Teaching Case

A 50-year-old woman presented with bilateral palpable breast lumps and protrusion of left eye for 1 month, which was gradually progressive. Back pain for 1 month. No significant family history of breast or ovarian cancer. Clinical examination revealed a 4 x 3 cm firm lump in the upper outer quadrant of right breast and a 3 x 3cm vague lump in the left breast, bilateral nipple retraction and inversion was noted. Orbital examination demonstrated left eye proptosis, diplopia, and lateral gaze palsy.

2D mammogram and tomosynthesis showed irregular, spiculated masses in the upper outer and central quadrant of right breast and lower inner and central quadrant of left breast, causing nipple retraction and enlarged bilateral axillary lymph nodes (Figures 1a–1d). Corresponding breast ultrasound showed spiculated hypoechoic lesion with desmoplasia and internal vascularity in both breasts extending to the nipple-areolar complex: BI-RADS 5 and enlarged bilateral axillary lymph nodes with architectural distortion and cortical thickening likely metastatic (Figures 2a–2d). X-ray lumbar spine done outside our facility showed lytic lesions in the lumbar spine, suggestive of metastases. In view of multiple lytic lesions involving the lumbar vertebrae, patient was subjected to 68 Gallium FAPI PET/CT for further metastatic workup, which revealed enhancing and metabolically active lesions in bilateral breast infiltrating the nipple–areolar complex (SUV max 9.2 on right and 9.4 on left), metabolically active bilateral axillary lymph nodes (SUV max 14) (Figures 3a–3e), enhancing and metabolically active mass in the intraconal compartment of the left orbit involving the superior and medial recti muscles, sparing the optic nerve (SUV max 10.6) (Figures 4a–4d). Bilateral ovarian metastases (SUV max 6.2), diffuse omental metastases (SUV max 4.8) and lytic metastases in multiple lumbar vertebrae and right acetabulum (SUV max 21) (Figures 5a–5e). Patient is due for a breast MRI, which was delayed due to her low socio-economic status.

Histopathology and immunohistochemistry revealed bilateral invasive lobular carcinoma (ILC) grade 2, ER-positive, PR-positive, HER/2-neu-negative and E-Cadherin-negative.

ILC is the 2nd most common (10%) after invasive ductal carcinoma (IDC). IDC often metastasizes to the lung, liver, bone, and brain, whereas ILC has affinity towards the GIT, uterus, ovary, peritoneum, retroperitoneum, skin, leptomeninges and orbits [2]. As seen in our case, multifocality and bilateral incidence are more frequent in ILC [1]. Loss of E-cadherin, a cell-cell adhesion molecule, causes the monomorphic cells to proliferate in a single-file (“Indian-file”) pattern causing diffuse infiltration with minimal anatomical disruption in comparison to IDC. Hence, ILC often fails to form a distinct palpable mass, making early detection a challenge and locally advanced disease more common [3].

Metastasis to the orbit is rare, accounting for 2-3% of all metastatic cancers [5]. Breast is the most common primary cancer (28.5-58.8%) to metastasize to the orbits, followed by prostate, lung, melanoma, and renal carcinoma [10]. The most common type of breast primary metastasizing to extra orbital muscles (EOMs) is ILC [6]. Isolated involvement of the EOMs is extremely rare, accounting for 9% of all orbital metastases [7]. Our case demonstrated metastatic lesions in the left superior, medial, and lateral recti muscles. Unlike IDC, it causes diffuse fusiform thickening of the muscles, replacing the post-septal fat causing proptosis [7].

Our case highlights the unique growth pattern (cellular tropism) and selective sites of metastases (organotropism) of bilateral breast ILC. Reasons for this unique tropism, as proposed are: Inactivation of CDH1 gene, which is responsible for encoding E-cadherin, facilitates the metastatic process. Like primary ILC, metastatic ILC tends to infiltrate the affected organs in an analogous manner [3,4]. Cellular tropism caused by estrogens produced by the periorbital fat, conjunctiva, lacrimal gland, and tarsal plate makes it a favourable site for metastases [9,7].

Our case also presented other selective sites of metastases, to bone, bilateral ovaries, and omentum. More than 90% of ILCs express ER and PRs, and only 3% to 13% express HER2 neu receptors. Estrogen concentrations are up to 1000-fold higher in ovarian tissue, peritoneum, dermis, adipose tissue, and bone. Accordingly, ILCs seem to metastasize to sites of estrogen production [2]. Bone metastases from ILC are higher than those from IDC. Like primary ILC, it infiltrates diffusely, causing total replacement of the bone marrow [12]. Ovarian metastases are presented as bilateral cystic-solid masses. Omental metastases presented as tiny nodules coalescing to form “omental cakes.” In contrast, IDC often presents as focal, larger masses and nodules [12].

In the era of molecular imaging, PET-CT scans can provide both morphological and functional information and play an important role in both disease staging and treatment response assessment. Commonly used tracer,¹⁸F-FDG-PET, has limitations in low-grade hormone-positive tumours and in lobular breast carcinomas [13]. Fibroblast activation protein (FAP)-directed PET tracers are being recently used in primary breast tumours as FAP is abundantly expressed in invasive breast cancer [14]. This new molecule in the present era, Gallium-68 (⁶⁸Ga)-conjugated FAP inhibitor (FAPI), provides better tumour stromal visualization when compared to ¹⁸F-FDG in various cancers with minimal background uptake [15]. Recent studies have shown that FAPI-PET can detect more lymph nodal, liver, bone, gastrointestinal, genitourinary and brain metastases due to the lower background activity and higher uptake in subcentimetric lesions, with sensitivity and specificity being 100% and 95.6%, respectively [16].

Conclusion

We presented a unique case of bilateral ILC with orbital, peritoneal, bilateral ovarian and skeletal metastases, which is a rare occurrence. The understanding of cellular tropism and organotropism of metastatic ILC is essential for timely intervention, accurate imaging interpretation and treatment planning.

Patient received 12 cycles of neoadjuvant chemotherapy followed by radiotherapy, and follow-up 68 Gallium FAPI PET/CT showed regression in size and metabolic activity of both breast lesions, axillary lymph nodes, left orbital and omental metastases. (SUV max: Nil) (Figures 6a–6e].