Extensive fibrosis in mediastinal seminoma is a diagnostic pitfall in small biopsies: two case reports

Introduction

The mediastinum can be affected by many different types of tumors and inflammatory conditions, with differing therapeutic options. Therefore, the work-up of an anterior/prevascular mediastinal mass includes clinical, laboratory (serum β-human chorionic gonadotropin (β-hCG), alpha fetal protein (AFP), lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), and autoantibodies against acetylcholine receptors), and imaging studies to hone the differential diagnosis and clarify the extent of disease. Primary mediastinal seminomas, while rare, are the second most common (10–37%) primary germ cell tumor of the mediastinum, behind teratomas. Mediastinal seminoma occurs almost exclusively in young men, more frequently in the second and fourth decades (range, 9 to 79 years old) (1). Most patients are asymptomatic, with incidental discovery of a large mediastinal mass (1). Their serum markers are frequently within normal limits, although mildly elevated β-hCG and LDH levels have been reported. On imaging studies, mediastinal seminoma usually presents as a large and homogeneous mass with mild enhancement on contrast-enhanced computed tomography (CT) (2), which is radiographically nonspecific. Therefore, tissue sampling, most often by core needle or fine needle aspiration biopsy, is necessary for diagnosis. The most commonly recommended management of patients with seminoma is systemic platinum-based chemotherapy, or radiation for localized disease if chemotherapy is contraindicated. Surgery may be considered as salvage therapy, but is not recommended as the primary modality of therapy, unless the tumor is very small and localized (3-6).

Here we report two cases in which preoperative clinical evaluation and biopsies failed to render a specific diagnosis of primary mediastinal seminoma, leading to surgical excision. Pathologic examination of both resected tumors revealed extensive areas of fibrosis suggestive of spontaneous tumor regression. Tumor regression is not well-defined, and there is no standard for grading regression. Some have proposed scoring tumor regression by comparing the volume of viable tumor cells to the volume of fibrosis (7). Fibrous septa/stroma is mentioned in the morphologic description of primary mediastinal seminoma in the World Health Organization (WHO) Classification of Thoracic Tumors (1), and it is seen in many slow-growing tumors. However, extensive fibrosis to the degree seen in our cases is not described by the WHO book, and is not well-described in the existing literature (1). It is important to raise awareness of this diagnostic pitfall in mediastinal biopsies (8,9). We present the following cases in accordance with the CARE reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-22-15/rc).

Case presentation

Case 1

A 14-year-old male patient presented for workup of shoulder pain and concern for shoulder asymmetry following a sports injury. He denied chest pain and shortness of breath. He had a history of growth hormone deficiency, and was on daily growth hormone replacement therapy. Physical exam was unremarkable, including lack of significant shoulder asymmetry. Single view anteroposterior (AP) chest radiograph incidentally showed a left sided mediastinal contour abnormality concerning for a mediastinal mass. Chest CT with contrast showed a large lobulated, heterogeneous, and vascular left prevascular mediastinal mass isodense to surrounding soft tissue, with internal areas of enhancement (Figure 1). Serum AFP and β-hCG were within normal limits. Scrotal Doppler ultrasound study showed no testicular mass. Abdominopelvic magnetic resonance imaging (MRI) and brain MRI were normal.

Figure 1 Case 1 imaging. Coronal contrast-enhanced pediatric protocol low dose CT showed a left prevascular mediastinal mass (arrow) that is well-circumscribed, and lobulated, with serpiginous heterogeneous enhancement. CT, computed tomography.

CT-guided biopsy yielded scant fragments of fibroconnective tissue with variable collagenization and myxoid change (Figure 2) associated with irregular and thin ectatic vessels. The stroma was variably cellular and contained reactive myofibroblasts, which were positive on immunohistochemical stains (IHC) for smooth muscle actin (SMA), had mild non-specific reactivity with pancytokeratin AE1/AE3, and were negative for S100 protein. Given the nonspecific findings, additional tissue sampling was performed.

Figure 2 Case 1 first biopsy. CT-guided biopsy was nonspecific. There was scant fibroconnective tissue with variable collagenization, myxoid change, and myofibroblasts (H&E stain; original magnification: 100×). Additional tissue sampling was recommended. CT, computed tomography; H&E, hematoxylin and eosin.

An open biopsy (Chamberlain procedure) showed extensive fibrosclerosis, lymphoplasmacytic inflammatory infiltration, and thin dilated vessels (Figure 3). IHC for spalt like transcription factor 4 (SALL4), a pan-germ cell marker, was negative. Cluster of differentiation 34 (CD34), SMA, and desmin highlighted an abundant vascular component. ALK (D5F3), β-catenin, calponin, caldesmon, epithelial membrane antigen (EMA), and S100 protein were negative. Chromogenic in-situ hybridization for EBV [Epstein Barr virus encoded RNA (EBER)] was also negative. The diagnosis was “vascular fibroblastic/myofibroblastic proliferation consistent with a reactive process”.

Figure 3 Case 1 second biopsy. Open biopsy showed extensive fibrosclerosis, lymphoplasmacytic infiltration, and thin dilated vessels (H&E stain; original magnification: 100×). H&E, hematoxylin and eosin.

Complete surgical resection of this lesion by left posterolateral thoracotomy was performed. Gross exam showed a 7.0 cm × 6.9 cm × 4.3 cm irregular circumscribed red-pink firm mass with mottled fibrotic cut surfaces (Figure 4A). Microscopic evaluation revealed that the vast majority of the mass consisted of mildly inflamed vascular sclerotic tissue morphologically similar to the previous two biopsies. Only approximately 5% of the total mass contained sheets of medium-sized malignant cells with relatively uniform, large central nuclei with prominent nucleoli, and amphiphilic to clear cytoplasm. The malignant cells were located mostly along the periphery of the mass and involved adjacent thymic parenchyma (Figure 4B,4C). IHC showed the tumor cells were diffusely and strongly positive for octamer-binding transcription factor-4 (OCT-4), cluster of differentiation 117 (CD117), placental-like alkaline phosphatase (PLAP) (Figure 4D-4F), and podoplanin (D2-40), while negative for AFP and S100 protein. The morphologic and IHC findings were diagnostic of seminoma. Resection margins were negative. One month post-resection, the patient started 4 cycles of chemotherapy (bleomycin, etoposide and cisplatin), which were completed in 80 days. There was no evidence of disease in 3.4 years of post-operative follow-up with serum and imaging studies. Table 1 summarizes the timeline of events for this patient.

Figure 4 Case 1 resection. Gross examination of the resection specimen showed a 115.6 g, 7.0 cm × 6.9 cm × 4.3 cm irregular well-circumscribed, red-pink firm mass with mottled fibrotic cut surfaces (A). Only approximately 5% of the mass showed tumor cells, mostly along the periphery and involving adjacent thymic parenchyma (B, middle and bottom; H&E stain; original magnification: 20×). The remainder of the mass consisted of inflamed vascular sclerotic tissue suggestive of regression (B, upper right). The tumor component consisted of sheets of medium-sized tumor cells with relatively uniform, large central nuclei with prominent nucleoli, and amphiphilic to clear cytoplasm (C; H&E stain; original magnification: 100×). The tumor cells were positive for immunostains OCT-4, PLAP, and D2-40, consistent with seminoma (D, E, F, respectively; immunohistochemical stains; original magnification: 100×). H&E, hematoxylin and eosin; OCT-4, octamer-binding transcription factor-4; PLAP, placental-like alkaline phosphatase; D2-40, podoplanin.

Case 2

A 66-year-old male with history of atrial flutter, Factor V Leiden, and coronavirus disease of 19 (COVID-19) infection (7 months prior) sought emergency care after an episode of syncope. Physical exam was unremarkable. CT pulmonary angiogram demonstrated pulmonary embolism, as well as an incidental large prevascular mediastinal mass with small peripheral calcifications (Figure 5). The mass was fluorodeoxyglucose (FDG)-avid on positron emission tomography (PET)-CT, with standardized uptake value (SUV) of 6.3, which was suspicious for malignancy. Upon retrospective review, approximately 50% of the mass was FDG-avid, while the remainder was not FDG-avid. The PET scan showed no evidence of metastatic disease, and no other mass, including in the head, retroperitoneum, coccyx, or scrotum. Seven and a half weeks before biopsy and 9 weeks before surgery, serum LDH was mildly elevated to 317 U/L (reference range, 125–220 U/L); 3.5 weeks before biopsy and 5 weeks before surgery, repeat serum LDH was within normal range. Serum β-hCG, AFP, and CEA levels were within normal limits.

Figure 5 Case 2 imaging. Axial CT angiogram of the chest showed a prevascular mediastinal mass (yellow arrow) with small peripheral calcifications (blue arrow). CT, computed tomography.

CT-guided biopsy was performed, with the needle (Figure 6A) passing through a portion of the mass that was not FDG-avid (Figure 6B). The biopsy demonstrated hypocellular dense fibrous tissue (Figure 6C). Congo red stain for amyloid was negative. IHC for signal transducer and activator of transcription 6 (STAT6), S100 protein, and β-catenin were negative. Flow cytometry analysis was negative for non-Hodgkin lymphoma.

Figure 6 Case 2 biopsy. During CT-guided biopsy, the needle (A, arrow) entered a non-FDG-avid portion of the mass (B; PET scan; arrow corresponds to biopsied area shown in A). The biopsy demonstrated hypocellular dense fibrous tissue (C; H&E stain; original magnification: 100×) that was negative for Congo red, STAT6, S100 protein, and β-catenin. CT, computed tomography; FDG, fluorodeoxyglucose; PET, positron emission tomography; H&E, hematoxylin and eosin.

The patient underwent a robotic thymectomy. Gross examination demonstrated a 7 cm × 6 cm × 1.5 cm lobulated tan-white firm tumor with focal hemorrhage (Figure 7A). Microscopic exam showed approximately 50% of the tumor consisted of a well-defined region of hypocellular dense fibrous tissue that was similar to what was seen in the preoperative biopsy. The resection additionally showed areas within the fibrosis that contained irregular thin ectatic vessels similar to the first case (Figure 7B). The tumor consisted of sheets and nests of medium sized cells separated by fibrous septa. Similar to the first case, the tumor cells also had amphiphilic to clear cytoplasm with relatively uniform, large central nuclei and prominent nucleoli. A lymphoplasmacytic infiltrate was seen in the fibrous septa (Figure 7C). IHCs showed the tumor cells were positive for OCT-4 (Figure 7D), CD117 (Figure 7E), SALL4 (Figure 7F), pancytokeratin CAM 5.2 (dot-like cytoplasmic pattern), and D2-40, while negative for Glypican-3 and cluster of differentiation 30 (CD30), which confirmed the diagnosis of seminoma. The resection margin was focally positive. No lymph node metastasis was present. Three and a half months post-resection, the patient underwent 4 cycles of chemotherapy (etoposide and cisplatin), which were completed in 67 days. There was no evidence of disease in 1 year of post-operative follow up with serum and imaging studies. Table 2 summarizes the timeline of events for this patient.

Figure 7 Case 2 resection. Gross examination of the resection specimen showed a 7.0 cm × 6.0 cm × 1.5 cm tan-white lobulated firm tumor with focal hemorrhage on cut sections (A). Approximately 50% of the tumor showed dense hypocellular fibrotic tissue with irregular thin ectatic vessels, suggestive of regression (B, left; H&E stain; original magnification: 40×). The tumor consisted of sheets and nests of medium sized tumor cells separated by fibrous septa. The tumor cells had amphiphilic to clear cytoplasm with relatively uniform, large central nuclei and prominent nucleoli. A lymphoplasmacytic infiltrate was seen in the fibrous septa (C; H&E stain; original magnification: 100×). The tumor cells were positive for immunostains OCT-4, CD117, SALL4 (D, E, F, respectively; immunohistochemical stains; original magnification: 100×), keratin CAM 5.2 (dot-like cytoplasmic pattern), and D2-40, while negative for Glypican-3 and CD30, consistent with seminoma. H&E, hematoxylin and eosin; OCT-4, octamer-binding transcription factor-4; CD117, cluster of differentiation 117; SALL4, spalt like transcription factor 4; D2-40, podoplanin; CD30, cluster of differentiation 30.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). The study was approved by the institutional review board of New York University (No. S21-01220), and individual consent for this retrospective analysis was waived.

Discussion

Summary & literature review

We have provided what is to date the most detailed clinicopathologic description of two cases of primary mediastinal seminoma with tumor regression. The regressed areas were sampled on biopsy and hindered accurate preoperative diagnosis. Spontaneous tumor regression is a rare phenomenon, and its real incidence is difficult to estimate (10). There is no standard for grading regression. Some have proposed scoring tumor regression according to the volume of radiation-induced or idiopathic (in our cases) fibrosis (7). The underlying mechanisms are unknown. One theory is that it is mediated by immune system activation (11), and some hypothesize it may be akin to a wound-healing process (12). It is well-described in gonadal seminomas, and is recognized in the WHO Classification of Tumors of the Urinary System and Male Genital Organs (13). For mediastinal germ cell tumors, although fibrous septa/stroma is mentioned in the WHO Classification of Thoracic Tumors (1), this type of limited fibrosis is seen in many slow-growing tumors. Extensive fibrosis to the degree consistent with tumor regression, as seen in our cases, is not described by the WHO, and is not well-described in the existing literature (1). It is important to raise awareness of this diagnostic pitfall in mediastinal biopsies (8,9).

In the testis, germ cell tumor regression usually manifests histologically as a well-defined to irregular nodular focus/foci of scar or fibrosis with various combinations of fibrosis, neovasculature, mixed chronic inflammation, calcification, and/or giant cell reaction (13-16). Both of our cases of mediastinal seminoma demonstrated histologic findings that correspond to the features of regression described in gonadal germ cell tumors. They both contained extensive areas of well-defined fibrosis with inflammation and irregular thin-walled ectatic vessels (consistent with neovasculature). In addition, there was transient elevation of serum LDH in patient #2, followed by spontaneous normalization; and upon retrospective review of the PET-CT scan and biopsy needle placement, the fibrotic region corresponded to a non FDG-avid region of the tumor. It is based on these facts that we propose the extensive fibrosis seen in our cases is consistent with regression (7).

In the existing English language literature, only two cases of mediastinal germ cell tumor with spontaneous regression have been reported (Table 3). In both cases, serum β-hCG was initially elevated, followed by normalization before any therapy was initiated. CT scans in both cases showed concomitant tumor size decrease as the serum hCG levels decreased. Histologic exam of one resected case showed combined teratoma and seminoma with evidence of regression in the form of fibrous granulation tissue (8). The other case was diagnosed on open biopsy, followed by chemotherapy and resection; histologic features of regression were not described in the paper (9).

Clinical relevance and differential diagnosis

Clinically, the differential diagnosis of an anterior/prevascular mediastinal mass includes (I) benign entities such as enlarged or ectopic thyroid tissue, thymic hyperplasia, and ectopic parathyroid tissue; (II) primary neoplastic diseases including thymic epithelial neoplasms, thymic neuroendocrine neoplasms, lymphoma, and extragonadal germ cell tumor; (III) metastatic disease; as well as (IV) inflammatory diseases, such as infection, lipid storage disease, sarcoidosis, fibrosing mediastinitis, immunoglobulin G subclass 4-related disease (IgG4-RD), histiocytosis X, and Castleman disease (17,18). Biopsy of the lesion is preferred for diagnosis, and contributes to the decision of whether to pursue surgical resection, radiation, or systemic therapy. The sensitivity and specificity of biopsies, including fine needle aspiration, for the diagnosis of mediastinal lesions is very good, although cystic and inflammatory conditions have lower sensitivity (19).

The presence of fibrous tissue in a mediastinal biopsy raises the possibility of the following entities in the pathologic differential diagnosis: fibrosing mediastinitis; IgG4-RD; Hodgkin lymphoma; as well as reactive fibrotic and inflammatory changes within or adjacent to other processes.

Fibrosing mediastinitis, or “sclerosing mediastinitis”, is a rare cause of mediastinal masses (20), and is regarded as an abnormal wound-healing response to triggers including histoplasmosis (in which case granulomas may be found), other fungal infections, tuberculosis, autoimmune diseases, and radiation. Radiographically, it often presents as an infiltrative process (21). In most cases, a cause cannot be found; in such idiopathic cases, some presume there may be an undiagnosed underlying infection, autoimmune disease, or IgG4-RD. Histologically, fibrosing mediastinitis can show a range of fibrotic and mixed chronic inflammatory changes that resemble the stages of wound healing (22,23). The fibrosis can consist of fibromyxoid tissue with numerous spindle cells and thin-walled vessels (similar to case 1); or it can consist of thick glassy bands of haphazardly arranged collagen with only focal spindle cells; or it can contain dense hypocellular collagen and occasional dystrophic calcification (similar to case 2). Some have postulated that tumor regression may also be a sort of wound-healing process (12). Unless tumor cells are sampled in the biopsy, it is not possible to separate fibrosing mediastinitis from tumor regression histologically.

IgG4-RD is an autoimmune systemic fibroinflammatory disease characterized by storiform fibrosis with lymphoplasmacytic infiltration, phlebitis, and increased numbers of IgG4-positive plasma cells. Elevated serum levels of IgG4 may or may not be present (24,25). IgG4-RD has been described in the mediastinum (26,27). In our cases, there were no elevated numbers of plasma cells in the biopsies to suggest this diagnosis.

Nodular sclerosis (classical) Hodgkin lymphoma is the most common type of lymphoma to affect the mediastinum. Histologically, the tumor is characterized by nodules of polymorphous inflammatory cells surrounded by broad fibrous bands. Reed-Sternberg cells are required for histopathological diagnosis. Similar to seminoma, poorly-formed granulomata can be seen in association with classical Hodgkin lymphoma. The presence of extensive sclerosis in biopsy specimens can also hinder the diagnosis of this entity.

Conclusions

In cases like ours where fibrosis comprises the majority of the lesion, biopsy diagnosis can be very challenging. The biopsy sample may not reveal the true nature of the lesion that may be present nearby, even with the use of ancillary studies such as immunohistochemistry. Pathologists should always question whether the observed findings account for the entire lesion, or represent reactive or fibrotic changes associated with a different underlying lesion. Here we also postulate that primary mediastinal seminomas can contain extensive areas of fibrosis (beyond just fibrous septa/stroma) consistent with tumor regression. Prospective knowledge of this diagnostic pitfall and attempts to target biopsies toward FDG-avid portions of a mediastinal mass may increase diagnostic yield and accuracy, thereby helping to prevent non-indicated surgical interventions.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-22-15/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-22-15/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). The study was approved by the institutional review board of New York University (No. S21-01220), and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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