Vulvar amyloidosis

Presentation

A 51-year-old patient presents for evaluation of possible vulvar lichen sclerosus. The patient describes a 12-month history of vulvar discomfort. The pain was initially intermittent but is now continuous. She describes “pinching and stretching” extending from the perineum spreading to the anus. She notes “ripping” with intercourse. She describes “raised clear blisters” on her inferior vulva. A biopsy done at the referring hospital demonstrated “stromal sclerosis, favor lichen sclerosus over amyloidosis.”

Patient had no improvement with topical clobetasol ointment 0.05% for 1 month and therefore was referred to Michigan Medicine Center for Vulvar Diseases for further evaluation.

Examination showed tender, raised areas on the perineum approaching the perianal tissue.

Diagnosis

Repeat vulvar biopsies were performed. Pathology showed amyloidosis (evaluated with Congo red histochemistry). Mass spectrometry for amyloid typing was performed at the Mayo Clinic, which revealed AL (kappa)-type amyloid deposition. This type of amyloid is usually associated with systemic disease due to an underlying clonal plasma cell proliferative disorder or a B-cell lymphoma.

Management

The patient was referred to Michigan Medicine Hematology/Oncology clinic for further evaluation and management of the underlying disease. Bone marrow biopsy showed Kappa light chain myeloma with t(11;14). She was initially treated with cyclophosphamide, bortezomib, dexamethasone, followed by ixazomib and lenalidomide.

She again presented to Michigan Medicine Center for Vulvar Diseases 6 months after initial presentation. She was still suffering from vulvar discomfort. Examination of the vulva was unchanged.

After extensive review of the literature, she was offered laser ablation of the amyloidosis of the vulva. Risk of recurrence, pain after surgery, prolonged recovery time with healing, and inability to remove all of the affected tissue were reviewed. At that time, the amyloidosis extended to the anus but did not appear to go into the anus.

Risk of injury to surrounding tissue, especially anus/rectum given proximity of disease was reviewed. We reviewed concern for hemostasis given the friable nature of the tissue.

The patient was taken to the operating room for laser ablation of amyloidosis of the vulva. The area of concern was carefully demarcated with a 0.5 cm border using a marking pen.

Figure 1. Perineum with multiple plaques with papillary projections

We first followed the border outlined preoperatively using a CO2 silk touch laser. We then filled in our outline working to create a surgical plane. As expected, the tissue was highly friable and bled easily.

The lesions required multiple cautious passes with laser and subsequent cautery. We varied between a 4 mm and 6 mm spot size and power of 20-25 watts. Despite our efforts with the laser, mechanical dissection was ultimately needed in order to separate the planes of disease and normal tissue. We used gentle scraping with the Bovie cautery in order to separate the planes.

Figure 2. Amyloidosis on perineum and in perianal area

A tactical difference could be appreciated between the abnormal and normal tissue.

We repeated our mixed method approach through the entire affected area. We eventually cleared all grossly visible disease and achieved excellent hemostasis.

Figure 3. Perineum with raised tender plaques

Ultimately, the patient underwent bone marrow transplant for treatment of her systemic disease with excellent results. At 9 months post-operative evaluation there was no evidence of recurrence of amyloidosis on the vulva.

Discussion

Amyloidosis is a term used to describe fibril deposition of proteins.AL amyloidosis is due to deposition of protein from immunoglobulin light chain fragments. A monocolonal protein is detected in the urine and or blood of more than 95% of patients with amyloidosis.¹

Figure 4. Perianal area with similar raised tender plaques

Amyloidosis can be present by itself or associated with underlying systemic disease such as plasma cell dyscrasias (multiple myeloma, Waldenström macroglobulinemia). These are malignant disorders of plasma cells or lymphoplasmacytic cells.

Figure 5. Vulva immediately following laser ablation of amyloidosis

Since AL amyloidosis is a clonal cell disorder, it is treated with chemotherapy to destroy the underlying clone. In our patient, diagnosis of AL amyloidosis (deriving from a light chain fragment) was confirmed by mass spectrometry. This differentiates AL from other types of amyloidosis such as AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis. These types are not neoplasms and therefore not susceptible to chemotherapy.

AL amyloidosis is a very rare disease. It is estimated that in the United States the incidence is 9 to 14 cases per million person-years. ^2,3,4 Patients present in a variety of ways. Since AL amyloidosis is often associated with plasma cell dyscrasias such as multiple myeloma, it can present as a myeloma defining event such as bone pain that is shown to be an osteolytic bone lesion.⁵

Some common symptoms on presentation include unintentional weight loss and fatigue.⁶ It can also present in a variety of organ systems.

Common presentations include nephrotic syndrome, cardiomyopathy, peripheral neuropathy, hepatosplenomegaly, and bleeding diasthesis. It can also present with skin manifestations such as thickening of the skin, easy bruising, and infiltration of subcutaneous fat.

Diagnosis is made through biopsy that demonstrates amyloid fibrils. It can be confirmed with Congo Red staining that demonstrate green birefringence under polarized light.⁷ The amyloid is then typed using a variety of techniques (in our patient’s case using mass spectrometry). This can identify the amyloid type with 100% specificity.⁸

The Mayo Clinic and the International Myeloma Working Group have established diagnostic criteria for AL amyloidosis. All 4 must be met to confirm diagnosis.^9,10,11

These include:

1. An amyloid-related systemic syndrome. Organ damage must be confirmed to be related to amyloid protein deposition;
2. Amyloid that is Congo red positive;
3. Confirmation that amyloid is light chain (mass spectometry);
4. Confirmation of monoclonal plasma cell proliferative disorder.

For treatment of our patient’s vulvar amyloidosis she was offered laser ablation to the affected areas. Case reports suggest CO2 laser is successful in managing nodular disease, satisfactory cosmetic results and no recurrences at follow-up. There is no consensus on particular settings/technique, especially with gynecologic lesions.^12,13

It is imperative that AL amyloidosis is differentiated from other forms because treatment and prognosis is markedly different. Our patient ultimately underwent bone marrow transplant to cure her underlying multiple myeloma.

She continues to do well without evidence of recurrence of multiple myeloma and with no recurrence of vulvar amyloidosis.

In conclusion, systemic AL amyloidosis can manifest as atypical nodular lesions on the vulva. Extensive amyloid deposits can cause significant discomfort, warranting surgical management. A combination of ablative therapy and mechanical dissection may be needed to create the necessary surgical plane for successful treatment.

Maintenance of hemostasis and avoidance of sensitive structures are key operative concern.

Vulvar amyloidosis is a rare, but important clinical entity. Its diagnosis can facilitate the recognition of a potentially life-threatening systemic condition. Proper treatment provides symptomatic relief without significant disfigurement or loss of function.

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References

1. AU Merlini G, Dispenzieri A, Sanchorawala V, Schönland SO, Palladini G, Hawkins PN, Gertz MA SO Nat Rev Dis Primers. 2018;4(1):38.

2. Kyle RA, Linos A, Beard CM, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood 1992; 79:1817.

3. Quock TP, Yan T, Chang E, et al. Epidemiology of AL amyloidosis: a real-world study using US claims data. Blood Adv 2018; 2:1046.

4. Kyle RA, Larson DR, Kurtin PJ, et al. Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015. Mayo Clin Proc 2019; 94:465.

5. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014; 15:e538.)

6. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995; 32:45.)

7. Glenner GG. Amyloid deposits and amyloidosis. The beta-fibrilloses (first of two parts). N Engl J Med 1980; 302:1283.

8. Dasari S, Theis JD, Vrana JA, et al. Amyloid Typing by Mass Spectrometry in Clinical Practice: a Comprehensive Review of 16,175 Samples. Mayo Clin Proc 2020; 95:1852).

9. Kourelis TV, Kumar SK, Gertz MA, et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol 2013; 31:4319.

10. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009; 23:3.

11. Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 2016; 91:719.)

12. Quddus, M. R., Sung, C. J., Simon, R. A., & Lawrence, W. D. (2014). Human pathology, 45: 2037-2042.

13. Al Yahya, R. S. (2016). Lasers in medical science, 31: 1-9.