- Email: [email protected]
Otolaryngologic manifestations of Cowden syndrome
644
Otolaryngology– Head and Neck Surgery November 2000
MALONE et al
Otolaryngologic manifestations of Cowden syndrome JAMES P. MALONE, MD, ROGER J. LEVIN, MD, and FRED G. FEDOK, MD, Hershey, Pennsylvania
A
46-year-old woman was referred to the otolaryngology– head and neck surgery clinic for evaluation and treatment of a previously diagnosed, poorly differentiated follicular thyroid car-
From the Division of Otolaryngology–Head and Neck Surgery, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine. Presented at the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, New Orleans, LA, September 26-29, 1999. Reprint requests: Roger J. Levin, MD, Associated Otolarynologists of Pennsylvania, 101 W Cherry St, Palmyra, PA 17078. Otolaryngol Head Neck Surg 2000;123:644-6. Copyright © 2000 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/2000/$12.00 + 0 23/4/108276 doi:10.1067/mhn.2000.108276
cinoma. The patient denied symptoms of hypothyroidism or hyperthyroidism, hoarseness, dysphagia, or shortness of breath. There was no history of exposure to ionizing radiation. She denied any family history of endocrine disorders or cancer. Her only medication was levothyroxine 0.150 mg daily. The patient had the following complex history of various endocrinopathies that were treated and managed at an outside institution. In 1969 she underwent a neck exploration and parathyroidectomy for hypercalcemia. She then began thyroid suppression therapy because of a nodular thyroid gland noted at the time of the neck exploration. Her hypercalcemia persisted despite the surgical intervention. Subsequently, a mediastinal dissection and thymectomy was performed, but she remained persistently hypercalcemic. In 1971 she had bilateral, simple mastectomies performed for “florid mammary dysplasia,” and her calcium level normalized. No further medical intervention was
Otolaryngology– Head and Neck Surgery Volume 123 Number 5
required until January 1994, when the patient noted progressive enlargement of the thyroid gland. A nuclear medicine scan demonstrated no uptake in the left thyroid lobe. A thyroid ultrasound revealed a 3.5 × 2.7 × 3.1 cm solid mass in the right thyroid lobe and an enlarged, inhomogeneous left thyroid lobe. Fineneedle aspiration was consistent with a follicular neoplasm. In May 1994 a left thyroid lobectomy was performed, and the pathology revealed a follicular adenoma. Two years later, the patient again noted enlargement in the region of the left thyroid lobe. An ultrasound of the neck demonstrated a 4.8 × 2.9 cm solid mass at the previous site of the left thyroid lobectomy and no change in the right thyroid lobe mass. Fine-needle aspiration was suspicious for malignant cells. Her surgeon performed a neck exploration and encountered a large mass in the left neck adherent to the surrounding structures. The mass was deemed unresectable, and an incisional biopsy specimen was obtained. The pathology revealed a poorly differentiated neoplasm that was positive for cytokeratin and thyroglobulin on immunostaining. She was subsequently referred to our institution for evaluation. Physical examination demonstrated macrocephaly with a head circumference of 60 cm (>98th percentile). Numerous flesh-colored papules covered the face. There were papillomatous changes on the gingiva and cobblestoning on the dorsal surface of the tongue. A 7 × 4 cm, firm, mobile mass was noted in the region of the left thyroid bed. There were no other palpable masses in the neck. Flexible laryngoscopy revealed a complete left, true vocal cord paralysis with good compensation by the contralateral vocal cord. The remainder of the head and neck examination was normal. An enhanced CT scan of the neck demonstrated a 4.2 × 3.0 cm heterogeneous, calcified mass in the right submandibular/sublingual region and a 4.7 × 4.8 cm partially necrotic mass deep to the left sternocleidomastoid muscle extending from the level of the hyoid bone to the thoracic inlet with displacement of the larynx and trachea. On the basis of the above findings, the patient underwent a total thyroidectomy and a right selective neck dissection in April 1997. During surgery, a densely scarred thyroid mass was found adherent to the strap muscles and carotid sheath. There were multiple enlarged right jugular chain lymph nodes. In addition, a completely separate mass was excised deep to the hyoglossus muscle and within the substance of the tongue. Pathologic examination revealed an atypical, spindle-shaped follicular adenoma of the left thyroid gland and multinodular goiter in the right thyroid gland. There was no evidence of malignancy in 18 of 18 lymph nodes. The right submandibular mass was a calcified arteriovenous malformation. Metastatic endometrial cancer subsequently developed in this patient, and she was treated with chemotherapy. Currently, she is alive with chemotherapeutic control of her endometrial cancer. Based on the patient’s medical history and physical findings, Cowden syndrome (CS) was diagnosed. Evaluation of
MALONE et al
645
Table 1. Otolaryngologic manifestations of CS Facial trichilemmomas/papules Oral cavity papules Goiter Thyroid adenoma Nonmedullary thyroid carcinoma Parathyroid adenoma Macrocephaly Adenoid facies High-arched palate Basal cell carcinoma Squamous cell carcinoma Merkel cell carcinoma Arteriovenous malformation Hemangioma
her daughter revealed macrocephaly, the presence of facial trichilemmomas, and papillomatous changes of the tongue and oral cavity mucosa. Both mother and daughter are undergoing genetic counseling to identify family members at risk. DISCUSSION CS is a hereditary, autosomal dominant, multiple hamartoma/familial cancer syndrome involving multiple organ systems. The clinical features vary widely, with many manifestations presenting in the head and neck region. Benign neoplasms and hamartomas are commonly found in the skin and mucous membranes, thyroid gland, breast, gastrointestinal tract, genitourinary tract, and nervous system in patients with this disorder.1-3 More importantly, patients with CS are at increased risk for the development of several malignancies. Carcinomas of the thyroid gland and breast appear to be the most frequently reported cancers. There is a 10% lifetime risk of thyroid cancer, especially follicular thyroid carcinoma, and a 25% to 50% risk in women of developing adenocarcinoma of the breast.3 Malignancies of the skin, central nervous system, gastrointestinal tract, genitourinary tract, and lungs may also occur. Many of the diagnostic features of CS appear in the head and neck region (Table 1). These findings typically present in the third decade of life and should alert the otolaryngologist to a possible diagnosis of CS and prompt further investigation for underlying malignancies. Mucocutaneous changes are a constant feature, occurring in 99% to 100% of patients with CS, and may be considered pathognomonic.1,3 Papillomatous changes in the oral cavity can involve the gingiva, buccal mucosa, and tongue, creating a cobblestone appearance. Facial trichilemmomas appear as firm, yellow-tan papules that may involve the entire face. Macrocephaly (>97th percentile) is present in approximately 80% of patients and may be confused for hydrocephalus.1 Other reported craniofacial abnormalities include a high, arched palate and adenoid facies. Thyroid disorders are common, occurring in 50% to 67% of patients, and include goiter, adenoma, and nonmedullary thyroid carcinoma.3 Parathyroid adenomas may develop, and vas-
Otolaryngology– Head and Neck Surgery Volume 123 Number 5
cular anomalies such as arteriovenous malformation and hemangiomas may also occur.4,5 The gene for CS has been localized to chromosome 10q2223. This gene, called PTEN (phosphate and tensin homolog deleted on chromosome 10), is believed to be a tumor-suppressor gene.3 Alterations in the PTEN gene also have been identified in other hamartomatous syndromes such as PeutzJeghers syndrome and juvenile polyposis syndrome. Because CS is an autosomal dominant trait, family members should receive genetic counseling, and genetic susceptibility testing is available. Finally, persons at risk for CS should undergo routine cancer surveillance given the increased risk for the development of breast, thyroid, and other malignancies. In summary, otolaryngologists should have an increased awareness of the manifestations of CS in the head and neck. Prompt diagnosis is important because of the increased risk
ANDERSON and WEINSTEIN
646
and possibly earlier development of thyroid and breast cancer. Patients and their families should be counseled, and those who are at risk should undergo routine surveillance for these cancers. Susceptibility gene testing is available and may assist in identifying family members at risk. REFERENCES 1. Mallory S. Cowden syndrome (multiple hamartoma syndrome). Dermatol Clin 995;13:27-31. 2. Porter S, Cawson R, Scully C, et al. Multiple hamartoma syndrome presenting with oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:295-301. 3. Eng C. Genetics of Cowden syndrome: through the looking glass of oncology [review]. Int J Oncol 1998;12:701-10. 4. Hamby L, Lee E, Schwartz R. Parathyroid adenoma and gastric carcinoma as manifestations of Cowden’s disease. Surgery 1995; 118:115-7. 5. Hanssen A, Fryns J. Cowden syndrome. J Med Genet 1995;32: 117-9.
Otolaryngology– Head and Neck Surgery November 2000
MALONE et al
Otolaryngologic manifestations of Cowden syndrome JAMES P. MALONE, MD, ROGER J. LEVIN, MD, and FRED G. FEDOK, MD, Hershey, Pennsylvania
A
46-year-old woman was referred to the otolaryngology– head and neck surgery clinic for evaluation and treatment of a previously diagnosed, poorly differentiated follicular thyroid car-
From the Division of Otolaryngology–Head and Neck Surgery, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine. Presented at the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, New Orleans, LA, September 26-29, 1999. Reprint requests: Roger J. Levin, MD, Associated Otolarynologists of Pennsylvania, 101 W Cherry St, Palmyra, PA 17078. Otolaryngol Head Neck Surg 2000;123:644-6. Copyright © 2000 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/2000/$12.00 + 0 23/4/108276 doi:10.1067/mhn.2000.108276
cinoma. The patient denied symptoms of hypothyroidism or hyperthyroidism, hoarseness, dysphagia, or shortness of breath. There was no history of exposure to ionizing radiation. She denied any family history of endocrine disorders or cancer. Her only medication was levothyroxine 0.150 mg daily. The patient had the following complex history of various endocrinopathies that were treated and managed at an outside institution. In 1969 she underwent a neck exploration and parathyroidectomy for hypercalcemia. She then began thyroid suppression therapy because of a nodular thyroid gland noted at the time of the neck exploration. Her hypercalcemia persisted despite the surgical intervention. Subsequently, a mediastinal dissection and thymectomy was performed, but she remained persistently hypercalcemic. In 1971 she had bilateral, simple mastectomies performed for “florid mammary dysplasia,” and her calcium level normalized. No further medical intervention was
Otolaryngology– Head and Neck Surgery Volume 123 Number 5
required until January 1994, when the patient noted progressive enlargement of the thyroid gland. A nuclear medicine scan demonstrated no uptake in the left thyroid lobe. A thyroid ultrasound revealed a 3.5 × 2.7 × 3.1 cm solid mass in the right thyroid lobe and an enlarged, inhomogeneous left thyroid lobe. Fineneedle aspiration was consistent with a follicular neoplasm. In May 1994 a left thyroid lobectomy was performed, and the pathology revealed a follicular adenoma. Two years later, the patient again noted enlargement in the region of the left thyroid lobe. An ultrasound of the neck demonstrated a 4.8 × 2.9 cm solid mass at the previous site of the left thyroid lobectomy and no change in the right thyroid lobe mass. Fine-needle aspiration was suspicious for malignant cells. Her surgeon performed a neck exploration and encountered a large mass in the left neck adherent to the surrounding structures. The mass was deemed unresectable, and an incisional biopsy specimen was obtained. The pathology revealed a poorly differentiated neoplasm that was positive for cytokeratin and thyroglobulin on immunostaining. She was subsequently referred to our institution for evaluation. Physical examination demonstrated macrocephaly with a head circumference of 60 cm (>98th percentile). Numerous flesh-colored papules covered the face. There were papillomatous changes on the gingiva and cobblestoning on the dorsal surface of the tongue. A 7 × 4 cm, firm, mobile mass was noted in the region of the left thyroid bed. There were no other palpable masses in the neck. Flexible laryngoscopy revealed a complete left, true vocal cord paralysis with good compensation by the contralateral vocal cord. The remainder of the head and neck examination was normal. An enhanced CT scan of the neck demonstrated a 4.2 × 3.0 cm heterogeneous, calcified mass in the right submandibular/sublingual region and a 4.7 × 4.8 cm partially necrotic mass deep to the left sternocleidomastoid muscle extending from the level of the hyoid bone to the thoracic inlet with displacement of the larynx and trachea. On the basis of the above findings, the patient underwent a total thyroidectomy and a right selective neck dissection in April 1997. During surgery, a densely scarred thyroid mass was found adherent to the strap muscles and carotid sheath. There were multiple enlarged right jugular chain lymph nodes. In addition, a completely separate mass was excised deep to the hyoglossus muscle and within the substance of the tongue. Pathologic examination revealed an atypical, spindle-shaped follicular adenoma of the left thyroid gland and multinodular goiter in the right thyroid gland. There was no evidence of malignancy in 18 of 18 lymph nodes. The right submandibular mass was a calcified arteriovenous malformation. Metastatic endometrial cancer subsequently developed in this patient, and she was treated with chemotherapy. Currently, she is alive with chemotherapeutic control of her endometrial cancer. Based on the patient’s medical history and physical findings, Cowden syndrome (CS) was diagnosed. Evaluation of
MALONE et al
645
Table 1. Otolaryngologic manifestations of CS Facial trichilemmomas/papules Oral cavity papules Goiter Thyroid adenoma Nonmedullary thyroid carcinoma Parathyroid adenoma Macrocephaly Adenoid facies High-arched palate Basal cell carcinoma Squamous cell carcinoma Merkel cell carcinoma Arteriovenous malformation Hemangioma
her daughter revealed macrocephaly, the presence of facial trichilemmomas, and papillomatous changes of the tongue and oral cavity mucosa. Both mother and daughter are undergoing genetic counseling to identify family members at risk. DISCUSSION CS is a hereditary, autosomal dominant, multiple hamartoma/familial cancer syndrome involving multiple organ systems. The clinical features vary widely, with many manifestations presenting in the head and neck region. Benign neoplasms and hamartomas are commonly found in the skin and mucous membranes, thyroid gland, breast, gastrointestinal tract, genitourinary tract, and nervous system in patients with this disorder.1-3 More importantly, patients with CS are at increased risk for the development of several malignancies. Carcinomas of the thyroid gland and breast appear to be the most frequently reported cancers. There is a 10% lifetime risk of thyroid cancer, especially follicular thyroid carcinoma, and a 25% to 50% risk in women of developing adenocarcinoma of the breast.3 Malignancies of the skin, central nervous system, gastrointestinal tract, genitourinary tract, and lungs may also occur. Many of the diagnostic features of CS appear in the head and neck region (Table 1). These findings typically present in the third decade of life and should alert the otolaryngologist to a possible diagnosis of CS and prompt further investigation for underlying malignancies. Mucocutaneous changes are a constant feature, occurring in 99% to 100% of patients with CS, and may be considered pathognomonic.1,3 Papillomatous changes in the oral cavity can involve the gingiva, buccal mucosa, and tongue, creating a cobblestone appearance. Facial trichilemmomas appear as firm, yellow-tan papules that may involve the entire face. Macrocephaly (>97th percentile) is present in approximately 80% of patients and may be confused for hydrocephalus.1 Other reported craniofacial abnormalities include a high, arched palate and adenoid facies. Thyroid disorders are common, occurring in 50% to 67% of patients, and include goiter, adenoma, and nonmedullary thyroid carcinoma.3 Parathyroid adenomas may develop, and vas-
Otolaryngology– Head and Neck Surgery Volume 123 Number 5
cular anomalies such as arteriovenous malformation and hemangiomas may also occur.4,5 The gene for CS has been localized to chromosome 10q2223. This gene, called PTEN (phosphate and tensin homolog deleted on chromosome 10), is believed to be a tumor-suppressor gene.3 Alterations in the PTEN gene also have been identified in other hamartomatous syndromes such as PeutzJeghers syndrome and juvenile polyposis syndrome. Because CS is an autosomal dominant trait, family members should receive genetic counseling, and genetic susceptibility testing is available. Finally, persons at risk for CS should undergo routine cancer surveillance given the increased risk for the development of breast, thyroid, and other malignancies. In summary, otolaryngologists should have an increased awareness of the manifestations of CS in the head and neck. Prompt diagnosis is important because of the increased risk
ANDERSON and WEINSTEIN
646
and possibly earlier development of thyroid and breast cancer. Patients and their families should be counseled, and those who are at risk should undergo routine surveillance for these cancers. Susceptibility gene testing is available and may assist in identifying family members at risk. REFERENCES 1. Mallory S. Cowden syndrome (multiple hamartoma syndrome). Dermatol Clin 995;13:27-31. 2. Porter S, Cawson R, Scully C, et al. Multiple hamartoma syndrome presenting with oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:295-301. 3. Eng C. Genetics of Cowden syndrome: through the looking glass of oncology [review]. Int J Oncol 1998;12:701-10. 4. Hamby L, Lee E, Schwartz R. Parathyroid adenoma and gastric carcinoma as manifestations of Cowden’s disease. Surgery 1995; 118:115-7. 5. Hanssen A, Fryns J. Cowden syndrome. J Med Genet 1995;32: 117-9.