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\begin{document}

\title{Invasive Cribriform Carcinoma of the Breast Detected Incidentally on
Computed Tomography: A Case Report}



\author[1]{Yasuhiro Adachi}%
\author[1]{Takefumi Katsuki}%
\author[1]{Takakazu Sasaguri}%
\author[2]{Keiji Hirata}%
\author[1]{Naoki Nagata}%
\affil[1]{Kitakyushu General Hospital}%
\affil[2]{University of Occupational and Environmental Health Japan}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Invasive cribriform carcinoma is a rare type of invasive breast
carcinoma, and few cases have been reported. Its features are a
cribriform pattern resembling the histological structures of cribriform
ductal carcinoma in situ and an excellent prognosis. However, the extent
of progress for intraductal extension must be carefully evaluated.%
\end{abstract}%



\sloppy


\textbf{Invasive Cribriform Carcinoma of the Breast Detected
Incidentally on Computed Tomography: A Case Report}

Yasuhiro Adachi MD\textsuperscript{1}, Takefumi Katsuki
MD\textsuperscript{1}, Takakazu Sasaguri MD, PhD \textsuperscript{3},
Keiji Hirata MD, PhD\textsuperscript{2}, Naoki Nagata MD,
PhD\textsuperscript{1}

E-mail

Yasuhiro Adachi: y-adachi@med.uoeh-u.ac.jp

Takefumi Katsuki: katsuki@med.uoeh-u.ac.jp

Takakazu Sasaguri: next1stage@yahoo.co.jp

Keiji Hirata: hirata@med.uoeh-u.ac.jp

Naoki Nagata: next1stage@gmail.com

Corresponding author: Yasuhiro Adachi, MD

Department of Surgery, Kitakyusyu General Hospital, 1-1
Higashijono-machi, Kokurakita-ku, Kitakyushu, Fukuoka, 802-8517, Japan

Tel: +81-93-921-0560, Fax: +81-93-922-7208

E-mail: y-adachi@med.uoeh-u.ac.jp

\textbf{Abstruct}

Invasive cribriform carcinoma is a rare type of invasive breast
carcinoma, and few cases have been reported. Its features are a
cribriform pattern resembling the histological structures of cribriform
ductal carcinoma in situ and an excellent prognosis. However, the extent
of progress for intraductal extension must be carefully evaluated.

\textbf{Keywords:} Invasive ductal carcinoma, Invasive cribriform
carcinoma, Breast cancer



\textbf{INTRODUCTION}

Invasive cribriform carcinoma (ICC) is a rare type of invasive breast
carcinoma that was first described by Page et al. in
1983\textsuperscript{1}, accounting for approximately 0.4\% of all
primary breast carcinomas\textsuperscript{1-4}. Its main characteristic
is a unique structure with most of its invasive component arranged in a
cribriform pattern. The prognosis of patients with pure and classical
ICC is excellent\textsuperscript{1-3}. This case was incidentally
discovered on CT as part of a preoperative examination for gynecological
surgery. This quite rare case is reported along with a literature
review.

\textbf{CASE REPORT}

A 68-year-old woman was scheduled to undergo surgery for pelvic organ
prolapse at the Department of Obstetrics and Gynecology of our
institute. No family member of the patient had a history of breast or
ovarian carcinoma. Contrast-enhanced CT performed as part of the
preoperative examination showed a 1.4-cm-diameter tumor in the upper
lateral quadrant of the left breast (Fig. 1a, b). The tumor shadow was
suspected to be a breast carcinoma, and the patient was referred to our
department. The patient had no complaints of nipple discharge or pain.
On physical examination, there was a mobile, irregular mass of 1 cm in
largest clinical diameter. In the preoperative diagnostic workup, the
patient underwent a bilateral mammogram (MMG) which showed a
high-density mass with no calcification in the breast parenchyma, highly
suspicious for malignancy (Fig. 1c). Breast ultrasonography (US) showed
a 1.3-cm, irregularly shaped, hypoechogenic mass (Fig. 1d). Serum tumor
markers were within normal limits. A core needle biopsy of the mass
demonstrated malignant cells proliferating in a cribriform or papillary
pattern.

With a diagnosis of invasive ductal carcinoma, tubule forming type, in
the upper lateral quadrant of the left breast, the patient underwent
total mastectomy and sentinel lymph node biopsy. The patient chose total
mastectomy to avoid postoperative radiotherapy. Intraoperative
pathological examination confirmed that the two sentinel lymph nodes
sampled in the axilla were negative for metastasis, and no axillary node
dissection was performed.

The surgical specimen contained a hard, grayish, solid, and lobulated
tumor with defined margins with a diameter of 1.5 cm (Fig. 2a).
Microscopically, the tumor was composed entirely of packed epithelial
islands with a cribriform appearance (Fig. 2b). The islands were
irregularly shaped with an ovoid outline and separated by relatively
thin fibrous connective tissue. Well-defined, rounded spaces (cribriform
growth pattern) were formed within the islands, and proliferating tumor
cells were columnar and rather uniform, having rounded to ovoid nuclei
with nuclear pleomorphism grade of G1 (Fig. 2c). Cribriform ductal
carcinoma in situ (DCIS) was seen around the tumor; on pathological
examination, total tumor area was 2.7 cm x 1.5 cm and invasive area was
1.5 cm x 1.0cm. No lymphovascular invasion was identified, and the
surgical margins were free of the tumor. On immunohistochemistry, the
tumor islands had no positive cells for the myoepithelial marker CD10
(Fig. 3b), whereas myoepithelial cells were preserved around the DCIS
(Fig. 3a). The tumor was classified as an invasive cribriform carcinoma
of pure type. Nuclear immunoreactivity was strong for both estrogen
receptor (ER) and progesterone receptor (PgR) and seen in 90\% of the
tumor cells (Fig. 3c, d). Human epidermal growth factor receptor 2
(HER2) expression was absent (Fig. 3e), and the Ki-67 labeling index was
low (7\%) (Fig. 3f). Two axillary sentinel lymph nodes were examined
intraoperatively and showed no metastasis. In accordance with the
8\textsuperscript{th} edition of the UICC TNM classification, the tumor
was staged as pT1cN0.

The patient is presently free from local recurrence and metastasis 10
months after surgery on adjuvant hormone therapy.

\textbf{DISCUSSION}

ICC is a unique type of invasive breast carcinoma that was first
described by Page et al. in 1983\textsuperscript{1}. ICC consists of
invasive epithelial islands containing well-defined, rounded spaces
similar in appearance to cribriform-type ductal carcinoma \emph{in
situ}(DCIS). The islands have an ovoid or angular outline and are set
within a desmoplastic stroma. They consist of multilayered epithelial
cells of small to intermediate size forming secondary glandular
structures lined by cuboidal to columnar cells. The World Health
Organization (WHO) classification (5\textsuperscript{th} edition)
required an invasive breast carcinoma to have \textgreater{} 90\% of the
tumor composed of cribriform islands of epithelial cells with low-grade
nuclei and sparse mitoses. ICCs are typically ER-positive (95-100\%),
PR-positive (69-89\%) and HER2-negative\textsuperscript{5,6}. The
present case showed that most of the tumor showed a cribriform pattern
and was classified as pure ICC. Pure ICC tends to have a smaller tumor
size and a lower rate of lymph node metastasis than mixed
ICC\textsuperscript{4}. However, there is no report yet whether there is
a difference in prognosis between the two types.

Adenoid cystic carcinoma (ACC) may also exhibit cribriform patterns.
However, the cribriform spaces in ACC lesions contain basaloid cells
(myoepithelial-like cells) and basement membrane material, and they are
negative for ER, PgR, and HER2\textsuperscript{7}.

The radiological features of ICC are indistinguishable from those of
other breast carcinomas\textsuperscript{8}. The imaging findings of the
present case showed no diagnostic features.

The mortality rate of patients with ICC is reported to be lower than
that of those with non-specific types of invasive ductal carcinoma
(IDC), and the 5-year survival rate is reported to be over
95\%\textsuperscript{2,3,9,10}. The reasons for the excellent prognosis
of ICC seem to be related to its characteristics. First, tumor size
tends to be small, less than 2 cm, 75\% of which are T1a to T1c. Next,
ICC has less nodal metastasis. Finally, ICC has higher rates of positive
ER and PR staining, which means that it is hormone-sensitive, and
negative HER2 expression.

In fact, ICC pathologically has smaller tumor diameters than IDC, and
has a higher rate of Lumpectomy in the previous study by Liu et al
{[}9{]}. However, in this case, the tumor diameter of the invasive
cancer was 1.5x1.0 cm, but the pathological tumor size was 2.7x1.5 cm,
which was 1.2 cm larger. Although ICC is a tumor type with a good
prognosis, we must consider the intraductal growth of the tumor and
measure the exact size of the tumor in ICC cases. ICC requires rapid
intraoperative pathological diagnosis and postoperative radiation
therapy, and if not, ICC is a tumor type that should be considered for
total mastectomy.

There is no consensus on ICC drug therapy yet. Colleoni recommended that
favorable luminal special type tumors may be suitable for no therapy or
endocrine therapy alone\textsuperscript{11}. However, it must be
cautious to make the decision. The case of pure ICC could still have
distant metastases (bones) if left untreated for a long period of time
(13 years)\textsuperscript{12}.

The patient is doing well and remains disease-free 10 months after
surgery on adjuvant hormone therapy.

\textbf{Conclusion}

A case of pure ICC of the breast with a good prognosis was presented.
Further studies of more patients with longer follow-up are needed.

\textbf{DECLARATIONS}

\textbf{Abbreviations}

ACC: Adenoid cystic carcinoma, CT: Computed tomography, DCIS: Ductal
carcinoma in situ, ER: Estrogen receptor, HER2: Human epidermal growth
factor receptor 2, ICC: Invasive cribriform carcinoma, IDC: Invasive
ductal carcinoma; MMG: mammogram, PgR: progesterone receptor, UICC:
Union for International Cancer Control, US: Ultrasonography, WHO: World
Health Organization.

\textbf{Ethics approval and consent to participate}

Not applicable.

\textbf{Consent for publication}

The patient provided written, informed consent to publish this case
report and any accompanying images.

\textbf{Availability of data and materials}

The data are not available for public access because of patient privacy
concerns but are available from the corresponding author on reasonable
request.

\textbf{Competing interests}

The authors declare that they have no competing interests.

\textbf{Funding}

No funding was received for this study.

\textbf{Authors' contributions}

Author 1: Yasuhiro Adachi drafted the manuscript.

Author 2: Takefumi Katsuki drafted and proofed the manuscript.

Author 3: Takakazu Sasaguri proofed the manuscript.

Author 4: Keiji Hirata proofed the manuscript.

Author 5: Naoki Nagata had given final approval of the version to be
published.

All authors read and approved the final manuscript.

\textbf{Acknowledgements}

None.

\textbf{Authors' Information}

\textsuperscript{1}Department of Surgery, Kitakyusyu General Hospital,
1-1 Higashijono-machi, Kokurakita-ku, Kitakyushu, Fukuoka, 802-8517,
Japan

\textsuperscript{2}Department of Surgery 1, School of Medicine,
University of Occupational and Environmental Health, 1-1 Iseigaoka,
Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan

\textsuperscript{3}Department of Pathology, Kitakyusyu General Hospital,
1-1 Higashijono-machi, Kokurakita-ku, Kitakyushu, Fukuoka, 802-8517,
Japan

\textbf{REFERENCES}

1. Page DL, Dixon JM, Anderson TJ, Lee D, Stewart HJ. Invasive
cribriform carcinoma of the breast. Histopathology. 1983; \textbf{7} :
525-36.

2. Marzullo F, Zito FA, Marzullo A, Labriola A, Schittulli F, Gargano G,
et al. Infiltrating cribriform carcinoma of the breast. A
clinico-pathologic and immunohistochemical study of 5 cases. Eur J
Gynaecol Oncol. 1996; \textbf{17:} 228-31.

3. Venable JG, Schwartz AM, Silverberg SG. Infiltrating cribriform
carcinoma of the breast: a distinctive clinicopathologic entity. Hum
Pathol. 1990; \textbf{21} : 333-8.

4. Zhang W, Zhang T, Lin Z, Zhang X, Liu F, Wang Y, et al. Invasive
cribriform carcinoma in a Chinese population: comparison with low-grade
invasive ductal carcinoma-not otherwise specified. Int J Clin Exp
Pathol. 2013; \textbf{6} : 445-57.

5. WHO Classification of Tumors Editorial Board e. WHO classification of
tumors, 5th edition -- Breast tumors. Lyon. International Agency for
Research on Cancer 2019.

6. Cserni G. Histological type and typing of breast carcinomas and the
WHO classification changes over time. Pathologica. 2020; \textbf{112} :
25-41.

7. Law YM, Quek ST, Tan PH, Wong SL. Adenoid cystic carcinoma of the
breast. Singapore Med J. 2009; \textbf{50} (1): e8-11

8. Lee YJ, Choi BB, Suh KS. Invasive cribriform carcinoma of the breast:
mammographic, sonographic, MRI, and 18 F-FDG PET-CT features. Acta
Radiol. 2015; \textbf{56} : 644-51.

9. Liu XY, Jiang YZ, Liu YR, Zuo WJ, Shao ZM. Clinicopathological
characteristics and survival outcomes of invasive cribriform carcinoma
of breast: A SEER population-based study. Medicine (Baltimore).
2015;\textbf{94} : e1309.

10. WHO Classification of Tumors Editorial Board e. WHO classification
of tumors, 5th edition -- Breast tumors. Lyon. International Agency for
Research on Cancer 2019.

11. Colleoni M, Russo L, Dellapasgua S. Adjuvant therapies for special
types of breast cancer. The Breast. 2011; \textbf{20} : 153-157.

12. Zhang W, Lin Z, Zhang T, Liu F, Niu Y. A pure invasive cribriform
carcinoma of the breast with bone metastasis if untreated for thirteen
years: a case report and literature review. World J Surg Oncol.
2012;\textbf{10} : 251. doi: 10.1186/1477-7819-10-251.

\textbf{FIGURE LEGENDS}

Figure. 1: Preoperative examination (Plain CT, MMG, US)

a and b: Plain CT shows an irregularly shaped tumor (arrow) with a
diameter of 14 mm in the upper-outer region of the left mammary gland.
No left axillary lymphadenopathy is observed.

c: MMG in the medio-lateral oblique view, a tumor shadow (arrow heads)
is seen in the upper region of the left mammary gland.

d: US shows a 1.3-cm, irregularly shaped, hypoechogenic mass in the
upper-outer region of the left mammary gland.

Figure. 2: Findings of the resected specimen,

a: Grayish white, solid, and lobulated tumor (arrow) in the mammary
gland.

b: HE staining shows tumor cells growing in a cribriform, partly
papillary pattern in a low-power field.

c: Most of the tumor shows a cribriform pattern in the high-power field.

Figure. 3: Immunohistological findings

a: The tumor islands have no positive cells for CD10, whereas
myoepithelial cells are preserved around the DCIS.

b: No CD10-positive cells were found in the invasive cribriform cancer
area.

c: ER is strongly stained

d: PgR is strongly stained.

e: HER2 expression is judged as score 0.

f: Ki67 staining is observed in 7\% of all cells.\selectlanguage{english}
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