Concurrent pulmonary Mycobacterium avium complex (MAC) infection and active Hürthle cell thyroid carcinoma: is there a connection?

doi:10.4236/health.2010.25058

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Vol.2, No.5, 391-394 (2010) Health

doi:10.4236/health.2010.25058

Concurrent pulmonary Mycobacterium avium complex

(MAC) infection and active Hürthle cell thyroid

carcinoma: is there a connection?

Kara M. Meinke Baehr, Whitney S. Goldner*

University of Nebraska Medical Center, Department of Internal Medicine–Diabetes, Endocrinology, and Metabolism, Omaha, USA

*Corresponding Author: [email protected]

Received 5 October 2009; revised 5 January 2010; accepted 8 January 2010.

ABSTRACT

We present two cases of pulmonary MAC infec-

tion in women with Hürthle cell thyroid carci-

noma. Both cases were asymptomatic octoge-

narian women with active Hürthle cell thyroid

carcinoma and prolonged periods of hypothy-

roidism prior to diagnosis of pulmonary MAC.

Mycobacterium avium complex has never been

reported in association with any type of thyroid

cancer, specifically Hürthle cell carcinoma. A

review of the literature and possible associa-

tions between the two are discussed in this ar-

ticle.

Keywords: Hürthle Cell Thyroid Cancer;

Hypothyroidism; Mycobacterium Avium Complex;

Cellular Immunity

1. INTRODUCTION

Hürthle cell thyroid carcinomas are a type of

well-differentiated thyroid carcinoma and are either

classified as a subset of follicular carcinoma or a sepa-

rate category of well-differentiated thyroid cancer [1].

Hürthle cell carcinomas usually produce thyroglobulin,

but are often less iodine avid, and are more aggressive

than the other types of well-differentiated thyroid carci-

noma such as papillary or follicular [2,3]. There is a fe-

male predominance with peak ages of incidence in the

seventh and eighth decades [2]. Specific treatment is

controversial, but generally total thyroidectomy and

remnant ablation is recommended [1]. Follow-up for

Hürthle cell thyroid cancer is similar to papillary and

follicular thyroid cancers, which entails anatomic imag-

ing of the neck and chest. This is usually done with neck

ultrasound and computed tomography (CT) scans of the

chest and occasionally neck; and when indicated,

TSH-stimulated I-131 whole body scan is performed.

Laboratory follow- up includes tumor marker evaluation

with serum thyroglobulin (Tg) and antibodies. Thyroid

hormone suppression is also a mainstay of therapy. De-

spite its more aggressive course, there are no known

associations between Hürthle cell thyroid cancer and

immunocompromised states; specifically, there are no

published reports of Hürthle cell thyroid carcinoma and

pulmonary MAC infection.

MAC refers to mycobacterium infections caused by

free-living nontuberculous organisms that are inhaled or

ingested from the environment [4]. Among nontubercu-

lous species, MAC is the most common cause of pul-

monary disease in the United States. Diagnosis of pul-

monary MAC requires both imaging consistent with

pulmonary disease and microbiologic confirmation in a

symptomatic patient to necessitate treatment [4]. In-

creased rates of MAC in immunocompromised patients

with AIDS were reported in the 1990s; however, with

improved anti-retroviral therapies, MAC infections in

HIV infected patients have been declining [5]. The in-

creased susceptibility of patients with AIDS to dissemi-

nated nontuberculous mycobacteria infections helps pro-

vide insight into the pathogenesis of these infections in

non-immunocompromised hosts. Disseminated MAC

infections usually occur when the CD4+ T-lymphocyte

count is < 50 µl, suggesting that some intrinsic activity

of the T-lymphocytes is important for immunity to my-

cobacteria [6]. We present two cases of pulmonary MAC

infection in octogenarian women with active Hürthle cell

thyroid carcinoma.

2. CASE 1

Case 1 is a 79 year-old female initially diagnosed with

stage 2 Hürthle cell carcinoma (pathologic stage T2N0M0)

in February 1999. She underwent total thyroidectomy

and remnant ablation with 100 mCi of I-131. Posttreat-

ment scan showed uptake in the central neck consistent

with thyroid remnant without evidence of local or distant

K. M. M. Baehr et al. / HEALTH 2 (2010) 391-394

392

metastases. She had no follow-up until 2006 when she

presented to our institution for evaluation of multiple

pulmonary nodules. Excisional biopsy of one of the le-

sions was consistent with metastatic Hürthle cell carci-

noma. Thyroid ultrasound showed no evidence of thy-

roid cancer in the neck. Thyroglobulin (Tg) was 136

ng/mL (goal < 0.1 ng/ml in remission) with negative anti-

thyroglobulin antibodies, and thyroid stimulating hor-

mone (TSH) of 11.5 mcIU/mL. I-123 whole body scan

showed uptake in the thyroid bed and superior medi-

astinum and stimulated Tg was 155 ng/mL. She under-

went repeat radioactive iodine ablation with 206 mCi of

I-131 using dosimetry to calculate her dose. Her post-

treatment scan showed heterogeneous uptake throughout

the lungs, most intense in the left lower lobe, and uptake

in the thyroid bed.

Despite successful uptake on radioactive iodine scans,

six months after treatment, Tg had risen to 341 ng/mL.

Repeat chest CT was unchanged. PET scan showed up-

take in the right middle lobe pulmonary nodule and bi-

lateral lower lobe lesions that were calcified with lower

SUVs suggesting more benign disease. Since most of the

pulmonary lesions were not PET avid, indicating they

were likely radioiodine avid, she received another 249.6

mCi of I-131 with dosimetry in March 2008. Post-

treatment scan showed faint uptake throughout the lungs

bilaterally, but no uptake to correspond with the largest

pulmonary nodules, suggesting the pulmonary metasta-

ses were no longer radioiodine avid. Following treatment,

Tg continued to rise and was 3976 ng/mL in July 2008

on thyroid hormone suppression. Follow-up chest CT

showed numerous pulmonary nodules, two lesions in-

creased in size in the right upper lobe, along with scat-

tered tree-in-bud opacities, bronchial wall thickening,

and bronchiectasis suggesting mycobacterium avium

complex (MAC). Induced sputum was culture positive

for MAC. The patient was referred to infectious disease

and no treatment was recommended since she was as-

ymptomatic.

A PET scan showed disease progression within the

mediastinum and right hilum with a maximum SUV of

12.4 in a subcarinal mass and multiple PET avid pulmo-

nary nodules. The hilar mass was felt to be

non-resectable, so she was treated with external beam

radiation therapy for her mediastinal mass and sensitiz-

ing chemotherapy with doxorubicin in November 2008.

After starting chemotherapy, she developed worsening

productive cough, chills, and fatigue and significant

oxygen desaturation. Since MAC was still present in her

sputum, she was started on triple antibiotic therapy

(azithromycin 500 mg daily, rifampin 300 mg daily, and

ethambutol 800 mg daily) for her symptomatic MAC in

January 2009. She has symptomatically improved and no

longer has a productive cough; however, continues to

require supplemental oxygen. Her most recent Tg was

1582 ng/ml (down from maximum 3976 ng/ml) with

negative antibodies and a TSH of 0.45 mcIU/ml. Chest

CT shows interval decrease in bilateral consolidations,

unchanged bilateral bronchiectasis and 2 right lower

lobe nodules, and a decrease in the subcarinal lymph

node size.

3. CASE 2

Case 2 is an 82 year-old female diagnosed with stage 2

Hürthle cell carcinoma (T3N0M0) in July 2004 and un-

derwent total thyroidectomy and remnant ablation with

45.8 mCi of I-131. Post-treatment scan showed only

uptake in the thyroid bed. In September 2005, she un-

derwent a TSH-stimulated (with thyrogen) whole body

scan that showed 1.6% minimal uptake in the area of the

thyroid bed. Tg stimulated to 0.2 ng/ml with a TSH of

315 mcIU/mL. She refused additional radioactive iodine

therapy due to severe sialoadenitis with the first treat-

ment. Thyroid ultrasound revealed residual thyroid tis-

sue in the right bed measuring 1.2 × 0.7 × 1.1 cm and no

evidence of focal nodules or lymphadenopathy.

Repeat thyroid ultrasounds in September 2006 and

August 2007 showed no evidence of recurrence. Tg level

ranged 0.3-0.8 ng/ml, antibodies remained negative, and

TSH ranged from undetectable to 3.6 mcIU/ml during

this time. Tg increased to 2.9 ng/mL in March 2008 with

an elevated TSH of 31.5 mcIU/ml; however, decreased

to 1.7 ng/mL in August 2008 (TSH 6.9 mcIU/ml) and

further to 1.5 ng/mL with a TSH of 0.14 mcIU/ml one

month later. Thyroid ultrasound in August 2008 showed

minimal right-sided residual thyroid tissue measuring

0.4 × 0.6 × 0.7 cm. Non-contrast chest CT showed a

right upper lobe semi-solid nodule measuring 1cm that

was suspicious for cancer. CT also revealed bronchiecta-

sis changes in anterior portions suspicious for MAC; and

her induced sputum was MAC culture positive. PET

scan was normal. After infectious disease consultation,

she was not treated for her MAC because she was as-

ymptomatic.

Follow-up chest CT in February 2009 showed stable

mixed solid and ground glass nodules in the right upper

lobe, bilateral patchy consolidations, and an enlarging

precarinal lymph node. This lymph node was biopsied

and pathology was negative for malignancy. Tg has con-

tinued to increase and is currently 8.4 ng/ml in August

2009, and TSH is 0.087 mcIU/ml. She is still asympto-

matic.

4. DISCUSSION

These cases are the first to report pulmonary MAC in-

fection in persons with active Hürthle cell thyroid carci-

noma. Interestingly, both these patients were asympto-

matic, octogenarian women and diagnosis was initially

suggested by radiographic findings and later confirmed

K. M. M. Baehr et al. / HEALTH 2 (2010) 391-394

393

with culture positive induced sputum. Typical radiologic

findings consistent with pulmonary MAC infection on

chest radiographs or computed tomography (CT) include

nodular infiltrates, multifocal bronchiectasis, cavitation,

and multiple small nodules [7]. The nodules and bron-

chiectasis are usually present within the same lobe and

occur most frequently in the right middle lobe and lin-

gula [8,9]. The keys to our patient’s diagnoses were the

presence of new, non-dependent bronchiectasis that was

different from the other pulmonary disease previously

seen on past CT scans.

Four different clinical syndromes of pulmonary MAC

infection have been described. These include classic

cavitary disease seen commonly in middle-aged smoking

males [6]; nonclassic forms such as bronchiectasis and

multiple nodules found in elderly women [6,8], MAC

lung disease in cystic fibrosis patients [10], and a hyper-

sensitivity pneumonitis associated with hot tub use [11].

The clinical syndrome that is most likely in our two

cases includes the group who presents with mid-lung

nodular bronchiectasis with multiple nodules and

tree-in-bud opacities due to MAC with no underlying

lung disease or immunosuppression. This bronchiectatic

form of the disease is frequently termed the “Lady Win-

dermere syndrome” and presents in slender, middle-aged

to elderly Caucasian women and involves the right mid-

dle lobe and/or lingula [6,12]. The first report of this

form of MAC cites 21 such patients, most non-smoking

women with a mean age of 66 years, who presented with

symptoms of persistent cough and purulent sputum [13].

This group is homogeneous, consisting of older, Cauca-

sian, otherwise healthy women, raising the possibility of

a host defense immune defect to explain disease suscep-

tibility [14]. Whereas mutations in the interferon-gamma

and interleukin-12 production and response pathway

have been proposed, no consistent immune phenotype in

pulmonary nontuberculous mycobacteria infection has

been clearly established [15]. Both of our patients were

Caucasian women in their late 70’s and early 80’s with

Hürthle cell thyroid carcinoma and no obvious form of

immunosuppression; however, they were both asymp-

tomatic which is in contrast to how the Lady Winder-

mere syndrome group usually present. There are no

studies linking thyroid cancer or its treatment with im-

munosuppression. However, Hürthle cell thyroid carci-

noma often has a more aggressive course than papillary

or follicular thyroid carcinoma [12] and tends to occur

more frequently in older women [2]. Case 1 had pulmo-

nary disease from her metastatic Hürthle cell carcinoma,

and case 2 had a pulmonary nodule, not definitively me-

tastatic thyroid cancer, so neither of the patients was

completely devoid of lung disease as described in the

Lady Windermere form of MAC pulmonary infection.

Another common feature for both cases was a pro-

longed period of hypothyroidism evidenced by an in-

creased TSH prior to diagnosis of MAC. Case 1 was

iatrogenically hypothyroid prior to both treatments with

radioactive iodine ablation using dosimetry in April

2007 and March 2008. Case 2 was hypothyroid due to

medication non-adherence from March through August

2008 which immediately preceded the diagnosis of pul-

monary MAC infection on chest CT. Animal studies

have shown a decrease in lymphocyte function during

hypothyroidism, with a return of normal lymphocyte

function during euthyroid states [16]. The number of

peripheral white blood cells, mainly lymphocytes, in

hypothyroid (thyroidectomized) animals is reduced to

half of normal levels [17]. Other studies have shown

dysregulation of CD4+ T lymphocyte responsiveness in

hypothyroid dogs suggesting a relationship between hy-

pothyroidism and cellular immunity [18]. Unfortunately

specific studies regarding cellular immunity in hypothy-

roid humans are lacking. Radioactive iodine treatment

can cause bone marrow suppression after treatment;

however, this happens in all types of thyroid cancer, not

exclusively Hürthle cell carcinoma, making it a less

likely etiology [19]. Given both women experienced

prolonged hypothyroidism immediately prior to their

diagnosis of MAC, we propose that the prolonged hypo-

thyroidism may have predisposed to suppression of

cell-mediated immunity in an already vulnerable host

(older, Caucasian women with potential lung pathology).

This may have resulted in both patients having an in-

creased susceptibility to acquire pulmonary MAC infec-

tion. There are no reports of altered immune function

associated with any thyroid carcinomas, and specifically

none that associate Hürthle cell thyroid carcinoma with

altered immune function; however, this is also a poten-

tial mechanism, especially given Hürthle cell thyroid

carcinoma often has a more aggressive course, and

should be considered and evaluated further. Also, ra-

diologic detection of MAC may be more common in

patients with more aggressive thyroid cancer due to

close monitoring of disease done by performing more

frequent radiographic scans.

5. CONCLUSIONS

To our knowledge, pulmonary MAC has not previously

been reported in association with any type of thyroid

cancer. We present two interesting cases of octogenarian

women with active Hürthle cell thyroid carcinoma who

developed pulmonary MAC infection after prolonged

periods of hypothyroidism. Further observations and

studies are necessary to understand the potential rela-

tionship between the two diseases.

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