HORMONE DONE IT? ABDOMINAL AND PELVIC IMAGING CORRELATES TO LABORATORY ABNORMALITIESNICOLE KURZBARD-ROACH, MD1 PRIYANKA JHA, MD1 CHRISTINE MENIAS, MD2

1. UNIVERSITY OF CALIFORNIA, SAN FRANCISCO 2. MAYO CLINIC, ARIZONA

GOALS & OBJECTIVES

GOALS & OBJECTIVES

▸ Biochemical and hormonal abnormalities are frequently associated with anatomic changes. Radiologists can contribute to the diagnosis and care of patients whose imaging reflects underlying hormonal abnormalities.

▸ Reviewers of this poster will understand and be better prepared to evaluate imaging findings associated with hormonal abnormalities in the abdomen and pelvis.

▸ Target Audience: Residents, Fellows, Abdominal Imaging Radiologists, General Radiologists

DISCLOSURES▸ The authors of this presentation have no relevant disclosures.

OVERVIEW

OVERVIEW - BY ORGAN SYSTEM

▸ HEPATOBILIARY: hepatic adenoma, focal nodular hyperplasia

▸ GASTROINTESTINAL: Zollinger-Ellison syndrome

▸ REPRODUCTIVE: endometrial hyperplasia & carcinoma, endometrioma, sex cord-stromal tumor, polycystic ovarian syndrome, ovarian theca lutein cysts, ovarian hyperstimulation syndrome, clear cell adenocarcinoma

▸ MUSCULOSKELETAL: renal osteodystrophy

▸ HEMATOPOETIC: erythropoetin-secreting renal cell carcinoma causing erythrocytosis

HEPATOBILIARY

HEPATOBILIARY

▸ Estrogen synthesis and the liver ▸ Liver is a site of estrogen synthesis via aromatase ▸ Also a site of biotransformation of estradiols to various metabolites ▸ Activity of estrogen-metabolizing enzymes has been reported to be

decreased in dysfunctional hepatocytes, for example, in cirrhotic livers ▸ Cirrhotic patients may therefore have increased circulating estrogens -

thought to be the mechanism for gynecomastia development in male patients with cirrhosis

▸ Liver is also a target organ for estrogen ▸ Estrogen and metabolites act on the liver by stimulating growth of

hepatocytes ▸ Growth stimulation is thought to contribute to the development of benign

hepatic neoplasms: ▸ Hepatic adenoma ▸ Focal nodular hyperplasia

HEPATOBILIARY

HEPATIC ADENOMA▸ Benign hepatic neoplasm ▸ Prevalence: <3/1000 ▸ Major risk factors include hormonal exposure - oral contraceptives in women and anabolic steroids in men ▸ Risks of the lesion include:

▸ Hemorrhage when size > 5 cm ▸ Potential for malignant transformation (<5%), related to lesion subtype

Axial opposed-phase, in-phase, and T2-weighted MR images show a large hepatic mass with lobulated contour. The mass is T2 hypointense relative to liver and has diffuse signal loss on opposed phase sequence, confirming the presence of intralesional fat characteristic of a steatotic-type HNF1a-inactivated hepatic adenoma, Large intralesional hemorrhage is demarcated by hypointense signal on in-phase and T2-weighted sequences.

HEPATOBILIARY

HEPATIC ADENOMA

Subtype Mutation/Genotypic Expression% of

AdenomasHORMONAL Risk Factors

Imaging FeaturesMalignant Potential

Steatotic

HNF1A (Hepatic nuclear factor 1-alpha) inactivation - Lack expression of liver-fatty acid binding protein (L-FABP)

35-40%Oral

contraceptivesSignal loss on opposed-phase MR imaging.

Rare

Beta-catenin mutated

CTNNB1 (Beta-catenin) activation 10-15%Anabolic steroids

No specific features. May have vague central scar. May take up hepatobiliary contrast.

High

InflammatorySAA (serum amylase A) and CRP (C-reactive protein) expression

35%Oral

contraceptives“Atoll” sign of peripheral and central T2 hyperintense signal

None

Unclassified 10% None specific.

▸ Some imaging features are specific to particular subtypes ▸ Lesion classification, if possible, is important, as potential for malignant transformation is

related to lesion subtype

HEPATOBILIARY

FOCAL NODULAR HYPERPLASIA

▸ Most common benign hepatic neoplasm ▸ Prevalence: 4-30/1,000; female:male ratio reported from 2:1 to 26:1 ▸ Etiology thought to be hyperplastic reaction of bile ducts to a vascular/perfusional insult or anomaly ▸ Female predominance suggests role of estrogen exposure in development ▸ Imaging features:

▸ Ultrasound: solid nonspecific lesion ▸ CT: arterial phase hyperenhancement, delayed enhancement of central fibrous scar ▸ MRI: variable T2 hyperintense signal relative to liver, arterial and venous phase hyperenhancement with both extracellular and

hepatobiliary contrast ▸ Delayed phase characteristics

▸ Extracellular contrast: enhancement of central fibrous stroma (“scar”) ▸ Hepatobiliary contrast: non-enhancement of central scar with contrast retention throughout the remainder of the lesion

Axial T1-weighted, arterial phase, venous phase, hepatobiliary phase, and T2-weighted images show mildly T2 hyperintense, enhancing mass with non-enhancing central “scar” and retention of contrast on hepatobiliary phase.

GASTROINTESTINAL

GASTROINTESTINAL

▸ Multiple hormones and small molecules act upon the gastrointestinal tract to facilitate digestion

▸ Gastrin: stimulates gastric mucosal proliferation, secretion of gastric acid

▸ Cholecystokinin: stimulates gallbladder emptying and pancreatic enzyme secretion

▸ Secretin: stimulates pancreas and bile ducts to secrete water

▸ Somatostatin: inhibits pancreatic secretion

▸ Ghrelin: stimulates appetite, also stimulates secretion of growth hormone

▸ Motilin: stimulates stomach and small intestine motility

▸ Excess and/or ectopic secretion of any of these hormones can result in pathologic changes

▸ Zollinger-Ellison syndrome (ZES) describes the constellation of abnormalities seen in the setting of excess gastrin

GASTROINTESTINAL

ZOLLINGER-ELLISON SYNDROME▸ Clinical syndrome includes peptic ulcer disease and chronic diarrhea secondary to increased gastric (hydrochloric) acid production in the setting of excess serum gastrin ▸ Screening tests typically performed when ZES is clinically suspected include fasting gastrin level (off proton-pump inhibitors) and gastric pH level, may include secretin

stimulation test ▸ Imaging findings:

▸ Thickened gastric rugae, due to gastric mucosa proliferation ▸ Gastric and/or duodenal ulcers ▸ Gastrinoma

▸ Usually the source of excess gastrin ▸ May occur as part of multiple endocrine neoplasia type 1 (MEN1) syndrome

▸ Typical location is within the “gastrinoma triangle” of the duodenum (30% tumors) and pancreatic head (60% tumors arise in the pancreas) ▸ Imaging features:

▸ CT/MRI: hyperenhancing mass on arterial phase ▸ Nuclear medicine: uptake on 111-In octreoscan, 68-Ga DOTATATE PET

Axial CT and MRI (pre-contrast, arterial phase, and venous phase) show enhancing mass in the duodeno-pancreatic groove. Endoscopic ultrasound-guided biopsy confirmed gastrinoma.

Images from upper GI fluoroscopic study show gastric rugal thickening, a nonspecific finding seen in gastritis, including gastritis in the setting of Zollinger-Ellison syndrome.

REPRODUCTIVE

REPRODUCTIVE▸ Estrogen is the predominant hormone involved in development and function of the female reproductive

system. ▸ Both benign and malignant processes can be seen in the uterus and ovaries in response to changes in

estrogen. Selective estrogen-receptor modulators (SERMs) can also have a stimulating action in the reproductive system akin to endogenous estrogen. ▸ Endometrial hyperplasia & carcinoma ▸ Endometrioma

▸ Hormone-secreting sex cord-stromal tumors are rarer causes of hyperestrogenism and/or virilization. ▸ Granulosa cell tumor ▸ Lipid-rich thecoma (estrogen-secreting) ▸ Sertoli-Leydig cell tumor, steroid cell tumor (virilization)

▸ Abnormalities of the hypothalamic-pituitary-gonadal axis can result in changes in ovarian function and appearance. ▸ Polycystic ovarian syndrome

▸ Exposure to high levels of beta-HCG can cause characteristic changes in ovarian appearance. ▸ Ovarian theca lutein cysts ▸ Ovarian hyperstimulation syndrome

▸ In-utero exposure to diethylstilbestrol, a synthetic nonsteroidal estrogen, is associated with increased risk for clear cell adenocarcinoma of the vagina and cervix. ▸ Clear cell adenocarcinoma

REPRODUCTIVE

ENDOMETRIAL HYPERPLASIA▸ Endometrial hyperplasia most commonly

occurs in response to unopposed estrogen exposure

▸ Unopposed estrogen exposure may be due to: ▸ Anovulation ▸ Estrogen-secreting tumor ▸ SERMs, specifically, Tamoxifen

▸ Imaging appearance ▸ Thickened endometrium ▸ >15 mm premenopausal ▸ >5 mm postmenopausal

▸ Cystic endometrial changes ▸ + Irregular borders ▸ + Increased vascularity

Transvaginal ultrasound in longitudinal plane and sagittal contrast-enhanced MRI of a patient taking Tamoxifen show shows thickened, cystic endometrium.

REPRODUCTIVE

ENDOMETRIAL CARCINOMA▸ Changes of endometrial hyperplasia are along a continuum that spans from simple hyperplasia to malignancy

▸ Simple hyperplasia —> complex hyperplasia —> complex hyperplasia with atypia —> well-differentiated carcinoma ▸ Most common gynecologic malignancy in industrialized nations ▸ Two histologic subtypes: endometrioid (type 1) accounts for 90% endometrial carcinoma

▸ Type 2 includes the more aggressive serous papillary and clear cell adenocarcinoma subtypes ▸ Imaging features of endometrial carcinoma include:

▸ Ultrasound: heterogeneous endometrial thickening and/or focal mass ▸ CT: heterogeneously enhancing endometrial thickening and/or focal mass ▸ MRI: T1 isointense, T2 hypointense mass relative to normal endometrium

▸ Hypoenhancement relative to myometrium and cervical stroma ▸ Diffusion-weighted imaging (DWI) and ADC maps are useful in identifying unanticipated metastases, including cervical/vaginal drop metastases

and lymph node involvement

Ultrasound performed for postmenopausal bleeding shows large heterogeneous endometrial mass. Endometrial biopsy confirmed high grade endometrioid adenocarcinoma. Initial staging CT showed thickened, enhancing endometrium without definite intraabdominal metastatic disease. Hysterectomy and bilateral salipingo-oophorectomy was performed following this staging CT. Four weeks post-operative and one week following initiation of chemoradiation, CT performed for pelvic pain shows a complex solid and cystic pelvic mass. Differential considerations included post-operative collection (hematoma versus abscess) and recurrent/residual disease. Surgical biopsy confirmed residual disease with possible transformation to sarcomatous features and/or dedifferentiation.

REPRODUCTIVE

ENDOMETRIOMA▸ Endometrioma describes a blood-containing cystic lesion which arises secondary to implanted endometrial tissue, frequently in the setting

of endometriosis ▸ Risk factors: estrogen, including SERMs ▸ Imaging findings

▸ Ultrasound: cyst with diffuse homogeneous low-level echoes, punctate mural echogenic foci ▸ MRI: T1 intrinsice hyperintense signal, T2 “shading” of low signal associated with layering hemorrhagic/proteinaceous products, T2

“dark spot” sign of a hypointense focus adjacent to the cyst wall ▸ Surveillance ultrasound is recommended on an annual basis if not surgically removed, given associated risk of malignant transformation

▸ Suspect malignant transformation if a mural nodule has associated vascularity on ultrasound and/or enhances with MRI

Axial T2, T1 fat-suppressed, and T1 fat-suppressed post-contrast MRI images of a patient taking Tamoxifen show a left ovarian cystic lesion with T2 shading, T2 dark spot sign, intrinsic T1 hyperintense signal, and peripheral enhancement. Multicystic appearance suggests multiple episodes of intracystic hemorrhage.

Ultrasound shows an adnexal cyst with diffuse low level echoes and a solid mural nodule with associated vascularity, suspicious for intracystic malignancy.

REPRODUCTIVE

GRANULOSA CELL TUMOR▸ Represent approximately 5% ovarian neoplasms

▸ Most common estrogen-secreting ovarian tumor, most common malignant sex cord-stromal tumors

▸ Usually occur in post-menopausal women

▸ Good prognosis with >90% 10-year survival, however, can recur as late as 10-20 years following diagnosis

▸ Imaging appearance

▸ Solid and/or multicystic ovarian lesion with variable intracystic hemorrhage and/or central fibrosis

▸ Hormonal action

▸ Can secrete estrogen, inhibin, Mullerian-inhibiting substance

▸ Endometrial carcinoma is associated with the increased estrogen exposure in up to 25% adult cases of granulosa cell tumor

▸ Juvenile estrogen-secreting granulosa cell tumor is associated with precocious puberty

Axial contrast-enhanced CT and transvaginal ultrasound show large, heterogeneous, multiseptated pelvic mass. Ultrasound better demonstrates varying intracystic echogenicity suggesting differing degrees of intracystic hemorrhage. Pathology confirmed granulosa cell tumor at surgical resection.

REPRODUCTIVE

SEX CORD-STROMAL TUMORS

Sagittal T2 HASTE and axial truFISP images of multi-cystic heterogeneous left ovarian mass in a pregnant patient. The mass was discovered at 1st trimester ultrasound. Pathology confirmed mixed tumor, 90% granulosa cell and 10% gonadoblastoma/dysgerminoma.

REPRODUCTIVE

POLYCYSTIC OVARIAN SYNDROME

▸ Polycystic ovarian syndrome (PCOS) is the most common endocrine abnormality in premenopausal women

▸ PCOS is characterized by increased circulating androgens secondary to abnormalities of the hypothalamic-pituitary-gonadal axis

▸ Etiology of PCOS is not entirely known, but is thought to relate to insulin resistance

▸ Increased luteinizing hormone (LH) to follicle-stimulating hormone (FSH) ratio causes the ovaries to preferentially produce androgens

▸ Increased androgen presence is thought to disrupt ovulation by arresting follicular maturation, causing ovarian dysfunction and anovulation/oligo-ovulation

REPRODUCTIVE

POLYCYSTIC OVARIAN SYNDROME▸ Diagnostic criteria for PCOS vary by group, but all include

some combination of: ▸ Other diagnoses excluded ▸ Hyperandrogenism (clinical and/or biochemical) ▸ Ovarian dysfunction/oligo-ovulation/anovulation ▸ Polycystic ovaries

▸ “Polycystic” appearance of the ovaries describes multiple similar-sized small cysts about the periphery of the ovary without a dominant follicle, due to follicular development arrest caused by increased androgens ▸ American College of Obstetricians and Gynecologists

(ACOG) guidelines for diagnosis of polycystic appearance require at least one ovary with one of the following: ▸ >12 follicles measuring 2-9 mm ▸ Volume > 10 mL

▸ While polycystic ovaries remain part of the diagnostic criteria, a polycystic ovary identified on US alone without relevant clinical history is not sufficient to confirm the diagnosis of PCOS

Transvaginal ultrasound shows enlarged left ovary with >12 similar small peripherally situated follicles. The ovary meets criteria to be described as polycystic.

REPRODUCTIVE

THECA LUTEIN CYSTS▸ Theca lutein cysts are anechoic ovarian cysts and large follicles which arise in the setting of exposure to high

levels of beta-HCG ▸ Also called hyperreactio luteinalis ▸ Risk factors include pregnancy (multiple > singleton gestation), molar pregnancy, diabetes ▸ Given the similar subunit structure of HCG and TSH, theca lutein cysts may rarely be seen in severe

hypothyroidism ▸ Cysts may resolve later in a normal gestation

Left ovary of a pregnant patient at 14 weeks gestation shows enlarged left ovary with multiple anechoic cysts. Follow up at 30 weeks gestation shows resolution of the cysts with normal size and appearance of the left ovary. Coronal contrast-enhanced CT of a patient with

complete hydatidiform molar pregnancy shows enlarged bilateral ovaries with multiple cysts.

REPRODUCTIVE

OVARIAN HYPERSTIMULATION SYNDROME▸ Ovarian hyperstimulation syndrome (OHSS) describes cystic enlargement of the ovaries and extravascular fluid shifts secondary to LH and/or

beta-HCG administered in the setting of assisted reproductive technology (ART) ▸ Hyperstimulated ovaries produce vascular-endothelial growth factor (VEGF), which increases vascular permeability and is thought to be the

etiology of the fluid shifts associated with OHSS ▸ Complications include adnexal torsion (risk up to 8%; up to 16% if pregnant), nausea/vomiting, ascites (simple or hemorrhagic),

hypercoagulability, pulmonary edema, pleural effusions ▸ Several classification schemes largely use clinical features to determine severity ▸ Imaging findings include:

▸ Enlarged ovaries with multiple follicles and corpus luteal cysts ▸ Cysts may be anechoic or hemorrhagic

▸ Ascites - simple or echogenic ▸ In ART patients, the presence of free fluid may also prompt suspicion for ruptured ectopic pregnancy in the appropriate clinical setting

Transvaginal ultrasound images of a patient with left lower quadrant pain following oocyte retrieval for donation. The left ovary is markedly enlarged with multiple hemorrhagic follicles. Echogenic free fluid suggests hemoperitoneum, either post-procedural, secondary to follicle rupture, or hemorrhagic ascites in the setting of OHSS.

REPRODUCTIVE

CLEAR CELL ADENOCARCINOMA

▸ Clear cell adenocarcinoma (CCA) is a rare neoplasm of the cervix and vagina ▸ Major risk factor for CCA is in-utero diethylstilbestrol (DES) exposure

▸ Risk is highest in cohort born between 1951 and 1956, corresponding to highest rate of DES prescriptions in the US ▸ Rarely, CCA of the cervix can present in postmenopausal women without a history of DES exposure ▸ May be associated with endometriosis ▸ May be asymptomatic or present with abnormal bleeding ▸ Imaging features: polypoid or sessile enhancing mass with variable T2 signal

Axial arterial-phase, diffusion-weighted, and ADC map images, and sagittal T2-weighted and post-contrast T1-weighted images of heterogeneous cervical mass. This patient had been exposed to diethylstilbestrol (DES) while in utero and her Pap smear was positive for adenocarcinoma. Surgical pathology at time of hysterectomy confirmed clear cell adenocarcinoma.

MUSCULOSKELETAL

MUSCULOSKELETAL▸ Several biochemical abnormalities can affect the muscles and osseous structures ▸ Estrogen

▸ Inhibits bone resorption ▸ Blocks synthesis of interleukin-6 (IL-6), a stimulator of bone resorption, by osteoblasts ▸ Also induces apoptosis of osteoclasts

▸ Steroids (glucocorticoids) - exogenous or endogenous ▸ Induce apoptosis in osteoblasts and osteocytes, and prolong life of osteoclasts

▸ Promote bone resorption without rebuilding ▸ Increased risk for avascular necrosis

▸ Impair immune system, increasing risk for osteomyelitis ▸ Parathyroid hormone

▸ Alterations in calcium/phosphate/vitamin D homeostasis in the setting of chronic renal insufficiency and end-stage renal disease (ESRD)

▸ Impaired renal function results in: ▸ Reduced renal phosphate excretion —> hyperphosphatemia —> increased levels of

parathyroid hormone (PTH) —> increased activity of osteoclasts and osteoblasts ▸ These alterations lead to the spectrum of bone findings which constitute renal osteodystrophy

MUSCULOSKELETAL

RENAL OSTEODYSTROPHY▸ Manifestations of renal osteodystrophy reflect the alterations in phosphate,

calcium, vitamin D, and parathyroid hormone levels due to renal failure ▸ Bone resorption

▸ Most commonly recognized manifestation of renal osteodystrophy on imaging

▸ Affects up to 70% patients with ESRD ▸ Characterized by bony irregularity ▸ Resorption may be cortical, endosteal, subperiosteal, subchondral,

subligamentous ▸ Hands are usually involved first

▸ Subperiosteal resorption of the radial aspect of the 2nd and 3rd finger middle phalanges

▸ Terminal tufts ▸ Subchondral resorption at joints

▸ Interphalangeal ▸ Acromioclavicular (clavicular aspect) ▸ Sacroiliac (iliac aspect) ▸ Sternoclavicular joints (symmetric about joint)

▸ Other manifestations: ▸ Brown tumor

▸ Lucent lesion composed largely of blood and fibrous tissue ▸ Also described as osteitis fibrosa cystica and/or osteoclastoma

▸ Periosteal reaction ▸ Due to PTH stimulation of osteoblastic activity

▸ “Rugger jersey spine” appearance of increased density at vertebral body endplates secondary to increased osteoid production by osteoblasts in response to bony resorption at other sites

Sagittal CT shows sclerotic vertebral endplates of “rugger jersey spine” in this patient with ESRD. Coronal CT shows subchondral resorption involving the iliac aspect of the right greater than left sacroiliac joints.

HEMATOPOETIC

HEMATOPOETIC▸ Erythropoetin (EPO)

▸ Produced entirely by the liver in the fetus; produced mostly by the kidney postnatally with small fraction still produced by liver

▸ Acts on hematopoetic tissue to stimulate erythropoesis

▸ Also acts on neoplastic tissue, stimulating angiogenesis, cell proliferation, and possibly contributing to development of chemotherapy drug resistance

▸ EPO production can be stimulated by hypoxia via upregulation of hypoxia inducible factor (HIF)

▸ Renal cell carcinoma can express both EPO and EPO receptors

▸ Mutation or methylation of the von Hippel Lindau (VHL) gene is associated with increased risk of RCC

▸ Germline VHL mutation —> VHL syndrome

▸ Major risk factor for development of familial RCC

▸ VHL mutation can also be seen in sporadic cases of RCC

▸ VHL mutation can increase EPO expression via several pathways

▸ Functional VHL inhibits HIF; non-functional VHL does not, which leads to stimulation of EPO production

▸ VHL mutations can also cause upregulation of EPO production directly without HIF intermediary

HEMATOPOETIC

RENAL CELL CARCINOMA & ERYTHROCYTOSIS▸ Renal cell carcinoma (RCC) is the most common renal neoplasm

▸ VHL mutation is the most common mutation associated with RCC

▸ Both in familial RCC (von Hippel Lindau syndrome) and in sporadic RCC

▸ VHL mutation causes upregulation of EPO production both directly and indirectly, via HIF

▸ Not only can EPO expressed by RCC contribute to erythrocytosis, but EPO can also act directly on RCC in an oncogenic fashion

▸ EPO administration has also been associated with worse outcomes in patients with breast cancer and head & neck cancer

Axial CECT in a patient with VHL syndrome shows multiple enhancing renal lesions suspicious for RCC as well as an arterially-enhancing pancreatic lesion suspicious for a neuroendocrine tumor.

Axial CECT in a different patient with VHL syndrome shows a dominant enhancing right renal mass consistent with RCC and multiple pancreatic cysts.

CONCLUSION

CONCLUSION

▸ Anatomic findings related to hormonal and laboratory biomarker changes may be identified by the radiologist.

▸ Familiarity with how radiologic findings may reflect hormonal changes will enable the radiologist to make meaningful contributions to the care of these patients.

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Contact: nicole.kurzbard-roach@ucsf.edu