Genotype-Phenotype

Correlations in Breast
Cancer
Jonathan D. Marotti, MDa,b, Stuart J. Schnitt, MDc,*

KEYWORDS
 Genotype-phenotype  Breast cancer  Molecular  IDH2

Key points
 Of the many breast cancer histologic subtypes recognized by WHO, only a few harbor known recur-
rent genetic alterations associated with a specific morphology.
 Secretory carcinoma, adenoid cystic carcinoma, invasive lobular carcinoma, and the recently defined
solid papillary carcinoma with reverse polarity have unique morphologic features and exhibit charac-
teristic recurrent genetic abnormalities.
 Identifying the genetic underpinnings of breast cancer subytpes permits more accurate diagnosis and
may provide new therapeutic targets.

ABSTRACT OVERVIEW

O
nly a few breast cancer histologic subtypes Genotype-phenotype correlation (ie, a recurrent
harbor distinct genetic alterations that are genetic abnormality associated with a specific
associated with a specific morphology (ge- morphology) is relatively common in some tumor
notype-phenotype correlation). Secretory carci- types. For example, nearly half of the diagnostic
nomas and adenoid cystic carcinomas are each entities described in the most recent edition of
characterized by recurrent translocations, and the WHO Classification of Tumors of Soft Tissue
invasive lobular carcinomas frequently have and Bone are associated with recurrent cytoge-
CDH1 mutations. Solid papillary carcinoma with netic and/or molecular alterations.1,2 Many he-
reverse polarity is a rare breast cancer subtype matopoietic and lymphoid neoplasms also have
with a distinctive morphology and recently identi- genetic abnormalities associated with a specific
fied IDH2 mutations. We review the clinical and morphology, such as the PML-RARA fusion
pathologic features and underlying genetic alter- gene defining acute promyelocytic leukemia.3
ations of those breast cancer subtypes with estab- In contrast, of the 21 breast cancer histologic
lished genotype-phenotype correlations and subtypes defined by the World Health Organiza-
discuss the phenotypes associated with germline tion (WHO),4 few are known to harbor distinct
mutations in genes associated with hereditary recurrent genetic alterations. Secretory carci-
breast cancer. nomas and adenoid cystic carcinomas (ACCs)
are characterized by recurrent ETV6-NTRK3 and

The authors have no financial disclosures.

surgpath.theclinics.com

a
Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, One Medical Cen-
ter Drive, Lebanon, NH 03756, USA; b Department of Pathology and Laboratory Medicine, Geisel School of
Medicine at Dartmouth, One Rope Ferry Road, Hanover, NH 03755-1404, USA; c Department of Pathology,
Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, 75 Francis Street, Bos-
ton, MA 02115, USA
* Corresponding author.
E-mail address: sschnitt@bwh.harvard.edu

Surgical Pathology - (2017) -–-

https://doi.org/10.1016/j.path.2017.09.008
1875-9181/17/Ó 2017 Elsevier Inc. All rights reserved.
2 Marotti & Schnitt

MYB-NFIB fusion genes, respectively,5,6 and inva- proportion of younger women are diagnosed with
sive lobular carcinomas commonly have somatic secretory carcinoma.14 Cases of secretory carci-
CDH1 mutations.7 Recently, a rare breast cancer noma arising in men also have been reported.15,16
subtype, solid papillary carcinoma with reverse The architecture of secretory carcinoma is typi-
polarity (SPCRP), was more fully defined.8 These cally microcystic (honeycomb), solid, or tubular,
tumors display a unique morphology and are asso- with many tumors containing a mixture of all 3 pat-
ciated with a high frequency of IDH2 R172 hotspot terns. Some tumors display a peripheral papillary
mutations.8 Finally, breast cancers associated architecture, and central sclerosis is often
with germline mutations in some breast cancer observed. The edges of the cancer are often well-
susceptibility genes, particularly BRCA1, have a circumscribed with pushing borders, but more infil-
characteristic constellation of histologic findings trative areas may be seen. The tumor cells are
in many cases.9,10 polygonal with granular to foamy amphophilic cyto-
Here we provide an updated review of those plasm, small bland nuclei, and few mitoses (Fig. 1).
breast cancer subtypes with established genotype- The histologic hallmark of secretory carcinoma is
phenotype correlations. Special emphasis is placed the presence of intracellular and extracellular
on the newly described molecular features of eosinophilic secretions that are periodic acid-
SPCRP. We also discuss the phenotypes associated Schiff (PAS)-positive and diastase-resistant.
with germline mutations in genes associated with he- Secretory carcinoma typically lacks estrogen re-
reditary breast cancer. ceptor (ER) and progesterone receptor (PR) expres-
sion, and is negative for human epidermal growth
factor 2 (HER2) overexpression and amplification
SECRETORY CARCINOMA
and is thus a “triple-negative” breast cancer. Jacob
Secretory carcinoma is an exceptionally rare spe- and colleagues14 suggested that contrary to prior
cial subtype that represents fewer than 0.02% of reports, up to 64% of secretory carcinomas may
all breast cancers.4 It was first described by be positive for ER. However, major limitations of
McDivitt and Stewart11 in 1966 as a distinct tumor this study include the lack of both central histologic
occurring in children and, therefore, was originally review and molecular status to confirm the diag-
named “juvenile carcinoma.” After this initial case nosis of secretory carcinoma. Furthermore, most
series, multiple reports of the tumor occurring in ER-positive secretory carcinomas are reported to
adults were described, prompting a change in ter- display only focal, weak ER immunoreactivity.
minology to secretory carcinoma.12 Recent ana- Based on variable immunoreactivity with the basal
lyses from larger population-based databases cytokeratins (CK) 5/6 and/or CK14, as well as
including the National Cancer Data Base and the CD117 and epidermal growth factor receptor
National Cancer Institute’s Survival, Epidemiology, (EGFR), secretory carcinoma can be considered a
and End Results program have shown that secre- basal-like carcinoma.17 S100 protein and a-lactal-
tory carcinoma largely affects older patients with a bumin are consistently positive, although the latter
median age of approximately 53 to 54 years13,14; stain is not used in current clinical practice. The tu-
however, when compared with invasive ductal mor cells also show expression of mammaglobin,
carcinoma of no special type (IDC), a greater GATA3, and STAT5a, and are usually negative for

Fig. 1. Secretory carcinoma. (A) This tumor is composed of cribriform islands of cells with numerous glandular spaces
containing eosinophilic secretions. (B) At higher power, the tumor cells have foamy cytoplasm and relatively uni-
form nuclei with variably prominent nucleoli.
 Genotype-Phenotype Correlation 3

gross cystic disease fluid protein (GCDFP) and

monoclonal carcinoembryonic antigen.
The differential diagnosis of secretory carcinoma
includes several other rare special types of breast
cancer, such as lipid-rich carcinoma, glycogen-
rich carcinoma, and acinic cell carcinoma, as well
as the more common IDC and invasive lobular carci-
noma (ILC). Whereas secretory carcinomas contain
PAS-positive, diastase-resistant secretions, lipid-
rich carcinomas demonstrate oil red O-positive
cytoplasmic vacuoles and glycogen-rich clear cell
carcinomas have PAS-positive, diastase-sensitive
secretions. In a small series of breast cancers initially
classified as secretory carcinoma, 3 of the 19 cases
were determined to be acinic cell carcinoma on re-
view.18 These 2 tumor types share morphologic
and immunohistochemical staining patterns, yet
Fig. 2. Dual-color break-apart FISH probes for ETV6 in
acinic cell carcinoma has yet to be confirmed in a secretory carcinoma. There is 1 pair of adjacent green
either young (prepubertal) or male patients and and red signals at the bottom of the nucleus represent-
they do not harbor the characteristic translocation ing the non-rearranged locus at chromosome 12 and 1
of secretory carcinoma discussed below.19 Like- pair of separated green and red signals in the center of
wise, ILCs, which may contain prominent intracyto- the nucleus representing the translocation (arrows).
plasmic mucin, and IDCs, which may have focal
secretory histologic features, also consistently lack
the specific translocation. Last, several benign en- In 2010, Skálová and colleagues22 described a
tities, such as lactational change, collagenous salivary gland tumor with morphology similar to
spherulosis, cystic hypersecretory change and secretory carcinoma of the breast and that also
cystic hypersecretory hyperplasia, as well as cystic contained the t(12;15) translocation. Initially
hypersecretory ductal carcinoma in situ (DCIS), referred to as mammary analogue secretory carci-
may also resemble secretory carcinoma. In all in- noma, this salivary gland tumor is regarded as a
stances, an appropriate panel of myoepithelial cell low-grade malignancy with overall favorable prog-
immunostains will confirm the presence of a myoe- nosis compared with other salivary gland carci-
pithelial cell layer surrounding the glands of these le- nomas, but with occasional reported cases
sions, although rare cases of cystic hypersecretory demonstrating a more aggressive course.23 Rare
DCIS have been reported to lack a surrounding cases in the salivary gland have also been shown
myoepithelial cell layer.20 to harbor ETV6 fusions with non-NTRK3 genes
Secretory carcinomas are characterized by a (eg, ETV6-X fusion)24,25; such fusions have yet to
recurrent translocation, t(12;15) (p13;q25). This be fully evaluated in secretory carcinoma of the
translocation, which results in a fusion of the ETS breast. The salivary gland tumor is not as rare as
variant gene 6 (ETV6) and the neurotrophic tyrosine initially perceived, and recent updates to the
kinase receptor 3 gene (NTRK3), was first demon- WHO classification of salivary gland tumors
strated in secretory carcinoma by Tognon and col- recommend using the term, “secretory carci-
leagues5 in 2002. The ETV6 gene on chromosome noma” to standardize nomenclature across organ
12 encodes an E26 transformation-specific tran- sites.23,26
scription factor and the NTRK3 gene on chromo- Secretory carcinoma of the breast is usually
some 15 encodes a membrane receptor tyrosine associated with a better prognosis than IDC13,14;
kinase. The resulting ETV6-NTRK3 fusion product only rare cases with distant metastases have
is a chimeric tyrosine kinase that has the ability to been reported.15 Treatment for secretory carci-
transform ductal epithelial cells via the Ras-MAP noma includes at least a wide excision with nega-
kinase and phosphatidyl inositol-3-kinase-Akt tive margins. Lymph node sampling is usually
(PI3K-Akt) pathways.21 The t(12;15) translocation recommended, but the benefit of adjuvant radiation
was first identified in the pediatric mesenchymal therapy and chemotherapy is uncertain given the
tumors, congenital fibrosarcoma and congenital limited number of reported cases.19 The relatively
cellular mesoblastic nephroma. ETV6 dual-color indolent clinical course of secretory carcinoma
break-apart fluorescence in situ hybridization despite its triple-negative, basal-like phenotype
(FISH) probes are now commercially available for highlights the heterogeneity of triple-negative
detection of ETV6 alterations (Fig. 2). breast cancer and provides support for the view
4 Marotti & Schnitt

that there are low-grade, triple-negative neo- arranged in tubular, cribriform, or trabecular pat-
plasms. Secretory carcinomas lack the complex terns. A solid variant with predominantly basaloid
genomic alterations seen in conventional triple- morphology can occasionally be seen (Fig. 3).
negative breast cancers and in particular do not The utility of grading ACC of the breast using
contain TP53 mutations.27,28 The ETV6-NTRK3 criteria accepted for salivary gland ACC remains
translocation of secretory carcinoma may serve unclear.4 Although one group was able to identify
as a potential therapeutic target for those cases prognostic differences between grades,31 other
that are more aggressive. For example, entrectinib studies were not able to confirm these results.32,33
(RXDX-101) and larotrectinib (LOXO-101), agents The lesional cells of ACC form 2 types of spaces:
that selectively inhibit tyrosine receptor kinases true glandular lumina and pseudolumina. True
encoded by the NTRK genes, are currently under glandular lumina are surrounded by luminal epithe-
clinical investigation.29,30 lial cells with variably abundant eosinophilic cyto-
plasm and often contain PAS-positive mucin.
ADENOID CYSTIC CARCINOMA These glandular lumina can be difficult to discern,
especially in solid ACC with basaloid features.
ACC of the breast is also a rare type, accounting In contrast, pseudolumina are surrounded by
for fewer than 0.1% of breast cancers.4 Although myoepithelial cells, are usually larger than true
morphologically similar to ACCs that arise in other glandular lumina, and typically contain dense,
sites, most commonly salivary glands, lung, and eosinophilic basement membrane material or a
skin, and that tend to have an aggressive clinical myxoid stromal substance.
course, ACC of the breast is generally considered ACC of the breast, like secretory carcinoma, is usu-
a carcinoma of low malignant potential. ACC is ally a triple-negative breast cancer lacking ER, PR,
composed of a proliferation of both epithelial and HER2 overexpression/amplification. However,
and myoepithelial/basaloid cells, most often in a series of 28 ACC cases, 46% of tumors (without

Fig. 3. Adenoid cystic carcinoma (ACC). Typical cribriform pattern adenoid cystic carcinoma at medium (A) and high (B)
power. (C, D) Solid ACC with basaloid features. Low-power view (C) shows irregular nests of basaloid tumor cells. At high
power (D), foci of eosinophilic, basement membrane material are present in association with the basaloid cells.
 Genotype-Phenotype Correlation 5

molecular testing) were reported to be ER-positive.34 evaluation of both components has demonstrated
The dual cell population of ACC can best be high- the presence of the MYB-NFIB fusion gene in each;
lighted by using CK7, p63, and CD117 (c-kit) immu- progression likely occurs through clonal selection
nostains. The luminal epithelial cells are most often and/or development of additional genetic alter-
CK7 and CD117 positive and p63 negative, whereas ations.38 Alternative fusions have been recently iden-
the myoepithelial cells express p63, but lack CK7 and tified in salivary gland ACC including MYBL1 to NFIB
CD117 expression. This distinctive staining pattern and MYBL1 to RAD51B.39,40 The MYBL1 gene,
permits differentiation from most other malignant located on chromosome 8q, encodes the A-MYB
cribriform lesions, particularly invasive cribriform car- protein. This protein is closely related to c-MYB, as
cinoma and cribriform pattern DCIS, in which the they both bind and activate similar reporter genes,
neoplastic cells are typically all CK7-positive and but appear to regulate different gene targets in human
lack staining for CD117 and p63. It should be noted, cells.39 The role of MYBL1 and A-MYB in breast ACC
however, that in some cases, the neoplastic cells of has yet to be determined.
ACC do not display the expected patterns of reac- Evaluation of MYB overexpression using
tivity. We have seen cases in which both luminal immunohistochemistry (IHC) or detection of the
epithelial cells and cells resembling myoepithelial/ MYB-NFIB translocation by FISH can assist in
basaloid cells express CK7 and CD117, and cases diagnosing ACC in cases with histologic uncer-
in which the myoepithelial/basaloid cells show little tainty (Fig. 4). Dual break-apart FISH probes are
or no staining for p63. Further, we have also observed commonly used to identify MYB rearrangements,
staining for basal cytokeratins such as CK5/6 in both and current next-generation sequencing platforms
luminal epithelial cells and myoepithelial/basaloid can also detect MYB fusions. Poling and col-
cells. Collagenous spherulosis, a benign myoepithe- leagues41 recently suggested that IHC is more sen-
lial cell proliferation, can mimic ACC with a nearly sitive and specific than FISH for the diagnosis of
identical low-power “sievelike” pattern. Rabban and breast ACC. They reported that MYB IHC showed
colleagues35 proposed using an expanded immuno- diffuse and strong nuclear immunoreactivity of pri-
histochemical panel to distinguish between these 2 marily the myoepithelial cells in 100% of breast
lesions. They demonstrated that whereas the luminal ACC (11/11) compared with detection of MYB rear-
epithelial cells of ACC were consistently positive for rangement in 8 (89%) of 9 evaluable cases.41 Only
CD117, the lesional cells of collagenous spherulosis weak and focal MYB staining was seen in mimics
were negative for CD117. Furthermore, due to p63 of ACC including basal-like triple-negative breast
positivity in both ACC and collagenous spherulosis, cancer, microglandular adenosis, and collagenous
they suggested also performing calponin and smooth spherulosis.41 In a series of solid ACCs with basa-
muscle myosin heavy chain, as these makers were loid features, a variant of ACC with a potentially
found to be uniformly positive in collagenous spheru- more aggressive clinical course, fewer tumors
losis, but negative in ACC.35
After secretory carcinoma, ACC was the second
special-type breast cancer found to harbor a unique
genetic translocation. Persson and colleagues6 first
reported the presence of a t(6;9) (q22–23;p23–24)
translocation in head and neck ACC and breast
ACC, resulting in a MYB-NFIB fusion gene. This
fusion gene has since been reported to occur in
23% to 100% of breast ACCs,36 and in most cases,
results in overexpression of c-MYB at the mRNA
and protein levels. The c-MYB protein is a transcrip-
tion factor that regulates progenitor cells and is
involved in breast cancer development.37 Molecular
analyses have shown that in addition to this charac-
teristic translocation, ACCs of the breast also have
a higher frequency of mutations of genes involved in
chromatin remodeling, cellular adhesion and cell
signaling pathways, including BRAF, FBXW7,
FGFR2, and MTOR.36 Notably, ACCs appear to
lack the TP53 and PIK3CA mutations that are often
present in the more common triple-negative ductal Fig. 4. MYB immunostain in adenoid cystic carcinoma
carcinomas.36 Occasionally, ACC may progress to showing strong nuclear staining of many of the tumor
high-grade triple-negative ductal cancers, and cells.
6 Marotti & Schnitt

were found to contain the MYB-NFIB fusion gene INVASIVE LOBULAR CARCINOMA
(2/16, 12%).42 Two patients with the solid ACC
variant had axillary lymph node metastases, 1 pa- ILC is the second most common histologic type of
tient developed distant metastasis, and 1 patient breast cancer, accounting for 5% to 15% of inva-
had a local recurrence.42 sive breast cancers.4 The histologic features of ILC
ACC of the breast has a very favorable outcome are well known to pathologists. These tumors are
with 5-year and 10-year survival rates of greater composed of relatively small, dyshesive epithelial
than 95% and 90%, respectively.4,43 The cells, some with intracytoplasmic lumens, infil-
additional benefit of lymph node sampling, trating the stroma in a single-file pattern with min-
chemotherapy, and radiation for the treatment of imal stromal reaction (Fig. 5). Several variants of
early-stage, “low-grade” ACC of the breast re- ILC have been described, including solid, alveolar,
mains questionable.44 Standard targeted therapy histiocytoid, and pleomorphic types. Most ILCs
for ACC currently does not exist; however, trials are of low to intermediate histologic grade, ex-
investigating downstream effectors of MYB, such as press ER and PR, and are negative for HER2 over-
vascular endothelial growth factor A (VEGFA) and expression or amplification. A few unusual entities
fibroblast growth factor 2 (FGF2) are underway.30 may mimic ILC, such as metastatic signet ring cell
Despite overexpression of CD117 (c-kit) in ACC, carcinoma, sclerosing epithelioid fibrosarcoma,
it is now clear that ACCs lack c-KIT mutations36,45 myeloid sarcoma, and plasma cell dyscrasias;
and therefore, targeting c-kit with imatinib appears the differentiation between these lesions has
to be largely ineffective.45 been discussed elsewhere.46

Fig. 5. Invasive lobular carcinoma (ILC). (A) High-power view of a classic ILC showing tumor cells with small, uniform
nuclei infiltrating fibroadipose tissue as single cells and linear strands, and with no desmoplastic stromal reaction.
(B) In this pleomorphic variant of ILC, the nuclei show more variation in size and shape than in classical ILC shown
in Fig. 5A. (C) Solid variant of ILC with striking cellular dyshesion. (D) E-cadherin immunostain of a classic ILC demon-
strates lack of membrane staining of the tumor cells. In contrast, normal ductal epithelium in the upper right part
of the field shows strong membrane staining for E-cadherin.
 Genotype-Phenotype Correlation 7

The molecular hallmark of all forms of lobular and germline CDH1 mutations have been identified
neoplasia (including ILC, lobular carcinoma in in families with increased incidence of ILC, but
situ, and atypical lobular hyperplasia), and which without evidence of diffuse gastric cancer.53
largely accounts for its dyshesive phenotype, is Recent clinical guidelines suggest considering
decreased or absent expression of E-cadherin CDH1 testing in patients with bilateral or familial
on the cell membranes47,48 (see Fig. 5). Loss of lobular breast cancer before the age of 50, and
E-cadherin expression has been observed in recommend annual breast cancer surveillance us-
approximately 90% of ILCs,48 and IHC evaluation ing MRI beginning at age 30 for those patients with
of E-cadherin can be used to distinguish ductal confirmed pathogenic CDH1 mutations.54
from lobular neoplasms, albeit with some ca-
veats.49 E-cadherin, encoded by the CDH1 gene, SOLID PAPILLARY CARCINOMA WITH
is a cell-cell adhesion glycoprotein and a key REVERSE POLARITY
component of the cadherin-catenin complex pre-
sent at the junction between adjacent epithelial SPCRP is the recently proposed name for a
cells.50 In addition to its role in cell-cell adhesion, distinctive histologic type of breast cancer not
E-cadherin also has important signaling activity recognized in the most recent WHO classification
via regulation of p120 catenin and b-catenin; of tumors of the breast.8 Due to cytomorphologic
sequestration of these proteins by E-cadherin re- overlap with papillary thyroid carcinoma, including
sults in decreased transcriptional activity.50 There- the variable presence of nuclear grooves and intra-
fore, loss of E-cadherin (a tumor suppressor) nuclear cytoplasmic inclusions, these tumors were
assists tumor proliferation and contributes to initially described as “breast tumor resembling the
increased invasiveness and development of tall cell variant of papillary thyroid carcinoma” and,
metastases. more recently, as “solid papillary carcinoma
The most comprehensive molecular analysis of resembling the tall cell variant of papillary thyroid
ILC to date confirmed a high percentage of carcinoma.”55–57
E-cadherin alterations.7 Nearly all of the ILCs SPCRP are seen primarily in older women.
analyzed (95%) had E-cadherin loss, either at Among the cases reported to date, the median
the DNA, mRNA, or protein level.7 Most CDH1 age was 64 years (range: 45–85 years); 61% of pa-
mutations were truncating mutations and they tients were older than 60.56,57 These tumors also
almost always occurred in combination with tend to be small, with a median reported tumor
chromosome 16q loss, which is the location of size of 1.5 cm (range: 0.6–5.0 cm); 64% of tumors
the CDH1 gene.7 Mutations in PTEN, TBX3, and were smaller than 2 cm.56,57
FOXA1 were enriched in ILCs as well, and when These tumors are characterized by solid,
compared with other breast cancer subtypes, circumscribed nodules of columnar epithelial
ILC also had the highest level of Akt phosphory- cells, often with a rounded contour but occasion-
lation.7 This latter finding, likely due to associated ally exhibiting a geographic, jigsawlike growth
PTEN loss, reinforces the possibility of targeting pattern. The nodules are distributed haphazardly
the PI3K/Akt pathway as a viable therapeutic throughout the breast stroma and extend around
approach in ILC. and between normal ductal lobular structures.
The prognosis of patients with ILC, as compared The stroma is typically composed of dense fibrous
with IDC, remains controversial.4 ILCs are more connective tissue without desmoplasia; some
likely to be of larger size, more advanced stage, nodules extend into adipose tissue without an
and have a higher frequency of lymph node involve- associated stromal reaction. Many nodules con-
ment.4 Furthermore, the metastatic pattern of ILC tained fibrovascular cores, some of which contain
is substantially different from that of IDC. In partic- foamy histiocytes. The columnar epithelium is
ular, ILC has a greater propensity for metastasizing often present as a double-layer. Taken together,
to the gastrointestinal tract, gynecologic organs, these features result in a solid papillary appear-
meninges, and peritoneal surfaces than IDC.4 ance. In occasional cases, nodules with true pap-
Germline mutations in the CDH1 gene were first illations can be seen. The cells in many nodules
described nearly 20 years ago in families with a appear back-to-back and, in particular, the nuclei
propensity for developing diffuse gastric cancer,51 are often present at the apical rather than basal
an epithelial malignancy demonstrating consider- pole of the cells, creating the impression of reverse
able cytomorphologic overlap with ILC. CDH1 mu- polarity. These tumor nodules invariably lack a sur-
tations have since been shown to be the genetic rounding myoepithelial cell layer supporting the
cause of hereditary diffuse gastric cancer (HDGC) invasive nature of these lesions8 (Fig. 6).
in up to 40% of cases.52 Not surprisingly, ILC is The cells comprising SPCRP show strong
relatively more common in families with HDGC, cytoplasmic expression of low molecular weight
8 Marotti & Schnitt

Fig. 6. Solid papillary carcinoma with reverse polarity (SPCRP). (A) Low-power view showing circumscribed tumor cell
nests distributed haphazardly through the breast stroma. A few normal ducts are present in-between the tumor cell
nests. (B) Medium-power view demonstrates that some of the nests have central fibrovascular cores, some with foamy
histiocytes. The nuclei of many of the tumor cells are at the apical rather than the basal pole of the cells. (C) High-
power view better demonstrates the apparent reversal of cell polarity with nuclei at the apical pole of the cells.
(D) Smooth muscle myosin heavy chain immunostain demonstrates absence of myoepithelial cells around the tumor
cell nests (myoepithelial cells are present around the normal duct in the lower part of the field). (E) ER immunostain
showing absence of staining in the tumor cells (epithelial cells of the normal duct at the top of the field show ER stain-
ing and serve as an internal positive control). The tumor cells show strong cytoplasmic staining for both luminal ker-
atins as shown in a CK7 immunostain (F) and basal cytokeratins as shown in a CK5/6 immunostain (G).

cytokeratins (as demonstrated on CK7 immunos- highlights the apical membranes of columnar epithe-
tains), but also strongly express high-molecular lial cells, was identified at the end of the tumor cell
weight/basal cytokeratins CK5/6 and CK34bE12. closest to the nucleus, further implying that the
GCDFP-15 and mammaglobin expression are seen nuclei were in an abnormal location (ie, apical rather
in slightly more than half of the cases, supporting than basal).8
the breast origin of the tumors, whereas thyroglob- Given some histologic similarity of SPCRP to
ulin and TTF-1 are consistently negative. In one papillary thyroid carcinoma, metastatic papillary thy-
recent study, the tumor cells were entirely ER- roid carcinoma to the breast is often considered in
negative in 62% of cases; ER expression was seen the differential diagnosis, but can usually be
in 1% to 10% of cells in the remaining tumors.8 PR excluded after thorough clinical and radiologic corre-
expression was seen in 15% of cases, and all cases lation, as well as consistently negative immunoreac-
studied were negative for HER2 protein overexpres- tivity in SPCRP for the thyroid markers TTF-1 and
sion. Androgen receptor (AR) was focally positive in thyroglobulin. SPCRP must also be differentiated
only 1 case. In 2 cases studied, the Ki67 proliferation from other primary papillary lesions of the breast,
rate was low (<5%). E-cadherin staining revealed particularly conventional forms of solid papillary car-
strong lateral membrane expression with absent api- cinoma. Whereas the usual type of solid papillary
cal or basal expression, suggesting that the epithe- carcinoma is strongly positive for ER and negative
lium is polarized. Mucin 1 (MUC1) staining, which for CK5 or CK5/6, the tumor cells of SPCRP are
 Genotype-Phenotype Correlation 9

usually negative or weakly positive for ER and posi- multiple molecular (intrinsic) subtypes of breast
tive for CK5/6. It should also be noted that the cancer.63,64 The most common molecular sub-
reverse nuclear polarity of SPCRP is different from types (luminal A, luminal B, HER2-enriched,
the “inside-out” pattern of invasive micropapillary basal-like) have been studied extensively.
carcinoma first described by Peterse in 1993.58 Although these subtypes differ with regard to
The tumor cell clusters of invasive micropapillary their patterns of gene expression, clinical course
carcinoma lack fibrovascular cores, and although and response to various forms of systemic ther-
cell orientation is inverted, the nuclei remain in the apy, phenotypic correlations are problematic
basal pole. This “inside-out” orientation is best high- because most of the breast cancers in each of
lighted by epithelial membrane antigen or MUC1 these subtypes are IDCs of no special type.
IHC; strong immunoreactivity for each is seen along Although molecular subtype is sometimes
the outer edges of the tumor cell clusters.59,60 inferred by using ER, PR, and HER2 status, often
To identify potential molecular alterations respon- in combination with histologic grade, these fea-
sible for the distinctive morphology of SPCRPs, tures alone are insufficient to reliably predict
Chiang and colleagues8 performed whole-exome, the underlying molecular subtype in an individual
targeted, and Sanger sequencing on a series of 13 case.65 However, basal-like cancers demon-
previously unreported cases. Interestingly, most strate a fairly high degree of correlation between
(77%) of the SPRCPs were found to contain muta- histologic features and molecular subtype. Tu-
tions at R172H of the isocitrate dehydrogenase mors that are basal-like by transcriptional
(NADP1), mitochondrial (IDH2) gene. Eight of these profiling are most often characterized histologi-
tumors also harbored PI3K pathway mutations. cally by solid sheets of tumor cells with high-
One tumor with wild-type IDH2 contained a TET2 grade nuclei and numerous mitoses, pushing
Q548-truncating mutation, coupled with a PI3KCA borders, a prominent lymphocytic infiltrate, and
hotspot mutation. Bhargava and colleagues56 sub- central zones of necrosis or fibrosis.66 They
sequently reported IDH2 and ATM mutations in 2 commonly demonstrate EGFR overexpression
of 3 additional cases, and a PIK3CA mutation in 1 or amplification and express the basal cytokera-
of their 3 cases. This is the first histologic type of tins CK 5/6 and/or 14. These tumors are most
breast cancer associated with IDH mutations, which often negative for ER and PR expression and
are more commonly found in glioma, acute myeloid lack HER2 overexpression and gene amplifica-
leukemia, chondrosarcoma, and cholangiocarci- tion (“triple-negative”). However, it should be
noma.61 The concurrent functional studies per- noted that not all tumors that are basal-like by
formed by Chiang and colleagues8 demonstrated gene expression analysis are triple-negative,
that the IDH2 and PI3KCA mutations are likely and not all tumors that are clinically triple-
drivers of tumor development and contribute to the negative are basal-like at the transcriptome
unique phenotype of SPCRP. Specifically, by using level.65
a 3-dimensional model system, they demonstrated Most tumors arising in patients with germline
that expression of IDH2R172S in a breast cancer cell BRCA1 mutations display basal-like histologic fea-
line resulted in an increased number of cells display- tures, and sporadic basal-like breast cancers
ing reversed nuclear polarity.8 often have a dysfunctional BRCA pathway.9,67
Review of the available cases with limited follow- The BRCA1 gene, located on chromosome 17q,
up suggests a generally favorable prognosis of is involved in multiple cellular processes, including
SPCRP with only a few cases containing regional DNA repair, X chromosome inactivation, transcrip-
nodal involvement or distant metastases.8,56,57 As tional regulation, and ER signaling. Conditional
with the previously discussed rare special types of mouse models with inactivated Brca1 and Trp53
breast cancer, negative surgical margins should be genes, a genotype frequently present in human
sought; however, the need for lymph node sampling, basal-like cancers, consistently develop tumors
radiation, and/or systemic therapy remains un- with histologic and IHC features similar to human
known. The IDH2 mutation may provide an opportu- basal-like tumors.68 It should be emphasized that
nity for targeted therapy in more aggressive cases. most basal-like breast cancers are not associated
Phase I trials evaluating IDH inhibitors in glioma with germline BRCA mutations, and these spo-
and acute myeloid leukemia are ongoing.62 radic tumors are essentially identical in appear-
ance to their hereditary counterparts.9 Therefore,
PHENOTYPIC CORRELATES OF MOLECULAR our ability as pathologists to accurately predict
SUBTYPES AND HEREDITARY BREAST CANCERS germline BRCA mutations based on the presence
of a basal-like morphology alone remains limited;
It has been nearly 2 decades since the seminal the addition of basal markers, ER status, and fam-
studies using gene expression profiling identified ily history increases sensitivity and specificity.67 A
10 Marotti & Schnitt

Table 1
Genotype-phenotype correlation in breast cancer

Potential Targeted
Histologic Type Genotype Ancillary Assay(s) Therapies
Secretory t(12;15) (p13;q25) translocation ETV6 dual TRK inhibitors
carcinoma resulting in ETV6-NTRK3 fusion break-apart FISH
gene
Adenoid cystic t(6;9) (q22–23;p23–24) MYB IHCa Inhibitors of
carcinoma translocation resulting in MYB dual downstream effectors
MYB-NFIB fusion gene break-apart FISH of MYB (VEGFA, FGF2)
Invasive lobular CDH1 mutations E-cadherin IHCb PI3K/Akt inhibitors
carcinoma
Solid papillary IDH2 mutations (often in NGS PI3K inhibitors
carcinoma with association with PIK3CA IDH2 inhibitors
reverse polarity mutations)
Abbreviations: FGF2, fibroblast growth factor 2; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry;
NGS, next-generation sequencing; TRK, tropomyosin receptor kinase; VEGFA, vascular endothelial growth factor A.
a
MYB IHC has been shown to be more sensitive and specific than FISH for evaluation of ACC41; however, focal, weak
immunostaining can be seen in ACC mimics.
b
Aberrant E-cadherin immunostaining has been reported to occur in up to 24% of ILCs.49

specific phenotype that consistently identifies FANCC mutations), and Fanconi anemialike disor-
BRCA2-associated tumors has yet to be identified, der (RAD51C mutations).10
although these tumors tend to be high grade and
ER-positive.69 Although most luminal A-type can- SUMMARY
cers are IDCs of no special type, some special-
type tumors, such as tubular carcinomas, A few special-type breast cancers are now known
mucinous carcinomas, and carcinomas with to be underpinned by recurrent genetic alterations
neuroendocrine features are invariably of luminal that are associated with their unique morphology
A molecular subtype, whereas ACCs, secretory and clinical features. These include secretory
carcinomas, and carcinomas with medullary fea- carcinoma, adenoid cystic carcinoma, ILC, and
tures typically cluster in the basal-like group.70 SPCRP (Table 1). The mechanistic relationship
For non-BRCA hereditary breast cancers, other between genetic alteration and histologic appear-
than the familial lobular breast cancers associated ance has been determined for ILC (CDH1 muta-
with CDH1 mutations discussed previously, tions), and recently, it was discovered that IDH2
genotype-phenotype correlations are less well- mutations likely account for the distinctive reverse
defined. It has been suggested that breast cancers nuclear polarity of SPCRP. In the future, advances
arising in the setting of Lynch syndrome or hered- in molecular methods may result in the identifica-
itary nonpolyposis colorectal cancer syndrome tion of genotype-phenotype correlations in other
with germline mutations in the mismatch repair subtypes of breast cancer.
genes (MLH1, MSH2, MSH6, PMS2) may have a
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