Endocrine Journal
Online ISSN : 1348-4540
Print ISSN : 0918-8959
ISSN-L : 0918-8959
CASE REPORT WITH REVIEW OF LITERATURE
Pembrolizumab with external radiation therapy effectively controlled TMB-high unresectable recurrent parathyroid cancer: a case report with review of literature
Hiroshi Katoh , Tomoya Mitsuma, Riku Okamoto, Kanako Naito, Takaaki Tokito, Mariko Kikuchi, Takafumi Sangai
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Keywords: Pembrolizumab, Radiation therapy, Parathyroid cancer, Unresectable, Tumor mutational burden (TMB)
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2024 Volume 71 Issue 11 Pages 1069-1075

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Abstract

Parathyroid cancer (PC) is extremely resistant to chemotherapy and radiotherapy (RT), but hormonally functional by producing excessive parathyroid hormone (PTH), causing remarkable hypercalcemia even in biochemical disease recurrence. Accordingly, management of hypercalcemia by calcimimetics and bisphosphonates has been main treatment for unresectable PC. Here, we report a case of unresectable tumor mutational burden (TMB)-high recurrent PC that has been effectively controlled by pembrolizumab (PEM) with RT. A 48-year-old male patient, with previous history of left single parathyroidectomy for primary hyperparathyroidism, underwent surgeries for recurrent hyperparathyroidism at 47 and 48 years of age, and was pathologically diagnosed with PC. He was referred to our hospital due to persistent hypercalcemia and elevated PTH. The recurrent tumors were identified in the superior mediastinum and radically resected, then the hyperparathyroidism was improved. A FoundationOne® CDx of the specimen called TMB-high. He demonstrated recurrent hyperparathyroidism at 49 years of age, and underwent a gross curative resection. However, hyperparathyroidism achieved only insufficient improvement, indicating biochemical residual cancer cells. PEM treatment was initiated in combination with RT to the left central-lateral neck and superior mediastinum. He successfully achieved evocalcet and zoledronate withdrawal, and the PTH level improvement was continuously observed for 8 months at present, with only grade 2 subclinical hypothyroidism. Interestingly, leukocyte fraction ratios were reversed corresponding to disease improvement. A combination of PEM and RT is a promising treatment of unresectable TMB-high PC. Recent evidence on the immunomodulatory effect of RT provides the rationale for the combination of RT and PEM.

 Background

Parathyroid cancer (PC) is a rare malignant tumor with a 0.005% occurrence among all malignant tumors [1], and comprises ~0.5% of primary hyperparathyroidism [2-4]. Complete surgical resection has been the only curative treatment for PC [4-7]. The tumor must be completely resected en-bloc with clear margins because of the strong ability of residual PC cells for local recurrence. Moreover, most (90%~) of PCs are hormonally functional by producing excessive parathyroid hormone (PTH), causing remarkable hypercalcemia even in biochemical disease recurrence [8]. Therefore, the severity of hypercalcemia and treatment response to hypercalcemia determines the prognosis in most patients with unresectable PC.

Calcimimetics and/or bisphosphonates have been the main treatments that focus on the management of hypercalcemia for patients with unresectable PC since PC is extremely resistant to chemotherapy or radiation therapy (RT). Recently, pembrolizumab, a programmed death-1 inhibitor, has effectively decreased the disease burden in microsatellite instable (MSI) unresectable PC [9].

Here, we report a case of tumor mutational burden (TMB)-high unresectable recurrent PC treated with a combination of pembrolizumab and external-beam RT. To the best of our knowledge, this is the first report of TMB-high unresectable recurrent PC that responded to pembrolizumab treatment.

 Case presentation

A 49-year-old male patient underwent left single parathyroidectomy for primary hyperparathyroidism with renal lithiasis at 31 years old (detailed information is unavailable) (first operation). He exhibited hypercalcemia (serum calcium [Ca]: 12.5 mg/dL) and elevated level of plasma intact PTH (iPTH) at 497 pg/mL (reference range: 10–65 pg/mL) 15 years after initial surgery (at 46 years old) for the colic pain caused by ureterolithiasis. Cervical ultrasonography and 99mTc-methoxy-isobutyl-isonitrile (MIBI)-single photon emission computed tomography (SPECT)/ computed tomography (CT) scan revealed an 18-mm mass between the left common carotid artery (CCA) and internal jugular vein with avidity to 99mTc-MIBI. He was diagnosed with hyperparathyroidism due to a recurrent parathyroid tumor and underwent radical resection with left hemithyroidectomy, central neck dissection, and combined resection of the left vagus nerve (second operation). Immediately after the second operation, the serum Ca level was improved to the reference range. The pathological diagnosis confirmed a recurrence of PC with a microscopic positive margin. He presented with nausea and demonstrated remarkable hypercalcemia (serum Ca: 14.2 mg/mL) and elevated iPTH at 825 pg/mL 19 months after the second operation (at 48 years old). The laboratory data revealed a decreased estimated glomerular filtration rate (eGFR) (36.4 mL/min/1.73m2), indicating hypercalcemia-induced renal dysfunction. Cervical ultrasonography and a CT scan indicated a recurrent tumor in the left neck, with negative scans both in 99mTc-MIBI-SPECT/CT and fluorine-18 fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/CT scans. A high dose of evocalcet (24 mg/d at the maximum) and weekly zoledronate failed to control hypercalcemia; thus, the patient underwent the third operation, comprising tumorectomy with left modified neck dissection and combined resection of the left internal jugular vein. Hypercalcemia (corrected serum Ca: 12.2 mg/dL) and elevated iPTH at 755 pg/mL persisted even after the third operation; thus, he was referred to our hospital. A magnetic resonance imaging (MRI) revealed a superior mediastinal mass that was suspected of recurrent tumor responsible for sustained hyperparathyroidism (Fig. 1A). Hypercalcemia (corrected serum Ca: 13.3 mg/dL) was controlled to <12 mg/dL by hydration and elcatonin and zoledronate administration in addition to 24 mg/d of evocalcet before the fourth operation (Fig. 2). The recurrent tumor was determined with a daughter tumor and was radically resected with superior mediastinal dissection in the fourth operation (Fig. 1B). These tumors were pathologically confirmed as PC recurrences with a MIB-1 labeling index of 30%. A comprehensive cancer genome profiling (CGP) using a FoundationOne® CDx called TMB-high (35 muts/Mbp) as a druggable target with actionable gene alterations (MLH1, TERT, SPOP, TET2, CDC73, BRCA2, and NOTCH3 (Table 1), and with microsatellite stable (MSS) status also shown in a mismatch repair (MMR) immunohistochemistry as proficient MMR (pMMR) (Fig. 3). The iPTH level was decreased to the reference range, and the serum Ca was decreased below the reference range requiring calcium replacement, immediately after the fourth operation (Fig. 2). Plasma iPTH and corrected serum Ca levels were re-elevated after cardiac surgery for concomitant severe mitral regurgitation. The corrected serum Ca was elevated to >11 mg/dL 192 days after the fourth operation, and evocalcet treatment was restarted. Hypercalcemia persisted with the corrected serum Ca of >12 mg/dL, requiring frequent elcatonin administration, despite dose escalation of evocalcet to 8 mg/d with zoledronate administration (Fig. 2). An MRI and ultrasonography revealed a 9-mm mass posterolaterally to the left CCA (Fig. 1C and D), without any avidity to 99mTc-MIBI. The recurrent tumor was identified posteriorly and laterally to the left CCA with severe adhesion on the fifth operation. Multiple small nodules suspicious of dissemination of recurrences were observed; thus, modified neck dissection was concurrently performed as a gross curative surgery (Fig. 1E). The pathological diagnosis proved the recurrence and dissemination of PC. iPTH achieved insufficient improvement (1,108 to 525 pg /mL) and hypercalcemia persisted (13.1–12.2 mg/dL) despite the fifth operation (Fig. 2), indicating biochemical residual cancer cells. Pembrolizumab (PEM) treatment with 200 mg/triweek was started after 36 days of the fifth operation. External-beam radiation therapy (RT) was concurrently performed to the left central to lateral neck and superior mediastinum with 60 Gy/30 fr. The first improvement of the plasma iPTH and corrected serum Ca levels was observed followed by gradual hyperparathyroidism improvement 21 days after PEM introduction, just before the second cycle of PEM administration. He successfully achieved evocalcet withdrawal after five PEM cycles, and the continuing iPTH level improvement remained (Fig. 2). The normalized corrected serum Ca level preceded the iPTH level normalization. Remarkably decreased serum 25-hydroxyvitamin D to 12.5 ng/mL and hyperplasia of residual right parathyroid glands caused by chronic renal dysfunction may also contributed to sustained high iPTH level. No severe adverse effect has been observed for over 9 months. Only grade 2 subclinical hypothyroidism (thyroid stimulating hormone: 7.19 μIU/mL [reference range: 0.50–5.00 μIU/mL], free T3: 3.14 pg/mL [reference range: 2.30–4.00 pg/mL], and free T4: 1.16 ng/dL [reference range: 0.90–1.70 ng/dL]) without any clinical sign and symptom was observed after 8 PEM treatment cycles. Interestingly, the lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR) values were reversed corresponding to cancer-induced hyperparathyroidism improvement by PEM (Fig. 2).

Fig. 1  Images of recurrent tumor(s). (A) A neck MRI before the fourth operation showed a superior mediastinal tumor (red arrow) that was supposed to be recurrent parathyroid cancer responsible of severe hypercalcemia. (B) At the fourth operation, recurrent tumors (arrows) were radically resected with superior mediastinal dissection under partial sternotomy. In addition to the tumor that was pointed out preoperatively in a neck MRI (A), there was a daughter tumor laterally to the main recurrent tumor behind the left clavicle head (arrows). (C and D) A neck MRI and a ultrasonography showed mass adjacent to left CCA (arrows) before the fifth operation. (E) Image after resection of recurrent tumor and left modified neck dissection on the fifth operation. The posterior space of CCA indicated where the recurrent tumor was existed. Left modified neck dissection was performed including multiple small nodules (or lymph nodes) suspicious of disseminated recurrences.
Fig. 2  Trends of plasma intact PTH and corrected serum calcium levels from the fourth surgery for recurrence(s) (upper) with trends of NLR and LMR (bottom). A number in evocalcet represents a dose (mg) of evocalcet. Abbreviations: iPTH, intact parathyroid hormone level; Ca, corrected serum calcium level; EBRx, external-beam radiation therapy; PEM, pembrolizumab; op, operation; MR, mitral regurgitation; NLR, neutrophil-to-lymphocyte ratio; LMR, lymphocyte-to-monocyte ratio.
Table 1 Genetic alterations called by CGP

Druggable Actionable
TMB-high (35 Muts/MBp) TMB-high
MLH1 p.Q537 MLH1 p.Q537
TERT c.-146C>T
SPOP p.F102L
TET2 p.S1798
CDC73 p.R77P
BRCA2 c.68-1G>A
NOTCH3 p.S497
Fig. 3  Microscopic images of recurrent tumor resected in the fourth operation. (A) H&E staining. (B–E) MMR immunohistochemistry (B, MLH1; C, MSH2; D, MSH6; E, PMS2).

 Discussion

Complete resection is the golden standard for PC treatment because of the high risk for local recurrence. Most PC is hormonally functional; thus, the severity of hypercalcemia and treatment response to hypercalcemia determine the prognosis in most patients with unresectable/recurrent PC even in biochemical recurrence. Conversely, recurrent disease management has been mainly surgical resection because of the refractoriness to chemotherapy or RT [10]. Surgical debulking of functioning tumors can reduce and sometimes normalize serum PTH and calcium levels [4, 6, 11, 12], making them amenable to hypercalcemia treatment such as calcimimetics and bisphosphonates. Accordingly, multiple surgical resections are often performed for recurrent diseases over time. However, repeated operations are challenging in identifying recurrent tumors, and aggressive surgery needs a balance between benefits and morbidity. Moreover, the efficacy of surgical intervention is very limited in the case of disseminated disease or biochemically functional disease. Therefore, advances in the treatment of unresectable/recurrent PC have been eagerly warranted.

Cytotoxic chemotherapy has been notoriously ineffective in the treating PC, except for partial responses in a few reported cases using dacarbazine or combination therapy consisting of fluorouracil, cyclophosphamide, and dacarbazine or a combination of methotrexate, doxorubicin, cyclophosphamide, and lomustine [13, 14]. A multikinase inhibitor, sorafenib, has demonstrated efficacy in recurrent/metastatic and unresectable PC [12, 15, 16]. A single case report indicated that anti-PTH immunotherapy controlled hypercalcemia that is unresponsive to conventional treatments [17] although the efficacy should be confirmed in multiple patients. In the current patient, remarkable hypocalcemia after the cardiac surgery may have triggered residual cancer cell activation and iPTH re-elevation (Fig. 2). Anti-PTH immunotherapy may be useful in such biochemical residual diseases as an adjuvant therapy.

In recent years, immunotherapy, particularly immune checkpoint inhibitors (ICIs), has been applied as one of the most powerful approaches in treating solid cancers [18]. High microsatellite instability (MSI) is associated with strong programmed death (PD-1) and PD-L1 expression; thus, anti-PD1 (or anti-PD-L1) immunotherapy has been indicated for advanced solid cancers [19]. Recently, pembrolizumab (PEM), a PD-1 inhibitor, has decreased tumor burden in MSI unresectable PC [9]. Additionally, TMB-high predicts survival after immunotherapy across multiple solid cancers [20-22]. Most patients show MSS status despite the more frequent MSI-high status in patients with TMB-high (13.3%) than in those with TMB-low (0.7%) multiple solid cancers [22]. To the best of our knowledge, the present case is the first report of TMB-high unresectable recurrent PC that responded to PEM treatment, giving hope to patients with unresectable PC.

A couple of reports indicated the role of RT in reducing local recurrence after curative resection [23-25]. However, the efficacy of palliative RT is unclear as the reported case is very limited. Christakis et al. reported postoperative RT after salvage surgery has temporarily controlled serum Ca and PTH levels [26]. In the present case, RT in combination with PEM treatment normalized hypercalcemia and significantly decreased iPTH level despite the unknown contribution level of each therapy, and further study is warranted to clarify the detailed mechanism. Recent literature has reported that RT triggers a systemic immune response via inducing in situ vaccination by killing cancer cells [27-30]. The abscopal effect is well-known, in which local RT may shrink non-irradiated tumors at remote [31, 32]. Growing evidence revealed the immunomodulatory effect of RT on various tumor-associated immune cells (e.g., tumor-associated macrophages, myeloid-derived suppressor cells, dendritic cells, and natural killer cells) [32, 33], giving a rationale to the combination of RT and immunotherapy. Notably, NLR and LMR ratios were reversed corresponding to the treatment response of PEM and RT in the current case. These results may represent the immunomodulatory effect of treatment.

On the contrary, ICIs can cause immune-related adverse events (irAEs) caused by excessively increased T-cell activation, which may affect various organs, particularly including the multiple endocrine systems as potential life-threatening toxicities [34, 35]. Endocrine-related irAEs include primary hyperthyroidism/hypothyroidism, thyroiditis, primary adrenal insufficiency, type 1 diabetes mellitus, and hypophysitis, of which primary hypothyroidism is most prevalent [36]. Longer ICI duration is an independent risk factor for multisystem irAE development [36]. Conversely, multisystem irAEs were associated with improved long-term prognosis in non-small cell lung cancer [36]. Long-term use of PEM would be necessary to keep remission in the patients with unresectable PC; thus, periodic screening for multisystem irAEs is prerequisite.

In conclusion, we first report a combination therapy of PEM and RT that effectively improves hyperparathyroidism caused by unresectable disseminated PC with TMB-high status. Recent evidence of immunomodulatory effects of RT gives rationale to the combination of PEM and RT despite the unknown detailed mechanism of the combination therapy of PEM and RT (the limitation of this case report). This report would be great hope for patients with unresectable PC that is extremely resistant to conventional chemotherapy and RT.

 Author contributions

HK drafted the manuscript. HK, TM, RO, KN, TT, MK, and TS treated the patient. All authors read and approved the final version of the manuscript.

 Funding

The authors declare that this case report was not funded externally.

 Availability of data and materials

The data supporting the findings of this case report are available from the corresponding author upon reasonable request.

 Declarations

Ethics approval and consent to participate

All procedures followed were under the ethical standards of the committee responsible for human experimentation (institutional and national) and the Helsinki Declaration of 1964 and later versions. Approval of our manuscript by an ethics committee was unnecessary. The patient provided informed consent for this study.

 Consent for publication

The patient signed written informed consent for the publication of this case report and accompanying images.

 Competing interests

The authors declare no competing interest in this case report.

 Acknowledgement

The authors would like to thank Enago (www.enago.jp) for the English language review.

References
 
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