Pulmonary ossifying carcinoid - MEN in a male?

Pulmonary carcinoid tumors are considered as low-grade neoplasms, seen as centrally located endobronchial masses or as peripheral circumscribed nodules. Calcification or ossification is a known phenomenon, but presentation as large bony mass is extremely uncommon. Herein, we report a case of ossifying bronchial carcinoid along with nodular Hashimoto's thyroiditis as incidental autopsy findings in a 32-year-old patient with a prior recent excision of pituitary macroadenoma. This association suggests the possibility of multiple endocrine neoplasia in this young male.

Introduction

Among the various neuroendocrine tumors of the lung, carcinoid tumors represent 2% of all pulmonary neoplasms. They are considered as low-grade tumors and present as centrally located endobronchial masses or as peripheral circumscribed nodules. Clinical presentation depends on the tumor location, presence of metastases, or paraneoplastic syndromes. Calcification or ossification is a known phenomenon in carcinoids, but presentation as large bony mass is very rare, a feature documented by Troupin[1] way back in 1968. Herein, we report a case of ossifying bronchial carcinoid as an incidental autopsy finding in a young adult male with a prior excision of pituitary macroadenoma. An additional association also detected at autopsy was nodular Hashimoto's thyroiditis. The presence of these three lesions suggested the possibility of multiple endocrine neoplasias (MEN) in this patient.

Case Report

A 32-year-old male, in 5 years, had developed coarsening of facial features and broadening of shoulders, fingers, and toes, followed by diminished vision, weakness, increased thirst, and increased frequency of urination. Based on hormonal assays [Table 1] and radiological investigations, he was diagnosed as a case of pituitary macroadenoma with acromegaly and diabetes mellitus type 2 (HbA1c of 18.6). Antidiabetic medications were started. After 7 months, he was admitted at our tertiary care center (second admission) for a transsphenoidal resection of pituitary macroadenoma [Figure 1a] after repeat hormonal estimations [Table 1]. His growth hormone level reached normal levels (0.5 ng/mL) by the fifth postoperative day and he was discharged with prednisolone supplementation. He was readmitted after 6 months with a 10-day history of diarrhea and vomiting and was managed symptomatically. All routine investigations were normal, hormonal assays have been tabulated [Table 1]. He developed a fever on day 5 of the ward stay and the next day, he had a sudden cardiac arrest.

Table 1

Hormonal investigations

Investigation	First admission	Second admission	Third admission	Normal range
Basal growth hormone (GH)	>40 ng/mL	76.2 ng/mL	0.8 ng/mL	0.003-0.97 ng/mL
Post-glucagon GH	56.7 ng/mL	-	-
Insulin-like growth factor 1	269 ng/mL	757 ng/mL	-	87-238 ng/mL
Serum Prolactin	57 ng/mL	105.7 ng/mL	-	2-15 ng/mL
Free Thyroxine 4	0.95 ng/mL	1.18 ng/mL	1.74 ng/mL	0.8-1.8 ng/mL
Thyroid stimulating hormone	1.59 mU/L	1.53 mU/L	-	0.4-4.2 mU/L
Basal cortisol	14.2 µg/dL	15.77 µg/dL	<0.5 µg/dL	5-25 µg/dL
Follicle stimulating hormone	0.68 mIU/mL	0.78 mIU/mL	-	1.6-8.0 mIU/mL
Luteinising hormone	0.17 mIU/mL	0.27 mIU/mL	-	1.5-9.3 mIU/mL
Testosterone	-	0.52 ng/mL	1.17 ng/mL	4-11 ng/mL

Figure 1

(a) Pituitary macroadenoma showing clusters of polygonal cells with moderate eosinophilic cytoplasm with stippled chromatin devoid of any pleomorphism (H and E ×400); (b) Cancellous bone-like cut surface of a large subpleural mass seen in the apical segment of the right lower lobe

A complete autopsy was performed. The apical segment of the right lower lobe showed an extremely firm well-circumscribed 5 cm mass, abutting the lobar bronchus. The cut surface appeared like a cancellous bone with a peripheral rim of pale brown tissue [Figure 1b]. The decalcified sections revealed classical features of a carcinoid tumor [Figure 2a], confirmed on immunohistochemistry (IHC) with extensive osseous metaplasia [Figure 2b]. IHC for osteopontin was negative. The thyroid showed moderate diffuse enlargement with multiple pale yellow soft nodules of varying sizes on the cut surface [Figure 3a and b]. All these nodules showed features of Hashimoto's thyroiditis [Figure 3c-e]. The heart was normal in size (weight 270 g) but on histopathology, there was mild hypertrophy and multi-focal interstitial/peri-vascular scarring, particularly in the left ventricle [Figure 3f], which would have been the cause of the sudden death. Besides, there was bilateral acute pyelonephritis. Other organs were normal.

Figure 2

(a) The peripheral region of the mass showing nests of monotonous small polygonal cells with scanty eosinophilic cytoplasm and round nuclei with salt and pepper chromatin (H and E ×400); Inset shows immunohistochemical positivity for synaptophysin (×400); (b) The central portion of the tumor was entirely composed of bony trabeculae with intervening vascularized fibrofatty tissue (H and E 400)

Figure 3

(a) Uniformly enlarged and firm thyroid gland with an undulant intact capsular surface, (b) The cut surface showed creamy nodules of varying sizes, separated by congested parenchyma, The histology showed features of Hashimoto's thyroiditis with (c) prominent lymphoid follicles (H and E ×250), (d) Oncocytic metaplasia (H and E ×400) and, (e) Lymphocytic infiltrate (H and E ×400); (f) Longitudinally cut cardiomyocytes of the left ventricle with mild hypertrophy and prominent fine interstitial scarring (H and E ×250)

Discussion

Sudden, unexpected death in this young patient previously operated for pituitary macroadenoma lead to a discovery of a series of findings, notably ossifying bronchial carcinoid, nodular Hashimoto's thyroiditis, and dilated cardiomyopathy. Though calcification (30%) and ossification (10%) are seen as long-standing changes in lung carcinoids, massive ossification, bearing resemblance to a pulmonary osteoma[2] is distinctly uncommon. So far, there have been only six such surgically excised cases have been reported [Table 2].[134567] Atypical carcinoid was present in one other patient6; metastases were noted in two cases.[56] The pathogenesis is explained based on “osteomimicry” due to the release of osteopontin and osteocalcin.[5] In our case, osteopontin immunohistochemistry was negative; staining for osteocalcin was not performed.

Table 2

Cases of ossifying pulmonary carcinoids

S. No. and reference	Age and sex	Clinical presentation	Therapy	Pathological features
1. Troupin[1]	38 years, Male	Initial fever and chest pain Slowly growing, partially calcified, lobulated left hilar mass lesion for 5 years	Left pneumonectomy	4.5 × 3 × 3 cm arising from the wall of left upper lobe bronchus - Typical carcinoid; No metastasis documented
2. Shin et al.[3]	58 years, Male	Long-standing chronic lymphocytic leukemia	Right middle and lower lobectomy	1.5 cm at the right middle and lower lobe bronchial bifurcation - Typical carcinoid; Leukemic infiltrate in hilar and mediastinal lymph nodes
		Recurrent episodes of pneumonia, Hemoptysis, Rock-hard mass at the junction of the right middle and lower lobe bronchi with atelectasis
3. Vanmaele et al.[4]	49 years, Female	Fever, cough, fatigue and weight loss Narrowing of anterior segmental bronchus of the left upper lobe	Left upper lobectomy	1 cm submucosal nodule in the origin of anterior segmental bronchus of the left upper lobe - Typical carcinoid (Chromogranin positive); No metastasis documented
4. Tsubochi et al.[5]	29 years, Female	Asymptomatic 4.5 cm coarsely calcified tumor in the left lower lobe	Left lower lobectomy	4.7 × 3.6 × 3.5 cm - Typical carcinoid (Cytokeratin, chromogranin, synaptophysin, BMP-2, osteocalcin positive); Metastases in carinal and right hilar lymph nodes
5. Khalil et al.[6]	47 years, Male*	Fever, cough, shortness of breath, fatigue, weight loss calcified right lung mass with atelectasis	Right pneumonectomy	8 cm mass involving right mainstem bronchus - Atypical carcinoid (chromogranin, synaptophysin positive, Ki 67 10%) Metastases in right hilar lymph nodes
6. Osmond et al.[7]	45 years, Male*	Hemoptysis, Exertional wheezing Hilar mass with associated right middle lobe collapse	Right upper and middle lobectomy	5.0 cm - Typical carcinoid (Cytokeratin AE1/AE3, chromogranin, synaptophysin positive); No metastasis documented

*Smoker

The association of an asymptomatic ossifying bronchial carcinoid with pituitary macroadenoma suggested the possibility of multiple endocrine neoplasia (MEN) type 1 in this young male.[8] The syndrome classically presents as the “P-triad,” which corresponds to parathyroid (95%), pituitary (30%), and pancreatic (40%) endocrine tumors; the latter is now expanded to include gastroenteropancreatic neuroendocrine tumors.[9] Furthermore, bronchopulmonary neuroendocrine tumors occur in about 2% of patients with MEN 1.[8] The disorder affects all age groups and manifestations are usually seen by the fifth decade in over 98% of patients. The diagnosis of MEN 1 can be clinical (presence of two or more MEN 1-associated endocrine tumors), familial (occurrence of one MEN 1-associated endocrine tumor with MEN 1 in a first-degree relative), or genetic (identification of a germline MEN 1 mutation in an individual who can even be asymptomatic).[8] However, sporadic mutations are also known. With these observations, we feel our patient may fit into the category of probable MEN 1 as there was no family history and genetic studies had not been performed. It is also possible that in this case pituitary macroadenoma was the first clinical manifestation. We were unable to explain the cause of diarrhea, which otherwise could have been a paraneoplastic syndrome in a setting of MEN 1.

About 15 to 27% of MEN 1 patients also have thyroid lesions, including Hashimoto's thyroiditis, not causally related to the MEN1 gene.[10] However, there is no mention of nodular Hashimoto's thyroiditis, as was classically seen in this case. The unfortunate sudden demise could be explained based on acromegalic cardiomyopathy, which is associated with both systolic and diastolic dysfunctions and even arrhythmias.[11] It is, therefore, highly recommended for acromegalic patients to undergo cardiac evaluation even when they are asymptomatic. In this case, only an electrocardiogram (EKG) was done as a part of preanaesthetic work-up for adenoma excision and echocardiography had not been performed.

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Conflicts of interest

There are no conflicts of interest.