When a Parathyroid Tumor Returns After 11 Years: The Diagnostic Challenge Between Atypical Adenoma and Carcinoma

Table of Contents

• Key Points
• Background: Understanding Primary Hyperparathyroidism
• The Patient's Story: Initial Diagnosis in 1996
• The Tumor Returns: 2007
• The Second Surgery: July 2007
• What the Pathologist Found
• Recovery and Long-Term Follow-Up
• Why Parathyroid Tumors Are So Difficult to Diagnose
• What This Means for Patients
• Limitations of This Case Report
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• Parathyroid tumors can recur many years after surgery, even 11 years later, so lifelong follow-up is essential.
• Distinguishing atypical parathyroid adenoma from carcinoma is difficult; vascular invasion and distant metastases are key signs of cancer.
• Capsular rupture during parathyroid surgery may facilitate tumor recurrence through cell seeding or incomplete removal.
• The overall recurrence rate of atypical parathyroid adenomas is about 3% after surgical removal.
• Long-term vitamin D supplementation and regular blood tests for calcium and PTH help detect recurrence and maintain health.

Background: Understanding Primary Hyperparathyroidism

Primary hyperparathyroidism is a condition in which one or more of the four parathyroid glands—tiny glands located in the neck behind the thyroid—produce too much parathyroid hormone (PTH). This hormone normally regulates calcium levels in the blood, so when too much of it is produced, calcium levels rise, a condition called hypercalcemia.

While primary hyperparathyroidism is the most common cause of hypercalcemia, the condition itself is relatively uncommon, affecting less than 1% of the general population.

The causes of primary hyperparathyroidism break down as follows:

• Parathyroid adenomas or atypical adenomas (benign tumors): 85% of cases
• Parathyroid hyperplasia (enlargement of all four glands): 10% of cases
• Multiple adenomas: 4% of cases
• Parathyroid carcinoma (cancer): less than 1% of cases

Parathyroid carcinoma is exceptionally rare, but it is a serious and often fatal cause of primary hyperparathyroidism. To date, there is still no clear-cut diagnostic pathway established for parathyroid carcinoma, which results in significant diagnostic ambiguity and complexity. Clinical differentiation between a benign parathyroid adenoma and a carcinoma is extremely challenging, and ultimately the diagnosis remains a histopathological one—meaning it requires examining the tissue under a microscope after surgery.

The Patient's Story: Initial Diagnosis in 1996

In 1996, a 32-year-old, otherwise healthy woman was diagnosed with primary hyperparathyroidism during a routine health check. Her parathyroid hormone (PTH) serum levels were elevated to 127 ng/L (normal range: 10–65 ng/L), and her calcium serum levels were elevated up to 3.6 mmol/L (normal range: 2–2.5 mmol/L). Other laboratory investigations from 1996 that led to the diagnosis are no longer accessible.

Interestingly, at the time of diagnosis, the patient did not exhibit any specific symptoms attributable to hypercalcemia. This is not unusual—many patients with hypercalcemia have subtle or no symptoms at all, which is one reason the condition can go undetected for years.

A neck ultrasound scan revealed a caudal (lower) parathyroid tumor on the left side. On June 3, 1996, surgeons performed a subtotal left-sided thyroid lobectomy (removal of part of the left thyroid lobe) and a caudal parathyroidectomy (removal of the lower parathyroid gland) to surgically remove the presumed benign parathyroid adenoma.

During the operation, however, an important complication occurred: the capsule of the tumor ruptured. This detail would later become highly significant in understanding the patient's disease course.

After the operation, the patient's calcium levels returned to normal, and PTH levels were reported in the medical record to be within the normal range, though the exact PTH serum levels after the 1996 operation are no longer available.

The histological report from 1996 showed an atypical, predominately oncocytic parathyroid adenoma (oncocytic refers to tumor cells packed with mitochondria, giving them a distinctive appearance under the microscope). No secure signs matching the criteria of parathyroid malignancy—such as vascular invasion (cancer cells entering blood vessels) or breaches through the capsule with invasion of surrounding soft tissue—were found.

However, some signs that can favor parathyroid carcinoma were present, including:

• Relatively high mitotic figures (cells dividing more rapidly than normal)
• A distinct nuclear morphology with prominent nucleoli (enlarged structures inside the cell nucleus)
• Fibrous septa (bands of scar-like tissue) emerging from a thick fibrous capsule

Unfortunately, the original histopathological material from 1996 is no longer available, but this specific information is recorded in the pathology report.

Despite the ambiguous pathological findings, the tumor was classified at that time as an atypical parathyroid adenoma, and regular follow-up of local findings, blood calcium, and PTH levels was recommended.

The Tumor Returns: 2007

During a routine follow-up appointment in 2007—11 years after the first presentation—elevated levels of intact PTH of 703 ng/L were found. A control test 2 weeks later still showed elevated levels of 218 ng/L. This difference in PTH values was initially explained by the fact that PTH is secreted in a pulsatile manner, meaning levels naturally fluctuate.

At that time, the patient's calcium levels were in the upper normal range at 2.48 mmol/L (normal range: 2–2.5 mmol/L). Three weeks later, another laboratory control showed elevated levels of intact PTH of 104.6 ng/L and elevated calcium levels of 2.59 mmol/L.

Additionally, the patient's 25-OH vitamin D3 level was low at 7.1 ng/mL (normal range: 20–50 ng/mL), which was explained as a result of decreased dietary intake and reduced sun exposure, since the patient lacked clinical symptoms.

The laboratory results from June 26, 2007, when the recurrence was diagnosed, are summarized below:

• Intact PTH: 104.6 ng/L (normal: 10–65 ng/L)
• PTH-related peptide: <1.5 pmol/L (normal: <1.5 pmol/L)
• Total serum calcium: 2.59 mmol/L (normal: 2–2.5 mmol/L)
• Ionized serum calcium: 1.36 mmol/L (normal: 1.17–1.29 mmol/L)
• Urinary calcium: 8.1 mmol/24h (normal: <6.20 mmol/24h)
• Serum phosphate: 0.64 mmol/L (normal: 0.84–1.45 mmol/L)
• 25-OH vitamin D3: 7.1 ng/mL (normal: 20–50 ng/mL)
• Alkaline phosphatase: 113 U/L (normal: 40–140 U/L)
• Bone alkaline phosphatase: 8.9 μg/L (normal: 4.9–22.7 μg/L)
• Osteocalcin: 18.0 μg/L (normal: 15–46 μg/L)
• N-telopeptide: 5.9 nmol/L (normal: 6.2–19 nmol/L)

A magnetic resonance imaging (MRI) scan of the neck was performed and showed a 5 mm left-sided paratracheal soft tissue tumor (a small growth located next to the windpipe on the left side). At that point, the suspicion arose that the initial tumor classified as an atypical adenoma might have been misdiagnosed.

Because the initial tumor showed features suspicious of parathyroid carcinoma, and the patient now presented with a tumor recurrence, doctors suspected she might have a parathyroid carcinoma recurrence.

A Tc-99m sestamibi scintigraphy (a nuclear medicine scan that helps locate parathyroid tissue) was performed and showed a well-defined left-sided activity enhancement corresponding to the tumor detected on the MRI. Notably, no evidence of distant metastases or suspicious lymph nodes was found.

Subsequently, a neck sonography (ultrasound) was performed, showing an inhomogeneous hypoechoic polycystic defined area measuring 17 × 10 mm—meaning the tumor appeared as an irregular, fluid-filled area that was clearly outside the thyroid gland and distinctly located below the small remaining portion of the left thyroid lobe.

The Second Surgery: July 2007

The patient was referred to an endocrine surgical center in Halle, Germany, for the ensuing operation. On July 6, 2007, at the age of 43, she received an en-bloc resection (removal of the tumor as a whole, along with surrounding tissue) of the tumor recurrence, which measured 12 mm.

The tumor was in very close proximity to the left recurrent laryngeal nerve—the nerve that controls the vocal cords on the left side—but the nerve's function could be preserved during the operation. The intra-operative photographic documentation clearly demonstrated that the surgical team assumed this was a parathyroid carcinoma recurrence at that point.

The patient's intraoperative PTH was initially 113 ng/L and normalized to 11.1 ng/L after the tumor was resected—a strong indicator that all hyperfunctioning parathyroid tissue had been successfully removed.

What the Pathologist Found

The pathological findings from the second surgery suggested parathyroid carcinoma, including several concerning features:

• Trabecular and diffuse growth patterns distinctly different from normal parathyroid tissue
• Tumor cell pleomorphism (cells of varying shapes and sizes) with macronucleoli (enlarged nucleoli)
• Mitotic figures: up to 3 mitoses per one high-power field, and 52 mitoses per 50 high-power fields
• A proliferation index (Ki-67) of up to 10%, indicating relatively rapid cell division
• Tumor necrosis (areas of dead tissue within the tumor)
• Tumor infiltration into surrounding soft tissue and striated muscle

Under the microscope, the pathologist observed desmoplastic stroma reaction (dense scar-like tissue induced by the tumor), invasion of soft tissue and skeletal muscle, dysplastic (abnormal) tumor cells adjacent to normal parathyroid tissue, and cord-like infiltrating tumor cells. Immunohistochemistry for parafibromin—a protein that is often lost in parathyroid carcinoma—was negative in tumor cells but positive in normal parathyroid tissue.

The tumor met certain World Health Organization (WHO) criteria for malignancy because of three features:

1. Macronucleoli (enlarged nucleoli within the cell nucleus)
2. More than five mitoses per 50 high-power fields (the tumor had 52)
3. Tumor necrosis (dead tissue within the tumor)

However, no clear-cut diagnosis of carcinoma could be made due to the lack of decisive criteria—specifically, vascular invasion (tumor cells invading blood vessels) was not found, neither by conventional staining methods like hematoxylin and eosin (H&E) and Elastica van Gieson (EvG) staining, nor by immunohistochemistry (CD31, a marker for blood vessel lining cells).

The resection borders (edges of the removed tissue) and the lymph nodes were free from tumor.

Recovery and Long-Term Follow-Up

After the second surgery, the patient's calcium levels normalized. However, she developed mild symptoms such as irritability, muscle cramps, and fatigue, which were attributed to symptoms of hypocalcemia (temporarily low calcium levels after removal of the overactive parathyroid tissue). Oral calcium supplementation was started and discontinued after several weeks.

During all follow-up appointments over the subsequent years—the last one being held in September 2022 when the patient was 58 years old—the patient was feeling well, and both PTH and serum calcium levels remained in normal ranges without any oral calcium supplementation.

One ongoing issue was the patient's vitamin D status. Her 25-hydroxy vitamin D levels were low on follow-up at 14.6 ng/mL (normal range: 20–50 ng/mL). To date, the patient receives 1,000 units of 25-hydroxy vitamin D orally once a day to ensure an optimal vitamin D3 status.

The patient's vitamin D3 levels were tracked over many years:

• 26.06.07: 7.1 ng/mL
• 15.03.12: 14.6 ng/mL
• 15.12.15: 7.25 ng/mL
• 19.02.16: 44 ng/mL
• 19.05.16: 24.6 ng/mL
• 24.11.16: 41 ng/mL
• 18.05.17: 41.9 ng/mL
• 17.06.21: 35.3 ng/mL
• 09.12.21: 42.7 ng/mL
• 29.09.22: 29.8 ng/mL

Retrospectively, this patient was classified to have a recurrence of the atypical parathyroid adenoma, because only some, but not all, histopathological findings were indicative of parathyroid carcinoma. During the 15 years of follow-up after the second operation, no further tumor has recurred to date.

Why Parathyroid Tumors Are So Difficult to Diagnose

This case highlights the formidable difficulties in diagnosing parathyroid carcinoma. The tumor removed during the second operation in 2007 was initially classified as a parathyroid carcinoma, but was later reclassified as an atypical parathyroid adenoma recurrence because of the lack of distant metastases and vascular invasion.

Parathyroid carcinoma is often diagnosed retrospectively—only after a recurrence of hypercalcemia or hyperparathyroidism occurs, either due to local tumor spread or distant metastases. This is a recurring theme in the medical literature, with several reported cases of parathyroid carcinoma that were originally diagnosed as benign parathyroid adenomas.

Biochemical markers can provide clues. Leading biochemical markers suggestive of parathyroid carcinoma include:

• Calcium levels >3 mmol/L (normal range: 2–2.5 mmol/L)
• PTH elevations greater than 2–3 times the normal range (normal range: 10–65 ng/L)

In clinical practice, calcium levels of >4 mmol/L and PTH levels of >1,000 ng/L are often seen in patients with parathyroid carcinoma. In this patient, the PTH was found to be in the range of 703 ng/L only once on follow-up, with a drop to 218 ng/L just 2 weeks later. This drop could be explained both by the pulsatile (fluctuating) secretion of PTH and by vitamin D deficiency, since the patient's 25-OH vitamin D3 level was 7.1 ng/mL at that time. Other factors that might affect PTH levels—dehydration, chronic kidney injury, or bisphosphonate intake—were not documented in the medical record. Regardless of this variation, the repeated laboratory findings in this patient were considered too low to be strongly indicative of parathyroid carcinoma.

Other conditions must also be considered in the differential diagnosis. Parathyromatosis is a rare cause of recurrent hyperparathyroidism in which several nodules of hyperfunctioning parathyroid tissue form in the neck or mediastinum (the space between the lungs). Usually, parathyromatosis presents as small, numerous nodules with no real fibrous capsule, unlike parathyroid adenoma or carcinoma. In this patient, the mitotic activity, histomorphological growth pattern, tumor necrosis, presence of a solitary nodule, and the fibrous capsule ruled out parathyromatosis. Additionally, parathyromatosis does not typically infiltrate the surrounding soft tissues and striated muscle as was shown in this patient's tumor. Four-gland hyperplasia was also ruled out by neck imaging.

No clear-cut diagnostic workup has been established so far for parathyroid carcinoma. The American Joint Committee of Cancer (AJCC) proposed a classification system for parathyroid cancer using the TNM classification of malignant tumors (T = tumor size/extent, N = lymph node involvement, M = metastasis). However, there is limited data on tumor characteristics and associated prognosis, so no prognostic stages can be concluded from this staging system as yet.

After surgical excision, certain distinct histological findings can aid the diagnosis of malignancy:

• Mitotic figures
• Trabeculated parenchyma (a distinctive ribbon-like growth pattern) including thick fibrous bands
• Capsular or vascular invasion

Most importantly, vascular invasion should lead to a strong suspicion of malignancy. Additionally, in contrast to benign parathyroid tissue seeding (as seen in parathyromatosis), real lymph node or distant metastases are the biological evidence of malignancy. In this case, neither the presence of abnormal mitosis nor the thick fibrous bands initially led to critical clinical judgment and suspicion of malignancy after the first operation in 1996—even though it is doubtful whether the disease course in this particular patient would have changed significantly even if malignancy had been suspected then.

What This Means for Patients

Recurrence of a parathyroid tumor should always be evaluated critically. Parathyroid carcinoma has a high tendency of recurrence after surgical excision, affecting 25%–80% of patients. The mean time to recurrence is 3 years, but it can range from 1 to 20 years after the initial surgery. A cure is unlikely once a malignant tumor has recurred, but prolonged survival is common.

Benign hyperparathyroidism is generally not considered a precancerous condition for the development of parathyroid carcinoma. In contrast, atypical parathyroid adenomas are classified to have an uncertain malignant potential—they exhibit some features of parathyroid carcinoma but lack unequivocal features like invasive growth.

The single most effective therapy for parathyroid carcinoma is complete surgical resection. An en-bloc resection (removing the tumor whole, along with its capsule and surrounding tissue) should be performed at the time of the first presentation, as this reduces the rate of capsule injury and cell seeding concurrently. In clinical practice, however, only about 12% of parathyroid carcinoma cases are en-bloc excised at first presentation—meaning most patients do not receive this optimal initial surgery.

This case is particularly instructive because the capsule of the first tumor ruptured during surgery in 1996. The authors note that it is most likely that the tumor recurrence was facilitated by this capsular rupture, either through cell seeding (tumor cells spilling into the surrounding tissue) or incomplete removal of the tumor after the rupture.

The overall recurrence rate of atypical parathyroid adenomas after surgical removal is 3%, according to the research literature. However, no studies have been conducted on the recurrence rate of atypical parathyroid adenomas after capsular rupture during surgery, so no definitive conclusion can be drawn about the exact effect of capsular rupture on tumor recurrence.

Limitations of This Case Report

As with any case report, this article describes a single patient's experience, which limits how broadly the findings can be generalized. Several specific limitations are also worth noting:

• The histopathological material from 1996 is no longer available, so the original tumor could not be re-examined with modern techniques
• The exact PTH serum levels after the 1996 operation are no longer accessible
• Other laboratory investigations from 1996 that led to the diagnosis of primary hyperparathyroidism are also unavailable
• The final classification of the tumor as an atypical parathyroid adenoma recurrence rather than parathyroid carcinoma was made retrospectively, based on the absence of distant metastasis and vascular invasion
• There are no established guidelines for follow-up regimes for atypical parathyroid adenomas, meaning the follow-up schedule used in this case was determined by clinical judgment rather than evidence-based protocol

Recommendations for Patients

Based on this case and the broader medical literature, patients with parathyroid tumors—particularly atypical adenomas—should be aware of the following recommendations:

1. Undergo lifelong follow-up. Life-long monitoring after parathyroid surgery is essential, since the development of metastases has been documented up to 20 years after initial diagnosis.
2. Monitor PTH and calcium levels regularly. In this case, the first follow-up after the second surgery occurred every 6 months, and after several years without recurrence, the interval was prolonged to 1 year. Regular blood tests for PTH, calcium, and vitamin D levels can detect recurrence early.
3. Pay attention to vitamin D status. This patient required ongoing vitamin D supplementation (1,000 units daily). Low vitamin D levels can affect PTH measurements and bone health.
4. Seek specialized surgical expertise. If surgery is needed, an experienced endocrine surgeon should perform an en-bloc resection to minimize the risk of capsule rupture and cell seeding.
5. Be aware that symptoms can be silent. Hypercalcemia often causes no symptoms, which is why routine follow-up blood tests are critical even when you feel well.
6. Understand that diagnosis can evolve. As this case demonstrates, the distinction between atypical parathyroid adenoma and parathyroid carcinoma can be extremely difficult, and classifications may change as more information becomes available.

In the future, additional molecular markers might enable a more distinct diagnosis between these conditions. For now, the authors emphasize that a greater level of suspicion of malignancy is required to optimize patient care and achieve a favorable long-term outcome. This case should raise awareness for the differential diagnosis of hypercalcemia and primary hyperparathyroidism, including parathyroid carcinoma and atypical adenoma, and highlight the diagnostic challenges.

Frequently Asked Questions

What is an atypical parathyroid adenoma?

An atypical parathyroid adenoma is a benign tumor with some features seen in cancer, such as rapid cell division or fibrous bands, but it lacks clear signs of malignancy like invasion into blood vessels. It is considered to have uncertain cancer potential. Diagnosis is made by examining the tumor tissue under a microscope after surgery.

Why did the parathyroid tumor come back 11 years later?

The first surgery in 1996 caused the tumor capsule to rupture. The authors believe the recurrence was most likely facilitated by this rupture, either from tumor cells spilling into surrounding tissue or from incomplete removal after the rupture. Not all suspicious features of cancer were present, so it was later classified as a recurrence of the atypical adenoma.

How can doctors tell an atypical adenoma from parathyroid carcinoma?

It is very difficult. A cancer diagnosis requires clear evidence such as vascular invasion or distant metastases. Features like mitotic figures, tumor necrosis, and invasion into soft tissue suggest cancer, but they are not always conclusive. In this case, the tumor was reclassified as an atypical adenoma because no vascular invasion or distant spread was found.

Why is lifelong follow-up needed after parathyroid surgery?

Tumor recurrence can occur many years later, sometimes up to 20 years after initial diagnosis. Regular blood tests for calcium, PTH, and vitamin D can detect recurrence early. In this patient, the tumor returned after 11 years. Even if you feel well, follow-up is essential.

What is the risk of recurrence after removal of an atypical parathyroid adenoma?

The overall recurrence rate of atypical parathyroid adenomas after surgical removal is about 3%, according to research. However, no studies have looked specifically at recurrence after capsular rupture during surgery, so the exact effect of rupture on recurrence is not known. Lifelong monitoring is still recommended.

What symptoms did the patient have after surgery, and were they serious?

After the second surgery, the patient developed mild symptoms such as irritability, muscle cramps, and fatigue. These were attributed to temporarily low calcium levels, called hypocalcemia. Oral calcium supplementation was started and stopped after several weeks. No serious complications occurred.

If my parathyroid tumor is called an atypical adenoma, should I get a second opinion to check for parathyroid carcinoma after a recurrence?

Parathyroid carcinoma is exceptionally rare and may be misdiagnosed as an atypical adenoma; recurrence can occur up to 20 years later. In one case, a tumor initially classified as atypical adenoma was reclassified only after an 11-year recurrence, because the microscopic features were ambiguous and vascular invasion was absent. Because the diagnosis is histopathological and can evolve, a second opinion that includes review of pathology slides, imaging, and PTH/calcium trends may help determine whether en-bloc resection is needed. Lifelong monitoring of PTH and calcium levels is essential. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Late recurrence of a single gland primary hyperparathyroidism

Authors: Jessica Kotliarevskaia, Udo Siebolts, Henning Dralle, Frank Schuppert

Publication: Clinical Case Reports, 2024, Volume 12, Article e8440. Published by John Wiley & Sons Ltd. Received October 26, 2023; revised December 20, 2023; accepted December 21, 2023. DOI: 10.1002/ccr3.8440

Affiliations: Department of Gastroenterology, Endocrinology, Diabetology and General Medicine, Klinikum Kassel, Kassel, Germany; Department of Gastroenterology and Oncology, Vivantes Klinikum Spandau, Berlin, Germany; Institute of Pathology, Martin Luther University, Halle, Germany; Institute of Pathology Cologne University, Cologne, Germany; Department of Surgery, Martin Luther University, Halle, Germany; Department of Endocrine Surgery, University Hospital Essen, Essen, Germany.

Funding: No public or commercial funding was received for this case report. The authors declared no conflicts of interest.

This patient-friendly article is based on peer-reviewed research. Written informed consent was obtained from the patient to publish the original report in accordance with the journal's patient consent policy.