Material and Method: Cases of mediastinal masses were retrospectively reviewed from January 2011 till January 2016. Clinico-radiological records of these cases were retrieved. Fine needle aspiration cytology (FNAC) was performed wherever feasible. Histopathological and immunohistochemical evaluation of the excised specimens was undertaken.
Results: Of the 60 cases included in our study, 22 were anterior, 20 were middle and 18 posterior mediastinal masses. The majority of the patients were symptomatic (96.8%). The most common pathology was thymoma (12 cases) followed by ten cases of lymphoma, eight cases each of tubercular lymphadenopathy and schwannoma, six cases of neurofibroma, four cases of extragonadal germ cell tumours, two cases each of thymic cyst, bronchogenic cyst, retrosternal goitre, ganglioneuroma and neuroblastoma, and one case each of lipoma and thymolipoma. FNAC was done in 54 cases of which 7 cases yielded inadequate material. Immunohistochemistry was required for classification of lymphoma cases and confirmation of a mixed component in germ cell tumours.
Conclusion: Mediastinal masses create significant diagnostic dilemma for the clinicians, radiologists and histopathologists. While imaging studies help in narrowing the differential diagnosis, accurate categorisation is not always possible. FNAC is a useful and cost effective tool. However, sampling error and complexities in performing the technique are major hurdles in the usefulness of this diagnostic modality.
Despite being a well-delineated narrow space, the diversity of lesions arising in the mediastinum pose an interesting diagnostic challenge for the clinicians, radiologists and pathologists[2]. There is limited data regarding the clinical and pathological features of these enigmatic mediastinal masses.
Our study highlights the clinico-pathological features in patients presenting with mediastinal masses with special emphasis on the utility of pre-operative diagnostic modalities like imaging and FNAC.
The FNAC smears, H&E stained sections and immunohistochemistry slides were reviewed by two pathologists and correlated with the clinical findings including radiology.
Table I: Histopathological diagnosis of the mediastinal masses
Retrospective analysis of the clinical and radiological findings of these patients was done. The most common presenting complaint was cough, seen in 54 patients (87.0%), followed by chest pain (50; 80.6%), weight loss (36; 58.0%), dyspnoea (26; 41.9%) and hoarseness (14; 22.5%). Myasthenic symptoms were seen in four patients with thymoma (Table II). Two patients each of thymic cyst and mediastinal lipoma were diagnosed incidentally. Routine blood investigations including complete hemogram, liver function tests and kidney function tests were normal in all patients except four cases of tubercular lymphadenitis with raised erythrocyte sedimentation rate (ESR). Chest X-ray showed mediastinal widening in 40 patients. CT scan revealed the presence of mediastinal masses in their respective compartments in all cases. Mediastinal lymphadenopathy was noted in 18 cases on CT scan. CT guided FNAC was performed in 54 patients.
Table II: Clinical features of patients with mediastinal tumours
Histopathological examination revealed 73.33% benign and 26.67% malignant lesions. Among the twelve cases of thymoma, the most common variant was the AB subtype (9 cases) followed by two cases of B1 subtype and one case of thymic carcinoma. Thymic tumours were classified as per the World Health Organisation (WHO) classification. Six patients with anterior mediastinal masses showed a biphasic population of spindle-shaped epithelial cells interspersed with lymphoid cells on FNA smears. A provisional diagnosis of thymic hyperplasia versus thymoma was considered. The excision biopsy specimen showed features suggestive of thymoma, AB subtype. On the other hand, FNA smears from three patients predominantly showed presence of haemorrhage along with few scattered lymphoid cells and were inconclusive. Subsequently they were diagnosed as thymoma, AB subtype on histopathological examination (Figure 1A-C). Two female patients suffering with myasthenia gravis, aged 42 years and 46 years respectively, showed cellular FNA smears consisting of monomorphic lymphoid cells. A few scattered spindle-shaped epithelial cells were also seen along with occasional atypical mitosis. Differential diagnosis of lymphoma versus thymoma was considered. Histopathology revealed diffuse effacement of thymic architecture by a monomorphic population of lymphoid cells intermixed with epithelial cells. On IHC, the lymphoid cells were positive for TdT and CD3 while the epithelial cells were positive for CK, thereby excluding lymphoma. A final diagnosis of thymoma, B1 subtype was made in both the cases. On the other hand, an elderly female presented with a rapidly enlarging mediastinal mass associated with vague chest pain and dyspnoea. Histopathological examination revealed an unencapsulated, poorly circumscribed tumour composed of large polygonal cells arranged in nests and diffuse sheets. The individual tumour cells were polygonal with moderate amount of dense eosinophilic cytoplasm and central vesicular nucleus with single nucleolus. Numerous atypical mitoses and tumour necrosis were seen. Foci of keratinisation were evident. Features were suggestive of keratinizing squamous cell carcinoma in concordance with the FNAC findings. A thorough clinico-radiological work up was done to rule out the possibility of metastasis, and a final diagnosis of primary thymic carcinoma was rendered.
Mediastinal lymphadenopathy was seen in 18 cases. Among 10 cases of lymphoma, there were 6 cases of Non- Hodgkin Lymphoma (NHL) and four cases of classical Hodgkin lymphoma (HL). There was no difficulty in FNAC diagnosis of these lesions except for three cases predominantly showing haemorrhage with few scattered lymphoid cells, inconclusive for an opinion. Histologically, most common type of NHL was diffuse large B cell lymphoma, seen in 5 cases (Figure 2A-D). On IHC the cells were positive for CD45, CD19, CD20 and negative for CD15, CD30 and EMA. Nodular sclerosis subtype was reported in all 4 cases of Hodgkin’s lymphoma. IHC showed that the Reed-Sternberg (RS) cells were positive for CD45, CD 15 and CD 30 (Figure 3A-F). In another case, a 45-yearold man presented with dyspnoea and excision biopsy of the mediastinal lymph node revealed diffuse effacement of architecture by clusters of epithelioid histiocytes. Interspersed in between were small lymphoid cells with scant cytoplasm and round to oval hyperchromatic nuclei showing mild atypia. Few binucleate RS like cells were also seen. On IHC, the lymphoid cells were positive for CD45 and CD3. The RS like cells were negative for CD15 and CD30, thereby excluding Hodgkin’s lymphoma (Figure 4A-F). Thus a final immunomorphological diagnosis of Lennert’s lymphoma was rendered. On the other hand, necrotizing granulomatous lymphadenitis was seen on histopathology of the remaining 8 patients with mediastinal lymphadenopathy. Stain for acid fast bacilli (AFB) was positive in these cases and a diagnosis of tubercular lymphadenitis was given (Figure 5A,B). Of these, seven patients had disseminated tuberculosis while one patient was diagnosed with isolated tubercular lymphadenopathy involving the mediastinal lymph nodes only.
Germ cell tumours were seen in four cases located in the anterior mediastinum. Two cases showed moderately cellular FNA smears against a tigroid background with presence of scattered lymphocytes. The individual tumour cells were large with moderate amount of vacuolated cytoplasm and a large vesicular nucleus with one or two prominent nucleoli. Provisional diagnosis of germ cell tumour, possibly seminoma, versus lymphoma was considered. Histopathological examination and immunohistochemical positivity for OCT3/4 confirmed the diagnosis of classical seminoma in both these cases (Figure 6A-C). A single case of mature teratoma (Figure 6D-F) was diagnosed in a 22-year-old male patient. CT scan revealed a large mediastinal mass involving the anterior mediastinum with foci of calcification. FNA smears showed presence of nucleated and anucleated squamous cells only. Another case was diagnosed as mixed germ cell tumour showing histomorphological features of seminoma and yolk sac tumour confirmed by OCT3/4 and AFP IHC respectively. While there was no difficulty in the FNA diagnosis of seminoma, the yolk sac component could not be identified cytologically.
Eighteen cases of neurogenic tumours were identified in the posterior mediastinum. Of these, schwannoma was the most common and seen in 8 patients (Figure 7A), followed by six cases of neurofibroma (Figure 7B) and two cases of ganglioneuroma. FNA smears in the majority of these cases were moderately cellular with presence of spindle-shaped cells either in clusters or singly scattered. The individual cells were spindle-shaped with scant to moderate cytoplasm and hyperchromatic spindle-shaped nucleus. No Verocay bodies, nuclear atypia or stromal fragments were seen. A provisional FNA diagnosis of spindle cell tumour was given in ten of these cases, while the remaining cases showed paucicellular smears and were labelled inconclusive for opinion. Two cases of neuroblastoma (Figure 8A,B) were seen in a 2- and 4-year-old male child respectively, FNA smears of which were inadequate for diagnosis.
Cystic lesions of the mediastinum consisted of two cases each of bronchogenic cyst, thymic cyst and retrosternal goitre with cystic change respectively, diagnosed on histopathological examination of the excised specimen. FNAC was not performed in these cases owing to the cystic nature of the lesion. One case each of mediastinal lipoma was readily diagnosed on cytology and confirmed on histopathology. Also, a 22-year-old female patient showed a large fat-containing anterior mediastinal mass extending along the right pericardium on CT scan (Figure 9A). FNA showed features suggestive of lipoma. On histopathology, a well-encapsulated tumour was seen showing intermixed thymic tissue within mature adipocytes, suggestive of thymolipoma (Figure 9B).
Nearly 50% of all mediastinal masses involve the anterior compartment, including thymoma, teratoma, lymphoma, thyroid and parathyroid lesions. Congenital cysts and neurogenic tumours are most commonly observed in the middle and posterior mediastinum respectively[3]. In our study, the anterior compartment (36.7%) was maximally involved followed by the middle mediastinum (33.3%) and posterior mediastinum (30%). Thymoma was the most common tumour of the anterior compartment followed by germ cell tumours. The middle mediastinum showed mainly nodal involvement with lymphoma most commonly followed by tubercular lymphadenitis. Neurogenic tumours were seen in the posterior mediastinum only. Studies conducted in the past showed nearly similar trends[5-7].
In the present study, 96.8% of the subjects were symptomatic at presentation. Dubashi et al.[5] reported a similar incidence of 97% with other studies reporting a range of 60-88%[2,4].
In 1987 however, Davis et al.[4] reported a much higher incidence of asymptomatic cases (38%). This difference may be attributed to the fact that most of the patients in our setting visit the hospital for their symptoms rather than for routine examination. The most common symptoms reported in this study was cough followed by chest pain, dyspnoea and weight loss which was similar to the previously reported incidence[8,9].
Pre-operative diagnosis of mediastinal masses is a challenging task owing to the non-specific clinicoradiological signs and technical difficulty in performing FNAC. The investigation of choice for the detection of mediastinal masses is CT scan[10]. Magnetic resonance imaging (MRI) is of help in further categorisation of the lesions[11]. In our study, CT scan identified mediastinal masses in all cases but was unable to categorise the lesion in any. CT scan thus helps in compartment localisation of the mediastinal mass. This further helps in narrowing the probable differential diagnosis.
CT‑guided FNAC is a safe, useful and cost-effective method for the diagnosis of mediastinal masses. However, close proximity to vital organs can be a hindrance for this technique. In our study, FNAC was performed in 54 cases. There were 7 cases which revealed inadequate material. Thymic lesions often pose a diagnostic challenge for the reporting cytologist. While the lymphocyte-rich variant of thymoma (B1 subtype) can easily be misdiagnosed as lymphoma[11], epithelial rich variant (A subtype) on the other hand is a close mimicker for carcinoma[12]. Similar to previous studies, our study also highlights the difficulty encountered in the FNA diagnosis of thymic lesions especially two cases of B1 subtype where the possibility of a lymphoma could not be ruled out and six cases of AB subtype in which thymic hyperplasia versus thymoma could not be accurately diagnosed on FNAC. Thymic carcinoma on the other hand was readily diagnosed due to the frank malignant features.
Apart from the thymic lesions, neurogenic tumours are difficult to categorise on cytology. Schwannomas are usually difficult to differentiate from neurofibroma unless characteristic Verocay bodies are seen, while ganglioneuroma cannot be diagnosed till ganglion cells are aspirated. Both these findings were not seen in our cases and a final diagnosis of spindle cell tumour was rendered on FNAC. Further, some degree of cellular and nuclear atypia is commonly seen in neurogenic tumours. This warrants a careful search for mitotic figures and excision biopsy for proper histopathological evaluation. Thus characterisation of benign versus malignant on FNAC is a diagnostic difficulty which is then overcome on histopathology. On the other hand, germ cell tumours cannot readily be diagnosed on FNAC since tigroid background is not entirely specific for seminoma and when lymphocytes/ lymphoglandular bodies are present, a confusion with malignant lymphoma is possible, as seen in two of our cases. Furthermore, smears showing discohesive pattern on cytology should be differentiated from poorly differentiated adenocarcinoma, melanoma and lymphoma. In our study, the component of yolk sac tumour was missed in a single case of mixed germ cell tumour. This can be attributed to selective sampling which is a well-known hurdle in aspiration cytology. As reported earlier by Chhieng et al. particularly in case of mixed germ cell tumours may also pose diagnostic challenge[13]. Similarly, fat fragments were selectively sampled from an anterior mediastinal mass in a 22-yearold female which was diagnosed later as thymolipoma on histopathological evaluation.
A rather rare case encountered in our study which deserves special mention was Lennert’s lymphoma in a 33-year-old male patient with mediastinal lymphadenopathy involving the middle compartment. Lennert’s lymphoma is a variant of peripheral T-Cell lymphoma, not otherwise specified in the WHO classification of 2008[14]. Its rarity and the lack of strict diagnostic criteria explain why only a few reports on Lennert’s lymphoma have been published so far. Our case showed presence of RS like cells mimicking Hodgkin’s lymphoma and posed the same diagnostic dilemma as the previously published cases. In 2013, Parimal et al.[15] reported a series of 5 cases of Lennert’s lymphoma which constituted 0.71% of all peripheral T-cell lymphomas in their institution. They concluded that classical Hodgkin’s lymphoma is a close mimicker of Lennert’s lymphoma and suggested T cell gene rearrangement studies when distinction cannot be made on morphology and IHC.
To conclude, we evaluated the role of clinico-radiological, cytological and histopathological findings in the differential diagnosis of mediastinal masses. Owing to rather nonspecific clinical and radiological signs, histopathological examination remains the mainstay of diagnosis. Further, the proximity of this area to vital visceral organs decreases the usefulness of FNAC and leads to a failure to adequately describe cytomorphological characteristics of the mediastinal mass.
CONFLICT OF INTEREST
The authors declared no conflict of interest.
1) Shabb NS, Fahl M, Shabb B, Haswani P, Zaatari G. Fine Needle
aspiration of the mediastinum. A clinical, radiological, cytological
and histologic study of 42 cases. Diagn Cytopathol. 1998;19:428-
36)
2) Duwe BV, Sterman DH, Musani AI. Tumors of the mediastinum.
Chest 2005;128:2893‑909.
3) A roor AR, Prakasha SR, Seshadri S, Teerthanath S, Raghuraj
U. A study of clinical characteristics of mediastinal mass. J Clin
Diagn Res. 2014;8:77‑80.
4) Davis RD, Oldham HN, Sabiston DC. Primary cysts and
neoplasms of the mediastinum: Recent changes in clinical
presentation, methods of diagnosis, management, and results.
Ann Thorac Surg. 1987;44:229-37.
5) Dubashi B, Cyriac S, Tenali SG. Clinicapathological analysis and
outcome of primary mediastinal malignancies-A report of 91
cases from a single institute. Ann Thorac Med. 2009;4:140-2.
6) Singh G, Amin Z, Wuryantoro, Wulani V, Shatri H. Profile and
factors associated with mortality in mediastinal mass during
hospitalization at Cipto Mangunkusumo Hospital, Jakarta. Acta
Med Indones. 2013;45:3-10.
7) A degboye VO, Ogunseyinde AO, Obajimi MO, Ogunbiyi O,
Brimmo AI, Adebo OA. Presentation of primary mediastinal
masses in Ibadan. East Afr Med J. 2003;80:484-7.
8) Shrivastava CP, Devgarha S, Ahlawat V. Mediastinal tumors:
A clinicopathological analysis. Asian Cardiovasc Thorac Ann.
2006;14:102‑4.
9) Bastos P, Magalhães A, Fernandes G, Cruz MR, Saleiro S,
Gonçalves L, Pinon M. Primary cysts and tumors of the
mediastinum. Rev Port Pneumol. 2007;13:659‑73.
10) Juanpere S, Cañete N, Ortuño P, Martínez S, Sanchez G, Bernado
L. A diagnostic approach to the mediastinal masses. Insights
Imaging. 2013;4:29‑52.
11) Pérez Dueñas V, Torres Sánchez I, García Río F, Valbuena
Durán E, Vicandi Plaza B, Viguer Garcia‑Moreno JM. Usefulness
CT‑guided F.N.A.C. in the diagnosis of mediastinal lesions. Arch
Bronconeumol. 2010;46:223‑9.
12) Matsuura B, Tokunaga H, Miyake T, Utsunomiya S, Minami
H, Onji M. A case of malignant thymoma mimicking thyroid
carcinoma: A pitfall in fine‑needle aspiration. Endocr J.
2004;51:237‑41.
13) Chhieng DC, Lin O, Moran CA, Eltoum IA, Jhala NC, Jhala DN,
Simsir A. Fine-needle aspiration biopsy of nonteratomatous germ
cell tumors of the mediastinum. Am J Clin Pathol. 2002;118:418–24.