Int J Clin Exp Pathol 2020;13(7):1915-1923 www.ijcep.com /ISSN:1936-2625/IJCEP0112784 Case Report Follicular lymphoma with paraneoplastic pemphigus as the first symptom: a case report and review of the literature Shishou Wu1,2, Dong Gao3, Yuanfeng Zhang4, Ping Yang2, Yunjun Wang1,2, Ning Wang2, Jianfeng Xu5, Guohua Yu1,2 1Department of Clinical Medicine, Binzhou Medical University, Yantai, China; Departments of 2Pathology, 3Dermo- tology, 4Hematology, 5Respiratory Medicine, Affiliated Yantai Yuhuangding Hospital, Qingdao University, Yantai, China Received April 18, 2020; Accepted June 3, 2020; Epub July 1, 2020; Published July 15, 2020 Abstract: Paraneoplastic pemphigus (PNP) is an autoimmune bullous dermatosis associated with tumors, first de- scribed by Anhalt et al. in 1990. Reports of paraneoplastic pemphigus complicated by follicular lymphoma (FL) are rare in the medical literature. Here, we retrospectively analyze a case of PNP accompanied by FL. The patient was a 54-year-old woman who suffered from PNP associated with FL at the beginning. She had received a pathological diagnosis and was treated with R-CHOP and other drugs. Her mucosal lesions and cutaneous lesions improved, and the FL was in remission. Eleven months later, she died of BO after receiving the diagnosis of PNP. We also review most of the studies and reports about PNP accompanied by FL. We list the clinicopathologic features, therapeutic schedule, and prognosis in order to improve hematologists’ understanding and treatment of the diseases. Keywords: Follicular lymphoma, paraneoplastic pemphigus, bronchiolitis obliterans Introduction Bronchiolitis obliterans (BO) is a life-threaten- ing form of irreversible, obstructive lung dis- PNP is a rare paraneoplastic, systemic autoim- ease. Cases of BO were first reported in 1999, mune bullous disease characterized by severe and BO may occur in chronic graft-versus-host mucosal lesions and various cutaneous lesions. disease patients undergoing allogenic hemato- Most of the basic tumors originate from the poietic stem cell transplantation [5]. Evidence lymphatic reticular system associated with confirms that the BO can form after PNP, and it Hodgkin’s lymphoma, thymoma, and leukemia is a major cause of death in PNP patients. [1]. The patients suffering from PNP are charac- terized by autoantibodies acting against the Case report plakin family of proteins. There are many pa- tients with PNP who also get BO. An initial treat- A 54-year-old woman was admitted to the hos- ment with systemic corticosteroids is often pital in March 2018 with itchy erythema on her attempted, and other immunosuppressive ag- limbs and trunk. Her eyes, mouth, and labia ents are also used in combination with system- also had painful erosions. A dermatological ic corticosteroids in patients who have PNP [2]. examination showed blisters and erosions on However, most patients have a poor prognosis her lips, tongue, mucosa, and labia (Figure 1A). independent of the status of the underlying Her pharynx mucosa and eyes were swollen. A neoplasms [3]. Though treatments for neo- purplish-red rash could be seen on her hands, plasms are effective particularly in FL, in PNP feet, and torso (Figures 1B, 1C). The pimples associated with malignant neoplasms, the were target-shaped, well-defined and partially response of PNP to the treatment of the under- colorfast when pressed. Computed tomogra- lying neoplasm appears to be less favorable phy showed multiple enlarged lymph nodes in [4]. the bilateral axillary, mediastinal, retroperito- A case of PNP associated with FL Figure 1. Blisters and erosion on the lips and erosion on the tongue mucosa (A). A purplish-red rash can be seen on her hands, feet, and torso (B, C). The pimples are target-shaped, well-defined, and partially colorfast when pressed. Oral mucositis and vulvar lesions improved during the treatment (D). Figure 2. The PET-CT showed: enlarged lymph nodes in bilateral axilla (A), pelvic and bilateral inguinal (B), retroperi- toneal (C); spleen enlargement (D). neal and bilateral inguinal areas. Chronic infl- cells were observed. The small vessels in the ammation was found in the lower lobe of both superficial dermis were dilated around which lungs. A PET-CT examination showed that: 1. the lymphocytes infiltrated densely and necrot- FDG was increased in the tongue and right ton- ic keratinocytes were seen in the epidermis sil; 2. Enlarged lymph nodes were found in her (Figure 3A-C). Direct immunofluorescence (DIF) bilateral neck region, bilateral supraclavicular showed IgG deposition between the epidermal region, bilateral pectoralis minor muscle, bilat- cells and the basement membrane zone (Figure eral axilla (Figure 2A), mediastinum, abdominal 3D). One week after the skin biopsy, cervical cavity, mesentery, bilateral inguinal (Figure 2B), and inguinal lymph node biopsies were per- pelvis, and retroperitoneal space (Figure 2C); formed: small atypical lymphocytes showed a 3. Spleen enlargement (Figure 2D); 4. The FDG nodular hyperplasic pattern in the lymph nodes. metabolism increased in all the above lesions. Those nodules were back to back, the nuclei One week after admission, the patient under- were cleaved, and the chromatin was fine- went a thigh skin biopsy. Under a microscope, grained (Figure 4A). Immunohistochemistry mild hyperkeratosis of the skin epidermis, an showed that the tumor cells were positive for irregular thickening of the granular layer, CD20 (Figure 4B), CD10 (Figure 4C), Bcl-2 (Fi- edema, and a vacuole liquefaction of the basal gure 4D), and Bcl-6 but negative for CD3, CD5, 1916 Int J Clin Exp Pathol 2020;13(7):1915-1923 A case of PNP associated with FL PNP reported in the English- language medical literature [6-21]. The clinical pathology characteristics can be drawn from these cases (Table 1): ① The patients’ ages range from 49 to 77 years old with a medi- an age of 61; ② Gender: there are 8 males and 9 females with a ratio of M:F=8:9; ③ 6/17 of the patients’ clinical stages are IV; ④ 6/17 of the patients’ FL classifications are grade I; ⑤ PNP occurrence time: most patients (10/17, 58.8%) also had occurrences of primary tumors; ⑥ During the course of the disease, Figure 3. Mild hyperkeratosis of the skin epidermis, irregular thickening of the granular layer, edema, and vacuole liquefaction of the basal cells. 5/17 of the patients had sec- The small vessels in the superficial dermis dilated, lymphocytes infiltrated ondary symptoms of BO within densely around the vessels, and necrotic keratinocytes were seen in the 1 week to 11 months after the epidermis (A-C). Direct immunofluorescence (DIF) showed IgG deposition appearance of PNP, and half of between the epidermal cells and the basement membrane zone (D). 8 patients died directly from BO induced by respiratory fail- and CyclinD1. Meshwork showed that the CD21 ure (4/8, 50%); ⑦ 16 of the 17 patients (Figure 4E) and CD23 were slightly irregular, received chemotherapy with rituximab (16/17, and the positive rate of Ki67 (Figure 4F) was 94.1%) and 8 patients were treated with an about 20%. Combined with the morphology and R-CHOP regimen (8/16, 50.0%). According to the immunohistochemical results, the lesions the literature, the maximum survival time of the were consistent with grade I FL. A bone marrow 17 patients was 42 months, and the maximum biopsy showed the bone marrow was involved. survival time of the patients with BO was only A diagnosis of FL with PNP was made, and the 27 months. patient was then transferred to the Department of Hematology for treatment with R-CHOP (ritux- PNP is a rare and lethal type of paraneoplastic imab, cyclophosphamide, epirubicin, vincris- autoimmune skin vesicular disease [1]. The di- tine, prednisone). During her standard course agnosis of paraneoplastic pemphigus depends of chemotherapy, she received methylpredniso- on a histopathological examination and a direct lone tablets, recombinant human interleukin, or indirect immunofluorescence examination. and sodium thiosulfate. And she also improved The clinical features include painful mucosal with the administration of recombinant bovine erosions and pleomorphic skin lesions which basic fibroblast growth factor, erythromycin eye can be involved in the skin and mucosa of the ointment, TobraDex ophthalmic ointment, and whole body, and the damage is severe and potassium permanganate sitz baths (1:10,000). extensive. There are also large patches of pur- The oral mucositis and vulvar lesions were ple erythema, blisters, moss-like, keratinizing relieved during the treatment (Figure 1D), but lesions, and special serum immunoprecipita- the patient died of a pulmonary infection and tion. The histopathological characteristics in- bronchiolitis obliterans eleven months after her clude acantholysis, the formation of intraepi- diagnosis in February 2019. thelial blisters, necrosis of the keratinocytes and an infiltration of inflammatory cells domi- Discussion nated by lymphocytes in the superficial dermis. IgG and C3 depositions between the epidermal Reports of PNP associated with FL are relative- cells and/or the basement membrane can be ly rare in the medical literature. There are 16 seen using a direct immunofluorescence (DIF) cases of patients who suffered from FL with examination, and positive pemphigus antibod- 1917 Int J Clin Exp Pathol 2020;13(7):1915-1923 A case of PNP associated with FL Figure 4. Small atypical lymphocytes showed a nodular hyperplasia pattern in the lymph nodes. Those nodules were back to back, the nuclei were cleaved and the chromatin was fine-grained (A). Immunohistochemistry showed that the tumor cells were positive for CD20 (B), CD10 (C), and Bcl-2 (D). The meshwork seen using CD21 (E) was slightly irregular, and the positive rate of Ki67 (F) was about 20%. ies based on mouse bladder epithelia is seen noglobulins and complements in cancer pa- using indirect immunofluorescence (IIF) [22]. tients are self-protective responses. But most of the tumors that are associated with PNP FL is a type of indolent B cell lymphoma derived originate from the lymphatic reticulum system, from follicular central cells and central blasts.