Int J Clin Exp Pathol 2020;13(7):1915-1923 www.ijcep.com /ISSN:1936-2625/IJCEP0112784

Case Report Follicular with paraneoplastic 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, , and leukemia is a major cause of death in PNP patients. [1]. The patients suffering from PNP are charac- terized by 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 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 [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 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 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 were seen in the sil; 2. Enlarged lymph nodes were found in her (Figure 3A-C). Direct (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 , cervical cavity, mesentery, bilateral inguinal (Figure 2B), and inguinal lymph node 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,

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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 (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, , epirubicin, vincris- autoimmune skin vesicular disease [1]. The di- tine, ). 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 , the formation of intraepi- diagnosis in February 2019. thelial blisters, 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-

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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 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 lymphoma derived originate from the lymphatic reticulum system, from follicular central cells and central blasts. and whether they are related to the chemother- The mechanism of incorporating PNP is not yet apeutic drugs or to the characteristics of the clear, but PNP is closely related to the primary tumor itself needs further research. tumor. Published studies indicate that after the primary tumor is treated, the PNP symptoms The treatment for PNP mainly includes the improve. Takashi and others [12] believe that treatment for the primary tumors, skin and the use of bendamustine can trigger PNP mucosal damage, and for the complications of because the skin toxicity of the drug causes a the affected organs [22]. The treatment of pri- well-known adverse reaction. But the patient mary tumors is critical, and the involved skin Jain et al. reported on [14] was treated with and mucosa can be improved after treating the bendamustine/rituximab, and the PNP didn’t primary tumors [26]. R-CHOP is a first line che- appear until 29 months after the treatment. motherapy regimen for FL and is effective for Therefore, the relationship between benda- patients with PNP [21, 27]. The application of mustine and PNP needs to be explored further. rituximab in this scheme can kill tumor cells Braess [23] believed that fludarabine seems to and B cells. Based on the summary of the cur- induce or worsen the process of PNP. But sum- rent relevant literature, FL patients with PNP marizing the prognosis of three patients treat- treated with rituximab or R-CHOP can achieve ed with fludarabine, he indicated that the induc- tumor remission or even complete remission. tion of fludarabine cannot be denied, for two of But the rash and mucosal lesions cannot be the patients did not achieve a longer survival completely cured. This phenomenon may be time from this treatment plan. The immunologi- caused by the continuous release (or helpful cal features of patients with PNP include the release) of a specific in the patient. presence of -recognizing proteins For skin and mucosal lesions, we often chose a in the stratified squamous epithelium, the tran- large dose of glucocorticoid and maintain it in sitional columnar epithelium, and the monolay- small doses. Although this can alleviate skin er epithelium in sera. So they were positive for and mucosal lesions to a certain extent, the DIF and IIF. Complement and immunoglobulin patient’s resistance is severely damaged. Re- have been confirmed to have antitumor activity garding the above patients, most did not have a in a variety of tumors [24, 25]. Increased immu- good survival time during the follow up period.

1918 Int J Clin Exp Pathol 2020;13(7):1915-1923 A case of PNP associated with FL

Table 1. The main clinical features of the 17 FL patients with PNP or BO Case Clinical Diagnostic Diagnostic References Age Gender FL Level Treatment Plan Curative effect Prognosis Num. stage Time of PNP Time of BO 1 Moustafa, et 68 M Unknown I Simultaneous Unknown B*/R*→R*/Prednisone Improvement of skin lesion Died of infectious compli- al. [6] diagnosis with Tumor shrinking cations 10 months after tumor The symptoms of infection are still diagnosis. repeated. 2 Lee, et al. [7] 53 M IVA Unknown Simultaneous Simultaneous R-CHOP* Complete remission of tumor, stomatitis, Died of respiratory failure diagnosis with diagnosis with other skin lesions and BO are persistent caused by BO 27 months tumor PNP existence. after diagnosis. 3 Borradori, et 61 F Unknown I Simultaneous Unknown P*→CHOP*/antibiotics/Cyclo- The tumor was relieved and there was Unknown al. [8] diagnosis with sporin/0.5% Retinaldehyde/ no progress. Stomatitis and palmar tumor Sucralfate→R* erythema were relieved and the patient was well tolerated by rituximab. 4 Aoi, et al. [9] 60 M Unknown Unknown Simultaneous Unknown P*→P*/R*→R* combined with The condition improved and the skin Unknown diagnosis with chemotherapy lesion recovered. The FL was relieved tumor partly. 5 Lim, et al. 58 M Unknown Unknown Simultaneous 1 week after Before BO: R-CHOP* Atypical pneumonia caused by cyto- Died of septic shock one [10] diagnosis with PNP diagnosis AfterBO: R-CHOP* megalovirus infection one week after month after diagnosis tumor treatment. of BO. 6 Lachenal, et 52 F Unknown Unknown Simultaneous Unknown R-CHOP* The skin lesions were improved obvi- Unknown al. [11] diagnosis with ously, the oral erosion was improved, but tumor the tumor reaction was unknown. 7 Higo, et al. 77 F Unknown Unknown Simultaneous Unknown R-CHOP*→Bendamustine/ The skin lesion recovered and the muco- Unknown [12] diagnosis with R*→Prednisone sal rash did not improve. tumor 8 Morikawa, et 65 F IIIA Unknown Simultaneous 5 months Before BO: R-CHOP*→R*→R-CVP* The tumor shrank and the symptoms Unknown al. [13] diagnosis with after FL After BO: Palliative and symptom- such as conjunctivitis, oral mucosal ulcer tumor diagnosis atic treatment and the rash improved. 9 Jain, et al. 60 M IVB I 29 months after Unknown Bendamustine/R*→R* The tumor was remission completely Unknown [14] FL diagnosis at the beginning and relapsed after 18 months. 10 Hirano, et al. 60 M Unknown Unknown Simultaneous 3 months Before BO: R*/Prednisone The blisters disappeared completely and Died 7 months after the [15] diagnosis with after FL After BO: Plasma exchange the autoantibodies decreased to the diagnosis of BO. tumor diagnosis →R-CHOP*→Bendamustine/R* normal level. But the BO appeared later. 11 Hoque, et al. 49 F Unknown Unknown 9 years after FL Unknown CHOP*→Radiotherapy/F*/Mitoxa- The tumor was completely relieved, the After the occurrence of [16] diagnosis none/Prednisone→F→R-CVP* rash improved after treatment, but the PNP, the condition wors- general condition of the patient was ened and the patient died poor. after palliative treatment. 12 Martínez, et 70 F IVA I 4 years after FL Unknown CHOP*→Chlorambutyronitrile→P The tumor was completely relieved, the 40 months after the diag- al. [17] diagnosis skin blisters disappeared, but the lesions nosis of PNP, there was of oral mucosa persisted. no recurrence of skin and mucosal lesions. 13 Prodanovic, 73 M IV I 3 years after FL Unknown R*/F*/D*/Mitoxantrone/ The tumor was relieved, the skin blisters Unknown et al. [18] diagnosis Granisetron→R* were cured and there was no recurrence during the follow-up period.

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14 Maruta, et al. 70 M IVB Unknown 5 years after FL Unknown Chlorambutyronitrile/ The tumor was relieved, the skin lesions Died of left heart failure [19] diagnosis C*/O*→P*/F*/ were improved, but the oral mucosal and pulmonary edema 9 Chlorambutyronitrile→P*/Rad lesions were relieved very little. months after the diagnosis iotherapy→Chlorambutyronitri of PNP. le/P*→D*/→R*/P* 15 Heizmann, et 73 F Unknown Unknown Simultaneous Unknown P*/C*→R*/P* The tumor was relieved partly and con- Unknown al. [20] diagnosis with junctival and mucosal erosion recovered tumor completely. 16 Barnadas, et 77 F IIB Unknown Later than FL Unknown Chlorophenylbutyronitrile→P*/ The tumor was relieved partly and the The patient died 42 al. [21] diagnosis time, Valaciclovir→R*/P*→P*/Cyclo- oral ulcer was completely cured. months after the FL diag- the certain time sporin nosis. The cause of death is unknown is unknown, but acid-fast bacilli is active. 17 Present case 54 F IV I-II Simultaneous 11 months R-CHOP* and so on The FL was relieved and mucositis and Died of respiratory failure diagnosis with after FL vulvar lesions were improved. caused by BO 11 months tumor diagnosis after the diagnosis of PNP. *R: Rituximab; C: Cyclophosphamide; O/V: Vincristine; P: Prednisone; D: Dexamethasone; F: Fludarabine.

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Regardless of whether BO appears, the patients determine whether the patient has diffuse lung often die from respiratory infections from which retention (in the expiration phase), bronchial we can infer that the use of chemotherapeutics thickening, or secondary dilatation using HRCT and glucocorticoids has a direct relationship as soon as possible [32-35]. As for the absence between the suppression of the patients’ auto- of specific medicines, it is necessary to find out immune function and atelectasis. whether the patients have BO in time in order to strengthen the management of the respiratory About 30% of patients with PNP also suffer tract and to inhale oxygen earlier, control the from BO, and the mechanism [28, 29] involves increase of inflammation, and improve their the infiltration of T cells below the bronchial breathing difficulties. tubes, as determined by autopsies. In addition, immunoglobulin and complement are deposit- Summary ed in the bronchial columnar epithelium, result- ing in the exfoliation of the respiratory tract cili- FL with PNP is rare. Grade 1 and clinical stage ated columnar epithelium from the basal cell IV of FL are more common. The emergence of layer. Mixed inflammatory infiltration composed PNP indicates the potential of tumors and then of lymphocytes, neutrophils, eosinophils, and the need to actively look for primary lesions. plasma cells can be seen in the submucosa. The mechanism of BO in PNP patients associ- Nousari’s experiment [28] confirmed that the ated with FL is still unclear, and preventing the acantholysis of the respiratory epithelium ca- occurrence of BO is still a clinical challenge. used by Plakin proteins can lead to distal bron- chial occlusion and scar formation, which grad- Acknowledgements ually block the bronchioles. Then they cause breathing difficulties and aggravate respiratory The present study was supported by the Yantai infections. Therefore, we believe that the sec- Key Research and Development Project (grant ondary BO symptoms in patients with PNP are no. 2017WS101). irreversible pathological changes caused by Disclosure of conflict of interest the deposition of autoimmune asso- ciated with tumor tissues in the bronchiolar None. mucosa. Address correspondence to: Guohua Yu, Depart- BO usually occurs quickly and irreversibly in the ment of Pathology, Affiliated Yantai Yuhuangding terminal stage of the disease, eventually lead- Hospital, Qingdao University, Yantai 264001, China. ing to fatal respiratory failure. Patients with BO Tel: +86-13854501211; E-mail: ygh0535@hotmail. have a poor prognosis [30] and BO has become com the leading cause of death in patients with PNP. Theoretically, patients can receive a lung trans- References plant after the appearance of BO. But due to the lack of available lungs, the anti-host re- [1] Anhalt GJ, Kim SC, Stanley JR, Korman NJ, sponse after transplantation, and the chance Jabs DA, Kory M, Izumi H, Ratrie H 3rd, Muta- that the BO will reappear after the transplanta- sim D, Ariss-Abdo L, et al. Paraneoplastic pem- tion, many clinical studies are needed to con- phigus. An autoimmune mucocutaneous dis- firm this theory. Bronchoscopic transmural or ease associated with neoplasia. N Engl J Med open lung biopsies are often missed due to the 1990; 323: 1729-35. lesions mainly involving the terminal or respira- [2] Frew JW and Murrell DF. Current management tory bronchioles and showing an uneven patchy strategies in paraneoplastic pemphigus (para- neoplastic autoimmune multiorgan syndrome). or patch distribution. Therefore, clinical doctors Dermatol Clin 2011; 29: 607-12. often based their examinations on symptoms, [3] Leger S, Picard D, Ingen-Housz-Oro S, Arnault pulmonary function, and imaging manifesta- JP, Aubin F, Carsuzaa F, Chaumentin G, tions in order to reach a comprehensive diagno- Chevrant-Breton J, Chosidow O, Crickx B, sis [31, 32]. D’incan M, Dandurand M, Debarbieux S, Dela- porte E, Dereure O, Doutre MS, Guillet G, Jul- For such patients who may have BO, pulmonary lien D, Kupfer I, Lacour JP, Leonard F, Lok C, function measurement and fiberoptic bron- Machet L, Martin L, Paul C, Pignon JM, Robert choscopy should be started earlier. They should C, Thomas L, Weiller PJ, Ferranti V, Gilbert D,

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