The

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case records of the massachusetts general hospital

Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor
Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor
Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor
Christine C. Peters, Assistant Editor

Case 24-2009: A 26-Year-Old Woman

with Painful Swelling of the Neck
John H. Stone, M.D., M.P.H., Paul A. Caruso, M.D.,
and Vikram Deshpande, M.D.

Pr e sen tat ion of C a se

Dr. John H. Stone: A 26-year-old woman was seen in the rheumatology clinic of this
hospital because of painful swelling on both sides of the neck.
She had been well until approximately 3 months earlier, when dry mouth and
increased thirst developed. Two weeks later, submental swelling occurred that was
associated with local tenderness, pain on swallowing (with solids more than with
liquids), and decreased appetite. Approximately 4 weeks after the onset of symptoms, she saw a physician; cephalexin was prescribed, with no improvement. During the next 2 weeks, pain developed in both ears. Seven weeks before evaluation
at this hospital, she went to the emergency department of the Massachusetts Eye
and Ear Infirmary.
On examination there, the vital signs were normal. Anterior rhinoscopy revealed
a minimally deviated septum and mildly edematous turbinates. The submandibular glands were symmetrically enlarged, irregular, bosselated, and tender. There was
mild discomfort in the temporomandibular joints, more on the left than on the
right. The remainder of the physical examination and fiberoptic endoscopic inspection of the larynx were normal. The level of plasma sodium was 132 mmol per liter
(reference range, 135 to 145); the results of other laboratory tests, including a complete blood count, levels of other electrolytes, and tests of liver and renal function,
were normal. Computed tomography (CT) of the neck after the intravenous administration of contrast material showed prominently enhancing submandibular glands
that were enlarged and prominently enhancing parotid glands, all of which appeared
nodular. No sialoliths or sialodocholiths were observed. Periodontal disease was
present in the tissue surrounding both third mandibular molars, which were partially impacted. Ibuprofen was prescribed, to be taken as needed.
Ten days later, fine-needle aspiration of the left and right submandibular glands
was performed. Cytologic examination revealed a paucicellular specimen with polymorphous lymphoid cells, normal salivary-gland tissue, and no malignant cells.
Two weeks after the fine-needle aspiration, the patient was seen in the infectious disease clinic of this hospital. Additional history was obtained. She had been
born in an urban area of Morocco and immigrated to the United States 22 months
before presentation at this hospital; a chest radiograph was reportedly normal at

From the Division of Rheumatology, Allergy, and Immunology, Departments of

Medicine (J.H.S.), Radiology (P.A.C.), and
Pathology (V.D.), Massachusetts General
Hospital; and the Departments of Medicine (J.H.S.), Radiology (P.A.C.), and Pathology (V.D.), Harvard Medical School.
N Engl J Med 2009;361:511-8.
Copyright 2009 Massachusetts Medical Society.

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that time. Six months before presentation, a tuberculin skin test had been positive. The patient
did not know whether she had received immunization with bacille CalmetteGurin (BCG) vaccine
in the past. Prophylaxis with isoniazid was recommended, but she declined. She had lost 7 kg
in weight during the previous 2 months because
of discomfort associated with eating and swallowing food. She lived with her husband and young
children, attended school, and worked in sales.
She did not smoke, drink alcohol, or use illicit
drugs. She reported having no contacts with anyone who was sick and had not drunk unpasteurized milk or traveled recently. She was taking no
other medications and had no allergies. On examination, the submandibular glands were tender,
firm, and enlarged (3 to 4 cm in diameter). There
was no cervical, axillary, or inguinal lymphadenopathy. The remainder of the examination was
normal.
The results of a complete blood count were
normal, as were serum levels of electrolytes, calcium, glucose, total protein, albumin, bilirubin,
immunoglobulins, and angiotensin-converting enzyme. Test results for renal and liver function and
a urinalysis were also normal. Findings for the
EpsteinBarr virus and cytomegalovirus were consistent with past infection; a test for hepatitis B
surface antibody was also positive, but a test for
antigen was negative, as were test for human immunodeficiency virus, hepatitis C virus, brucella,
and syphilis. A chest radiograph was also normal.
Magnetic resonance imaging of the neck, performed without the administration of contrast
material, revealed small, nonspecific cervical
lymph nodes. The submandibular glands were
prominent, with no focal masses. A 10-day course
of penicillin was administered.
Twelve days later, the patient was seen in the
oral and maxillofacial surgery clinic. There was
moderate generalized plaque-induced gingivitis
and periodontitis, and two lower molars were
impacted. No purulent discharge was noted on
milking the salivary glands. A panoramic radiograph showed no dental decay or bony abnormalities. Amoxicillinclavulanic acid was administered
for 2 weeks.
Two weeks later, the patient was seen in the
rheumatology clinic. She reported thirst, xerostomia, dry eyes, vaginal dryness, mild hair loss,
and weight loss of 10 kg. She did not have joint
pain, weakness, alopecia, photosensitivity, ma512

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lar rash, oral or tongue ulcers, lymphadenopathy,

shortness of breath, chest pain, fevers, or night
sweats. Her menses were normal. Her mother had
type 2 diabetes mellitus and thyroid dysfunction;
her father had allergies, and her siblings and
children were healthy.
On examination, the vital signs were normal
and the weight was 55 kg. There was no skin
thickening, sclerodactyly, dilatation of the nail-bed
capillaries, fingertip pitting, or synovitis and no
indication of Raynauds phenomenon. The oropharynx was dry, with a diminished salivary pool.
The submandibular glands were enlarged symmetrically and mildly tender. The remainder of
the examination was normal, including examination of the hair; the parotid, sublingual, and thyroid glands; the cervical, supraclavicular, axillary,
and inguinal lymph-node chains; and the eyes.
Serum and urine protein electrophoresis studies
were normal, as were levels of serum immunoglobulins and serum and urine free light chains.
A test for antinuclear antibodies was positive, at
1:160, with a speckled pattern, and tests for antibodies to SSA (Ro), SSB (La), double-stranded
DNA, and rheumatoid factor were negative. The
level of complement C3 was 81 mg per deciliter
(reference range 86 to 184), and the level of C4 was
11 mg per deciliter (reference range, 20 to 58).
The same day, fine-needle aspiration of both
submandibular glands was repeated. Cytologic
examination revealed no malignant cells. Flow
cytometry showed normal B cells and T cells.
Grams stain and stains for acid-fast bacilli showed
no organisms, and bacterial, mycobacterial, and
anaerobic cultures were sterile.
A diagnostic procedure was performed.

Differ en t i a l Di agnosis
Dr. Stone: This previously healthy 26-year-old woman from Morocco presented with a 4-month history of thirst and submandibular-gland enlargement on both sides of the neck (Fig. 1). May we
review the imaging studies?
Dr. Paul A. Caruso: CT of the neck after the
administration of contrast material shows largely symmetric enlargement and prominent enhancement of the submandibular glands (Fig. 2A) and
the sublingual glands, more on the right than on
the left (Fig. 2B). Both parotid glands, although
normal in size, were enhanced prominently. The
scan showed no discrete mass, sialolith, sialodo-

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case records of the massachusetts gener al hospital

Figure 1. Photograph of the Patients Neck.

There is submandibular-gland swelling on both sides
of the neck. A puncture wound from a fine-needle aspiration can be seen over the right submandibular gland.
ICM
REG F

AUTHOR Stone
FIGURE 1

RETAKE

1st
2nd
3rd

CASE ductal
TITLE dilatation, adjacent phlegmon,
cholith,
abRevised
EMail
4-Cor periodontal
Line
scess,Enon
cyst, significant periapical
SIZE
ARTIST: mst
H/T
H/T
disease,
16p6 glands
FILL or lymphadenopathy.
ComboThe lacrimal
were not included
in the
scan.
AUTHOR,
PLEASE
NOTE:
Figure has
been redrawn
andpatient
type has been
Dr. Stone:
I cared
for this
andreset.
am aware
Please check carefully.
of her diagnosis. Her case is no exception to the
rule that
diagnoses
JOB: many
ISSUE: 7-30-09
36105 interesting differential
in medicine require consideration of infectious,
malignant, and immunologic causes. I will consider the most likely diagnoses within each of
these categories.

Infectious Diseases

The major focus of the infectious disease evaluation was the exclusion of tuberculosis specifically, mycobacterial cervical lymphadenitis. Lymphadenitis is the most common clinical manifestation
of extrapulmonary tuberculosis. However, aside
from weight loss, which appeared to have other
explanations, the patient had no constitutional
symptoms, particularly fever. In addition, the imaging studies localized the abnormality to the submandibular glands rather than to lymph nodes,
and specimens from two fine-needle aspirations
failed to show any evidence of granulomatous inflammation or acid-fast bacilli.
Other infectious disease considerations in the
context of submandibular-gland enlargement are
bacterial, viral, and fungal infections. Infections
of dental origin and infection of the tonsils are
the most common causes for submandibular
lymph-node enlargements. However, such infections are highly symptomatic and would not have
remained subclinical for weeks. Other infections,

Figure 2. CT of the Neck after the Administration

of Intravenous Contrast Material.
Both submandibular glands (Panel A, arrows) and both
sublingual
glands (Panel
diffusely en1st
AUTHOR
Stone B, asterisks) are RETAKE
ICM
2nd
larged
show prominent
enhancement. No abscessREGand
F FIGURE
2a&b
es, adjacent
phlegmons, or focal masses are seen. 3rd
CASE
TITLE
EMail

4-C
Line
Enon
ARTIST: mst
H/T
H/T
Combo
such FILL
as infectious mononucleosis,
cat

Revised

SIZE

16p6
scratch
disAUTHOR,
PLEASE
NOTE: may produce
ease, and hepatitis
C virus
infection,
Figure has been redrawn and type has been reset.
painless submandibular-gland
enlargement, as can
Please check carefully.
mycoses, particularly those caused by actinomyISSUE: 7-30-09
ces. IJOB:
will 36105
assume that the thorough
assessment
for infectious disease constituted a true negative evaluation and that infection was not the
cause of swelling in the patients neck.

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Neoplastic Diseases

A variety of benign and malignant tumors must

be excluded in a patient with long-standing submandibular-gland swelling.1 In contrast with tumors of the parotid glands, 85% of which are
benign, approximately 80% of submandibulargland tumors are malignant.1 Adenocarcinomas,
adenoid cystic carcinomas, mucoepidermoid carcinomas, and squamous-cell carcinomas can all
occur in the salivary glands.2 The asymptomatic
nature of malignant epithelial tumors of the submandibular gland is reflected in the fact that
most submandibular-gland cancers are detected
at advanced stages.2 However, such tumors are unlikely to be bilateral or to cause the level of pain
experienced by this patient.
In contrast, lymphoma of mucosa-associated
lymphoid tissue (MALT) involving the salivary
glands can be bilateral and is often associated
with pain and tenderness.3 MALT lymphoma,
which may involve both the salivary and lacrimal
glands, is more common in the parotid glands
than in submandibular glands, but it may involve
either of these. MALT lymphoma is more common
in older adults, but it may occur in people in their
teens and 20s; women are affected slightly more
often than men. MALT lymphoma of the salivary
gland may occur de novo but is seen more commonly in association with the autoimmune disorder Sjgrens syndrome.4 The patients presenting symptoms of dry mouth and increased thirst
suggest Sjgrens syndrome.
An aggressive lymphoma, such as diffuse largeB-cell lymphoma, is less likely in this case because of the fairly indolent course of the disease
and the involvement of glands on both sides of
the neck; in addition, the morphologic features
of the lymphocytes observed in the fine-needle
aspirates do not suggest a large-cell lymphoma.
In fact, examination of specimens from the fineneedle aspirates suggests a benign process. However, the findings from fine-needle aspiration are
not sufficient to exclude malignant disorders; an
open biopsy should be considered if a malignant
tumor is suspected.
Immunologic Diseases

An autoimmune disease should be considered in

this young woman. The evaluation for infectious
diseases was negative, and neither her clinical presentation nor the results of cytologic examination

514

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of fine-needle aspirate suggest a malignant tumor.

It was the suspicion of autoimmune disease that
led to her referral to me. Autoimmune diseases that
should be considered include systemic lupus erythematosus, Sjgrens syndrome, and chronic sclerosing sialadenitis.
Systemic Lupus Erythematosus

The patients epidemiologic profile fits the diagnosis of systemic lupus erythematosus, as this disorder tends to afflict young women. It commonly
causes lymphadenopathy and can be associated
with salivary-gland enlargement in the presence
of Sjgrens syndrome, but disproportionate swelling of the submandibular glands as compared with
other salivary glands is not typical. A thorough review of systems related to rheumatic disease did
not reveal other common clinical features of systemic lupus erythematosus. The patient did not
have alopecia, oral ulcers, rash, photosensitivity,
Raynauds phenomenon, arthralgias, or a history
of pregnancy losses. The complete blood count
did not show leukopenia, lymphopenia, or thrombocytopenia, all hallmarks of systemic lupus erythematosus. She had antinuclear antibodies in
her serum, but the titer was low (1:160) and antibody assays more specific for systemic lupus erythematosus were negative. She had hypocomplementemia, which is often associated with the
consumption of immune complexes, but the low
levels of complement proteins C3 and C4 are not
specific for systemic lupus erythematosus.
Sjgrens Syndrome

Salivary-gland swelling is characteristic of Sjgrens

syndrome,5 but is not seen in all patients. This
patients first symptoms were dry mouth and
thirst. As an immune-mediated attack on exocrine glands (among other organs), Sjgrens
syndrome is associated with dryness (sicca syndrome) of the eyes, mouth, and other mucosal
surfaces, as well as a characteristic lymphocytic
infiltrate of the affected glands the so-called
lymphoepithelial lesion.6 The results of the fineneedle aspirations are consistent with Sjgrens
syndrome, with the presence of polyclonal B cells
and T cells. There has been some confusion in
the rheumatology literature about the relationship
between Sjgrens syndrome and the Mikulicz
syndrome7 symmetrical swelling of both lacrimal and salivary glands with lymphocytic infil-

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case records of the massachusetts gener al hospital

tration and glandular atrophy but most cases

of the Mikulicz syndrome are now regarded as
being examples of Sjgrens syndrome.8
A number of the patients clinical features
argue against Sjgrens syndrome. She has dental caries, but her dentition is generally good; in
Sjgrens syndrome dental caries typically develop along the gingival margins and cusp tips
of multiple teeth. She does not have antibodies
directed against the SSA (Ro) or SSB (La) antigens,
and the test for rheumatoid factor was negative.
In addition, the finding of submandibular-gland
swelling in the absence of parotid-gland swelling is highly atypical for Sjgrens syndrome.
Parotid enlargement is usually predominant when
there is any increase in the size of exocrine
glands.9

the disproportionate enlargement of the submandibular glands, and one would be left with the
nagging concern about a possibility of MALT lymphoma. Similarly, chronic sclerosing sialadenitis
can be distinguished from malignant tumors only
by means of histopathologic examination. Thus,
the next step in the diagnosis involved more extensive sampling of the submandibular gland. In
cases such as this, otolaryngologists typically remove the entire gland.

Cl inic a l Di agnosis
Sjgrens syndrome or chronic sclerosing sialadenitis (Kttners tumor); lymphoma must be
ruled out.

Pathol o gic a l Discussion

Chronic Sclerosing Sialadenitis

One condition that must be considered in this

case is chronic sclerosing sialadenitis, also known
as Kttners tumor. Kttner described a tumorlike
inflammatory condition of the salivary glands,
usually the submandibular glands, which manifested as firm swelling of the involved gland
clinically suggestive of the presence of a malignant tumor.10 Often, only one gland is involved,
but both glands can be affected.11-13 Most patients
with chronic sclerosing sialadenitis are older than
50 years of age. The limited literature on this
disorder suggests a slight predominance in men
but cases in young adults and in women have
been reported. The condition is characterized by
extensive fibrosis. Initial reports postulated that
the cause was sialolithiasis, dysfunctional secretory function leading to ductal inspissation, or an
autoimmune reaction.12,13 More recently, it has
become clear that some cases of chronic sclerosing sialadenitis are associated with a condition
known as IgG4-related systemic disease.14 Some
authors have suggested that some cases of the
Mikulicz syndrome are also examples of IgG4related systemic disease.15
Approach to the Diagnosis

Sjgrens syndrome, chronic sclerosing sialadenitis, and MALT lymphoma are all reasonable diagnostic possibilities in this case. A lip biopsy, which
would allow examination of minor salivary glands,
might reveal lymphoepithelial lesions compatible
with Sjgrens syndrome.6 However, this explanation would remain less than satisfactory given

Dr. Vikram Deshpande: The resected submandibular

gland was characterized by a marked lymphoplas
macytic infiltrate, with florid reactive lymphoid
follicular hyperplasia, acinar atrophy, and interstitial fibrosis (Fig. 3). Lymphoepithelial lesions,
which are characteristic of Sjgrens syndrome,
were not evident. In situ hybridization for kappa
and lambda light chains showed numerous polytypic plasma cells. The morphologic findings are
consistent with chronic sclerosing sialadenitis
(Kttners tumor), a chronic inflammation of the
salivary gland that most often affects the submandibular glands.
The histopathology of chronic sclerosing sialadenitis bears a striking resemblance to that of an
inflammatory condition of another exocrine organ, the pancreas. In the pancreas, these histopathologic findings are termed autoimmune pancreatitis. Alternative names for this condition in
recent decades have included sclerosing pancreatitis, idiopathic tumefactive chronic pancreatitis,
idiopathic chronic pancreatitis with periductal
lymphoplasmacytic infiltration, and nonalcoholic
duct-destructive chronic pancreatitis, among others. The hallmark features of autoimmune pancreatitis that are also present in the submandibular
gland of our patient are a dense lymphoplasmacytic infiltrate, sclerosis, and acinar atrophy.
Obliterative phlebitis, detected in nearly all cases
of autoimmune pancreatitis and in a high percentage of cases of chronic sclerosing sialadenitis,
was not present in our patients submandibular
gland.

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Figure 3. Histopathological Studies of the Submandibular Gland.

At low magnification, bands of fibrous tissue give the submandibular gland a nodular appearance (Panel A), and numerous germinal centers are present (arrows). The acini are atrophic (Panel B) and surrounded by a dense inflammatory infiltrate. LymphoepithelialICM
lesions,
characteristic
are
RETAKE
1st not seen. At higher magnificaAUTHOR
Stone of Sjgrens syndrome,
2nd
tion (Panel C), both the lobules and
the
fibrous tissue contain a mixed infiltrate
of lymphocytes and
REG
F bands
FIGUREof 3a-d
plasma cells. (Panels A, B, and C stained
with hematoxylin and eosin.) The use of 3rd
immunoperoxidase stain for IgG4
CASE
TITLE
Revised
(Panel D) reveals numerous plasma
cells containing cytoplasmic
IgG4.
EMail
4-C
Line
Enon
FILL

ARTIST: mst

H/T
Combo

H/T

SIZE
33p9

AUTHOR, PLEASE NOTE:

Figure has been

beenThe
reset. serum level of IgG4 in our paApproximately two thirds of patients
withredrawn
au- and type
Dr. has
Stone:
Please check carefully.
toimmune pancreatitis have both elevated serum tient was 12.5 mg per deciliter (reference range,
levels of IgG4 and increased numbers
140.0).
The spectrum of IgG4-associated
JOB: 36105of IgG4- 8.0 to
ISSUE:
7-30-09
positive plasma cells in the involved tissues.16-20 disease includes not only exocrine glands but
IgG4-positive plasma cells are rare in most in- also the biliary tree, salivary and lacrimal glands,
flammatory infiltrates, making up less than 50% orbital tissues, kidneys, lungs, and aorta (Table
of the IgG-positive cells. In chronic sclerosing 1).18,22-25 The pathophysiology of this disease is
sialadenitis,14 there are ordinarily more than 10 not understood.
IgG4-positive plasma cells per high-power field.21
It is important to recognize this entity and
In our patients submandibular gland, immuno- distinguish it from Sjgrens syndrome, since the
histochemical stains for IgG and IgG4 showed natural history and complications differ. IgG4that the proportion of IgG4-positive plasma cells associated systemic disease is typically highly rewas significantly increased, with 19 IgG4-positive sponsive to glucocorticoid therapy, with a low
cells per high-power field and an IgG4:IgG ratio frequency of recurrence.23,26 Many cases of what
of more than 0.5 (Fig. 3D). As in this case, most diagnosticians believed to be Sjgrens syndrome
cases of IgG4-associated sialadenitis are not as- with pancreatic disease have been reported,27-30
sociated with autoimmune pancreatitis.
but, in retrospect, most were probably cases of

516

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case records of the massachusetts gener al hospital

the pancreas, biliary tree, kidneys, or retroperitoneum. When no such lesions were identified, we
decided against instituting treatment at that time,
Autoimmune pancreatitis
and the patient concurred.
Sclerosing cholangitis
Nine months after the operation, the patient
Chronic sclerosing sialadenitis (Kttners tumor)
returned
to the rheumatology clinic reporting
Riedels thyroiditis
tenderness
of the right submandibular gland
Retroperitoneal fibrosis
and
pain
in
the right ear, but no dry mouth or
Lymphoplasmacytic aortitis
increased
thirst.
On examination, the submanLacrimal gland enlargement
dibular
gland
had
enlarged slightly and was tenDacryocystitis
der.
We
elected
to
treat
the patient with 40 mg of
Pseudotumors of the lung, kidney, and orbit
oral prednisone per day for 2 weeks, which led to
prompt resolution of her pain. The serum IgG4
IgG4-associated systemic disease, with both auto- level remained normal. The dose of prednisone
immune pancreatitis and involvement of the sali- was tapered, and the drug was discontinued after
vary glands.
3 months; her symptoms have not recurred.
By the time of our patients first postoperative
visit, the remaining submandibular gland had deA nat omic a l Di agnosis
creased in size and was less tender. Such spontaneous improvement has been reported in auto- Chronic sclerosing sialadenitis (IgG4-associated
immune pancreatitis and other components of chronic sclerosing sialadenitis, Kttners tumor).
Dr. Stone reports receiving consulting fees from Merck and
IgG4-associated systemic disease.23 We performed
Stryker; and Dr. Deshpande, receiving consulting fees from Noa CT scan of the abdomen to exclude the possi- vartis. No other potential conflict of interest relevant to this arbility that there were any subclinical lesions of ticle was reported.
Table 1. Conditions That May Be Associated with IgG4Related Systemic Disease.

References
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17. Finkelberg DL, Sahani D, Deshpande

V, Brugge WR. Autoimmune pancreatitis.

N Engl J Med 2006;355:2670-6.
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al. A new clinicopathological entity of
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25. Stone JH, Khosroshahi A, Hilgenberg

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Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences
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