Chapter
28
Glycogen-Rich Carcinoma
Frederick C. Koerner
Carcinomas that accumulate abundant glycogen arise in
many organs, including the lungs, endometrium, cervix,
ovary, and salivary glands.1 Extraction of the water-soluble
glycogen during histologic processing causes the cytoplasm
to become vacuolated or completely clear in conventional
­hematoxylin and eosin (H&E)–stained sections, and this
phenomenon has led pathologists to designate such tumors
as clear cell carcinomas. In 1981, Hull et al.2 described an
in situ and invasive mammary carcinoma composed of cells
with clear cytoplasm and proposed the diagnosis of glycogen-rich clear cell carcinoma of the breast for this variant
of mammary duct carcinoma. These writers did not establish criteria for this diagnosis, nor did they estimate the
frequency of the lesion; however, subsequent observers
have commented on both points. Fisher et al.3 required that
50% or more of the cells contain “optically clear cytoplasm
and, usually, centrally placed nuclei” to make the diagnosis of glycogen-rich clear cell carcinoma. Having done so,
the authors classified 45 of 1,555 breast carcinomas (3%) as
glycogen-rich clear cell carcinoma. Kuroda et al.4 used the
same threshold and discovered 20 glycogen-rich clear cell
carcinomas in a group of 723 primary breast carcinomas
(2.7%). Toikkanen and J­oensuu5 required that 90% of the
carcinoma cells contain clear ­cytoplasm to make the diagnosis of glycogen-rich clear cell carcinoma. They found 6
of 439 breast carcinomas (1.4%) met their criteria for this
diagnosis. Hull and Warfel6 did not specify their diagnostic
criteria, but they regarded only 9 of 936 breast carcinomas
(1%) as glycogen-rich clear cell carcinomas. These findings
indicate that glycogen-rich clear cell carcinoma is an exceedingly rare form of primary breast carcinoma. Fewer than 150
well-documented examples have been described since the
first case was reported in 1981.
CLINICAL PRESENTATION
The patients, whose ages ranged from 32 to 81 years,7 presented with a mass accompanied by skin dimpling, nipple
retraction, or pain in some cases. Both in situ and invasive
lesions may be detected by mammography2,8–12 and sonography.2,11 The imaging studies reveal an irregular spiculated
mass8,10,11,13 that may contain calcifications.10,11,13
GROSS PATHOLOGY
Glycogen-rich carcinomas resemble conventional breast
carcinomas to the unaided eye. Distinctive macroscopic
features have not been recorded. Most tumors measured
between 2 and 5 cm; the largest spanned “about 15 cm.”13
In one series, the mean size was 3 cm.7 Observers have described the masses as “brownish pink-gray or whitish-gray.”7
The carcinoma can form multifocal or multicentric masses,
and macroscopically evident involvement of the skin occurred in several cases.7,14 The seminal authors could appreciate an in situ papillary component during macroscopic
examination.2
MICROSCOPIC PATHOLOGY
Glycogen-rich clear cell carcinomas have basic structural features of ductal carcinoma in situ (DCIS) alone or of DCIS and
infiltrating duct carcinoma. The intraductal component can
grow in papillary, solid, cribriform, micropapillary, and “intracystic” patterns. Cytoplasmic clearing appears most evident in
solid areas that also exhibit moderate nuclear atypia (Fig. 28.1).
The cells in cribriform and micropapillary regions usually have
low-grade atypia and less often appear water-clear. The neoplastic cells can undergo focal necrosis, but abundant, comedolike necrosis associated with high-grade nuclear atypia does not
occur commonly.9 In most cases, one can detect small regions
in which the cells contain eosinophilic and granular cytoplasm
or exhibit other clear-cut apocrine features. The invasive component usually exhibits the histologic growth pattern of a conventional invasive duct carcinoma, but it can also display the
patterns seen in lobular, medullary, and tubular carcinomas.3
The tumor cells typically form cords, solid nests, or papillary
structures (Fig. 28.2). The formation of ductular or tubular
structures occurs only rarely. The cells exhibit sharply defined
borders and polygonal rather than rounded contours. The cytoplasm is clear or, less often, finely granular or foamy. Like the
noninvasive component, the invasive carcinoma sometimes
contains foci in which the cells have eosinophilic and granular cytoplasm that suggests an apocrine nature, and these cells
often form a continuum with the clear cells. Observers have
noted PAS-positive, diastase-resistant, intracytoplasmic hyalin
droplets in rare cases.9 The nuclei appear hyperchromatic and
757
758
Chapter 28
A
B
C
D
FIG. 28.1. Glycogen-rich carcinoma. A,B: DCIS and invasive carcinoma composed of cells with
clear cytoplasm and small, dark, punctate nuclei. C: The tumor is strongly positive with the PAS
reaction. D: After treatment with diastase, PAS reactivity is almost entirely abolished. The same
pattern of PAS staining occurred in the intraductal carcinoma.
sometimes contain clumped chromatin and nucleoli. Mitotic
figures are easily identified in most cases. One group15 found as
many as 70 mitotic figures per 10 high-power fields. Patches of
necrosis often occur in large tumors. A linear pattern consisting of strands of cells resembling invasive lobular carcinoma
may be seen, and glycogen-rich variants of tubular, medullary,
and endocrine carcinomas have been d
­escribed.3,7,16,17 The
carcinoma cells can invade lymphatic vessels and nerves. The
histologic ­appearance of the primary tumor is duplicated in the
metastases, which also contain abundant glycogen.6
Differential Diagnosis
The differential diagnosis of glycogen-rich carcinoma
­includes benign and malignant mammary and extramammary neoplasms. The clear cell type of hidradenoma (eccrine
­acrospiroma) shares the presence of many ­glycogen-laden
clear cells with glycogen-rich carcinoma. However, hidradenomas are centered in the dermis, they have well-defined,
smooth contours, and they consist of uniform bland cells.
Atypical and malignant hidradenomas pose greater challenges
in differential diagnosis (see Chapter 42). Myoepithelial cells
# 150439 Cust: LWW Au: HODA Pg. No. 758
with clear cytoplasm can dominate uncommon examples
of mammary adenomyoepithelioma. Detection of a second
population consisting of glandular cells and immunohistochemical demonstration of proteins characteristic of myoepithelial cells will distinguish this tumor from glycogen-rich
carcinoma.
The detection of glycogen in a mammary carcinoma does
not establish the diagnosis of glycogen-rich clear cell carcinoma, for Fisher et al.3 found that 58% of breast carcinoma
lacking clear cells contained intracytoplasmic glycogen.
Among the types of primary mammary carcinomas, lipidrich, secretory, histiocytoid lobular, and apocrine carcinomas
exhibit certain features that may bring to mind the appearance of glycogen-rich carcinoma, but one can usually distinguish these tumors without difficulty. Lipid-rich carcinomas
contain lipid rather than glycogen (see Chapter 27). Secretory
carcinomas feature microcystic spaces containing eosinophilic
secretions (see Chapter 22). Invasive lobular carcinomas of
the histiocytoid type possess intracytoplasmic mucin rather
than glycogen. Apocrine carcinomas can contain clear cells
(see Chapter 19), and focal apocrine features are identified
in the majority of glycogen-rich carcinoma. This association
C/M/Y/K
DESIGN SERVICES OF
Glycogen-Rich Carcinoma
759
FIG. 28.2. Glycogen-rich carcinoma. A: This tumor has moderate cytoplasmic clearing and a
gland-forming structure. B: PAS reactivity is strong. C: PAS reactivity is abolished by diastase treatment. D: Strong nuclear reactivity for ER is present.
suggests that that glycogen-rich carcinoma might constitute
a variant of apocrine carcinoma.9 These overlapping findings
and the possibility of an etiological relationship notwithstanding, the usual apocrine carcinoma contains intracytoplasmic,
diastase-resistant eosinophilic granules or droplets, a finding
that does not characterize glycogen-rich carcinomas.
Metastatic clear cell carcinomas can mimic the appearance of glycogen-rich carcinoma. Carcinoma of the kidney
is the most notable culprit in this regard (see Chapter 34).
CYTOLOGY
Descriptions of the cytological characteristics of specimens obtained by fine-needle aspiration vary somewhat
from case to case depending on the attributes of the carcinoma.7,11,14,15,18,19 Most authors report that the smears appear
cellular and that the carcinoma cells form loosely cohesive
groups. The aggregates sometimes display a branching architecture, and papillary formations can occur. At least a
few intact dissociated cells can be seen in the background
of the smears in most cases. The cells typically exhibit distinct cell membranes, but syncytial groups can be seen. The
# 150439 Cust: LWW Au: HODA Pg. No. 759
cytoplasm usually appears finely granular and eosinophilic
or vacuolated; however, the degree of vacuolization and
clearing of the cytoplasm varies and it sometimes represents
only an inconspicuous cellular feature. The oval or round
nuclei vary in size. They have irregular membranes and
prominent nucleoli. In many cases, the nuclei demonstrate
obvious pleomorphism and anaplasia. One can sometimes
appreciate occasional mitotic figures.
IMMUNOHISTOCHEMISTRY
The cytoplasm gives a positive, diastase-labile reaction with
the periodic acid–Schiff (PAS) stain (Figs. 28.1 and 28.2).
The cells stain only focally or not at all with Alcian blue, mucicarmine, and colloidal iron stains,6,8,10,11,14,15 and the oil red
O and Sudan black B stains for lipid are negative.8,11 The tumor cells are reactive for CK7, AE1/AE3, CK8/18, CAM5.2,
and E-cadherin,10,13,15,16,19 variably or weakly reactive for
carcinoembryogenic antigen (CEA)15,19 CK19, CK34βE12,
and epithelial membrane antigen (EMA),8,11,16,18 and only
weakly reactive or unreactive for actin, smooth muscle actin (SMA), desmin, vimentin, S-100, α-lactalbumin, CK5/6,
C/M/Y/K
DESIGN SERVICES OF
760
Chapter 28
CK14, CK20, CD31, and CD34.8,10,16,19,20 Several case reports
document staining for gross cystic disease fluid protein-15
(GCDFP-15).10,11,20 Glycogen-rich carcinomas do not display a consistent pattern of staining for hormone receptors.4,7,9,11,13–16,20,21 About one-half of the tumors express
estrogen receptor (ER) (Fig. 28.2 D); the reported frequency
varies from 35%4 to 62%.7 Most authors report the absence
of progesterone receptor (PR)9,14,16,21; however, Satoh et al.11
observed staining for PR in their single case, and Akbulut
et al.7 detected PR in 43% of their cases. Researchers have
observed staining for human epidermal growth factor 2
(HER2) in 20% to 43% of cases.4,7,15 The mean Ki67 score
was 20% in one series,7 and a value of 48% was recorded in
a single case.11 Observers have noted an elevated S-phase
­fraction (SPF) and nondiploid DNA content.5,14
ELECTRON MICROSCOPY
At the ultrastructural level, the cells have polygonal to columnar shapes.2,6,8,11,17,19 The cytoplasmic borders can appear smooth or form complex interdigitations harboring
junctional complexes and desmosomes. The cytoplasm
contains intracytoplasmic lakes of non–membrane-bound
glycogen and abundant small aggregates of glycogen intermixed with rough endoplasmic reticulum, mitochondria,
ribosomes, lysosomes, and Golgi apparatus. In certain cases,
the cytoplasm becomes distinctly segregated into two compartments: one containing the organelles and the other containing the glycogen. The nuclei appear oval to rectangular.
Most exhibit smooth borders, but others have deep clefts.
They contain moderate amounts of heterochromatin and
nucleoli that vary from small to prominent, depending on
the case. Lumens sometimes form among clusters of cells or
within individual cells (intracytoplasmic lumens). The cells
forming these primitive glands have short, broad microvilli
on their luminal borders, and one can observe tight junctions and desmosomes between the cells.
TREATMENT AND PROGNOSIS
With rare exceptions, reported examples of invasive glycogen-rich carcinoma have been treated by mastectomy and
axillary dissection. In one case,13 neoadjuvant chemotherapy resulted in the reduction of the cellularity of the infiltrating tumor by 30% or less. Approximately 30% of the
patients had metastatic tumor in their axillary lymph nodes.
In one series, 50% of the patients treated by mastectomy
died of metastatic mammary carcinoma 1 to 175 months
(median, 15 months) after diagnosis, and one patient was
alive with recurrent carcinoma 36 months after local excision and lymph node dissection.6 Except for one woman
who underwent simple mastectomy without axillary dissection, all patients with recurrent or fatal carcinoma had
axillary nodal metastases. Toikkanen and J­oensuu5 found
axillary nodal metastases in five of six cases. All five of
these patients died of metastatic carcinoma within 7 years
from the time of diagnosis, and the single woman with
negative lymph nodes died of intercurrent disease without
recurrence. Among the group described by ­Kuroda et al.,4
5 of 15 patients followed for 1 to 72 months died within
5 years of the time of diagnosis. Hayes et al.9 reported that
three of eight patients with follow-up information died of
metastatic carcinoma. The length of follow-up was not reported. These data suggest that the prognosis of patients
with glycogen-rich mammary carcinoma is not particularly
favorable and that it may be similar to ordinary invasive
duct carcinoma when analyzed on a stage- and gradematched basis.3,9
The Senior Editor has examined slides from an unusual
instance of glycogen-rich DCIS detected when calcifications
FIG. 28.3. Glycogen-rich carcinoma. A: DCIS with calcifications, which were detected by mammography. B: DCIS and invasive duct carcinoma with osteoclast-like giant cells (arrows) found in
the breast 9 years after breast conservation treatment of the glycogen-rich DCIS shown in (A).
# 150439 Cust: LWW Au: HODA Pg. No. 760
C/M/Y/K
DESIGN SERVICES OF
Glycogen-Rich Carcinoma
were found by mammography (Fig. 28.3). Nine years after
breast conservation therapy with radiotherapy, the patient
developed recurrent DCIS and invasive duct carcinoma with
osteoclast-like giant cells in the same breast. The recurrent
carcinoma was not glycogen rich.
REFERENCES
1. Mohamed AH, Cherrick HM. Glycogen-rich adenocarcinoma of minor salivary glands. A light and electron microscopic study. Cancer
1975;36:1057–1066.
2.Hull MT, Priest JB, Broadie TA, et al. Glycogen-rich clear cell carcinoma of the breast: a light and electron microscopic study. Cancer
1981;48:2003–2009.
3. Fisher ER, Tavares J, Bulatao IS, et al. Glycogen-rich, clear cell breast
cancer: with comments concerning other clear cell variants. Hum
Pathol 1985;16:1085–1090.
4. Kuroda H, Sakamoto G, Ohnisi K, et al. Clinical and pathological features of glycogen-rich clear cell carcinoma of the breast. Breast Cancer
2005;12:189–195.
5.Toikkanen S, Joensuu H. Glycogen-rich clear-cell carcinoma of the
breast: a clinicopathologic and flow cytometric study. Hum Pathol
1991;22:81–83.
6.Hull MT, Warfel KA. Glycogen-rich clear cell carcinomas of the
breast: a clinicopathologic and ultrastructural study. Am J Surg Pathol
1986;10:553–559.
7. Akbulut M, Zekioglu O, Kapkac M, et al. Fine needle aspiration cytology of glycogen-rich clear cell carcinoma of the breast: review of
37 cases with histologic correlation. Acta Cytol 2008;52:65–71.
8. Sorensen FB, Paulsen SM. Glycogen-rich clear cell carcinoma of the
breast: a solid variant with mucus. A light microscopic, immunohistochemical and ultrastructural study of a case. Histopathology 1987;11:
857–869.
# 150439 Cust: LWW Au: HODA Pg. No. 761
761
9. Hayes MM, Seidman JD, Ashton MA. Glycogen-rich clear cell carcinoma of the breast. A clinicopathologic study of 21 cases. Am J Surg
Pathol 1995;19:904–911.
10. Trupiano JK, Ogrodowczyk E, Bergman S. Pathologic quiz case: mass
in the right breast. Glycogen-rich clear cell carcinoma of the breast.
Arch Pathol Lab Med 2003;127:1629–1630.
11. Satoh F, Umemura S, Itoh H, et al. Fine needle aspiration cytology of
glycogen-rich clear cell carcinoma of the breast. A case report. Acta
Cytol 1998;42:413–418.
12. Pak I, Kutun S, Celik A, et al. Glycogen-rich “clear cell” carcinoma of
the breast. Breast J 2005;11:288.
13.Martíίn-Martíίn B, Berná-Serna JD, Sánchez-Henarejos P, et al. An
unusual case of locally advanced glycogen-rich clear cell carcinoma of
the breast. Case Rep Oncol 2011;4:452–457.
14. Kern SB, Andera L. Cytology of glycogen-rich (clear cell) carcinoma of
the breast: a report of two cases. Acta Cytol 1997;41:556–560.
15.Satake N, Uehara H, Sano N, et al. Cytological analysis of glycogen-rich carcinoma of the breast: report of two cases. J Med Invest
2002;49:193–196.
16. Gurbuz Y, Ozkara SK. Clear cell carcinoma of the breast with solid
papillary pattern: a case report with immunohistochemical profile.
J Clin Pathol 2003;56:552–554.
17.di Tommaso L, Pasquinelli G, Portincasa G, et al. Carcinoma della
mammella a cellule chiare ricche in glicogeno con aspetti di differenziazione neuroendocrina. Pathologica 2001;93:676–680.
18. Das AK, Verma K, Aron M. Fine-needle aspiration cytology of glycogen-rich carcinoma of breast: report of a case and review of literature.
Diagn Cytopathol 2005;33:263–267.
19. Alexiev BA. Glycogen-rich clear cell carcinoma of the breast: report of
a case with fine-needle aspiration cytology and immunocytochemical
and ultrastructural studies. Diagn Cytopathol 1995;12:62–66.
20. Shirley SE, Escoffery CT, Titus IP, et al. Clear cell carcinoma of the
breast with immunohistochemical evidence of divergent differentiation. Ann Diagn Pathol 2002;6:250–256.
21. Benisch B, Peison B, Newman R, et al. Solid glycogen-rich clear cell
carcinoma of the breast (a light and ultrastructural study). Am J Clin
Pathol 1983;79:243–245.
C/M/Y/K
DESIGN SERVICES OF