Breast amyloidosis associated with Sjögren syndrome: A diagnostic pitfall in breast pathology

Abstract

BACKGROUND:

Amyloidosis is an uncommon disorder characterized by the extracellular deposition of amorphous and insoluble proteins in an abnormal fibrillary configuration. Mammary amyloidosis is an unusual and easily overlooked diagnosis with an ambivalent presentation that could mimic breast cancer.

CASE REPORT:

We here report the case of 60-year-old Caucasian woman who presented to our surgical oncology department for clinically and radiologically suspicious breast mass. A fine needle biopsy was irrelevant, so we performed a lumpectomy. Final histology revealed an amyloid deposit and further workup was consistent with nodular cutaneous and breast AL amyloidosis associated with Sjögren’s syndrome.

CONCLUSION:

Although rare, an awareness of the clinicopathologic characteristics of this easily overlooked entity is of great importance for breast surgeons.

1. Background

Sjögren’s syndrome (SS) is a chronic autoimmune exocrinopathy of unknown etiology characterized by salivary and lacrimal glands immune-mediated damage, leading to mouth dryness (xerostomia) and eyes (xerophthalmia). Its pathogenesis is marked by dysregulation of both innate and adaptive immunity with B cells and Th1 and Th17 lymphocytes. SS is known for its extra-glandular involvement and association with other autoimmune diseases and plasma cell dysregulation [1].

AL amyloidosis is a relatively rare disease that affects 6,72 to 14,3 in 1 million people worldwide [2]. It is caused by the deposition of complete and/or aminoterminal fragments of free immunoglobulin light chains. It is responsible for varied clinical manifestations, depending on the affected organs. AL amyloidosis can be systemic or localized. It commonly involves the heart, kidney, gastrointestinal tract, and tongue when systemic. The amyloid deposition could have uncommon sites like breast and skin. Such an infrequent presentation could seriously mimic breast cancer.

We herein report a case of Sjögren Syndrome revealed by BA, which to the best of our knowledge the eighth case of BA reported in the literature.

2. Case report

A 60-year-old Caucasian woman was referred to our department for a palpable right breast lump. The patient had a medical history of type 2 diabetes and post-thyroidectomy hypothyroidism on levothyroxine (150 μg/day).

At presentation, her vital signs were unremarkable, with a temperature of 37 °C, pulse rate of 88 beats/minute, respiratory rate of 17 breaths/minute, blood pressure of 135/87 mmHg, and oxygen saturation of 99%.

Physical examination revealed an oblong solid mass measuring 2, 5 ∗ 2 cm in the right breast at the 4 o’clock position, occupying over twenty percent of her breast volume and close to the overlying skin. There was no palpable mass or lump in the left breast. A-15 mm -lymphadenopathy was found in the right axilla.

Multiple pink, firm, and raised bumps measuring between 1, 5 cm, and 3 cm were noted on the right forearm and left leg. Mammogram and ultrasonography showed a 2,3 ∗ 1,8 cm heterogeneous hypoechoic and vascularized mass on the right breast with spiculated margins accompanied by many rounds and tight clustered microcalcifications. On the left breast, there were two masses at 12 and 10 o’clock positions of 0,6 cm and 0,4 cm, respectively. Both of them were hypoechoic, well-defined, and vascularized. Breast Imaging Reporting and Data System (BI-RADS) was interpreted as category 5 for the right and 4c for the left breast (Supplementary Figs a+b). There were also bilateral axillary lymphadenopathies. Thoraco-abdomino-pelvic computed tomography didn’t show any metastasis. The tumors were staged T1N1M0 at the right and T1mN0M0 at the left according to the 8th edition of the American Joint Committee on Cancer (AJCC).

The patient had an ultrasound-guided biopsy of the three masses, which wasn’t conclusive. We also performed a cutaneous biopsy of the nodular forearm lesion that showed masses of eosinophilic deposits with positive red congo coloration consistent with cutaneous amyloidosis. We decided to perform a bilateral lumpectomy. The final histology of the left breast masses was consistent with adenofibromas. However, histopathological examination of the right breast mass showed polymorphous infiltrate and eosinophilic deposit with negative anti-amyloid AA serum (SAA) (Supplementary Figs c+d+e), diffuse positive 𝜅 light chain (Supplementary Fig. g) and rare positive 𝜆 light chain (Supplementary Fig. f). Immuno-chemistry with multiple markers, including cd3, cd20, and cd138. CD3 and CD20 were negative whereas CD138 was positive (Supplementary Fig. h). Consequently, plasmacytoma was eliminated. The patient was referred to the Internal Medicine Department for further workup. Further investigations revealed diffuse paresthesia with a neuropathic pain diagnostic questionnaire (DN4) score of 4. No recent weight loss nor night sweats were reported. At the same time, the patient reported arthralgias and xerophthalmia without xerostomia. The physical examination was normal except for multiple subcutaneous nodules on limbs which were already biopsied. Biological explorations noted normocytic normochromic anemia at 11.4 g/dl, C-reactive protein at 16 mg/l, and serum calcium at 2.46 mmol/l with correct renal function. Immunological assays revealed positive antinuclear antibodies at 1/640 with positive antibodies anti-SSA. Serum protein electrophoresis showed polyclonal hyper-gammaglobulinemia at 21.9 g/l. Blood and urine immunoelectrophoreses were normal. Given the absence of hypercalcemia, anemia Hb < 10 g/dL, renal failure, bone lesions on imaging, and the normality of plasma protein electrophoresis, plasma and urine immunoelectrophoreses, and serum free light chain (FLC) ratio, multiple myeloma and plasmacytoma were ruled out. The extension assessment for other amyloidosis localizations objectified the presence of bilateral carpal tunnel syndrome at electromyography and lymphocytic Chisholm grade IV infiltration of the accessory salivary gland without amyloid deposits. Schirmer’s test confirmed dry eye syndrome. The thoracic-abdominopelvic computed tomography scan was normal.

The assessment of systemic amyloidosis concluded, apart from skin and breast involvement, that there was no renal or digestive, or cardiac involvement. The patient had normal albumin level and renal function with no proteinuria. Digestive endoscopies, electrocardiogram, cardiac echocardiography, cardiac magnetic resonance imaging, and NT-ProBNP level were normal. Regarding peripheral neurological involvement, the metabolic origin of the carpal tunnel couldn’t be ruled out due to the medical history of hypothyroidism and old diabetes.

The diagnosis of nodular cutaneous and breast AL amyloidosis associated with SS was thus confirmed. She was put on 20 mg of methotrexate per week combined with folic acid. After a 6-month follow-up, the patient reported a marked reduction in arthralgia and stabilization of the subcutaneous nodules.

3. Discussion

Amyloidosis is a heterogeneous group of diseases defined by deposits of abnormal extracellular fibrillary proteins that cause tissue damage. The most common types are amyloid light chain amyloidosis (AL) and amyloid A (AA) amyloidosis.

Breast amyloidosis (BA), first described in 1973, is a rare entity. It has been reported as a localized amyloid deposition or a systemic disease manifestation.

This diagnostic entity poses much uncertainty for physicians and pathologists, with its non-specific clinical presentation and often subtle histopathological findings.

In the literature, only six series (Table 1) of BA cases have been published in the past 40 years and comprise a mixture of patients with either localized breast or systemic involvement. The association of Sjögren syndrome with localized BA is scarce. It appears to be an emerging association, with 7 cases reported up to date (Table 2).

Table 1

Case series of breast amyloidosis published in the past 40 years

Number of cases	Number of cases with Sjögren syndrome	Year of publication	Reference
3	1	2002	[3]
7	0	2011	[4]
40	0	2013	[5]
3	0	2015	[6]
10	1	2019	[7]
32	0	2021	[8]

Table 2

Reported cases of breast amyloidosis associated with Sjögren syndrome

Age (year)	Breast clinical/radiological findings	Associated condition	Amyloid type	Year of publication	Reference
60	Induration	Left BA associated with invasive carcinoma	–	2002	[9]
37	Micro-calcifications	Marginal B-cell lymphoma	AL	2003	[10]
63	Micro-calcifications	–	AL	2006	[11]
67	Calcifications	–	–	2019	[7]
45	Palpable lump, a normal mammogram	-	-	2019	[12]
41	Calcifications	–	–	2020	[12]
61	Calcifications	–	–	2020	[13]

Cutaneous nodular amyloidosis associated with SS is also rare, with less than twenty cases reported in the literature. Given these two entities’ rarity, we think our case is valuable.

Clinically, the patient may present with a hard, non-painful, and palpable breast mass, increased breast density, or cutaneous manifestations such as skin thickening, edema, and erythema. Isolated axillary lymphadenopathy was reported in four cases. Hence, amyloidosis may mimic several breast pathologies, both benign and malignant.

Radiologically, common mammographic findings of BA are made of a variety of solitary or multiple masses or nodules, whether including or excluding calcifications. According to previous reports, microcalcifications may be clustered, pleomorphic, fine linear and branching, and smooth branching, rod-like shapes. All these mammographic findings were assessed either as intermediate or suspicious of malignancy, and pathological confirmations were recommended.

In front of such concerning findings, a fine needle biopsy should be performed.

In breast localization, the amyloid is histologically evident as depositions at periductal, interstitial, or perivascular spaces with multiple multinucleated giant cells and calcifications. Given their affinity for calcium, amyloid fibrils are usually found around mammary ducts and blood vessels. If deposits of nonstructural substances are observed by hematoxylin and eosin staining, Congo red staining, which identifies amyloid deposits through apple-green birefringence under polarized light, should be added for confirmation.

Amyloidosis of the breast remains a challenging diagnosis for pathologists, given its rarity in this anatomical location, non-specific clinical presentation, and subtle histopathological features. Besides, many difficulties have been recognized in the distinction with breast malignancies, especially after reporting a few cases of BA associated with breast cancers, such as ductal carcinoma in situ, ductal carcinoma, and invasive lobular carcinoma.

Once the diagnosis of BA is confirmed, a staging workup should be performed to rule out systemic disease and distinguish between primary and secondary subtypes. It includes a physical examination, electrocardiography, echocardiography, blood analysis, urine analysis, nerve conduction test, bone marrow biopsy, and biopsy of sites suspected of amyloid deposition. In our case, cutaneous biopsy and workup were consistent with nodular cutaneous and breast AL amyloidosis associated with SS.

This makes our report one of the rarest cases of localized amyloidosis deposits, revealing SS. Despite the rare occurrence, 18 cases of cutaneous amyloidosis [14] and 7 cases of BA [13] associated with SS have been reported in the literature to date. Other sporadic cases of localized amyloidosis of the lung and breast have been described as associated with SS.

Meijer et al. proposed in 2008 the acronym SALNA for SS associated localized nodular amyloidosis to define this entity [14]. The proposed hypothesis states that a localized plasma cell clone, considered such an extramedullary plasmacytoma, is responsible for synthesizing light chains of immunoglobulins that degenerate into amyloid substances [14]. The presence of this clone is often challenging to note. This shows the interest in rigorous and continuous controls, although damage to other organs seems rare over time. Hernandez-Molina et al. suggest that localized amyloidosis and Sjogren’s syndrome coexistence should be suspected in patients with consistently high serologic activity and suggestive lesions. Belfeki et al. reported a case where breast MALT lymphoma and AL amyloidosis complicating SS [15]. This suggests that AL amyloidosis could also be a complication of SS.

4. Conclusion

BA is a rare entity that carries a wide range of clinical and radiographic presentations. It should be considered among the differential diagnosis of all mass-forming lesions and calcifications of the breast.

When recognized on biopsy, the diagnosis of amyloid can prevent unnecessary surgical interventions and guide further workup towards potentially associated conditions such as primary breast lymphoma, chronic autoimmune disease, or plasma cell neoplasms.

Although rare, an awareness of the clinicopathologic characteristics of this easily overlooked entity is of great importance for practicing breast surgeons.