Diabetic MastopathyA Clinicopathologic Review
Diabetic Mastopathy A Clinicopathologic Review
Kim A. Ely 0
Gary Tse 0
MB BS 0
Jean F. Simpson 0
Rick Clarfeld 0
David L. Page 0
0 Address reprint requests to Dr Ely: Dept of Pathology, Division of Anatomic Pathology, Vanderbilt University Medical Center , Nashville, TN 37232 , USA
Diabetic mastopathy; Diabetes; Ductitis; Lobulitis; Vasculitis
A b s t r a c t
Diabetic mastopathy, an uncommon form of
lymphocytic mastitis and stromal fibrosis, typically
occurs in longstanding type 1 diabetes. Nineteen cases
meeting predetermined histopathologic criteria for
diabetic mastopathy were correlated as to clinical
history and disease recurrence. Physical examination
revealed palpable discrete masses or diffuse nodularity,
both predominantly in the subareolar region. One
nonpalpable lesion was detected incidentally during
reduction mammoplasty. All cases contained
lymphocytic ductitis and lobulitis with varying degrees
of keloidal fibrosis, vasculitis, epithelioid fibroblasts,
and lymphoid nodule formation. Single mammary
lesions were found in 11 patients with type 1 diabetes, 1
with type 2 diabetes, and 3 without diabetes. Four cases
were bilateral (3 patients with type 1 and 1 patient with
type 2 diabetes). Six of 19 cases recurred (3 ipsilateral,
2 contralateral, and 1 bilateral). We confirm the
histopathologic constellation for diabetic mastopathy.
However, we question the specificity of these features
because of identical findings in patients with type 2
diabetes and nondiabetic patients. We found diabetic
mastopathy in men and women, as a solitary mass or
bilateral disease, and recurrence in either breast,
sometimes multiple. Recognition of potential recurrence
is important because it might spare patients with
documented diabetic mastopathy from repeated breast
An association between diabetes mellitus and fibrous
breast disease was reported initially in 1984 by Soler and
Khardori,1 who described 12 patients with longstanding type
1 diabetes mellitus, multiple diabetic complications, and
palpable breast masses. Three years later, the term diabetic
mastopathy2 was coined for the combination of connective
tissue overgrowth with perivascular lymphocytic infiltrate
characteristic of this lesion. As similar histopathologic
features may be seen in patients with autoimmune disease,3-5
Tomaszewski et al6 proposed defining microscopic and
clinical criteria that uniquely describe diabetic mastopathy.
According to their report, although lymphocytic lobulitis,
ductitis, and vasculitis occasionally may be encountered in
nondiabetic breast biopsy specimens, distinctive epithelioid
cells (epithelioid fibroblasts) set within a densely fibrous
stroma seem unique to the diabetic condition.
While the microscopic features of diabetic mastopathy
have been well documented,6,7 few reports have addressed
the natural history of this lesion with regard to recurrence
after biopsy.6,8-10 We followed up 19 cases (representing type
1 diabetes, type 2 diabetes, and no diabetes) that met the
currently accepted criteria for diabetic mastopathy for up to
14 years. The incidence of recurrence in either breast is
described, as is the relationship between diabetic mastopathy
and its clinical associations.
Materials and Methods
The breast consultation archives of Vanderbilt
University Medical Center, Nashville, TN, were searched for the
pathologic diagnosis of diabetic mastopathy given between
January 1984 and July 1998. Eighteen cases with the
accompanying clinical history and follow-up were
identified. The computerized files from the surgical pathology
department of Vanderbilt University Medical Center were
searched by the key words diabetic mastopathy, fibrous
mastopathy, and chronic mastitis during a similar interval.
Four additional cases with corresponding demographic data
were retrieved. All of the available H&E-stained slides
were reviewed in a blinded fashion by 3 authors (K.A.E.,
G.T., and D.L.P.). The slides were evaluated for the
presence of lymphocytic ductitis, lymphocytic lobulitis,
lymphoid nodule formation with or without germinal center
formation, mononuclear vasculitis, epithelioid fibroblasts,
and keloidal fibrosis. As defined by Seidman et al,7 the
latter required involvement of at least a 5-mm area by thick
alternating bands of collagen.
Patient clinical information was obtained through 2
modes. Consultation data were collected via submission of
a detailed questionnaire to the referring pathologist and,
when necessary, through telephone contact with the
respective surgeons and primary care physicians. Demographic
data from the cases processed through the surgical
pathology department at Vanderbilt University Medical
Center were obtained by medical chart review. Information
was gathered on patient age and sex, diabetic history with
regard to type (type 1or 2), duration of illness, therapy, and
complications of diabetes. In addition, information on
previous breast lesions or subsequent development of
masses was sought.
A total of 22 cases with diagnoses of diabetic
mastopathy, fibrous mastopathy, and chronic mastitis were
retrieved. H&E-stained slides were available for review for 20
cases; the number of glass slides ranged from 1 to 15 per case
(mean, 3.5 slides). Nineteen of 20 cases demonstrated
histologic evidence of lymphocytic ductitis or lobulitis ❚Image 1❚
and ❚Image 2❚, keloidal fibrosis, and perivasculitis (diabetic
mastopathy). While ductitis was present universally, lobulitis
was present only in the female breast. This is an expected
finding as the male breast lacks lobules. In many cases (13
[68%]), dense collections of lymphocytes in close association
with vessels, atrophic ducts, or both, and lacking germinal
centers ❚Image 3❚ were observed. Epithelioid fibroblasts
❚Image 4❚, first described by Tomaszewski et al6 as large
plump fibroblasts that show a mild degree of pleomorphism,
also were a frequent feature (14 [74%]). In some cases, they
were arranged in a whorled, vaguely nodular pattern.
The 19 cases represented 15 from the consultation service
and 4 from the Vanderbilt University Medical Center surgical
pathology files. The study group ❚Table 1❚ included 17 women
and 2 men with ages ranging from 27 to 75 years (mean ± SD,
39 ± 12). Fifteen patients had a single mammary lesion when
first examined, and 4 had bilateral disease. The breast lesions
were characterized on physical examination as palpable
discrete masses (n = 17) or as diffuse nodularity (n = 1). An
additional case was discovered during bilateral reduction
mammoplasty. In 7 (37%) of 19 cases, localization of the
lesion to the subareolar region was reported.
A history of diabetes was elicited in 16 cases (type 1, 14
cases; type 2 insulin-requiring, 1 case; and type 2 non–insulin
dependent, 1 case). Three patients had no diabetic history. Of
the cases of type 1 diabetes, the exact duration was known in
12 and ranged from at least 15 to 36 years. Secondary
complications were determined in 11 of 14 cases of type 1 diabetes,
including retinopathy, 8 cases; nephropathy, 6 cases; and
neuropathy, 3 cases. Seven patients were hypertensive, and 2
of these patients had undergone kidney transplantation. One
patient with type 1 diabetes had hypothyroidism; however, no
other patients had clinical evidence of possible autoimmune
disease. Epithelioid fibroblasts were observed in 14 cases (11
with type 1 diabetes and 3 without diabetes). They were
absent in both men.
Six women (5 with type 1 and 1 without diabetes) had
biopsy-proven recurrence. This represented 1 bilateral
recurrence, 1 ipsilateral recurrence, 1 ipsilateral recurrence that
recurred twice, 1 ipsilateral occurrence that recurred thrice, 1
contralateral recurrence, and 1 contralateral recurrence that
recurred twice. Physical examination revealed 2 additional
patients recurrences; however, subsequent biopsy was not
performed to further characterize these changes.
Since the first description of fibrous breast lesions in
diabetic patients, known as diabetic mastopathy, in 1984,1
several series2,6,7 have attempted to define and confirm the
histologic features that specifically identify diabetic
mastopathy. In 1992, Tomaszewski et al6 studied 8 patients
with longstanding type 1 diabetes with breast masses and
compared them with nondiabetic patients or patients with
diabetes of short duration with fibrosis and chronic mastitis.
The former cases contained lymphocytic lobulitis and ductitis,
vasculitis, and dense keloidal fibrosis that in 6 cases
demonstrated epithelioid fibroblasts. The control group did not have
the complete constellation of changes. Seidman et al7
subsequently tested the specificity of these findings in patients with
diabetes and age-matched control subjects. They identified 5
insulin-requiring diabetics (type 1, 2 cases; type 2, 3 cases)
with extensive keloidal fibrosis, mononuclear perivasculitis,
and mononuclear ductitis, and/or lobulitis, whereas none of
the cases with non–insulin-requiring type 2 diabetes or control
542 Am J Clin Pathol 2000;113:541-545
© American Society of Clinical Pathologists
❚Image 1❚ Collections of lymphocytes surrounding a
mammary duct (H&E, ·25).
❚Image 2❚ Dense infiltrate of small, mature lymphocytes
affecting a lobular unit (H&E, ·25).
❚Image 3❚ An aggregate of lymphocytes in association with
a blood vessel (H&E, ·40).
❚Image 4❚ Vaguely nodular arrangement of epithelioid
fibroblasts set within a fibrous stroma (H&E, ·25).
subjects had all of these features.7 Epithelioid fibroblasts were
present in 3 of their 5 cases but did not seem essential for
making the diagnosis. In the present study, which represents
the largest series of patients, we found cases meeting the
proposed histopathologic criteria for diabetic mastopathy6 and
correlated them with the underlying clinical condition and
mode of presentation. The patients were followed up for up to
14 years after biopsy to study the natural history of the lesion
with regard to recurrence.
All 19 of our cases displayed evidence of lymphocytic
ductitis or lobulitis, keloidal fibrosis, and perivasculitis on
breast biopsy. Similar to other reports,5,6 diabetic mastopathy
occurred in men and women, underscoring the need for
awareness of this lesion in the male diabetic population. As noted,
the insulin-requiring diabetics had disease of long duration
(>15 years) and a high rate of secondary complications.
Unique to our study is the percentage of lesional
recurrences and the number of patients with bilateral disease.
Four cases (21%) manifested as synchronous bilateral
breast masses. These demonstrated histologic features
similar to and the same predilection for a subareolar
location as those with unilateral disease. The recurrence rate in
our series was 32%. Recurrences were ipsilateral,
contralateral, or bilateral. In some instances, they were multiple,
© American Society of Clinical Pathologists
Am J Clin Pathol 2000;113:541-545 543
Clinical Data for Patients With Diabetic Mastopathy
and Other Clinical Data
occurring 2 and 3 additional times. Usually the recurrences
developed within 5 years of the initial diagnosis; keloidal
fibrosis dominated the microscopic picture. Recognition of
this capacity for disease recurrence is important as it might
help to avoid repeated breast biopsy. In fact, Rollins11
recommends that in a patient with a prior diagnosis of
diabetic mastopathy, the lesion be assessed by fine-needle
aspiration. If the cytologic and clinical findings are
consistent with diabetic mastopathy, conservative clinical
management could be considered.
The inclusion of 3 nondiabetic cases and 1
non–insulin-dependent type 2 diabetic case with
microscopic characteristics of diabetic mastopathy adds further
to the interesting findings from our series. This
constellation of features occurring outside the setting of
insulinrequiring diabetes mellitus is in contradistinction to
previous reports.6,7 Although this set of histopathologic
criteria can be observed in association with autoimmune
disease in the absence of diabetes,3,4 the non–insulin
requiring type 2 diabetic case and the nondiabetic cases in
our study had no clinical evidence of an autoimmune
process. Surprisingly, epithelioid fibroblasts, believed to be
specific for diabetic mastopathy,6 also were seen in our
patients without a diabetic history. Similarly, in their series
of 14 biopsies, Ashton et al5 found examples of
epithelioidtype cells in nondiabetic patients with systemic lupus
erythematosus and hypothyroidism. They concluded that
epithelioid stromal cells are not unique to patients with
insulin-dependent diabetes mellitus.5 Thus, it seems that
the proposed features are not as specific as previously
maintained, or the appearance of diabetic mastopathy in the
breast may precede the onset of clinical diabetes or another
autoimmune processes. It may even be that some patients
with this compilation of histopathologic findings will never
develop diabetes or an autoimmune illness. The situation
might be analogous to recent observations made by
O’Toole et al12 about the relationship between diabetes
mellitus–glucose intolerance and necrobiosis lipoidica.
They concluded that necrobiosis lipoidica can be associated
with diabetes mellitus, but only a minority of patients
develop the disease.12
Although the pathogenesis of diabetic mastopathy
remains unknown, several mechanisms have been
suggested. Seidman et al7 proposed that exogenous insulin
might lead to the development of diabetic mastopathy
through an inflammatory or immunologic reaction to
insulin, the vehicle, or a contaminant in the vehicle. The
observations made in the present case series with bilateral
presentations and multiple recurrences would indicate a
systemic cause rather than a local event. It is known that
544 Am J Clin Pathol 2000;113:541-545
© American Society of Clinical Pathologists
among the metabolic disturbances in diabetes, matrix
expansion may occur.13,14 Tomaszewski et al6 hypothesized
that these fibroinflammatory lesions were attributable to
extracellular matrix expansion secondary to increased
collagen production and decreased degradation, in part
related to the hyperglycemic state. According to their
model, advanced glycosylated end products are formed and
act as neoantigen, triggering an autoimmune response with
B-cell proliferation and autoantibody production. The
resultant cytokine release would lead to matrix expansion.
The role of autoimmunity in the cause of diabetic
mastopathy first was suggested by Soler and Khardori.1 They
observed a link between diabetes, thyroid disease, and
connective tissue abnormalities. Interestingly, HLA-DR3,
HLA-DR4, and HLA-DR5 were expressed in cases in their
study. Such expression of these class II human leukocyte
antigens has been associated with autoimmune disease.15
Furthermore, while normal nonlactating breast epithelium
lacks major histocompatibility complex class II products,
they are seen in the epithelium of inflamed lobules.3 These
inflamed lobules also are very reminiscent of the
lymphoepithelial lesions seen in other autoimmune diseases such
as Hashimoto thyroiditis and Sjögren syndrome.3,4
Although many mechanisms have been offered about
the cause of diabetic mastopathy, none has been proven.
While some of the discussed theories may explain the
findings in a setting of hyperglycemia and exogenous insulin
use, an autoimmune basis would best address their presence
outside this population. As mentioned, the set of
histopathologic criteria used to define diabetic mastopathy may be seen
in other autoimmune diseases. Lammie et al3 reported
stromal sclerosis and chronic perivasculitis and perilobulitis
in a patient in whom Hashimoto thyroiditis subsequently
developed. It may be that after continued clinical follow-up,
our patients without a diabetic history eventually will
manifest diabetes mellitus or another autoimmune condition.
While our study confirms the histopathologic features
for diabetic mastopathy, we question the specificity of these
criteria. We identified 4 biopsy specimens from 3
nondiabetic cases and 1 non–insulin-requiring diabetic case that
contained the complete constellation of findings described
by Tomaszewski et al.6 We demonstrate that diabetic
mastopathy is not exclusive to females and can affect
males. It is manifested by solitary or synchronous bilateral
masses, as well as nonpalpable lesions, with a propensity
for the subareola. Recurrences are not uncommon and
occurred in 32% of cases in our series. Recurrences can be
ipsilateral, bilateral, or contralateral on repeated occasions.
From the 1Division of Anatomic Pathology, Vanderbilt University
Medical Center, Nashville, TN; the 2Department of Anatomic and
Cellular Pathology, Prince of Wales Hospital, Chinese University
of Hong Kong; and 3The Polyclinic, Seattle, WA.
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