Download Primary Neuroendocrine Carcinoma of the Breast

J Med Sci 2006;26(2):065-068
http://jms.ndmctsgh.edu.tw/2602065.pdf
Copyright © 2006 JMS
Wen-Chiuan Tsai, et al.
Primary Neuroendocrine Carcinoma of the Breast
Wen-Chiuan Tsai1, Jyh-Cherng Yu2, Lai-Fa Sheu1, and Shin Nieh1*
1
Department of Pathology, 2Division of General Surgery, Department of Surgery,
Tri-Service General Hospital, National Defense Medical Center,
Taipei, Taiwan, Republic of China
Definitions and classifications of primary neuroendocrine (NE) carcinomas of the breast were first proposed by the World
Health Organization (WHO) in 2003. Here we present a case of large-cell neuroendocrine carcinoma of the breast with
regional nodal metastasis, which was diagnosed using cell morphology and immunohistochemical staining. We also reviewed
32 reported cases of primary breast NE carcinoma to identify prognostic factors associated with classes of this type of breast
carcinoma defined according to the most recent WHO classification system. To our knowledge, this is the first study of breast
carcinoma prognosis using the new WHO classification system.
Key words: breast cancer, carcinoid tumor, neuroendocrine carcinoma, solid growth pattern
INTRODUCTION
Primary NE carcinoma of the breast is rare, and histological patterns vary between cases1. The World Health
Organization (WHO) classifies this type of breast cancer
into three histological types according to the morphology
of the tumor cells: solid neuroendocrine (NE) carcinoma,
small or oat-cell carcinoma, and large-cell NE carcinoma2.
Most studies show that prognosis is correlated with the
clinical stage of the cancer, as compared with other breast
malignant tumors1. However, a report by Sapino and associates revealed that the growth pattern of neuroendocrine
differentiation may influence the classification of the tumor when it is classed according to the current grading
system3. Until now, prognostic and therapeutic protocols
have been controversial. The aim of this study was to
provide sufficient clinical data to resolve this issue.
CASE REPORT
An 83-year-old female patient presented with a firm,
nontender mass in the upper, outer quadrant of the left
breast without associated symptoms. A mass-lesion of the
left breast was identified by laboratory and physical
Received: August 1, 2005; Revised: September 15, 2005;
Accepted: September 22, 2005.
*
Corresponding suthor: Shin Nieh, Department of Pathology,
Tri-Service General Hospital, 325, Cheng-Gong Road Section 2, Taipei 114, Taiwan, Republic of China. Tel: +886-28792-7155; Fax: +886-2-8792-7159; E-mail: ab95057@
hotmail.com
Fig. 1 (A): Nests of tumor cells with hyperchromatic nuclei,
granular cytoplasm and abundant extracellular mucin secretion separated by dense collagen bundles (H & E stain,
×200). (B): More than 50% of tumor cells showed diffuse
staining for chromogranin A (IHC, ×200).
examination. Subsequent mammography and mammary
ultrasound both revealed a solitary and poorly demarcated
tumor. As we suspected malignancy, we performed a core
biopsy and diagnosed infiltrating ductal carcinoma of the
breast. We recommended modified radical mastectomy
and dissection of the axillary lymph nodes, which were
subsequently performed.
On gross examination, the resected breast measured 24 cm
×23 cm×9 cm and contained one tumor measuring 1.7
cm×1.5 cm×1 cm and several axillary lymph nodes.
Microscopically, median-sized, hyperchromatic tumor cells
with faintly granular cytoplasms were separated by dense
collagen bundles arranged in solid nest pattern with abundant extracellular mucin production (Fig. 1A). The dissected axillary lymph nodes showed no evidence of tumor
metastasis. Immunohistochemical studies revealed that
65
Prognosis of breast neuroendocrine carcinoma
the tumor cells were immunoreactive for
chromogranin A (Fig. 1B), synaptophysin, neuron-specific enolase (NSE), mucin, estrogen and
progesterone receptors, but negative for thyroid
transcription factor-1 (TTF-1) and carcinoembryonic antigen (CEA). These morphological and
immunohistochemical findings confirmed the diagnosis of primary large-cell NE carcinoma. The
patient was given tamoxifen (20 mg/d) and was
healthy and showed no evidence of recurrence at a
follow-up visit 6 months after surgery.
Table 1 The classification and prognosis of the 32 reported primary
breast NE carcinoma cases
Paper
No. of
Cases
Zekioglu9
Growth
WHO
Type classification
Solid
cohesive
Solid NE
carcinoma
No LNs
metastasis
MRM and
adjuvant C/T
Still alive after 48
months follow up
2
Solid
papillary
Solid NE
carcinoma
No LNs
metastasis
MRM and
adjuvant C/T
Still alive after 54
months follow up
5
Cellular Large cell NE
mucinous
carcinoma
Only one
case had
LNs meta
MRM and
adjuvant C/T
Still alive after 24
months follow up
Yamasaki10 1 Small cell
66
Outcome
(Mean follow
up time: 26.2
months)
4
DISCUSSION
carcinoma of the breast is a specific type of
cancer that exhibits a high level of histological
Shin11
neuroendocrine marker expression in the majority
of tumor cells. In 1963, Ferter and Hartmann first
described two breast carcinomas with carcinoid
patterns4. The term “primary carcinoid tumor” of
the breast was introduced in 1977 by Cubilla and
Woodruff to characterize a new group of
neoplasms5. They also concluded that primary
Our case
mammary carcinoid tumor is a neuroendocrine
neoplasm derived from argyrophilic cells of neural-crest origin. In most of the early studies, primary breast NE carcinoma was diagnosed using Grimeliu’s
stain and electron microscopy6. However, according to
some reports, only 5-10% of ordinary breast carcinomas
contain tumor cells with dense core granules and are
positive for Grimeliu's stain7,8. Together with the 2003
WHO classification, the diagnosis of primary breast NE
carcinoma has emphasized the importance of morphological features and immunohistochemical expression2. Our
case revealed nested, hyperchromatic tumor cells with
extracellular mucin production, which were surrounded by
collagenous fibers and exhibited diffuse, positive staining
for neuroendocrine markers. We also performed chest Xray, abdominal sonography, and panendoscopy, which
revealed no evidence of distal metastasis. The diagnosis of
primary solid NE carcinoma of the breast was confirmed
by morphological and immunohistochemical findings.
The prognosis of primary breast neuroendocrine carcinoma has not been extensively studied and, according to
most of the available information, seems to correlate to a
greater extent with presentation of clinical stage than with
the degree or pattern of neuroendocrine differen-tiation.
We reviewed 32 reported cases of primary breast NE
carcinoma with long-term follow-up between 2000 and
2004, which were classed into three categories according
LN status
Treatment
Small cell
No LNs Lumpectomy and Still alive after 18
NE carcinoma metastasis
adjuvant C/T
months follow up
10 Small cell Small cell NE
carcinoma
MRM and
adjuvant C/T or
R/T
6 cases expired 4
cases still alive
(mean follow up
time: 19 m)
9 Small cell Small cell NE 6 of 9 cases
carcinoma
had LNs
meta.
MRM and
adjuvant C/T
6 cases expired 3
cases still alive
(mean follow up
time 23 m)
1
MRM and
adjuvant H/T
Still alive after 6
months follow up
Alveolar
Solid NE
carcinoma
6 of 10
cases had
LNs meta
No LNs
metastasis
to the most recent WHO classification system (Table 1).
Those tumors included seven cases of the solid type of
primary carcinoma, five of the large-cell type, and 20 of the
small-cell type9-11. All of the subjects with solid and largecell types of breast NE carcinoma survived tumor excision
with adjuvant chemotherapy and/or radiotherapy, and only
one case had axillary lymph node metastasis. However, 12
of the 20 cases with primary small-cell NE carcinoma of
the breast had axillary lymph node metastasis and expired
after tumor excision and adjuvant therapy. Regional lymph
node metastasis may be the most important determinant of
a poor prognosis in primary neuroendocrine carcinoma of
the breast. Small-cell carcinoma tends to develop metastasis along the lymphatic channel (Table 2). However, the
relationship between lymph node metastasis and survival
rate was not statistically significant (P>0.05, Pearson product moment correlation) because of the small number of
cases studied. More information is required before a definitive conclusion is made regarding primary NE carcinoma of the breast.
In conclusion, with exception of the small-cell type,
cases of primary breast NE carcinoma displayed satisfactory prognosis after adequate tumor excision and adjuvant
therapy. However, it is important to distinguish between
Wen-Chiuan Tsai, et al.
Table 2 The relationship between lymph node metastasis
and survival of 32 reported cases of primary breast
NE carcinoma classed according to the 2003 WHO
classification system
WHO classification
Solid NE carcinoma
Large cell NE carcinoma
Small cell NE carcinoma
No. of
No. of Cases of LNs Survival cases/
total cases metastasis/ total cases
total cases
7
5
20
0/7
1/5 (20%)
12/20 (60%)
7/7 (100%)
5/5 (100%)
8/20 (40%)
metastatic carcinoid tumors and primary NE carcinoma of
the breast because of differences in the required management and the prognoses. To date, there have been 15
reported cases of metastatic carcinoid tumors of the breast,
12 of which metastasized from the small intestine; the
remaining three metastasized from the pancreas, bronchus,
and ovary13. In our opinion, further examinations such as
panendoscopy, abdominal sonography, and chest X-ray
should be performed to prevent incorrect diagnosis and
management.
REFERENCES
1. Ajisaka H, Maeda K, Miwa A, Yamamoto K. Breast
cancer with endocrine differentiation: report of two
cases showing different histologic patterns. Surg Today 2003;33:909-912.
2. Tavassoli FA, Devilee P. WHO Classification of
Tumors: Tumors of the Breast and Female Genital
Organs. Lyon: IARC press, 2003:32-34.
3. Sapino A, Righi L, Cassoni P, Papotti M, Pietribiasi F,
Bussolati G. Expression of the neuroendocrine phenotype in carcinomas of the breast. Semin Diagn Pathol
2000;17:127-137.
4. Feyrter F, Hartmann G. On the carcinoid growth from
of the carcinoma mammae, especially the carcinoma
solidum (gelatinosum) mammae. Frankf Z Pathol 1963;
73:24-39.
5. Cubilla AL, Woodruff JM. Primary carcinoid tumor of
the breast: A report of eight patients. Am J Surg Pathol
1997;1:283-292.
6. Clayton F, Sibley RK, Ordonez NG, Hanssen G. Argyrophilic breast carcinomas. evidence of lactational
differentiation. Am J Surg Pathol 1982;6:323-333.
7. Azzopardi JG, Muretto P, Goddeeris P, Eusebi V,
Lauweryns JM. “Carcinoid” tumor of the breast; the
morphological spectrum of argyrophil carcinomas.
Histopathology 1982;6:549-569.
8. Toyoshima S. Mammary carcinoma with argyrophil
cells. Cancer 1983;52:2129-2138.
9. Zekioglu O, Erhan Y, Ciris M, Bayramoglu H. Neuroendocrine differentiated carcinoma of the breast: a
distinct entity. Breast 2003;12:251-257.
10. Yamasaki T, Shimazaki H, Aida S, Tamai S, Tamaki
K, Hiraide H, Mochizuki H, Matsubara O. Primary
small cell (oat cell) carcinoma of the breast: report of
a case and review of the literature. Pathol Int 2000;50:
914-918.
11. Shin SJ, DeLellis RA, Ying L, Rosen PP. Small cell
carcinoma of the breast: a clinicopathologic and immunohistochemical study of nine patients. Am J Surg
Pathol 2000;24:1231-1238.
12. Rubio IT, Korourian S, Brown H, Cowan C, Klimberg
VS. Carcinoid tumor metastatic to the breast. Arch
Surg 1998;133:1117-1119.
13. Mosunjac MB, Kochhar R, Mosunjac MI, Lau SK.
Primary small bowel carcinoid tumor with bilateral
breast metastases: report of two cases with different
clinical presentations. Arch Pathol Lab Med 2004;128:
292-297.
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