Pheochromocytoma in Denmark during 1977–2016: validating diagnosis codes and creating a national cohort using patterns of health registrations

Figures & data

Table 1 Eligibility criteria

	Danish National Patient Registry	Danish Registry of Causes of Death	Danish National Pathology Registry
Registration date	Date of start of in- or outpatient contact	Date of death or found dead	Date of requisition of pathological examination
Type of diagnosis code	Diagnosis code for primary, secondary, or supplementary cause of contact or referral	Diagnosis code for immediate, contributing, or other cause of death	Pathology code for diagnostic conclusion of pathological examination
PPGL diagnosis codes	ICD-8	ICD-8c	SNOMED
	255.29 Pheochromocytoma	255.2 Pheochromocytoma	M8700xa
	ICD-10	ICD-10c	Pheochromocytoma
	D350A Pheochromocytoma	D350 Benign neoplasm of adrenal gland	S29740
	E275xa Catecholamine hypersecretion	E275 Catecholamine hypersecretion	Pheochromocytoma syndrome
	R825A Elevated urine levels of catecholamines	R825 Elevated urine levels of drugs, medicaments, and biological substances
	SNOMEDb
	ZM8700xa Pheochromocytoma

Notes: Individuals were considered eligible if they had a PPGL diagnosis code as the specified type of diagnosis code in a registry, and the date of their first registered diagnosis code was between January 1, 1977, and December 31, 2017, and while they lived in Denmark. Only individuals living in the North Denmark Region and Central Denmark Region at time of first registration were included in the validation cohort.

a Including underlying diagnosis codes.

b In the Danish National Patient Registry, SNOMED diagnosis codes can only be used as optional supplementary diagnosis codes.

c Diagnosis codes in the Danish Registry of Causes of Death have a maximum length of four characters making them less detailed than in ICD-8 and ICD-10 codes in the Danish National Patient Registry.

Abbreviations: ICD-8, International Classification of Diseases 8th edition; ICD-10, International Classification of Disease 10th edition; PPGL, pheochromocytoma and catecholamine-secreting paraganglioma; SNOMED, Systematized Nomenclature of Medicine.

Table 2 Expanded eligibility criteria

	Danish National Patient Registry
Registration date	Date of hospital admission or outpatient contact
Type of diagnosis code	Diagnosis code for primary, secondary, or supplementary cause of contact
Possibly PPGL-related diagnosis codes	ICD-8
	194.0 Malignant neoplasm of endocrine glands—suprarenal gland
	194.8 Malignant neoplasm of endocrine glands—other
	194.9 Malignant neoplasm of endocrine glands—unspecified
	226.0 Benign neoplasm of endocrine glands—suprarenal gland
	226.8 Benign neoplasm of endocrine glands—other
	226.9 Benign neoplasm of endocrine glands—unspecified
	239.1 Neoplasm of uncertain behavior of endocrine glands and nervous system
	255.9 Other and unspecified diseases of adrenal glands
	743.4 Neurofibromatosis (von Recklinghausen)
	ICD-10
	C741 Malignant neoplasm of medulla of adrenal gland
	C749 Malignant neoplasm of unspecified part of adrenal gland
	C754 Malignant neoplasm of carotid body
	C755 Malignant neoplasm of aortic body and other paraganglia
	D093B Carcinoma in situ of other endocrine gland
	D350 Benign neoplasm of adrenal gland
	D355 Benign neoplasm of carotid body
	D356 Benign neoplasm of aortic body and other paraganglia
	D358 Benign neoplasm, pluriglandular involvement
	D359 Benign neoplasm of endocrine gland, unspecified
	D361B Benign neoplasm of autonomic nervous system
	D441 Neoplasm of uncertain behavior of adrenal gland
	D446 Neoplasm of uncertain behavior of carotid body
	D447 Neoplasm of uncertain behavior of aortic body and other paraganglia
	D448A Multiple endocrine adenomatoses
	D449 Neoplasm of uncertain behavior of unspecified endocrine gland
	E278 Other specified disorders of adrenal gland
	E279 Disorder of adrenal gland, unspecified
	E348 Other specified endocrine disorders
	Q850 Neurofibromatosis (nonmalignant)
	Q858D Von Hippel–Lindau syndrome
	Z031W Observation for suspected malignancy in adrenal gland

Notes: Individuals fulfilled expanded eligibility criteria if registered with a possibly PPGL-related diagnosis code as primary, secondary, or supplementary cause of contact in the Danish National Patient Registry, and the date of their first registered diagnosis code was between January 1, 1990, and February 28, 2015, and while they lived in Denmark. Only individuals living in the North Denmark Region and Central Denmark Region at time of first registration who also were registered with possibly PPGL-related diagnosis code at the Department of Endocrinology and Internal Medicine at Aarhus University Hospital were included in the expanded validation cohort.

Abbreviations: ICD-8, International Classification of Diseases 8th edition; ICD-10, International Classification of Disease 10th edition; PPGL, pheochromocytoma and catecholamine-secreting paraganglioma.

Figure 1 Identification of PPGL patients in area of validation, the North Denmark Region and Central Denmark Region.

Notes: ^aSeven cases of doubt refuted as non-secreting paragangliomas; twenty-four refuted due to weak clinical evidence despite some inconsistencies; and six refuted due to insufficient information to confirm PPGL. ^bThirty-five cases of doubt confirmed as PPGL based on pathology and clinic despite no lab tests performed (diagnosed at autopsy or by pathologist post-surgery); three confirmed despite no pathological examination (patient abstained from surgery or surgery not technically possibly); and fourteen confirmed due to strong clinical evidence despite some missing data or inconsistencies. ^cFive refuted as non-secreting paragangliomas; six refuted as workup were insufficient to confirm PPGL. ^dOne patient with confirmed PPGL who did not fulfill primary or expanded eligibility criteria was reported by endocrine specialist (MGR) at Department of Endocrinology at Aalborg University Hospital.
Abbreviation: PPGL, pheochromocytoma and catecholamine-secreting paraganglioma.

Table 3 PPGL diagnostic criteria for confirming or refuting PPGL

Confirmed

1. PPGL diagnosed by pathologist  and lab testsa confirming PPGL or with moderate to high suspicion for PPGL

2. PPGL diagnosed by pathologist  and lab testsa performed but report missing  and one or more tumors identified by radio imaging in location consistent with PPGL  and confirmed in health records by treating clinician

3. Lab testsa confirming PPGL or with moderate to high suspicion for PPGL  and pathological examination performed but report missing  and one or more tumors identified by radio imaging in location consistent with PPGL  and confirmed in health records by treating clinicians

4. Case of doubt further scrutinized by expert panel, which deemed PPGL the most likely diagnosis.

Examples on cases of doubt confirmed by expert panel:b

PPGL confirmed in health records by treating clinician but reports on both pathological examination and lab testsa missing.

PPGL diagnosed by pathologist but lab testsa with low suspicion for PPGL

PPGL diagnosed by pathologist but no lab testsa performed (eg, an incidental discovery at autopsy or after surgery on other indication)

Lab testsa confirming PPGL or with moderate to high suspicion for PPGL and PPGL confirmed in health records by treating clinician but no pathological examination performed (eg patient died before surgery, abstained from treatment or surgery was not technically possible)

Refuted

1. Never suspected of or evaluated for PPGL (eg, incorrect registration of wrong diagnosis code)

2. PPGL refuted by pathologist or other adrenal tumor diagnosed by pathologist (eg, adrenal cortical adenoma, metastasis)

3. Lab testsa refuting PPGL

4. Lab testa with low to moderate suspicion for PPGL  and refuted by treating clinician in health records

5. Lab testa with low to moderate suspicion for PPGL  and radio imaging performed with no tumors located in location consistent with PPGL

6. Radio imaging performed with no tumors located in location consistent with PPGL  and refuted by treating clinician in health records

7. Pathological examination, lab tests,a or radio imaging performed but report(s) missing  and refuted by treating clinician in health records

8. Case of doubt further scrutinized by expert panel, which deemed PPGL refuted, unlikely or with insufficient data to determine if confirmed or refuted.

Examples on cases of doubt refuted by expert panel:b

PPGL diagnosed by pathologist but lab tests refuting PPGL (eg, hormonally silent paraganglioma)

Insufficient workup (eg, some clinical suspicion but no relevant workup or lab test with low to high suspicion for PPGL but patient abstained from new test, imaging or any further investigations)

Inconsistencies in workup (eg, lab tests considered highly suspicious of PPGL but no tumors found by imaging or PPGL pathologically refuted)

Notes:

a PPGL lab tests include blood and urine measurements of catecholamines, vanillylmandelic acid, and metanephrines. A single lab test elevated fivefold or more above reference range not caused by interfering factors (interacting drugs, trauma, critical disease, etc) was considered as confirming PPGL. Three or more lab tests consistently elevated 2- to 4.9-fold were considered of moderate to high suspicion for PPGL. Varying lab tests with only one or two lab tests elevated 2- to 4.9-fold or lab tests consistently elevated less than twofold were considered of moderate to low suspicion for PPGL. One or more lab tests consistently within reference range was considered as refuting PPGL.

b List of examples of cases of doubt is not exhaustive.

Abbreviation: PPGL, pheochromocytoma and catecholamine-secreting paraganglioma.

Table 4 PPGL registrations and validity of diagnosis codes

Diagnosis code	Individuals in Denmark with diagnosis code	Individuals in validation area with diagnosis code (percentage of total)	Health records available	PPGL confirmede	PPV (95% CI)e
Danish National Patient Registry
255.29 Pheochromocytomaa	721	263 (36.5%)	249	49	20.2% (15.4–25.9)
D350A Pheochromocytomab	892	268 (30.0%)	268	82	30.8% (25.3–36.8)
E275x Catecholamine hypersecretionb,b	877	195 (22.2%)	194	46	23.7% (17.9–30.3)
R825A Elevated urine levels of catecholaminesb	2	1 (50.0%)	1	0	0.0% (0.0–97.5)
ZM8700x Pheochromocytomac,d	24	8 (33.3%)	8	5	71.4% (29.0–96.3)
Total individuals in registry	2323	688 (29.6%)	673	144	21.7% (18.6–25.0)
Danish Registry of Causes of Death
255.2 Pheochromocytomaa	31	9 (29.0%)	8	6	100.0% (54.1–100.0)
D350: Benign neoplasm of adrenal glandb	63	11 (17.5%)	11	3	27.3% (6.0–61.0)
E275: Adrenomedullary hyperfunctionb	1	1 (100.0%)	1	0	0.0% (0.0–97.5)
R825: Elevated urine levels of drugs, medicine or biological substancesb	0	–	–	–	–
Total individuals in registry	95	21 (22.1%)	20	9	50.0% (26.0–74.0)
The Danish National Pathology Registry
M8700x: Pheochromocytomab,d	630	214 (34.0%)	212	167	79.5% (73.4–84.8)
S29740: Pheochromocytoma syndromec	5	2 (40.0%)	2	2	100.0% (15.8–100.0)
Total individuals in registry	630	214 (34.0%)	212	167	79.5% (73.4–84.8)
Total individuals in all registries	2626	787 (30.0%)	771	193	25.3% (22.3–28.6)

Notes: Each person can be included in the table with more than one diagnosis code and in more than one registry.

a International Classification of Diseases 8th edition.

b International Classification of Disease 10th edition.

c Systematized nomenclature of medicine.

d Including underlying codes.

e Nine confirmed PPGL patients were excluded as they were diagnosed before 1977 or while living outside Denmark.

Abbreviations: CI, confidence interval; PPGL, pheochromocytoma and catecholamine-secreting paraganglioma; PPV, positive predictive value.

Table 5 Algorithms for identifying confirmed PPGL patients

Algorithms	PPV % (95% CI)	FP, N	Completeness % (95% CI)	FN, N
Registered with any PPGL diagnosis codes in more than one registrya	97.7% (93.4–99.5)	3	64.1% (57.0–70.8)	71
Registered in the Danish National Pathology Registry with a PPGL diagnosisb code + the examination was performed on a relevant tissuec or the patient is registered with a surgical procedure code for adrenal surgeryd in the Danish National Patient Registry	93.6% (88.9–96.8)	11	81.8% (75.7–86.9)	36
Registered with the ICD-8 diagnosis code 255.2 for pheochromocytoma in the Danish	100.0% (54.1–100.0)	0	3.0% (1.1–6.5)	192
Registry of Causes of Death
Registered with a diagnosis code for pheochromocytoma or catecholamine hypersecretion in the Danish National Patient Registry less than 30 days before date of death	83.3% (51.6–97.9)	2	5.1% (2.4–9.1)	188
All algorithms combined	93.1% (88.5–96.3)	13	88.9% (83.7–92.9)	22

Notes:

a See Table 1 for included registries and diagnosis codes.

b M8700 or S29740, including underlying codes.

c Relevant tissue defined as material code for autopsy “31: deceased body”, or with SNOMED diagnosis codes, including underlying codes: topography codes “T0010: body as a whole”, “T93: adrenal gland” and “T94-95: paraganglioma”, morphology codes “M868-869: paraganglioma” or etiology code “ÆF4330: originated from adrenal gland”.

d Procedure codes for adrenal surgery, including underlying codes: “086: explorative incision on adrenal gland”, “088: biopsy of adrenal gland”, “090: adrenalectomy”, and “KBC: surgery on adrenal gland”.

Abbreviations: CI, confidence interval; FP, false positive; FN, false negative; ICD-8, International Classification of Diseases 8th edition; PPGL, pheochromocytoma and catecholamine-secreting paraganglioma; PPV, positive predictive value.

Table S1 Important changes in health registries

	Danish National Patient Registry	Danish Registry of Causes of Death	Danish National Pathology Registry
Contents	Administrative and clinical information for all hospital contacts, including dates, diagnosis codes, and performed procedures. Diagnoses are registered by the physician discharging the patient. Procedures are registered by the responsible surgeon.	Time and cause(s) of death for every Danish decedent. Cause(s) of death are registered by the physician with most accurate knowledge of patient either hospital physician or practitioner. If autopsy is performed, the pathologist adds his or her findings.	Information on pathological examinations including tests performed, free text description of examination and SNOMED codes on topography and diagnostic conclusions. Data are reported by requisitioning department and pathologist(s) performing examination.
Coverage	Somatic hospital admissions discharged after January 1, 1977, psychiatric admissions discharged after January 1, 1995, and still-active admissions from 2015, and onward. Outpatient contacts ending in or active since 1995. Emergency department contacts since 1995.	Danish residents dying while residing in Denmark since 1970. Danish residents dying in Greenland and the Faroe Islands and Greenlanders and Faroese living in Denmark were included in 1983.	Includes incomplete data from some public pathology departments back to 1970 with national coverage from 1997. Registration became mandatory for private practicing pathologist in 2005.
Important changes in data	Diagnoses registered using Danish adaptions of ICD-8 1977–1993 and ICD-10 1994–now. Changes in registration of surgical procedures in 1981, 1989, and 1996, currently using Danish adaptation of Nordic Classification of Surgical Procedures. Has been basis for reimbursing departments and hospitals since 2000.	Diagnoses registered using Danish adaptions of ICD-8 1977–1993 and ICD-10 1994–now. Data were submitted by paper death certificates in 1970–2006 and electronically since 2007. In the 1970s, 75% of patients dying at hospitals were autopsied compared to less than 20% today.^Citation13	Data were submitted by different computer-based systems and with varying data recorded 1970–1996. In 1997 a national standard for which data to register were defined. In 1999 a single national online tool for registering data were introduced.

Note: Data from references 9 and 13 to 16.

Abbreviations: ICD-8, International Classification of Diseases 8th edition; ICD-10, International Classification of Disease 10th edition; SNOMED, Systematized Nomenclature of Medicine.

Table S2 PPV and completeness of diagnosis codes in Danish National Patient Registry by number of in- or outpatient contacts

Diagnosis codes	PPV or completeness	At least one contact	At least two contacts	At least three contacts
255.29, D350A, E275xa, R825A, or ZM8700xa as primary, secondary, supplementary, or referral diagnosis code	PPV	21.7% (18.6–25.0)	54.5% (47.7–61.3)	72.3% (64.0–79.6)
	Completeness	72.7% (66.0–78.8)	60.6% (53.4–67.5)	50.0% (42.8–57.2)
255.29, D350A, or ZM8700xa as primary, secondary, supplementary, or referral diagnosis code	PPV	24.9% (21.1–28.9)	56.4% (48.6–63.9)	75.7% (66.8–83.2)
	Completeness	63.1% (56.0–69.9)	49.0% (41.8–56.2)	43.9% (36.9–51.2)
255.29, D350A, or ZM8700xa without referral diagnosis codes	PPV	27.0% (23.0–31.3)	59.3% (51.3–66.9)	76.3% (67.4–83.8)
	Completeness	62.1% (55.0–68.9)	48.5% (41.3–55.7)	43.9% (36.9–51.2)
255.29, D350A, or ZM8700xa as primary diagnosis codes	PPV	47.7% (41.3–54.2)	75.9% (67.0–83.3)	85.9% (76.6–92.5)
	Completeness	58.1% (50.9–65.0)	44.4% (37.4–51.7)	36.9% (30.1–44.0)
255.29, D350A, or ZM8700xa at any endocrine departmentsb	PPV	42.4% (35.6–49.4)	77.3% (66.2–86.2)	82.1% (66.5–92.5)
	Completeness	44.9% (37.9–52.2)	29.3% (23.1–36.2)	16.2% (11.3–22.0)
255.29, D350A, or ZM8700xa at tertiary endocrine departmentsb	PPV	46.3% (39.1–53.7)	77.0% (65.8–86.0)	82.1% (66.5–92.5)
	Completeness	44.4% (37.4–51.7)	28.8% (22.6–35.6)	16.2% (11.3–22.0)

Notes:

a Including underlying codes.

b Not including referral diagnosis codes to endocrine departments.

Abbreviations: PPV, positive predictive value.

Helweg-LarsenKThe Danish register of causes of deathScand J Public Health20113972629

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