Metastatic Large Cell Calcifying Sertoli Cell Tumor: A Case Report,Diagnostic Pitfalls,and Literature Review

Abstract

Large cell calcifying Sertoli cell tumor (LCCSCT) is a rare testicular neoplasm, with only a small subset of clinically malignant tumors. We report a diagnostically challenging, clinically and histologically malignant LCCSCT in a 37-year-old man with a misleading initial presentation. The patient initially presented with testicular pain and swelling following trauma and was clinically diagnosed with epididymitis and hydrocele. Despite antibiotic therapy, symptoms progressed to include weight loss, night sweats, fever, diffuse pain, and lymphadenopathy. Computed tomography performed 2 months later demonstrated diffuse lymphadenopathy and enhancement of the right testicular tunica. Fine-needle aspiration and core biopsy of a left supraclavicular lymph node revealed a malignant neoplasm with S100 and SOX10 expression, raising concern for a neural crest-derived tumor. Next-generation sequencing identified a PRKAR1A mutation, further confounding the diagnosis. Extensive imaging failed to identify a primary tumor, and the patient showed no response to chemotherapy. Due to progressive disease and persistent testicular pain, a right orchiectomy was performed, revealing a hydrocele, thickened tunica, and an intratesticular mass. Histologic evaluation demonstrated malignant LCCSCT with cytologic atypia, necrosis, invasive growth, and metastatic disease. A focused literature review identified 22 previously reported clinically malignant LCCSCTs, highlighting variable clinical presentations, frequent S100 positivity, and overlapping immunohistochemical and molecular features that represent important diagnostic pitfalls. This case report emphasizes the need to consider metastatic LCCSCT in the differential diagnosis of metastatic S100/SOX10-positive tumors with PRKAR1A mutations, particularly when a testicular lesion is present or suspected.

Keywords

genitourinary cytopathology testis

Introduction

Large cell calcifying Sertoli cell tumor (LCCSCT) is a rare tumor in the sex cord stromal testicular tumor category. It has been associated with PRKAR1A mutation. Pathologically malignant features as refined by Al-Obaidy et al include necrosis, tumor size >40 mm, extratesticular growth, severe cytologic atypia, vascular invasion, and a mitotic rate >1 mitosis/mm², while clinical malignancy is defined by the presence of metastases. Importantly, the vast majority of large cell calcifying Sertoli cell tumors are clinically benign, and surgical excision is considered curative in most patients.¹

We present this unusual tumor in a 37-year-old male patient with multiple diagnostic challenges and conduct a literature review of clinically malignant LCCSCTsfor possible pitfalls in diagnosis.

Methods

The tumor was identified during routine sign-out of a supraclavicular lymph node fine-needle aspiration. The corresponding orchiectomy specimen, received later, demonstrated a discordant diagnosis due to an uncommon diagnostic pitfall. Both specimens were reviewed together.

All tissue was formalin-fixed and paraffin-embedded. Evaluation was performed on hematoxylin and eosin-stained sections with IHC studies as part of the diagnostic workup, detailed elsewhere in the manuscript. Targeted next-generation sequencing was performed on FFPE tissue.

Institutional Review Board approval was not required for this single case report. Verbal patient consent was obtained. Clinical and radiologic data were reviewed with the treating clinician and the signing pathologists. Follow-up was available; the patient died shortly after diagnosis.

A PubMed search was performed from inception to manuscript preparation using the name of the entity. English-language case reports and series were reviewed, with emphasis on metastatic tumors. Duplicates were excluded. Data extracted included age, tumor size, presentation, IHC findings, metastatic sites, outcome, and associated genetic syndromes.

Results and Case Report

Clinical History

A 37-year-old male patient without significant past medical history presented to the emergency department with 5 weeks of right-sided testicular pain and swelling which began after the patient had gone on a 50-mile bike ride with a broken saddle seat. There was no associated discharge, urinary symptoms or signs of systemic infection. Initial workup included a urinalysis with trace leukocyte esterase, no leukocytes, negative urine gonorrhea/chlamydia, and ultrasound imaging with right sided epididymitis with large complex hydrocele. He was given ceftriaxone and doxycycline in the emergency room and discharged on oral doxycycline with urology follow-up 3 days later. At the time of his follow up, it was suggested a trauma and a reactive fluid transudation resulted in an epididymal hematoma. Conservative management and follow-up in 2 to 3 months for a repeat scrotal ultrasound was recommended. Less than 2 weeks later, the patient reported persistent pain and swelling with associated fevers to 102F, chills, nausea, vomiting, weight loss, lower back pain, and generalized body aches and was instructed to go to the emergency department. Admission labs revealed mild leukocytosis (WBC 13.92 × 10³/µL) with elevated absolute neutrophil count (ANC 10.76 × 10³/µL), normocytic anemia (Hgb 11.8 g/dL, MCV 92.1 fL), thrombocytosis (PLT 596 × 10³/µL), normal CMP, negative UA, and negative urine gonorrhea/chlamydia. A repeat testicular ultrasound, CT chest/abdomen/pelvis, and PET were obtained.

Radiology

The repeat ultrasound showed an unchanged large volume complex fluid in the right hemiscrotum displacing the testis as well as an indeterminate calcified structure in the right epididymal head. Chest and abdomen CT showed extensive cervical, supraclavicular, mediastinal, retrocrural, and retroperitoneal lymphadenopathy. Pelvic CT showed a moderate hydrocele with mild uniform enhancement of the tunica and a rounded mildly enhancing 14 mm structure in the right testis, corresponding to the structure identified on scrotal ultrasound. Given the CT and scrotal ultrasound findings, differential considerations included metastatic testicular cancer and lymphoma. PET scan revealed increased uptake in the right testicle, liver, lungs, pericardial region, and rib. The left supraclavicular lymph node was found amenable to image guided biopsy for an attempt at definitive tissue characterization. A fine needle aspiration and a core biopsy of left supraclavicular lymph node were performed.

FNA and Core Biopsy

Core biopsy, cell block, and smears showed discohesive cells with atypical nuclear features including irregular nuclear borders, clumped chromatin, and hyperchromasia with plasmacytoid appearance. Cells were medium-sized with a normal to low nuclear to cytoplasmic ratio (Figure 1).

Figure 1.

Discohesive, plasmacytoid cells on cell block, H&E, 400x magnification (A), Positive SOX10 IHC labeling of the cells of interest, 200x magnification (B), Positive S100 IHC labeling of the cells of interest, 200x magnification (C), and Positive steroidogenic factor 1 (NR5A1) IHC labeling of cells of interest, 200x magnification (D).

A panel of IHC showed the tumor to be positive only for S100, SOX10, and synaptophysin and negative for CD45, CD20, CD3, MUM1, SALL4, KIT, keratinAE1/AE3, keratin CAM5.2, keratin 7, keratin 20, Melan-A, HMB-45, chromogranin, CD99, INSM1, NUT, myogenin, and desmin with retained INI1 labeling and focal nonspecific labeling with CD138. Flow cytometry was performed but did not reveal an adequate number of cells and was canceled.

Given the positivity of SOX10 and S100 (Figure 1), the neoplasm was favored to be a malignant tumor of neural crest origin with differential diagnosis including melanocytic tumor and peripheral nerve sheath tumor. The specimen was submitted for next generation sequencing (NGS) per clinician's request. Genomic findings included MTAP loss, CDKN2A loss, CDKN2B loss, PRKAR1A R56fs*26, and TERT promoter −124C > T. The slides were sent out for consultation, where they agreed upon the previous differential.

Follow-up

Less than 2 weeks after the imaging and biopsy were completed, the patient rapidly deteriorated with hypotension, fevers, inability to tolerate oral intake, and failure to thrive. He was urgently initiated while inpatient with a regimen of etoposide and cisplatin for cancer of unknown primary with suspicion for primary nonseminomatous germ-cell tumor. This regimen was chosen because of his young age, distribution of disease, and the potential curative nature for nonseminomatous germ-cell tumor. The patient tolerated the first cycle well, and the decision was made to continue cycle two with the addition of bleomycin. The course was complicated by nausea, vomiting, and recurrent fevers which were refractory to anti-emetics and antipyretics. Given the NGS results which showed PRKAR1A frameshift mutation, and lack of radiographic response, the patient was started on adriamycin and ifosfamine. This regimen was initiated due to the association of PRKAR1A with primary peripheral malignant nerve sheath tumors which remained high on the pathologic differential. He completed two cycles and developed severe nausea and vomiting after the second cycle. He underwent right radical orchiectomy and had restaging CT chest/ abdomen/pelvis which showed disseminated disease progression. The third cycle of AI was held due to clinical and radiologic progression of the disease.

Surgical Procedure

The patient underwent a right orchiectomy. The testicular parenchyma measured up to 4 cm with a 6 cm hydrocele. The entire tunica within hydrocele was thickened and nodular and seemed to be involved by a smooth, tan lesion. Within the testis proper and not in direct continuity with the tunica, there was a 1.2 cm well-circumscribed and hemorrhagic mass. (Figure 2).

Figure 2.

Macroscopic appearance of hydrocele and intraparenchymal nodule (A), Intraparenchymal nodule, H&E, 40x magnification (B), Tumor involving tunica, H&E, 40x magnification (C), Coarse calcifications within the tumor, H&E, 100x magnification (D), Lymphovascular invasion, H&E, 100x magnification (E), Focal myxoid stroma within the tumor, H&E, 200x magnification (F), Positive steroidogenic factor 1 (NR5A1) IHC labeling of the tumor, 100x magnification (G), and Positive inhibin IHC labeling of the tumor, 100x magnification (H).

On histologic evaluation the intratesticular mass was composed of cords and nests of cells with abundant eosinophilic cytoplasm. The cells had round, fairly regular nuclei with prominent nucleoli. There were chunky calcifications and focal myxoid stroma associated with the tumor (Figure 2). Surrounding seminiferous tubules showed a lack of complete spermatogenesis. There were germ cells at the base but there was no maturation to sperm. No intratubular neoplastic Sertoli cells were identified.

In the hydrocele portion, within the tunica vaginalis, there was an abundant proliferation of neoplastic cells similar to that seen within the testis. Lymphovascular invasion by the tumor was identified.

IHC showed the tumor to be positive for S100, SOX10, WT1, CD34, steroidogenic factor 1 (NR5A1), inhibin, calretinin, HMB-45 (weak focal), synaptophysin (weak), keratin CAM5.2 (rare), and keratin AE1/AE3 (rare) and negative for keratin 5/6, keratin 7, GATA3, Melan-A, CD31, D2-40.

The final diagnosis was an LCCSCT with malignant features, which included extension beyond the testis with mitosis count greater than 3 per high-power field and lymphovascular invasion. The remaining testis showed atrophic changes.

A retrospective steroidogenic factor 1 (NR5A1) IHC stain was performed on the initial lymph node FNA cell block, which showed diffuse nuclear positivity in tumor cells (Figure 1).

Follow-Up

Peripheral blood analysis revealed no alterations in PRKAR1A gene, supporting a sporadic tumor rather than association with Carney complex. Follow-up radiology studies showed osseous lesions within T1, T3, T8, and L4 as well as the right ninth rib, extensive adenopathy throughout the neck, chest and abdomen, chest wall and hepatic lesions, and lytic bone lesions, all compatible with metastasis. The patient decided to continue with palliative care and passed away approximately nine months after initial presentation.

Literature Review and Discussion

Obaidy et al¹ refined the previous criteria defined by Kratzer et al² and characterized the tumors as clinically and/or histologically benign, ambiguous, or malignant. Necrosis, cytologic atypia, circumscription, vascular invasion, extratesticular growth, and mitotic activity were features of ambiguous or malignant LCCSCT on histologic examination. Clinical malignancy was defined as metastatic disease.¹ Our tumor fell under the malignant category both histologically and clinically.

We conducted a literature review for metastatic tumors of LCCSCT to identify possible pitfalls for this diagnosis. It revealed 22 published clinically malignant tumors (Table 1). The majority of the patients were presented with a unilateral testicular mass. Notably, five patients including our patient (Patient 1) had distinct presentations. Patient 2 was detected incidentally. Patients 8 and 16 presented with extratesticular symptoms; low back pain and respiratory symptoms, respectively. Patient 21 presented with bilateral testicular masses.

Table 1.

Published Metastatic LCCSCTs on Literature and Their Characteristics.

Metastatic LCCSCT	Age	Presentation	Size (cm)	Syndromic Association	IHC Findings	Location of Metastases	Outcome
Patient #1 (present patient)	37	Testicular swelling and pain	1.2 (with 6 cm hydrocele involved by the lesion)	No	S100 (+), SOX10 (+), WT1 (+), CD34, NR5A1 (+), inhibin (+), calretinin (+), HMB-45 (+ weak focal), synaptophysin (+ weak), keratin 5/6 (−), keratin 7 (−), GATA3 (−), Melan-A (−), CD31 (−), D2–40 (−)	Retroperitoneal lymph nodes, lungs, pericardium, ribs, vertebras, chest wall, liver, lymph nodes of neck, chest and abdomen, chest wall and hepatic lesions	Died of disease
Patient #2 ¹	27	Incidental after trauma	2.6	No	Inhibin (+), Melan-A (+), vimentin (+), calretinin (+), S100 (+)	Retroperitoneal lymph nodes	Died of disease
Patient #3 ¹	30	Mass	2	No	Inhibin (+), Melan-A (+), vimentin (+), calretinin (+), S100 (+)	Retroperitoneal lymph nodes	Alive
Patient #4 ²	36	Mass, gynecomastia	15	No	S100 (+ weak), vimentin (+), p53 (+ weak)	Retroperitoneal lymph nodes
Patient #5 ²	28	Mass	2	No	S100 (+), vimentin (+), p53 (+ weak)	Retroperitoneal lymph nodes, lung, liver, peritoneum, colon
Patient #6 ²	44	Mass	5.5	No	S100 (+), vimentin (+), p53 (+ weak)	Retroperitoneal lymph nodes	Died of disease
Patient #7 ²	29	Mass	3	No	S100 (+), vimentin (+ weak), p53 (+)	Retroperitoneal, bone, liver
Patient #8 ¹⁶	51	Low back pain	4.3	Carney complex	S100 (+), vimentin (+), p53 (+)	Retroperitoneal lymph nodes, vertebra	Died of disease
Patient #9 ²	35	Mass	2.5	No	S100 (+), vimentin (+ weak), p53 (+)	Retroperitoneal lymph nodes, lung
Patient #10 ³	45	Mass	4	No		Para-aortic lymph node
Patient #11 ⁴	42	Mass	1.6	No	S100 (+), Melan A (−), keratin CAM5.2 (−), Synaptophysin (−)	Mediastinal and retroperitoneal lymph nodes, liver, lung	Died of disease
Patient #12 ⁵	48	Mass		No	Vimentin (+)	Iliac and preaortic lymph nodes, lung
Patient #13 ⁶	29	Mass	12	No	ER (+)	Lung and retroperitoneal lymph nodes, kidney, small intestine	Died of disease
Patient #14 ⁷	73	Mass	3.2	No	Vimentin (+), S100 (+), NSE (+)	Iliac and preaortic lymph nodes	Died of disease
Patient #15 ⁸	28	Mass	6	No	Vimentin (+), S100 (+)	Sacral bone, lung, cervical lymph nodes	Died of disease
Patient #16 ⁹	44	Respiratory symptoms	10	PJS	Inhibin (+), calretinin(+), and CD56 (+), keratin 7 (−), EMA (−)	Lung	Died of disease
Patient #17 ¹⁰	36	Mass	3.7	No	Calretinin (+), inhibin (+), vimentin (+), S100 (partially +), AE1/AE3 (partially +), α-smooth muscle actin (−), AFP (−), CD30 (−), KIT (−), desmin (−), hCG (−), placental alkaline phosphatase (−), myogenin (−), myogenic differentiation 1 (−), HHF35 (−), and Melan-A (−)	Lung	Alive
Patient #18 ¹¹	37		2.7	No	PRKAR1A expression lost	Retroperitoneal lymph nodes	Alive
Patient #19 ^¹¹	24		3.5	No	PRKAR1A expression lost	Retroperitoneal lymph nodes	Alive
Patient #20 ^¹¹	28		6	No	PRKAR1A expression retained	Retroperitoneal lymph nodes, lung and bone	Died of disease
Patient #21 ^¹¹	37	Bilateral painless testicular masses	2.4 (R), 2.1 (L)	No	Vimentin (+), calretinin (+), inhibin (+), and keratin AE1/AE3 (+)	Lymph node, pleura, lung, bone	Died of disease
Patient #22 ¹²	31	Testicular pain	3.5	No	Inhibin (+), calretinin (+), Melan-A (+), S100 (+), vimentin (+), SALL4 (−), OCT3/4 (−)	Retroperitoneal, supraclavicular lymph nodes, lung	Died of disease

Our patient showed an atypical presentation from a few different aspects. He had a recent history of trauma with testicular pain and swelling, which was read as epididymitis and hydrocele on imaging, favoring an infection. Literature did not reveal any other LCCSCT patients with hydrocele, which was also involved by the tumor cells in our patient. It is unclear whether the hydrocele was present before or as a result of the tumor. Failed treatment of antibiotics and development of more systemic symptoms prompted a broader work-up.

The cytological examination and IHC profile of the subclavicular FNA sample, including S100 and SOX10 positivity and SALL4 negativity, resulted in a diversion from the testicular tumors. An S100 and SOX10 positive malignant tumor brought a variety of differential diagnoses into consideration; malignant melanoma, malignant peripheral nerve sheath tumor, clear cell sarcoma of soft tissue, even triple negative breast carcinoma. Another pitfall emerged with NGS results, which included PRKAR1A gene mutation, leading to strong consideration of malignant melanocytic nerve sheath tumor, which is known to harbor this mutation.¹³

The PRKAR1A gene encodes the regulatory subunit type 1 alpha of protein kinase A. PRKAR1A gene inactivation leads to production of a defective subunit which results in unregulated PKA activity and uncontrolled cell proliferation.^14,15 PRKAR1A mutations are primarily associated with the Carney complex. Carney complex is an autosomal dominantly inherited syndrome and approximately 30% arise as de novo mutations.^¹⁵ PRKAR1A mutations are associated with LCCSCT, cardiac myxomas, primary pigmented nodular adrenocortical disease, growth hormone-secreting pituitary adenomas, thyroid follicular adenomas and hyperplasia, prolactinomas, psammomatous melanotic schwannomas, sporadic adrenocortical adenomas, as well as pancreatic and liver cancers.^16,17–19 PRKAR1A-associated tumors can occur in both patients with Carney complex and individuals without the syndrome.¹⁶

There is one patient with Carney complex and one patient with Peutz-Jeghers syndrome (PJS) described in the literature as malignant LCCSCT.² With PJS, intratubular large cell hyalinizing Sertoli cell neoplasia should be considered as a well-defined association.²⁰ Remaining patients including our patient did not have any syndromic association. Pathologically malignant LCCSCTs were described with association of Carney complex and PJS.¹ These associations are rarer in the limited number of clinically malignant tumors but should still be considered.

The median age of the patients was 38 (24-73). The median size of the tumor was 5.4 cm (ranging between 1.2 and 12 cm). Twenty-two tumors were unilateral. Patient 21 presented with bilateral masses, an unusual finding for clinically malignant tumors, which metastasized 6 years after initial diagnosis.²¹ This signifies variability of the tumors; therefore, there isn’t a single feature that can rule out the risk of metastasis.

Broad panels of IHC stains were performed across tumors. Notably, S100 was positive in all 14 tumors when ordered. Other remarkably positive stains include inhibin (7/7 tumors), vimentin (14/14 tumors), p53 (6/6 tumors), and calretinin (7/7 tumors). Melan-A was positive in three tumors and negative in three tumors, including our patient. HMB-45 was only performed in our patient, which was weak and focal positive in excision and negative in FNA. This further underlines the possible pitfall of distinguishing LCCSCT from malignant melanocytic nerve sheath tumor. The diffuse steroidogenic factor 1 (NR5A1) positivity retrospectively demonstrated in the metastatic lymph node supported metastatic LCCDCT over an independent melanocytic neoplasm, despite unusual immunophenotype encountered in the initial workup for our patient. Keratin CAM5.2 has also showed rare positivity in excision, while being negative on FNA. These two IHC differences could be explained by sampling as both showed heterogenous staining.

The most common locations of metastasis include retroperitoneal lymph nodes, lungs, and bones including vertebra and ribs. Eleven patients died of disease and four patients were reported alive.

LCCSCT is a rare disease with little over 100 tumors reported,¹ of which a small subset were metastatic as discussed in this paper. The diagnosis can be rather linear with uncomplicated presentations of testicular masses. However, complex presentations with overlooked smaller size masses could be challenging given the rarity and perplexing differential. Our patient and the list of patients provided in table one highlight that it is important to consider metastatic LCCSCT in any patient with metastatic tumor with S100 and SOX10 positive IHC labeling and/or detection of PRKAR1A mutation specifically in the presence of testicular mass or lesion.

This study is limited by its single case report nature and the retrospective design of the literature review and small number of patients, which prevent broad conclusions. Case reports and series in the literature show variable clinicopathologic, IHC, and follow-up data, limiting uniform comparison.

Footnotes

ORCID iDs

Elif Demirci

Saeed Asiry

Ashley Rose

Nicholas Hornstein

Pamela Unger

Compliance With Ethical Standards

Institutional Review Board approval was not required for this single case report. Verbal patient consent was obtained.

Ethical Approval

Institutional Review Board approval was not required for this single case report. Verbal patient consent was obtained.

Author Contributions

ED: writing—original draft, methodology, investigation, formal analysis, data curation, and conceptualization. SA: writing—review and editing, formal analysis, and data curation. AR: writing—review and editing, formal analysis, and data curation. NH: writing—review and editing, formal analysis, and data curation. PU: writing—review and editing, visualization, supervision, methodology, conceptualization, and formal analysis.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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