A case of co-existing paraganglioma and thymoma

HPGLs overall are rare tumours and are known to have hereditary-familial tendency.
Their association with thymic tumour is not well known. To our knowledge thymoma associated
with paraganglioma has been reported only once before in the literature (Refior and
Mees 2000]) and we report this second case of HPGL coexisting with a thymic tumor in an adult
patient. Her mediastinal tumour was initially growing slowly and she was asymptomatic.
5 years after her initial surgery for paraganglioma she developed symptoms suggestive
of compression of anterior mediastinal structures, autoimmune pathology and her imaging
showed increase in the size of her mediastinal tumour. The tumor was presumed to be
benign as there was no metastasis (i.e., lymph node or distant metastases) after imaging.
Our patient had extensive biochemical testing. The mediastinal mass was not MIBG avid
and her urinary metanephrines were normal. Her genetic testing for hereditary paragangliomas
has been negative so far. For the coexistence of HPGLS and such tumors a common neuroectodermal
origin has been proposed as an explanation. The hypothesis is supported by combined
(mixed) thymoma-neuroendocrine tumours and the occurrence of either thymomas or thymic
neuroendocrine tumours in MEN1 syndrome patients (Rashid and Cassano 2013]).

Thymus has an important role in the development of an effective immune system as well
as endocrine function. Thymus has two main components; the lymphoid thymocytes and
the thymic epithelial cells. The thymic epithelium develops first from the third pharyngeal
pouch as two flask-shaped endodermal diverticula and extend laterally and backward
into the surrounding mesoderm and neural crest-derived mesenchyme. The mature thymus
epithelium has two main cell types: cortical thymic epithelial (cTECs) and medullary
thymic epithelial cells (mTECs) or stromal cells. These thymic stromal cells provide
signals for T cell differentiation. During the late stages of the development of the
thymic epithelium, hematopoietic bone marrow precursors migrate into the thymus. After
this stage the normal thymic development is dependent on the interaction between the
thymic epithelium and the hematopoietic thymocytes (Farley et al. 2013]). Tumours of the thymus are extremely rare and comprise 1 % of all adult cancers.
Thymoma is a benign tumour but has a malignant potential. There are two major types
of thymoma depending on the neoplastic epithelial cell type. In type A thymoma the
cells and their nuclei have a spindle or oval shape, and are uniformly bland. In type
B thymoma the cells have a predominantly round or polygonal appearance. In 50 % of
cases thymoma is detected as an incidental finding on imaging. It constitutes about
20 % of the mediastinal tumours so the differential diagnosis includes paraganglioma.
In 95 % of cases it presents as an anterior mediastinal mass. Thymic tumours occur
at almost all ages (range 7–89 years) with a peak incidence between 55 and 65 years.
There is no pronounced sex predilection. Patients exhibit an increased incidence of
second cancers irrespective of the histology of the thymic epithelial tumour. The
etiology of thymic tumours is largely unknown. Some epidemiologic clustering of thymomas
and neuroendocrine tumours has been observed among patients with multiple endocrine
neoplasia (MEN1) syndrome. Epstein–Barr virus (EBV) infection may play a role in a
minority of thymic carcinoma. Symptoms can be due to local complications such as superior
vena cava syndrome, pleural or pericardial effusions or patients may have systemic
symptoms such as fever or weight loss (Mikhail et al. 2012]). In addition, thymomas can cause parathymic syndrome in 40 % of cases. These syndromes
are often typical for a specific tumour type and may precede or follow thymoma resection.
Thymomas can exhibit a spectrum of autoimmune phenomena, comprising neuromuscular,
haematopoietic, dermatologic, rheumatic/vasculitic, hepatic and renal diseases. These
are more commonly seen in type A and B thymomas as in our patient. Myasthenia gravis
is more frequently associated with type B thymomas, while hypogammaglobulinaemia (Good
syndrome) and pure red cell aplasia are more typical for type A thymoma. 20 % of patients
can have non thymic cancers. Thymic carcinomas can occasionally be associated with
syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Carcinoid a neuroendocrine
tumour of the thymus is well reported. One-third of these patients have Cushings syndrome
due to ectopic ACTH production. 15 % of carcinoids can be associated with multiple
endocrine neoplasia (MEN) syndromes mostly with MEN type 1 and some with MEN type
2. Thymic carcinoid tumours associated with MEN syndromes are mostly malignant and
can present with bony metastasis (Kaltsas 2010]).

Recurrent genetic alterations have so far been reported for thymomas as well as for
thymic squamous cell carcinoma. Deletions of chromosome 6p are reported with type
A thymoma and gains of chromosome 1q and losses of chromosomes 6 and 13q are reported
with type B3 thymomas (Zettl et al. 2000]).

Paragangliomas (PGLs) are found mostly in the neck and abdomen, less commonly in the
pelvic sympathetic plexus of the urinary bladder, and rarely in the mediastinum. PGLs
may occur sporadically or as part of a hereditary syndrome. 60 % can develop metastatic
disease, indicating that these tumors are often aggressive and need follow up (Ghayee
et al. 2009]). Only 2 % of PGLs are found in the mediastinum and are associated with germ line
mutations in either SDHB or SDHD. 30 % are associated with elevated catecholamines
or metanephrines. Multiple endocrine neoplasia type 2, neurofibromatosis type 1, and
von Hippel–Lindau syndrome are familial syndromes that predominantly predispose to
adrenal pheochromocytomas. In our patient metanephrines were normal. Mutations in
the genes encoding succinate dehydrogenase (SDH) subunits B, C, and D cause extra-adrenal
PGLs. Other recently identified genes associated with PGLs are SDHA and TMEM127 (Offergeld
et al. 2012]).

The common neuroectodermal origin is thought to be the reason for coexistence of carotid
body tumour and a thymic tumour as in our patient. This was proposed in the first
case who presented with bilateral carotid body tumor, thyroid adenoma and a thymoma
(Refior and Mees 2000]). Neuroectodermal tumours are part of a family of tumours characterized by genotypic,
immunophenotypic, and functional properties of neuroendocrine differentiation. Within
thymus such tumors comprise lesions derived from neuroendocrine elements within the
thymus, from paraganglionic rests, or from misplaced embryonal structures within the
mediastinum. The most common neuroendocrine neoplasm of this anatomic region is the
neuroendocrine carcinomas of the thymus which is relatively rare (Moran and Suster
2000]). Such tumors can often also be the source of hormone secretion, either because of
adrenocorticotrophic hormone (ACTH) secretion by the thymic carcinoid itself or its
association with other endocrine neoplasms. These tumors manifest in one of four ways:
(1) they may be asymptomatic, found incidentally on routine chest radiography, (2)
they may produce symptoms of thoracic structure displacement or compression, (3) they
may present with symptoms related to an associated endocrinopathy, or (4) they may
present with symptoms and signs relating to a distant metastasis, most commonly to
the liver, lung, pancreas, pleura, and bone. It has been estimated that over one-third
of patients are asymptomatic and are incidentally discovered (Duh et al. 1987]). More rarely, the mediastinum also can be the seat of tumors derived from aorticopulmonary
or aorticosympathetic paraganglia or from ectopic or supernumerary parathyroid glands
(Suster and Moran 2001]).

The treatment options for HNPGLs comprise surgical resection, as well as irradiation
therapy, stereotactic radiosurgery and permanent embolization. If necessary combined
treatment strategy could be used. For carotid body tumours the principal is complete
tumor resection. With complete surgical resection, the tumor is controlled locally
in 89–100 % of cases. However, there is a possibility of postoperative cranial nerve
dysfunction even in cases of successful surgical removal of CBT and complication rates
are directly related to tumor size. Postoperatively our patient had vagal nerve palsy
and patient is left with hoarse voice (Boedeker et al. 2005]).

Complete surgical excision is the treatment of choice for non metastatic thymoma and
thymic carcinoma, even when the tumor is locally advanced. This is followed by postoperative
radiotherapy to decrease the incidence of local recurrence. In an advanced disease
surgical debulking, radiotherapy, and chemotherapy are recommended (Berman et al.
2011]). Our patient had surgical resection followed by radiotherapy and till date remains
symptoms free with normal imaging.