Multiple hamartoma syndrome: clinicoradiological evaluation and histopathological correlation with brief review of literature.

Cowden syndrome (CS) or multiple hamartoma syndromes (MHSs) is an uncommon condition and characterized by mucocutaneous lesions which may be associated with the lesions of breast, thyroid, gastrointestinal tract, skin, and often of central nervous system. A thorough evaluation of Cowden's disease is essential due to increased risk of malignancy in an organ or system of the affected patients. We are reporting a case of female patient who presented with multiple mucocutaneous papilloma associated with involvement of multiple organs and systems. The diagnosis was confirmed by multimodality diagnostic approach. This rare entity has not being reviewed in Indian literature till date. Being a rare case, we are discussing MHS with its clinicoradiological and histopathological correlation along with brief review of literature.

What was known?

Cowden syndrome is now well recognized as a highly variable, autosomaldominant hereditary cancer suscep-tibility syndrome that is characterized by multiple hamartomas and an increased risk of developing malignant transformations.

Introduction

Cowden's syndrome (CS) or multiple hamartoma syndromes (MHSs) is an uncommon autosomal dominant disorder and is characterized by hamartoma and neoplasm of ectodermal, mesodermal, or endodermal origin, affecting the multiple organs and systems.[1] Patients may present in their teens or early 20s, but almost all patients present in their late 30s with prevalence rate of 1 per 200,000 patients. Clinically, the patient presents with mucocutaneous lesions which are associated with lesions of gastrointestinal tract (GIT), thyroid, breast, and central nervous system. Eighty percent of patients have a mutation in the tumor suppressor gene phosphatase and tensin homolog, which is located on long arm of chromosome 10q22-23.[2] MHS has not been discussed in Indian literature till date. We are reporting this rare case of MHS with a brief review of literature.

Case Report

A 19-year-old female was referred to Radiodiagnosis and Imaging Department of our hospital for a diagnostic work up. She was presented with papillomatous lesions clustered on lower lip, papules on face and forehead, trichilemmomas, and multiple keratotic papules on tongue and palate, with history on recurrent episode of vomiting and diarrhea for past one year. She also gave history of palpable nodules of thyroid gland and breast. Her family history and genetic history were evaluated by a genetic councillor, which was unremarkable.

Clinical examination revealed multiple tiny (1-2 mm) nodules on forehead, nose, and maxillary region with pallor (anemia). The right half of lower lip showed cluster of papillomatous lesions [Figure 1]. There were keratotic papules on tongue and palatal surface along with thickening and furrowing of tongue [Figure 2]. Soft palpable nodules on palm and acral keratoses were also seen [Figure 3]. Both breasts and lobes of thyroid gland also showed small and palpable multiple nodules. The nodules in the breast were mobile without any change on overlying skin or nipple areola complex. Other systemic examination was unremarkable and no evidence of any lymphadenopathy was shown.

Figure 1

Mucocutaneous lesions on lip

Figure 2

Papules and furrowing on tongue

Figure 3

Nodules on palm

Hematological examination showed microcytic hypo chromic blood smear and hemoglobin concentration was 8 gm/dl with hematocrit value of 25%, which showed marked anemia. All other hematological and serological examinations, including thyroid profile, were within the limits of normal.

High resolution ultrasonography of breast and thyroid was done. In breast, multiple hypoechoic areas were shown in the ducts with complex cystic areas having solid eccentric region, occupying 50% of the cystic area [Figure 4]. The axillary region showed hypoechoic nodules and oval lymph nodes with echogenic hilum. Both the lobes of thyroid showed multiple echogenic and few cystic nodules with finger-like projections within the lumen [Figure 5]. High resolution sonography (HRS) of the region of palm also showed such hypoechoic nodular lesion [Figure 6]. All the hypoechoic areas were of low vascularity on color Doppler. General abdominal ultrasonography was within the limits of normal.

Figure 4

Breast nodules on USG

Figure 5

Nodule in thyroid lobes with low vascularity on USG

Figure 6

Nodules in the region of palm on USG

Barium studies showed multiple sessile, smoothly outlined polyps in the body of stomach, antrum, and jejunal regions. Few polyps were also seen in colon [Figure 7]. These were confirmed by upper G.I. endoscopy and colonoscopy. Endoscopy showed multiple polypoid lesions with smooth overlying mucosal surface. These nodules were hyperplastic, sessile, and adenomatous fibroid type. All these lesions were 2-5 mm in size in upper G.I. region and 2-8 mm in colonic region [Figure 8].

Figure 7

Barium examination shows polyps in stomach and colon

Figure 8

Upper GI endoscopy showing polyps in stomach and duodenal region

Computed tomography and magnetic resonance imaging were unremarkable.

Fine needle aspiration cytology (FNAC) and histopathological examinations of these different lesions have shown hyper keratinized epithelium with normal collagen and fibroadenomatoid hyperplasia of breast lesions.

Discussion

MHSs or Cowden's Syndrome is a multisystem disorder which involves the risk of malignancies and hamartomatous overgrowth of various tissues.[1] It was first described in 1963 by Lloyd and Denis and was named after the family in which it was reported.[3] Nothing much appeared in the literature until Weary et al. in 1972 reported five cases and coined a new terminology “Multiple Hamartoma Syndrome.”[4] The estimated prevalence of CS is to be between 1/200,000. The diagnostic criterion was initially presented by Salem and Steck.[5] The patients’ mucocutaneous lesions are considered to be diagnostic criterion of the disease and associated facial trichilemmoma are pathognomonic of MHS. The keratotic papules around the mouth and nose, oral mucosal papillomatoses, acral keratoses, and multiple sclerotic fibromas are the most characteristic lesions as an external marker for CS.[67] All these external features develop much before the internal and neoplastic manifestation of the disease.[8] All these features were evident in the present case, which are pathognomonic diagnostic criterion of MHS.

An extra-cutaneous abnormality as goitres and adenomas of thyroid gland is presented in 65% of patients. Both men and women are affected equally. Out of these, only 10% of the patients, usually females are reported for thyroid carcinoma, commonly with follicular and papillary carcinoma subtypes.[12345678]

Breast lesions are common in about 70% of women with MHS and fibrocystic disease is the most common findings, occurring in 50% of patients. Carcinoma of breast, often bilateral ductal cancer, is the most common malignant tumour in MHS, occurring in 25-50% of patients.[9]

Seventy to eighty per cent cases of MHS presents with polyps in all parts of GIT with frequent variable histology pattern of hamartomas, hyperplastic polyps, and adenomatous polyps, and less frequently followed by lipomas, ganglio-neuromas, and inflammatory fibroid polyps. When presented as hyperplastic polyps, they are usually located in the stomach or colon. These polyps are usually sessile and smaller, with less exophytic and arborizing proliferation of the muscularis mucosae. Hamartomas polyps are the most commonly described polyps in MHS. Radiographically these polyps are seen as multiple small sessile lesions with a segmental or diffuse distribution. They are commonly located in recto sigmoid colon, followed by the stomach, duodenum, small bowel, and esophagus, in decreasing order of frequency. MHS is described as rare cause of developing malignancy.[10]

The present case has an involvement of thyroid gland, breast, and GIT along with other pathognomonic major and minor criterion.

Some other rare lesions are also reported in MHS such as meningiomas, vascular malformations, macrocephaly, and lesions of genitourinary tract.[11] Smooth muscle hamartoma (SMH) is a proliferative disorder of cells originating from muscle cells and has also been reported as benign tumoral mass presenting as a single congenital skin-colored hypertrichotic plaque involving the trunk and extremities.[12]

The Lhermitte-Duclos disease (dysplastic gangliocytomas of cerebellar cortex), readily diagnosed by MRI, is also considered as pathognomonic criterion for the diagnosis of MHS.[13]

Conclusion

CS or MHS is a multiorgan and multisystem disease which presents as mucocutaneous lesions and involves thyroid, breast and GIT commonly. These lesions should be evaluated with multimodality imaging approach by Ultrasonography, Barium Studies, Computed Tomography and Magnetic Resonance Imaging along with clinical examination, endoscopic examination and histopathological correlation for an early diagnosis and management as well as to rule out any malignant changes in any organ or system.

What is new?

Though Cowden Syndrome is a multi-organ involvement syndrome, most of the literature reported either involvement of one or two organ/system. But in present case five different system were involved, perhaps a rarity, so an adequate screening for the organs known to develop malignancies in Cowden syndrome should be carried out in suspected patients. Even when benign lesions are suspected, the potential for malignant lesions must be kept in mind, and further pathologic examination and surgical resection should be aggressively performed without reservation.