A Collection of Thyroid Manifestations

Internuclear Ophthalmoplegia

Gregory M. Notz, DO, and Jing Cheng Zhao, MD

For a month, an obese 50-year-old woman with type 2 diabetes mellitus, hypercholesterolemia, and hypertension had blurry vision in both eyes. During this time, she also had ataxia and right-sided numbness. For the past 2 days, she had horizontal, binocular diplopia with right gaze.

Physical examination. Her examination revealed visual acuity of 20/40 in the right eye and 20/60 in the left eye, symmetrical 5 mm pupils, and no ptosis of either eyelid. Assessment of extraocular motility showed an adduction deficit of the left eye (Figure 1). Horizontal nystagmus occurred in the right eye with extreme right gaze. Left internuclear ophthalmoplegia was diagnosed, and a full neurological workup was undertaken.

Laboratory testing. A CT scan of the brain revealed 3 cm to 4 cm of vasogenic edema in the right posteroinferior parietal-occipital area. Axial T1-weighted (Figure 2) and T2-weighted (Figure 3) MRI images showed an enhancing lesion in the medial longitudinal fasciculus. A full-body CT scan was negative for malignancy. Lumbar puncture revealed oligoclonal bands in the cerebrospinal fluid; a workup for Lyme disease, Cryptococcus infection, fungal infection, HIV and other viral infections, and bacterial (including acid-fast bacilli) infection yielded negative results.

These results confirmed the suspected diagnosis of tumefactive (atypical) multiple sclerosis (MS). This rare form of demyelinating disease is characterized by atypical MRI findings of mass-like demyelination.¹ Patients with MS often present with unilateral or bilateral internuclear ophthalmoplegia² and typically report vague visual complaints, blurry vision, and—rarely—double vision. Signs include weakness or paralysis of adduction and horizontal jerk nystagmus of the abducting eye.

Discussion. Isolated decreased eye adduction is also associated with myasthenia gravis, thyroid-related eye disease, inflammatory pseudotumor, and tumors. Unilateral internuclear ophthalmoplegia is more common in elderly patients and is usually caused by a cerebral stroke.³

References: 

1. Selkirk SM, Shi J. Relapsing-remitting tumefactive multiple sclerosis. Mult Scler. 2005;11(6):731-734.
2. Keane JR. Internuclear ophthalmoplegia: unusual causes in 114 of 410 patients. Arch Neurol. 2005;62(5):714-717.
3. Kim JS. Internuclear ophthalmoplegia as an isolated or predominate symptom of brainstem infarction. Neurology. 2004;62(9):1491-1496.

Alopecia Areata
Robert P. Blereau, MD

A 32-year-old man presented with round, smooth, bald areas that had recently developed on his neck and chin. No other areas of the body were affected. The patient had a lifelong history of chronic anxiety. 

Discussion. He was diagnosed with alopecia areata of the beard, an area that is affected less often than the scalp. This disease usually occurs suddenly in persons younger than age 40 and may be at single or multiple sites. Typically, the skin is smooth or features poorly defined hair shafts that break easily at the skin surface. 

Microscopic examination of the hair demonstrates a normal upper shaft with a narrowed base and a lymphocytic perifollicular infiltrate. Regrowth often begins within several months; however, the condition can recur in the same or other locations. Patients with limited involvement have an excellent prognosis. 

The cause of alopecia areata is unknown. Although anxiety is frequently associated with the disorder and has been thought by some to be causative, at least 1 study found that stress has no significant role.¹ Associations between alopecia and thyroid disease, pernicious anemia, Addison disease, vitiligo, lupus erythematosus, ulcerative colitis, and Down syndrome have been noted.² 

Treatment. If the prognosis for regrowth is good, treatment is not necessary. In recalcitrant cases, intralesional corticosteroid injections can stimulate regrowth but may cause atrophy, and hair loss may recur. Other therapies that have shown some success include pulsed intravenous and oral corticosteroids, topical allergens, anthralin, minoxidil, oral or topical cyclosporine, nitrogen mustard, psoralen-UV-A therapy, and inosiplex. 

Outcome of the case. Paroxetine was prescribed to treat this patient’s anxiety but he did not return for follow-up.

References: 

1. van der Steen P, Boezeman J, Duller P, Happle R. Can alopecia areata be triggered by emotional stress? An uncontrolled evaluation of 178 patients with extensive hair loss. Acta Derm Venereol. 1992;72(4):279-280. 

2. Habif TP. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 3rd ed. St Louis, MO: Mosby; 1996:752-754.

Small-Cell Lung Cancer

Ronald N. Rubin, MD, and Bijoy Telivala, MD, MBBS

A 71-year-old man presented to the emergency department (ED) with chest pain, dyspnea, and hemoptysis. He had had a few ED visits for similar symptoms within the previous 4 weeks.

History. The patient had hypertension and a 40-pack-year smoking history; he currently smoked. There was no family history of malignancy.

Physical examination. Temperature was 36.8°C (98.3°F); heart rate of 86 beats per minute; respiration rate of 24 breaths per minute; and blood pressure of 120/70 mm Hg. Oxygen saturation was 98% on 2 liters of oxygen. Oral thrush was evident. There was no palpable lymphadenopathy. Heart rhythm was irregular with a loud P₂; there were no appreciable murmurs. Chest examination showed diffuse bilateral wheezes and dullness to percussion at both lung bases. There was no palpable hepatomegaly or splenomegaly. No pedal edema was noted. Results of a neurological examination were nonfocal.

Laboratory testing. White blood cell count was 3200/µL, hemoglobin level of 15.9 g/dL, and platelet count of 54,000/µL. The absolute neutrophil count was 900/µL. A chemistry panel revealed the following levels: sodium at 136 mEq/L, potassium at 3.4 mEq/L, chloride at 91 mEq/L, creatinine at 1.04 mg/dL, and calcium at 9.5 mg/dL. His coagulation profile showed a partial thromboplastin time of 28 seconds and an international normalized ratio of 1.0.

A CT scan of the chest showed an amorphous soft tissue mass that encased and constricted the right main pulmonary artery and the right main stem bronchus (Figure 1). Extensive round masses were visible in the liver; the largest mass was in the right medial hepatic lobe and measured 2.7 cm × 2.4 cm (Figure 2).

An extensive evaluation of the patient’s mass lesions and cytopenias was initiated. He was HIV-positive, but results of tests for hepatitis B and C were negative. Liver function tests revealed the following levels: albumin at 3.1 g/dL, total protein at 5.8 g/dL, direct bilirubin at 0.3 mg/dL, total bilirubin at 1.0 mg/dL, alkaline phosphatase at 175 U/L, alanine aminotransferase at 156 U/L, and aspartate aminotransferase at 92 U/L. Haptoglobin level was 27 mg/dL, and lactate dehydrogenase level was elevated at 1168 U/L. 

The fibrinogen level was normal at 274 mg/dL, but the D-dimer level was elevated at 602 ng/mL. Results of an enzyme-linked immunosorbent assay for heparin-induced platelet antibodies were negative. A review of the peripheral smear (Figure 3) showed no platelet clumping, schistocytes, or immature cells. Blood and urine cultures showed no bacterial or fungal growth.

Diagnosis. The central location of the lung mass, its rapid growth, and the patient’s strong smoking history all pointed to small-cell lung cancer. Also, there is a noted propensity for bone marrow involvement in small-cell lung cancer, which might have explained the patient’s neutropenia and thrombocytopenia.

Tissue was needed to confirm the diagnosis. The patient received a transfusion of 1 pool of platelets so that a CT-guided liver biopsy could be performed. The results of this biopsy were inconclusive. However, his platelet count rose dramatically in response to the transfusion—to 150,000/µL.

The patient then underwent a diagnostic bronchoscopy and a biopsy of the lung mass. The lung mass biopsy demonstrated small-cell lung carcinoma; immunohistochemical stains were positive for the neuroendocrine markers AE1/AE3, CAM5.2, cytokeratin 7, thyroid transcription factor-1, synaptophysin, chromogranin A, and CD 56.

Discussion. There are 2 major forms of lung cancer: small-cell lung cancer (SCLC) and non–small-cell lung cancer. SCLC accounts for a minority of lung cancer cases, and its incidence has gradually decreased over the past few decades. A Surveillance, Epidemiology, and End Results (SEER) database analysis has shown a decrease in the proportion of lung cancer cases represented by SCLC, from 17% in 1986 to 13% in 2002.¹ SCLC occurs mostly in heavy smokers. The decrease in the incidence of SCLC can be explained by the reduction in the rates of cigarette smoking in the United States.¹

SCLC is characterized by a high growth fraction, a rapid doubling time, and a propensity for early metastasis. Multiple classification systems for SCLC have been proposed. The most recent 1999 World Health Organization/International Association for the Study of Lung Cancer (WHO/IASLC) classification divides SCLC into 3 groups: classic small-cell carcinoma, large-cell neuroendocrine cancer, and combined small-cell carcinoma, consisting predominantly of small-cell cancer with a focal area of non-small-cell lung cancer.^2,3

Multiple genetic abnormalities have been described in SCLC. The most common of these are the p53 mutation, loss of heterozygosity at chromosome arms 9q and 10q, and loss of retinoblastoma gene function.^4,5

There are 2 major staging systems for SCLC. The one most commonly used is the Veterans Affairs Lung Study Group system, which divides SCLC into limited-stage disease and extensive-stage disease. Limited-stage disease is defined as disease confined to the ipsilateral hemithorax and within a single radiotherapy port. Extensive-stage disease is defined as evident metastatic disease outside the ipsilateral hemithorax; this may include malignant pleural or pericardial effusions.⁶ About 30% to 40% of patients have limited-stage SCLC at presentation. The other, more descriptive staging system, the TNM or IASLC system, is of limited value because of overlaps in treatment and prognosis among the various stages.

SCLC typically presents as a large central mass (as in this patient) with mediastinal adenopathy. SCLC can infiltrate the submucosa, causing either intrinsic or extrinsic compression of the bronchi. SCLC has a propensity for spreading to the liver, brain, bone, and bone marrow. The neutropenia and thrombocytopenia seen in this man can be explained by the infiltration of his bone marrow by the SCLC. In a series of 129 patients with SCLC, 30% had bone marrow involvement. However, in only 2.3% was the bone marrow the only site of metastatic disease.⁷ Other presenting symptoms include cough, dyspnea, hemoptysis, chest pain, postobstructive pneumonia, and the paraneoplastic syndromes mentioned above.

Treatment. The standard of care for the treatment of limited-stage SCLC is cytotoxic chemotherapy and thoracic radiation, administered concurrently. The most common chemotherapy regimen is cisplatin plus etoposide.⁸ The standard of care for the treatment of extensive-stage SCLC is generally cytotoxic chemotherapy with etoposide and either cisplatin or carboplatin. Various other chemotherapeutic agents are active against SCLC, including topotecan, paclitaxel, docetaxel, irinotecan, adriamycin, cyclophosphamide, and vincristine. In addition, prophylactic cranial irradiation is now considered standard of care for both limited-stage and extensive-stage SCLC.

SCLC is very sensitive to both chemotherapy and radiation; it responds well to treatment. However, in the majority of cases the disease recurs. Compared with its role in other forms of lung cancer, surgery has a very minimal role in the management of SCLC. There is only slight evidence to support surgery as a primary modality of treatment for limited-stage SCLC.

Outcome of the case. Unfortunately, his condition deteriorated during the hospital stay. His mental status started to wax and wane, progressive azotemia developed, and his neutropenia and thrombocytopenia continued to worsen. After a thorough discussion with the patient and his family, it was decided that he would not receive therapy for his cancer. He was transferred to an inpatient hospice service, and he died within 1 day.

References: 

1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24(28):4539-4544.
2. Travis WD, Colby TV, Corrin B, et al. Histological Typing of Lung and Pleural Tumors. 3rd ed. Berlin, Germany: Springer-Verlag; 1999.
3. Junker K, Wiethege T, Müller KM. Pathology of small-cell lung cancer. J Cancer Res Clin Oncol. 2000;126(7):361-368.
4. Wistuba II, Gazdar AF, Minna JD. Molecular genetics of small cell lung carcinoma. Semin Oncol. 2001;28(2 suppl 4):3-13.
5. Meyerson M, Franklin WA, Kelley MJ. Molecular classification and molecular genetics of human lung cancers. Semin Oncol. 2004;
6. 31(1 suppl 1):4-19.
7. National Comprehensive Cancer Network. Guidelines for the treatment of small cell lung cancer. 2010. www.nccn.org/professionals/physician_gls/f_guidelines.asp#site.Accessed October 8, 2015. 
8. Tritz DB, Doll DC, Ringenberg QS, et al. Bone marrow involvement with small cell lung cancer. Clinical significance and correlation with routine laboratory variables. Cancer. 1989;63(4):763-766.
9. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340(4):265-271.

Cowden Disease
David L. Sherr, MD

A patient presented with mucocutaneous lesions. The woman had metastatic breast carcinoma and was undergoing palliative radiation therapy. The lesions in these photographs were discovered during the radiation therapy along with a goiter and axillary skin tags, which are also well-described features of Cowden disease.

Discussion. Facial cutaneous papules and oral papillomas are the most constant diagnostic feature of Cowden disease (multiple hamartoma syndrome), a genodermatosis with an autosomal dominant pattern of inheritance. This disease is strongly associated with malignant tumors—especially those that involve the breast, thyroid, and GI and genitourinary tracts. 

Treatment. Because the mucocutaneous manifestations of Cowden disease generally precede the development of neoplasia, early recognition of these lesions may permit early intervention that may prevent malignancy or facilitate prompt detection of commonly associated malignancies.