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Dermatopathology: Practical & Conceptual

July – September 2010 | Volume 16, No. 3

What is the lesion and what is the syndrome (XI)?

González-Beato, María José

Introduction

There are syndromes that manifest themselves by one or more mucocutaneous lesions. When this is the case, the syndrome is likely to be diagnosed only if the dermatopathologist that encounters the lesion knows about these associations. Diagnosis of certain syndromes is still more important when they include malignant neoplasms. Moreover, as many syndromes are hereditary, diagnosis of one in a patient can mean the diagnosis of it in other family members.

In a series of articles, some of these mucocutaneous “clues” of syndromes are described, and the underlying conditions they can alert to are addressed. Previous articles of the series have already commented on the relationship between multiple tricholemmomas with Cowden’s syndrome, [1] multiple odontogenic keratocysts with nevoid basal-cell carcinoma syndrome, [2] tufted angioma with Kasabach-Merritt syndrome, [3] multiple fibrofolliculomas/trichodiscomas with Birt-Hogg-Dubé syndrome, [4] multiple fibrous papules of the face with tuberous sclerosis, [5] clear-cell syringomas with diabetes mellitus, [6] sebaceous adenoma / carcinoma with Muir-Torre syndrome, [7] multiple pilomatricomas with myotonic dystrophy, [8] myxomas with Carney’s complex, [9] and that between dermal clumps of basophilic distorted elastic fibers with pseudoxanthoma elasticum. [10]

The lesion

The following lesion, shown in two photographs, was located on the lower lip of a 7-year-old male (Figs. 1A-B).

Figs. 1A-B

What is the lesion? When multiple, what is the syndrome?

Answer

The diagnosis of the pictured lesion is neuroma on a mucous membrane.

Numerous mucosal neuromas are markers of multiple endocrine neoplasia type 2B.

Comment

Neuromas are nerve sheath tumors in which axons and Schwann cell fascicles are present approximately in the same numbers. Four types are distinguished: traumatic neuroma, rudimentary polydactyly, solitary neuroma, and neuroma associated with type 2B multiple endocrine neoplasia (MEN2B). [11]

Neuromas in MEN2B present as multiple 1-3 mm papules on the oral mucous membrane, often as raised bumps on the lips and tongue. On histopathology they have two presentations: They consist either of a single nodule on the submucosa made of well-developed nerve fascicles separated by a loose matrix, or they are prominent tortuous nerves with a thickened perineurium. [12]

The term “multiple endocrine neoplasia” or MEN includes several syndromes that characterize by co-presenting several endocrine gland tumors. Recently MEN4 has been added to the classical MEN1 and MEN2. [13]

All MEN2 varieties have in common the development of medullary thyroid carcinoma, an infrequent thyroid carcinoma that arises from the parafollicular (C) cells (Figs. 2A-B). Three distinct MEN2 syndromes are recognized: MEN2A, MEN2B (also known as MEN3) and familial medullary thyroid carcinoma. [14] MEN2 syndromes are transmitted in an autosomal dominant trait and they are due to germline activating mutations of the RET proto-oncogene on chromosome 10. [15,16]

Fig. 2A

In this figure, a normal thyroid is present on the bottom left corner and medullary thyroid carcinoma is the nodule on the right side.

Fig. 2B

At a closer look, medullary thyroid carcinoma is typified by round or polygonal cells with granular amphophilic cytoplasm and medium-sized nuclei with clumped chromatin. The tumor also displays a highly vascular stroma, hyalinized collagen and amyloid.

To medullary thyroid carcinoma, MEN2B associates pheochromocytoma in 50% of cases (Fig. 3). MEN2B is the most infrequent type of all MEN2 accounting for 5-10% of all cases, and it is estimated to occur in 1 in 1,000,000. In MEN2B, 50% of cases are estimated to be caused by de novo mutations. It is the most aggressive of all MENs and it may appear as early as in the first year of life. Other findings in these patients are mucocutaneous neuromas and hypertrophy of nerves, multiple intestinal ganglioneuromas, and a typical phenotype with characteristic facies and marfanoid habitus. [17] Patients have been reported to have inability to cry tears. [16]

Fig. 3

Pheochromocytoma is made of nests of cells that vary considerably in size and shape. They have a finely granular basophilic or amphophilic cytoplasm and pleomorphic and hyperchromatic nuclei with prominent nucleoli and inclusions.

Neuromas in MEN2B typically appear on mucous membranes and particularly on the tongue, lips, inner cheek, and inner eyelids. Confluence of these lesions leads to the “bumpy lips and eyelids” that contribute to the typical face of these patients. Diffuse intestinal ganglioneuromatosis is present in aproximately 40% and leads to loss of normal bowel tone and distention. A distinctive phenotype with slender build, long limbs, and high arched palate is in general described with the term “marfanoid habitus,” which associates joint laxity, scoliosis, and other skeletal deformations. [17]

In MEN2B, intestinal disturbances like chronic constipation or megacolon from birth are often initial manifestations. [18] Before age 6, the most common overt physical presentation is mucosal or tongue neuromas and foot abnormalities, each present in at least 60% of patients. All patients present the typical facies and 7.5% of patients have medullary thyroid carcinoma before age 7. By the age of 10 they already have regional lymph node or further metastases. After the teenage years chance for cure is remote. For this reason, the recommended age for prophylactic thyroidectomy in children with MEN2B is before 6 months of age or earlier. Thorough thyroidectomy and screening for concomitant pheochromocytoma is mandatory. [17,19]

Despite such early signs, the overwhelming majority of these patients fail to be diagnosed early due to physicians’ unfamiliarity with the disease and lack of family history in de novo cases. However, there exist few conditions in which early detection is as important.

Multiple mucocutaneous neuromas have also been described in PTEN hamartoma-tumor syndrome, in which they are usually extrafacial. [20]

Summary

Background: Some mucocutaneous lesions, usually when multiple, are clues to certain syndromes. Knowing about these relationships supposes early diagnosis of a number of syndromes that may still be unknown to the patient and, more importantly, are crucial if the syndrome bears malignant tumors. In addition, when the syndrome is hereditary, diagnosis of it benefits the whole family. Objectives: To make the associations between several mucocutaneous lesions and some syndromes familiar to the reader. Patients/Methods: Microscopic photographs of a mucosal neuroma are shown and are followed by a quiz about the underlying condition. Results: Multiple mucosal neuromas are a clue to type 2B multiple endocrine neoplasia that is characterized by medullary thyroid carcinoma in childhood. Conclusions: In MEN2B, medullary thyroid carcinoma has such early onset that there exist few conditions in which early detection is as important. As mucosal neuromas are a very early sign of this condition, all dermatopathologists should be familiar with their significance .

Dr. Beato is dermatopathologist at La Paz University Hospital in Madrid, Spain. This article was reviewed by Almut Böer-Auer, M.D., und Julia Röglin, M.D. Contact author via e-mail: mgbeato@yahoo.com .

References

1. González-Beato MJ. Quiz. What is the lesion and what is the syndrome (I)? Dermatopathology: Practical & Conceptual 2008;14(1):13. Available at: http://www.derm101.com.

2. González-Beato MJ. Quiz. What is the lesion and what is the syndrome (II)? Dermatopathology: Practical & Conceptual 2008;14(2):16. Available at: http://www.derm101.com.

3. González-Beato MJ. Quiz. What is the lesion and what is the syndrome (III)? Dermatopathology: Practical & Conceptual 2008;14(3):12. Available at: http://www.derm101.com.

4. González-Beato MJ. Quiz. What is the lesion and what is the syndrome (IV)? Dermatopathology: Practical & Conceptual 2008;14(4):17. Available at: http://www.derm101.com.

5. González-Beato MJ. Quiz. What is the lesion and what is the syndrome (V)? Dermatopathology: Practical & Conceptual 2009;15(1):10. Available at: http://www.derm101.com.

6. González-Beato MJ. Quiz. What is the lesion and what is the syndrome (VI)? Dermatopathology: Practical & Conceptual 2009;15(2):11. Available at: http://www.derm101.com.

7. González-Beato MJ. Quiz. What is the lesion and what is the syndrome (VII)? Dermatopathology: Practical & Conceptual 2009;15(3):7. Available at: http://www.derm101.com.

8. González-Beato MJ. Quiz. What is the lesion and what is the syndrome (VIII)? Dermatopathology: Practical & Conceptual 2009;15(4):11. Available at: http://www.derm101.com.

9. Beato MJ. Quiz. What is the lesion and what is the syndrome (IX)? Dermatopathology: Practical & Conceptual 2010;16(1):12. Available at: http://www.derm101.com.

10. Beato MJ. Quiz. What is the lesion and what is the syndrome (X)? Dermatopathology: Practical & Conceptual 2010;16(2):12. Available at: http://www.derm101.com.

11. Weedon D. Neural and neuroendocrine tumors. In: Weedon D, ed. Skin Pathology, 3rd ed. London: Churchill Livingstone, 2010:868-870.

12. Reed RJ, Fine RM, Meltzer HD: Palisaded, encapsulated neuromas of the skin. Arch Dermatol 1972;106:865-870.

13. Alevizaki M, Stratakis CA. Multiple endocrine neoplasias: advances and challenges for the future. J Intern Med 2009;266:1-4.

14. Moley JF, Traugott AL. Multiple endocrine neoplasia type 2: Clinical manifestations and management. Cancer Treatment and Research 2010;153:321-337.

15. Available at: http://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia, accessed 04/29/2010.

16. Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2. [Article in press] Familial Cancer, published online: 20 January 2010.

17. Wray CJ, Rich TA, Wagespack SG, et al. Failure to recognize multiple endocrine neoplasia 2B: More common than we think? Ann Surg Oncol 2008;15:293-301.

18. Lashgari AR, Friedlander SF. The importance of early diagnosis in multiple endocrine neoplasia III: Report of a case with thyroid C-cell hyperplasia. J Am Acad Dermatol 1997; 36(Pt 2):296-300.

19. Waguespack SG, Rich TA. Multiple endocrine syndrome type 2b in early childhood. Cancer 2010;116:2284.

20. Schaffer JV, Kamino H, Witkiewicz A, et al. Mucocutaneous neuromas: An underrrecognized manifestation of PTEN hamartoma-tumor syndrome. Arch Dermatol 2006;142:625-632.