suppressor genes compared with invasive ductal carcinomas and classical infiltrating lobular carcinomas. Histopathology. 2001;39:503-513.

  78. Kaya H, Aribal E, Yegen C. Apocrine differentiation in invasive pleomorphic lobular carcinoma with in situ ductal and lobular apocrine carcinoma: case report. Pathol Oncol Res. 2002;8:151-152.

  79. Middleton LP, Palacios DM, Bryant BR et al. Pleomorphic lobular carcinoma: morphology, immunohistochemistry, and molecular analysis. Am J Surg Pathol. 2000;24:1650-1656.

  80. Palacios J, Sarrio D, Garcia-Macias MC et al. Frequent E-cadherin gene inactivation by loss of heterozygosity in pleomorphic lobular carcinoma of the breast. Mod Pathol. 2003;16:674-678.

  81. Sneige N, Wang J, Baker BA et al. Clinical, histopathologic, and biologic features of pleomorphic lobular (ductal-lobular) carcinoma in situ of the breast: a report of 24 cases. Mod Pathol. 2002;15:1044-1050.

  82. Wahed A, Connelly J, Reese T. E-cadherin expression in pleomorphic lobular carcinoma: an aid to differentiation from ductal carcinoma. Ann Diagn Pathol. 2002;6:349-351.

  83. Cserni G. Reproducibility of a diagnosis of invasive lobular carcinoma. J Surg Oncol. 1999;70:217-221.

  84. Gabriel H. The dilemma of lobular carcinoma in situ at percutaneous biopsy: to excise or to monitor. AJR Am J Roentgenol. 1999;173:300-302.