Special Subtypes of Breast Carcinoma: Tubular Carcinoma ... · PDF fileTubular Carcinoma . Low...

ASCP Session 1012, Oct 8th 2014 Special Subtypes of Breast Carcinoma

E. Brogi and H.Y. Wen Special Subtypes of Breast Carcinoma:

Tubular Carcinoma

Low Grade Adenosquamous Carcinoma

Invasive Micropapillary Carcinoma

Mucinous Carcinoma

Edi Brogi, M.D. Ph.D and Hannah Yong Wen M.D. Ph.D.

Memorial Sloan Kettering Cancer Center

New York City, NY, USA

In the past 12 months, I have not had a significant financial interest or other relationship with the manufacturer(s) of the product(s) or provider(s) of the service(s) that will be discussed in my

presentation.

TUBULAR CARCINOMA

This outline is extracted from chapter 13 - Tubular carcinoma, 4th Edition of Rosen’s Breast

Pathology Textbook (1). Tubular carcinoma (TC) is a special subtype of mammary carcinoma. It

consists of simple neoplastic glands lined by a single layer of neoplastic cells with low to

intermediate nuclear grade. Pure tubular carcinoma constitutes less than 2% of all breast

carcinomas. Most TCs are smaller than 1 cm. In one series, 5% of 382 T1N0M0 breast

carcinomas were TC (2). When stratified by size, TC represented 9% of lesions 1.0 cm or

smaller (2). In a series by Rakha et al. (3), 59% of 102 tubular carcinomas were smaller that 1 cm

and only 4% were larger than 2 cm.

Clinical Presentation

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E. Brogi and H.Y. Wen TC is often nonpalpable, and it is usually detected mammographically as irregular or calcified

spiculated lesion. Louwman et al. (4) reported that TC constituted 8% of 9259 screen-detected

carcinomas, but only 2% of 5413 interval carcinomas. TC can be an incidental finding in a

surgical excision specimen for another lesion. The radiologic differential diagnosis of TC

includes benign sclerosing lesions such as radial scar or sclerosing adenosis, and invasive duct

carcinoma. TC can occasionally arise in association with a radial scar. TC can occur at any age,

but is more common in postmenopausal women. A study based on SEER data reported that

73.6% of 4,477 TC diagnosed in the US between 1992 and 2007 occurred in women 50 to 79

years old (5). Ninety percent of women with TC were non-Hispanic white (5). TC has also rarely

been reported in males. Paget’s disease is very rarely associated with TC. In one study, 90.5% of

women with TC presented at Stage I disease (5). Axillary lymph node metastases occur in

approximately 10% of cases (2, 6-16). TC constituted only 1.5% of all carcinomas in a series of

142 patients with T1N1M0 disease (17). Affected lymph nodes are usually in level I (8). Fedko

et al. (18) found lymph node metastases in five (5.4%) of 93 patients with pure TC and known

lymph node status: two patients had macrometastases, and the other three had micrometastases.

Two-additional patients had lymph nodes with isolated tumor cells (N0(i+)) (18). The size of the

primary tumor ranged from 0.9 cm to 1.5 cm. In a French study (19), 2.5% patients with TC had

lymph node macrometastases, 6.4% micrometastases and 0.8% had isolated tumor cells (N0(i+)).

All patients with macrometastatic carcinoma had a tumor greater than 1 cm. On multivariate

analysis, pathological tumor size >10 mm was the only parameter significantly associated with

lymph node involvement.

Microscopic pathology

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E. Brogi and H.Y. Wen TC consists of haphazardly arranged small glands and tubules lined by monostratified polarized

epithelial cells with low to intermediate nuclear grade. The diagnosis of pure TC requires that at

least 90% of the tumor be composed of monostratified, simple neoplastic tubules with low grade

atypia. Features incompatible with the diagnosis of TC include complex architecture, multiple

layers of cells, significant nuclear pleomorphism and frequent mitoses.

The glands of TC are angular and have irregular shape, with widely patent lumen. The cytoplasm

usually is amphophilic. Cytoplasmic “snouts” are often present at the apical cell border. Mitoses

are rarely seen and necrosis is always absent. The stroma between the glands of TC tends to be

more abundant than in non-tubular well differentiated ductal carcinomas. Stromal elastosis is

also common, but it is not present in all cases. Stromal elastosis is also common in ER-positive

non-tubular carcinomas and in some benign lesions, such as radial scars. Calcifications in the

glandular lumen or in the stroma are present in at least 50% of TC. DCIS, ADH and columnar

cell change associated with TC can also harbor calcifications.

DCIS associated with TC typically has papillary, micropapillary, or cribriform pattern. In a

significant number of cases, only ADH or columnar cell change with or without atypia are

present. TC may arise in association with a radial scar. High grade DCIS is only rarely associated

with TC. In a study by Aulman et al. (55), columnar cell change was associated with 24 (89%) of

27 TC and showed atypia in 22/24 cases. Low grade DCIS was present in 37% of cases and foci

of lobular neoplasia in 11%. Coexistent classical LCIS has been described in 0.7% to 40% of

patients with TC.

Differential diagnosis

Microglandular adenosis: Small TC measuring less than 1 cm may closely resemble

microglandular adenosis (MGA). The glands of MGA tend to be smaller than those of TC, and

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E. Brogi and H.Y. Wen round or oval throughout, with no angular contours. The epithelium of MGA is typically

cuboidal, with uniform height and pale to clear cytoplasm, whereas the epithelium of TC ranges

from columnar to more cuboidal or flattened, and cells of different height may coexist in the

same gland. The lumen of the MGA glands is open, but not overtly patent and often contains

dense homogenous eosinophilic secretion that may undergo calcification. TC and MGA are both

devoid of myoepithelium, but the glands of MGA are completely surrounded by basement

membrane. Some investigators however, have detected attenuated or focally discontinuous

basement membrane in association with some well differentiated invasive carcinomas. The

distinction between TC and MGA should be based on the results of immunoperoxidase studies

for S100 protein (positive in MGA but not in TC) and ER and PR (strongly positive in TC and

negative in MGA) (20).

Sclerosing lesions: Sclerosing adenosis has a lobulocentric proliferative pattern not seen in TC.

The glands of sclerosing adenosis are compressed, not patent, and they are surrounded by

myoepithelium. Stromal elastosis is a common feature of radial sclerosing lesions. The

myoepithelial cells in a radial scar can be markedly attenuated but they can be demonstrated with

immunoperoxidase stains, such as calponin and p63. Some of the cytoplasmic myoepithelial

antigens have variable cross-reactivity with myofibroblasts. It is recommended to use a panel of

myoepithelial antigens inclusive of p63 and calponin and/or SMA, because some of the other

myoepithelial markers may be markedly attenuated in sclerosing lesions (21). This is especially

important when dealing with a needle core biopsy sample.

Well differentiated invasive ductal carcinoma: In well-differentiated non-tubular ductal

carcinoma glands lined by two or more cell layers or showing complex bridging patterns

represent more than 10% of the lesion. The glands also show greater cytologic atypia than in TC.

4


E. Brogi and H.Y. Wen Tubulo-lobular carcinoma: A carcinoma with areas of invasive lobular and glandular

carcinoma is referred to as tubulo-lobular carcinoma. The relative proportion of the two

components tends to vary and this type of tumors is quite heterogenous, and also shows mixed

reactivity for E-cadherin. Axillary lymph node metastases are more frequent in tubulo-lobular

carcinoma than in TC.

Tubular Carcinoma and CBX

The diagnosis of pure TC can be difficult in this material, especially when only a small portion

of the lesion is present. Pure tubular morphology in a CBX sample does not guarantee that the

same morphology is present in the rest of the lesion. It is good practice to indicate in the CBX

report that the final classification of the carcinoma will depend on the findings in the core and

excisional biopsies.

Immunohistochemistry

Most TCs are strongly positive for ER and PR. AR is positive in 80% of cases (22). All TCs

studied by Rakha et al. (3) were negative for HER2/neu. KI67 proliferation index is usually low

(<10%) (14). TC is positive for EMA and negative for S100.

Genetics

Loss of 16q is the most frequent chromosomal abnormality in TC and is also found in other low

grade mammary epithelial neoplastic lesions, including columnar cell change with atypia, ADH,

low grade DCIS, ALH, classical LCIS, well differentiated invasive ductal carcinoma, tubulo-

lobular carcinoma, and invasive cribriform carcinoma (23). Aulmann et al. (24) documented

LOH involving the long arm of chromosome 16 as well as chromosome 8p21, 3p14, 1p36 and

11q14 in TC, and a high degree of homology with columnar cell changes with atypia and low

grade DCIS. Riener et al. (25) found loss of the CDH13 locus on chromosome 16q in 86% of 23

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E. Brogi and H.Y. Wen TC. The CDH13 gene encodes a cell surface glycoprotein, member of the cadherin family (25).

TC and well differentiated invasive ductal carcinoma share some genetic alterations, including

ER-driven signaling pathways, and phosphatidylinositol signaling (26).

Treatment and prognosis

TC carries very good prognosis. Patients with unifocal pure TC are usually treated with breast

conservation therapy. According to SEER data, about two thirds (64.3%) of patients received

adjuvant radiation treatment (5). Patients with TC treated with breast conservation therapy had a

low rate of distant metastases (1%) and of breast cancer specific death (1%) (27). Livi et al. (28)

reported a series of 307 patients with TC and median follow-up time of 8.4 years. Most (80%)

patients who underwent breast conserving surgery received adjuvant radiotherapy and 35% had

tamoxifen treatment. Only 21 women (7%) received chemotherapy, including 15 with lymph

node metastases. Twelve patients had recurrence of carcinoma after a median time of 4.1 years,

one patient recurred in the supraclavicular fossa (28). Rakha et al. (3) compared the outcomes of

102 TC and 212 grade 1 invasive ductal carcinoma. The median F/U time was 127 months. Local

recurrences developed in only 6.9% patients with TC initially treated by wide local excision.

Recurrences occurred in 25.1% of patients with grade 1 invasive ductal carcinoma and 9% of

patients died of disease. Disease free survival and breast cancer specific survival were

significantly longer for patients with TC than patients with grade 1 invasive ductal carcinoma,

even when analysis was limited to sub-centimeter tumors (3), confirming the good prognosis of

TC diagnosed based on strict morphologic criteria. Radiotherapy is usually administered to

patients treated with breast conserving surgery. Adjuvant hormonal therapy is also a mainstay of

treatment for patients with TC.

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E. Brogi and H.Y. Wen REFERENCES

1. Brogi E. Chapter 13 - Tubular carcinoma. In: Hoda SA, Brogi E, Koerner FC, Rosen PP, editors. Rosen's Breast Pathology. 4th ed: Wolters Kluver Lippincott Williams & Wilkins; 2014.

2. Rosen PP, Saigo PE, Braun DW, Jr., Weathers E, DePalo A. Predictors of recurrence in stage I (T1N0M0) breast carcinoma. Annals of surgery. 1981;193(1):15-25.

3. Rakha EA, Lee AH, Evans AJ, Menon S, Assad NY, Hodi Z, et al. Tubular carcinoma of the breast: further evidence to support its excellent prognosis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(1):99-104.

4. Louwman MW, Vriezen M, van Beek MW, Nolthenius-Puylaert MC, van der Sangen MJ, Roumen RM, et al. Uncommon breast tumors in perspective: incidence, treatment and survival in the Netherlands. International journal of cancer Journal international du cancer. 2007;121(1):127-35.

5. Li CI. Risk of mortality by histologic type of breast cancer in the United States. Hormones & cancer. 2010;1(3):156-65.

6. Carstens PH. Tubular carcinoma of the breast. A study of frequency. American journal of clinical pathology. 1978;70(2):204-10.

7. Peters GN, Wolff M, Haagensen CD. Tubular carcinoma of the breast. Clinical pathologic correlations based on 100 cases. Annals of surgery. 1981;193(2):138-49.

8. McDivitt RW, Boyce W, Gersell D. Tubular carcinoma of the breast. Clinical and pathological observations concerning 135 cases. The American journal of surgical pathology. 1982;6(5):401-11.

9. Oberman HA, Fidler WJ, Jr. Tubular carcinoma of the breast. The American journal of surgical pathology. 1979;3(5):387-95.

10. Deos PH, Norris HJ. Well-differentiated (tubular) carcinoma of the breast. A clinicopathologic study of 145 pure and mixed cases. American journal of clinical pathology. 1982;78(1):1-7.

11. Berger A, Miller S, Harris M. Axillary dissection for tubular carcinoma of the breast. The breast journal. 1996;2:204-8.

12. Winchester DJ, Sahin AA, Tucker SL, Singletary SE. Tubular carcinoma of the breast. Predicting axillary nodal metastases and recurrence. Annals of surgery. 1996;223(3):342-7.

13. Green I, McCormick B, Cranor M, Rosen PP. A comparative study of pure tubular and tubulolobular carcinoma of the breast. The American journal of surgical pathology. 1997;21(6):653-7.

14. Carstens PH, Huvos AG, Foote FW, Jr., Ashikari R. Tubular carcinoma of the breast: a clinicopathologic study of 35 cases. American journal of clinical pathology. 1972;58(3):231-8.

15. Rosen PP, Saigo PE, Braun DW, Weathers E, Kinne DW. Prognosis in stage II (T1N1M0) breast cancer. Annals of surgery. 1981;194(5):576-84.

16. Bradford W, Christensen W, Fraser H. Treatment of pure tubular carcinoma of the breast. The breast journal. 1998;4:437-40.

17. Beahrs O, Shapiro S, Smart C. Report of the working group to review the National Cancer Institute—American Cancer Society Breast Cancer Detection Demonstration Projects. J Natl Cancer Inst. 1979;62:640-709.

18. Fedko MG, Scow JS, Shah SS, Reynolds C, Degnim AC, Jakub JW, et al. Pure tubular carcinoma and axillary nodal metastases. Annals of surgical oncology. 2010;17 Suppl 3:338-42.

19. Dejode M, Sagan C, Campion L, Houvenaeghel G, Giard S, Rodier JF, et al. Pure tubular carcinoma of the breast and sentinel lymph node biopsy: A retrospective multi-institutional study of 234 cases. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2012.

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E. Brogi and H.Y. Wen 20. Khalifeh IM, Albarracin C, Diaz LK, Symmans FW, Edgerton ME, Hwang RF, et al. Clinical,

histopathologic, and immunohistochemical features of microglandular adenosis and transition into in situ and invasive carcinoma. The American journal of surgical pathology. 2008;32(4):544-52.

21. Hilson JB, Schnitt SJ, Collins LC. Phenotypic alterations in myoepithelial cells associated with benign sclerosing lesions of the breast. The American journal of surgical pathology. 2010;34(6):896-900.

22. Collins LC, Cole KS, Marotti JD, Hu R, Schnitt SJ, Tamimi RM. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses' Health Study. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2011;24(7):924-31.

23. Abdel-Fatah TM, Powe DG, Hodi Z, Reis-Filho JS, Lee AH, Ellis IO. Morphologic and molecular evolutionary pathways of low nuclear grade invasive breast cancers and their putative precursor lesions: further evidence to support the concept of low nuclear grade breast neoplasia family. The American journal of surgical pathology. 2008;32(4):513-23.

24. Aulmann S, Elsawaf Z, Penzel R, Schirmacher P, Sinn HP. Invasive tubular carcinoma of the breast frequently is clonally related to flat epithelial atypia and low-grade ductal carcinoma in situ. The American journal of surgical pathology. 2009;33(11):1646-53.

25. Riener MO, Nikolopoulos E, Herr A, Wild PJ, Hausmann M, Wiech T, et al. Microarray comparative genomic hybridization analysis of tubular breast carcinoma shows recurrent loss of the CDH13 locus on 16q. Human pathology. 2008;39(11):1621-9.

26. Lopez-Garcia MA, Geyer FC, Natrajan R, Kreike B, Mackay A, Grigoriadis A, et al. Transcriptomic analysis of tubular carcinomas of the breast reveals similarities and differences with molecular subtype-matched ductal and lobular carcinomas. The Journal of pathology. 2010;222(1):64-75.

27. Liu GF, Yang Q, Haffty BG, Moran MS. Clinical-pathologic features and long-term outcomes of tubular carcinoma of the breast compared with invasive ductal carcinoma treated with breast conservation therapy. International journal of radiation oncology, biology, physics. 2009;75(5):1304-8.

28. Livi L, Paiar F, Meldolesi E, Talamonti C, Simontacchi G, Detti B, et al. Tubular carcinoma of the breast: outcome and loco-regional recurrence in 307 patients. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2005;31(1):9-12.

LOW-GRADE ADENOSQUAMOUS CARCINOMA

This outline is in part extracted from chapter 16 – Carcinoma with metaplasia, 4th Edition of

Rosen’s Breast Pathology Textbook (1). Low-grade adenosquamous (LG-AdSq) carcinoma is an

unusual variant of metaplastic mammary carcinoma morphologically similar to adenosquamous

carcinoma of the skin. It was first described in 1987 by Rosen and Ernsberger (2), and more than

one hundred examples have since been reported in few small series and case reports. A case of

LG-AdSq has been described in a BRCA1 germline mutation carrier (3).

8


E. Brogi and H.Y. Wen CLINICAL PRESENTATION

All reported cases of LG-AdSq have occurred in women, usually of peri- or post-menopausal

age. The clinical presentation is usually as a palpable mass or a mammographic abnormality.

LG-AdSq carcinoma has no distinctive imaging findings. The tumor arises in the breast

parenchyma, including in the retroareolar region.

MICROSCOPIC PATHOLOGY

Some tumors have a stellate growth pattern, while others appear relatively more circumscribed.

The tumor tends to infiltrate peripherally in the form of small glands and/or squamous nests

surrounded by desmoplastic stroma that at least focally grow between normal and undistorted

lobules. This infiltrative pattern helps to differentiate LG-AdSq carcinoma from non-neoplastic

complex sclerosing lesions. This differential diagnosis can be challenging, as LG-AdSq

carcinoma often arises in association with sclerosing lesions such as a papilloma, an

adenomyoepithelioma, a radial scar, or even sclerosing adenosis. The glands of LG-AdSq

carcinoma are lined by neoplastic epithelium and myoepithelium (biphasic carcinoma).

Squamous nests of various size and shape, and even scattered single squamous cells are also part

of the carcinoma. Small cysts containing keratotic debris with calcification are sometimes

present. The tissue immediately around squamous foci often has a distinctive lamellar

arrangement of spindle cells that merges with the epithelium. Very rarely, LG-AdSq carcinoma

can shows transition to conventional high-grade spindle cell and squamous sarcomatoid

metaplastic carcinoma. DCIS can be present, and sometimes shows apocrine features, but it may

be difficult to distinguish from infiltrative areas.

Syringomatous adenoma of the nipple is a skin-based lesion morphologically and

immunophenotypically indistinguishable from LG-AdSq carcinoma, and differs from it because

9


E. Brogi and H.Y. Wen of its superficial location. The distinction between these two entities can be very challenging, and

few case reports have documented local recurrence requiring surgical management by

mastectomy for tumors initially misdiagnosed as syringomatous adenoma of the nipple (3).

CBX Diagnosis

The diagnosis of LG-AdSq carcinoma in CBX is very challenging. Disorganized syringomatous

squamous nests and duct-like structures surrounded by desmoplastic stromal cells may suggest

LG-AdSq carcinoma. The differential diagnosis usually includes a complex sclerosing lesion.

One should entertain the differential diagnosis of LG-AdSq carcinoma when the CBX material

shows a sclerosing lesion with unusual morphologic features.

IMMUNOREACTIVITY

The cells of LG-AdSq carcinoma show immunoreactivity for AE1:3, CK5/6, 34 beta E12 and

CAM5.2. In one study (4) some of the epithelial clusters in each tumor were negative for some

cytokeratins, although no single keratin was consistently negative in all the epithelial clusters of

a case. Another group found strong reactivity for the basal cytokeratins CK5/6, CK14 and CK17

in five tumors (5). The spindle stromal cells of LG-AdSq carcinoma usually show no staining

for cytokeratins. Due to the biphasic nature of the tumor, that shows a myoepithelial component,

staining for myoepithelial markers can yield different patterns. Most importantly, one needs to

entertain the differential diagnosis of LG-AdSq carcinoma when a sclerosing lesion shows an

inconsistent staining pattern for myoepithelial markers. Complete circumferential (4) staining

for p63, SMM-HC, SMA, CD10 and calponin around all epithelial nests was present in only 11%

of cases. About a third (36%) of cases showed a pattern of complete, discontinuous and absent

circumferential staining for myoepithelial markers in the same tumor. Glandular luminal staining

was seen 74% of the tumors evaluated for p63, suggesting that p63 positivity highlights areas of

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E. Brogi and H.Y. Wen squamous (not myoepithelial) differentiation. LG-AdSq carcinoma is negative for ER, PR and

HER2. Familiarity with the morphologic features of this tumor and with its different staining

patterns is required for accurate diagnosis of this carcinoma.

PROGNOSIS AND TREATMENT

Lymph node involvement by LG-AdSq carcinoma is extremely rare, with only one documented

case (6). In the study by Kawaguchi and Shin (4), one of two patients with SLN biopsy had

dispersed epithelial clusters in four lymph nodes that were interpreted as secondary to artifactual

displacement; the other patient had no SLN involvement.

A 33 years old woman with a 8.0 cm tumor metastatic to the lung at presentation constitutes the

only documented case of distant metastases of LG-AdSq carcinoma (6). LG-AdSq carcinoma,

however, tends to recur locally, and management of the local recurrence can require mastectomy

(6). It is unclear whether local recurrence occurs only if the index tumor has been incompletely

excised. The current management of LG-AdSq carcinoma is similar to that of other types of

invasive breast carcinomas. Radiotherapy is used in patients treated with breast-conserving

surgery. Although LG-AdSq carcinoma is a metaplastic triple negative carcinoma, chemotherapy

does not appear to be indicated given the low propensity of this tumor to develop distant

metastases.

REFERENCES 1. Brogi E. Chapter 16 - Carcinoma with metaplasia. In: Hoda SA, Brogi E, Koerner FC, Rosen PP, editors.

Rosen's Breast Pathology. 4th ed: Wolters Kluwer Lippincott Williams & Wilkins; 2014. 2. Rosen PP, Ernsberger D. Low-grade adenosquamous carcinoma. A variant of metaplastic mammary

carcinoma. Am J Surg Pathol. 1987;11:351-358. 3. Noel JC, Buxant F, Engohan-Aloghe C. Low-grade adenosquamous carcinoma of the breast--A case

report with a BRCA1 germline mutation. Pathol Res Pract. 2010;206:511-513. 4. Kawaguchi K, Shin SJ. Immunohistochemical Staining Characteristics of Low-grade Adenosquamous

Carcinoma of the Breast. Am J Surg Pathol. 2012.

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E. Brogi and H.Y. Wen 5. Geyer FC, Lambros MB, Natrajan R, et al. Genomic and immunohistochemical analysis of

adenosquamous carcinoma of the breast. Mod Pathol. 2010;23:951-960. 6. Van Hoeven KH, Drudis T, Cranor ML, Erlandson RA, Rosen PP. Low-grade adenosquamous

carcinoma of the breast. A clinocopathologic study of 32 cases with ultrastructural analysis. Am J Surg Pathol. 1993; 17:248-258.

INVASIVE MICROPAPILLARY CARCINOMA

This outline is extracted from chapter 29 – Invasive micropapillary carcinoma, 4th Edition of

Rosen’s Breast Pathology Textbook (1).

Invasive micropapillary (MP) carcinoma is a morphologically distinctive form of mammary

carcinoma in which the neoplastic cells are arranged in morule-like clusters devoid of

fibrovascular cores and located within empty stromal spaces. Pure invasive MP carcinoma has

MP morphology in 90% or more of the tumor mass. A carcinoma with less of 90% MP admixed

with invasive ductal carcinoma NST is referred as mixed invasive MP carcinoma.

CLINICAL PRESENTATION

The median age at diagnosis ranged from 46 (2) to 62 (3) years. Rare cases of invasive MP

carcinoma have been described in male patients. Most tumors present as a palpable breast mass,

but occasional lesions are detected mammographically as a density or because of associated

calcifications. The median tumor size in few different series ranges from 1.5 cm to 3.9 cm.

Tumors with more extensive MP component tend to be larger.


Invasive MP carcinoma consists of small clusters of neoplastic epithelial cells with serrated outer

border and suspended in tight clear spaces. The clusters have no fibrovascular cores and display

reverse polarity with the luminal aspect of the cell present on the outer surface of the cluster.

This growth pattern closely mimics lymphovascular invasion. Nuclear grade is usually

intermediate to high (4) and mitotic activity is easily detected. Pure invasive MP carcinoma is

12


E. Brogi and H.Y. Wen rare and constitutes less than 2% of all breast carcinomas. Invasive MP carcinomas are

significantly more likely to show lymphovascular invasion (68.1% vs 38.2%; p<0.0001) and

lymph node metastases with extracapsular extension (40.3% vs 28.9%; p=001) than control

tumors matched for age, size and stage (52.8% vs 37.5%; p=0.0387) (2).

IMMUNOHISTOCHEMISTRY

Most invasive MP carcinomas are positive for ER and PR. HER2 gene amplification was found

in 8.3% pure invasive MP tumors. Some invasive MP carcinomas could be HER2-gene

amplified even if they are HER2 (1+) by immunohistochemistry. For this reason, the 2013

ASCO/CAP guidelines (5) recommend that HER2 FISH testing be performed for invasive MP

carcinomas that have focal complete HER2 (1+) staining intensity. Forty-six percent of invasive

MP carcinomas in one study showed Ki67 staining in more than 30% of cells (6). No expression

of basal markers (EGFR, CK5/6 and CK14) and c-kit has been detected. EMA staining yields

continuous reactivity on the outer surface of the MP clusters (7, 8); MUC1 staining has similar

results. These findings support reversed cell polarity in the MP clusters.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of invasive MP carcinoma includes mucinous carcinoma of the breast

with areas of MP growth, as well extramammary carcinomas with MP pattern metastatic from

other primary sites, such as ovary (9), bladder, colon or lung. Serous ovarian carcinoma is

usually reactive for WT-1, while this marker is only rarely and focally positive in invasive MP

breast carcinoma. PAX8 is also negative in invasive MP carcinoma of the breast. CA125 stains

21% of invasive MP carcinomas (10), but is strongly and diffusely positive in over 90% of

serous papillary ovarian carcinomas.

TREATMENT AND PROGNOSIS

13


E. Brogi and H.Y. Wen Lymphovascular invasion is present in 50%-90% of invasive MP carcinomas, and 70-77% of

patients have axillary lymph node metastases at the time of diagnosis. Metastases to more than

three lymph nodes are common, as well as extranodal extension. Most studies report that breast

carcinomas with MP features tend to be more aggressive and carry a worse prognosis than non-

MP tumors. Small invasive MP carcinomas are currently treated with breast conserving surgery

and whole-breast irradiation; larger and multifocal tumors often require mastectomy. Some

patients with large tumors developed chest wall recurrence after a mean time of two years (11).

Yu et al. (2) compared the clinical F/U of 72 patients with invasive MP carcinomas and 144

patients matched for age, size, stage and treatment. Sixty-five percent of patients with MP

carcinoma had been treated by mastectomy; 35% had breast conserving surgery and whole-breast

irradiation. After a median F/U of 26 months a total of 21% of patients with invasive MP

carcinoma recurred, including 15.3% with local and/or regional recurrence, and 14% with distant

metastases. In this study the 5-years OS for patients with invasive MP carcinomas was 86.0%,

and the 5-years RFS was 68.2%. Loco-regional RFS was significantly lower in patients with MP

carcinomas than in patients with non-MP tumors.

REFERENCES

1. Corben AD, Brogi E. Chapter 29 - Invasive micropapillary carcinoma. In: Hoda SA, Brogi E, Koerner FC, Rosen PP, editors. Rosen's Breast Pathology 4th ed: Wolters Kluwer Lippincott Williams & Wilkins; 2014.

2. Yu JI, Choi DH, Park W, Huh SJ, Cho EY, Lim YH, et al. Differences in prognostic factors and patterns of failure between invasive micropapillary carcinoma and invasive ductal carcinoma of the breast: matched case-control study. Breast (Edinburgh, Scotland). 2010;19(3):231-7.

3. Siriaunkgul S, Tavassoli FA. Invasive micropapillary carcinoma of the breast. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 1993;6(6):660-2.

4. Guo X, Chen L, Lang R, Fan Y, Zhang X, Fu L. Invasive micropapillary carcinoma of the breast: association of pathologic features with lymph node metastasis. American journal of clinical pathology. 2006;126(5):740-6.

5. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: american society of clinical

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E. Brogi and H.Y. Wen oncology/college of american pathologists clinical practice guideline update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31(31):3997-4013.

6. Marchio C, Iravani M, Natrajan R, Lambros MB, Savage K, Tamber N, et al. Genomic and immunophenotypical characterization of pure micropapillary carcinomas of the breast. The Journal of pathology. 2008;215(4):398-410.

7. Pettinato G, Manivel CJ, Panico L, Sparano L, Petrella G. Invasive micropapillary carcinoma of the breast: clinicopathologic study of 62 cases of a poorly recognized variant with highly aggressive behavior. American journal of clinical pathology. 2004;121(6):857-66.

8. Luna-More S, Gonzalez B, Acedo C, Rodrigo I, Luna C. Invasive micropapillary carcinoma of the breast. A new special type of invasive mammary carcinoma. Pathology, research and practice. 1994;190(7):668-74.

9. DeLair DF, Corben AD, Catalano JP, Vallejo CE, Brogi E, Tan LK. Non-mammary metastases to the breast and axilla: a study of 85 cases. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2013;26(3):343-9.

10. Lee AH, Paish EC, Marchio C, Sapino A, Schmitt FC, Ellis IO, et al. The expression of Wilms' tumour-1 and Ca125 in invasive micropapillary carcinoma of the breast. Histopathology. 2007;51(6):824-8.

11. Middleton LP, Tressera F, Sobel ME, Bryant BR, Alburquerque A, Grases P, et al. Infiltrating micropapillary carcinoma of the breast. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 1999;12(5):499-504.

MUCINOUS CARCINOMA

This outline is extracted from chapter 18 - Mucinous carcinoma, 4th Edition of Rosen’s Breast

Pathology Textbook (1).

Pure mucinous carcinoma (MC) consists of clusters of carcinoma admixed with extracellular

mucin in at least 90% of the tumor mass. The term mixed mucinous carcinoma is used for tumors

in which the mucinous component represents between 50% and 90% of the lesion.

CLINICAL PRESENTATION

Pure MC constitute 1% to 2% of all breast carcinomas. In a SEER data based study (2) the

median age at diagnosis was 71 years and 66% of patients were 65 years or older. Most patients

with mucinous carcinoma are postmenopausal (3-5). MC is most frequent among Caucasian

women and can occur in men.

15


E. Brogi and H.Y. Wen The initial symptom of a pure MC is usually a soft breast mass or a non-palpable mammographic

abnormality. Tumors with abundant mucin production are mammographically and

sonographically lobulated or circumscribed, in contrast to most mixed mucinous carcinomas.

Mammographically detected calcifications occur in up to 40% of MC and/or in the associated

DCIS. On ultrasound, myxoid fibroadenoma, benign cystic lesions, high-grade matrix-producing

carcinoma and high-grade carcinoma with central acellular zone sometimes may resemble pure

mucinous carcinoma (6). In a large population based study (2), MC had a mean size 2.2 cm, with

83.2% of tumors measuring 3.0 cm or less. In another series (7), the average size of pure MC

with no lymph node metastases was 1.5 cm versus 2.6 cm for tumors with nodal involvement.


MC consists of carcinoma clusters admixed with abundant extracellular mucin. In a pure MC

more of 90% of the invasive component is admixed with stromal mucin. Carcinomas with less

than 90% mucinous component are referred as mixed mucinous. Multiple sections may be

required to detect carcinoma cells in an extremely hypocellular MC. The majority of pure

mucinous carcinomas are well or moderately differentiated. The presence of unusual

morphologic features, such as necrosis, high mitotic activity, high grade nuclear atypia, extensive

micropapillary morphology or goblet cells should be noted in the diagnosis. MC with these

morphologic features may have more aggressive clinical behavior.

Capella et al. (8) classified MC based on epithelial growth pattern and some associated features.

MC type A has abundant mucin and the epithelium is distributed in large trabeculae and ribbons.

MC Type B is more cellular and intracytoplasmic mucin is more common. Some MCs with type

AB morphology were also noted. Type B MCs often show neuroendocrine differentiation. The

morphologic distinction between type A and B MCs has no clinical significance. Ranade et al.

16


E. Brogi and H.Y. Wen (9) have reported that type A MCs may have more favorable characteristics than type B tumors,

but this finding needs confirmation in larger studies.

When assessing margin status of a MC it is important to look for transected protrusions that may

be obscured by cautery artifact or blend with fat. In a patient with known MC the presence of

mucin at ink is interpreted as tumor at margin, even if no tumor clusters are identified in the

transected mucin in deeper level sections, provided that artifactual displacement is excluded.

Micropapillary variant of pure mucinous carcinoma: A micropapillary (MP) variant of pure

MC has been described (9-11). The micropapillae are arranged in small tightly cohesive clusters

or have ring-like configuration. EMA decorates the outer surface of the micropapillae,

confirming reverse polarity of the epithelium, akin to invasive MP carcinoma. A MP component

was present in 20% to 66.6% of pure MC in three different series (9, 11, 12). Ranade et al. (9)

reported that pure MCs with MP component tended to occur in younger patients. In another

series (13), lymphovascular invasion was detected in 60% of MC with MP component, and 33%

had lymph node metastases. One of 13 patients with F/U developed a chest wall recurrence 9

months after mastectomy.

Signet ring variant of pure mucinous carcinoma: Carcinomas with abundant extracellular

mucin rarely also have signet ring cell morphology. Signet ring cells admixed with mucin are

commonly found in pure MC with neuroendocrine features (type B).

Mucinous carcinoma associated with solid and papillary carcinoma: MC may also arise from

solid and papillary carcinoma. It often has type B morphology and shows neuroendocrine

differentiation or neuroendocrine features. Genetic evidence supports a close relationship

between these two entities (14, 15).

DCIS and Mucinous Carcinoma

17


E. Brogi and H.Y. Wen DCIS associated with MC is usually cribriform, papillary, micropapillary, or solid. Abundant

mucin can be present in the lumen of DCIS. In one series (16) 70% of DCIS associated with MC

showed neovascularization of the intraluminal mucin. In the absence of overt invasion

neovascularization of the mucin present in the lumen of ducts with DCIS should not be

interpreted as evidence of tumor invasion.

STROMAL MUCIN AND THE ASSESSMENT OF STROMAL INVASION

A diagnostic problem arises in patients who have DCIS and extravasated mucin in the adjacent

stroma. Extravasation of mucin from DCIS may be secondary to a prior procedure, trauma,

handling of the tissue or it might occur spontaneously and does not necessarily always represent

evidence of MC. In these cases, deeper level sections should be obtained. The mucin associated

with stromal invasion usually shows a rounded to bulbous outline, neovascularization, and

admixed inflammatory cells and fibroblasts (so called “dirty mucin”).

Mucocele-like lesions: A mucocele-like lesion (MLL), first described by Rosen in 1986 (17),

consists of mucin-containing cysts that tend to rupture and discharge the mucin into the adjacent

stroma. MLLs are usually detected by mammography because of associated calcifications. The

term MLL is descriptive and should be further qualified indicating if epithelial atypia is present.

The epithelium lining the ducts is often attenuated or low cuboidal, but can show a spectrum of

changes ranging from columnar cells to ADH to DCIS (17-19). Verschuur-Maes and Van Diest

(20) described a mucinous variant of columnar cell lesions with acini variably dilated and filled

with mucin. Stromal mucin was detected in 18/20 (90%) of these 20 cases. No evidence of

carcinoma was found at surgical excision of 3/20 lesions (2 with ADH and one without atypia).

Mucocele-like lesions and CBX (see Table I): Benign and malignant mucinous lesions of the

breast can usually be reliably diagnosed by CBX, but distinguishing between pure and mixed

18


E. Brogi and H.Y. Wen mucinous carcinoma requires evaluation of the entire tumor. In some cases deeper level sections

are required to distinguish between a hypocellular MC and artifactual displacement of mucin into

the stroma. If stromal mucin devoid of cells is present in a surgical excision specimen, the entire

specimen (or at least some additional tissue) should be examined microscopically, and deeper

level sections of the areas with stromal mucin and/or ADH should be obtained.

Stromal mucin devoid of cells is a very rare finding in a CBX specimen, representing only 0.32%

of cases in a large retrospective series (21). The risk of upgrade to DCIS or invasive carcinoma

for a MLL with atypia at CBX is consistent with the upgrade rate of ADH diagnosed in a CBX,

whereas the excision of a MLL without atypia in a CBX can be safely spared provided that the

radiologic and pathologic findings are concordant (21-25). Excisional biopsy is recommended if

a MLL yields epithelial atypia at CBX and/or the radiologic and pathologic findings of the target

lesion are discordant (22-27).

DIFFERENTIAL DIAGNOSIS OF MAMMARY MUCINOUS LESIONS

Cystic hypersecretory lesions of the breast can resemble MLLs, but do not contain mucin. The

dense hypersecretory material often shows the characteristic “Venetian blinds” shattering effect.

Secretory carcinoma is a rare and distinct variant of breast carcinoma containing luminal and

sometimes intracellular secretion (28, 29), that is amphophilic or pale to eosinophilic, and often

bubbly in appearance. Other breast lesions to consider in the differential diagnosis of mucinous

carcinoma include myxoid fibroadenoma, myxoma and neurofibroma with prominent myxoid

change. Mucoid stroma can also be present in a phyllodes tumor, pleomorphic adenoma, adenoid

cystic carcinoma and metaplastic carcinoma. Metastatic mucinous carcinoma from an extra-

mammary site has been reported. Foreign material may also occasionally closely resemble

19


E. Brogi and H.Y. Wen extracellular mucin. In all these cases, in addition to evaluating the characteristics of the mucin,

it is very important to obtain an accurate clinical history.

IMMUNOREACTIVITY OF MUCINOUS CARCINOMA

Most MC are positive for ER and PR, and negative for HER2. AR is positive in 80% of pure MC

(30). Less than 5-10% of MC (9) overexpress HER2 and are likely to be more aggressive than

usual MC. In a study by Lacroix-Triki et al. (14) Ki67 was low (<10%) in 91.4% of cases.

Nuclear staining for WT1 is present in 65% mammary MC and 33% of mixed mucinous

carcinoma (14, 31).

GENETICS

Lacroix-Triki et al. (14) found that pure and mixed mucinous carcinomas of the breast have

genetic aberrations distinct from those of grade- and ER-matched invasive ductal carcinoma

NST. Gains of 1q and losses of 16q, commonly seen in invasive ductal carcinomas NST, are

uncommon in MC. Weigelt et al. (15) found that all mucinous and neuroendocrine carcinomas

cluster together and separately from invasive ductal carcinomas NST. In particular, type B MCs

and neuroendocrine carcinomas are closely associated.

TREATMENT AND PROGNOSIS

The relatively favorable prognosis of MC is supported by numerous studies (2, 7, 32-46). The

rate of lymph node metastases for small (<1 cm) MC was 2.9% in one series (47), with no lymph

node metastases for T1a MC and only 3.5% in T1b MC. Larger tumor size correlates

significantly with lymph node involvement (2, 7). Neoadjuvant chemotherapy is rarely used for

MC and yields only minimal, if any response (48). In a series of 61 patients treated by

lumpectomy (43), 90% received radiotherapy, 41% hormonal therapy and 13% chemotherapy.

20


E. Brogi and H.Y. Wen Local and loco-regional recurrence rates were both 5%, significantly lower than for invasive

ductal carcinoma NST. The DFS was 91.6% at 5 years and 75.3% at 10 years. The OS rate was

91.8% at 5 years and 74.5% at 10 years. In this study, the authors found no benefit of

chemotherapy in patients with mucinous carcinoma.

Prognostic factors that are relevant for most types of breast carcinoma are prognostic also for

pure MC (34, 35). Nodal status was the most significant prognostic factor by multivariate

analysis in one study (2). Other significant features include patient age, tumor size, PR status,

and nuclear grade. Late systemic recurrences have been described after mastectomy in patients

with mucinous carcinoma (32, 37, 38, 49-51). Some of the longest intervals to recurrence have

been 25 (52) and 30 years (53). Late recurrence (54, 55) or late death due to disease (34) does

not seem to occur in women with small, pure MC.

Cystic Papillary Mucinous Carcinoma (Mucinous Cystadenocarcinoma) (CP-MAC)

CP-MAC is a unique and extremely rare form of primary mucin-producing carcinoma of the

breast. It consists of multiple cysts filled by mucin and lined by micropapillary, papillary, and

cribriform carcinoma. The nuclei of the neoplastic mucinous epithelium usually show low grade

atypia; areas with higher nuclear atypia are associated with intracytoplasmic mucin depletion

(56-64). All reported cases have occurred in women (age range 41 to 96 years). Lack of

myoepithelial lining around the mucin filled cysts of CP-MAC supports an invasive process.

Rarely, areas of invasive ductal carcinoma NOS (58, 60) or foci of sarcomatoid metaplasia (56)

have been observed admixed with these tumors, but the usual morphology of pure MC has not

been identified. Focal DCIS is often present. CP-MAC is typically ER and PR negative (56-60,

21


E. Brogi and H.Y. Wen 62, 63, 65, 66). HER2 is also negative, except for one reported case (63). CP-MAC is also

negative for neuroendocrine markers, CDX2, CK20, PAX8, WT1 and TTF1.

CP-MAC appears to have a relatively good prognosis, and only few patients presented lymph

node metastases (56, 57, 66), that were morphologically similar to the primary tumor. Focal

squamoid differentiation was reported in one case (57). The differential diagnosis of CP-MAC,

an ER-negative and PR-negative mucinous carcinoma (56-60, 62, 63, 65, 66), includes

metastasis from an extramammary mucinous carcinoma, such as from ovary, pancreatobiliary or

GI tract.

22


E. Brogi and H.Y. Wen

Table 1

Findings at surgical excision of rad-path concordant lesions yielding stromal

mucin and with or without epithelial atypia at core needle biopsy

Study

Total

CBX

with

EXC

CBX without atypia CBX with atypia

Carcinoma

at EXC/

total CBX

Total

patients

with

carcinoma

or ADH

cases

ADH at

EXC/

cases

(%)

Carcinoma

at EXC/

cases (%)

cases

Carcinoma

at EXC/

cases (%)

Renshaw

2002 (21) 8 3

1/3

(33%) 0/3 5 0/5 0/8

6/8

(75%)

Wang

2007 (22) 11 7 0/7 0/7 4 0/4 0/11

4/11

(36%)

Begum

2009 (23) 23 10 0/10

1*/10

(*10%) 13

1/13

(7.6%)

2/23

(8.6%)

2*/23

(8.6%)

Sutton

2012 (24) 38 22

not

specified 0/22 16

5/16

(31%)

5/38

(13%)

5/38

(13%)

Edelweiss

2013 (25) 28 10

4/10

(40%) 0/10 18

4/18

(22%)

4/28

(14%)

8/28

(28%)

TOTAL 108 52 5/30

(17%)

1*/52

(2%) 63

10/56

(18%)

11/108

(10%)

25/108

(23%)

a= one case with discordant radiologic-pathologic findings

CBX= Core biopsy; EXC= surgical excision; ADH= atypical ductal ductal hyperplasia

23


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