Photodynamic therapy for treatment of recurrent hemoptysis secondary to pulmonary endometriosis: a case report

Abstract

Pulmonary endometriosis (PEM) is rare, and drug therapy remains the primary treatment. However, patients with PEM frequently experience recurrent hemoptysis that is refractory to pharmacological intervention. We herein describe a patient with PEM who developed recurrent hemoptysis and was successfully treated with photodynamic therapy (PDT) after drug withdrawal. The patient was admitted to our hospital because of recurrent hemoptysis despite repeated drug treatments for more than 1 year. Given that PDT targets specific tissues and destroys vascular endothelial cells through the cytotoxic effect produced by the photodynamic reaction of the photosensitizer, we considered that it may effectively control hemoptysis secondary to vascular morphological changes in PEM. Therefore, we performed PDT in this case, and the patient’s recurrent hemoptysis regressed. Approximately 2 years following PDT, the patient had recovered well and reported no discomfort. We recommend consideration of PDT as a treatment option for patients with PEM who develop recurrent hemoptysis after drug withdrawal. Notably, the patient’s lung lesions should be superficial and limited, and no contraindications should be present.

Introduction

Endometriosis (EM) is the clinical manifestation of active endometrium (glandular stroma) in areas other than the lining of the uterus, resulting in major symptoms including hypermenorrhea, dysmenorrhea, tissue pain at the ectopic site, and bleeding. ¹ As reported in the literature, approximately 1.14% of women aged 15 to 50 years suffer from EM, and the prevalence of EM has exhibited an increasing trend in recent years. EM can invade one or multiple organs in the body. Pulmonary EM (PEM) is rare, and its major symptoms include chest pain, hemoptysis, pneumothorax, and hemothorax during the menstrual period.^2–6 Numerous drugs are used to treat PEM, and significant therapeutic effects are achieved by danazol for induction of pseudomenopause and gonadotropin-releasing hormone (GnRH) agonist for induction of ovarian castration. However, drug therapy is associated with disadvantages such as side effects (even infertility), high costs, and high recurrence rates after treatment. Notably, drugs only relieve symptoms; they do not cure the disease. Patients undergoing drug withdrawal are extremely susceptible to recurrence.

In this case, PDT was applied after drug therapy failure in the treatment of PEM. PDT effectively controlled the patient’s hemoptysis with a favorable therapeutic effect and no recurrence or side effects.

Case report

A 34-year-old woman (body height, 164 cm; body weight, 58 kg) was admitted to our hospital on 23 December 2020 because of repeated hemoptysis for more than 1 year and lack of improvement after diagnosis and repeated treatments in other hospital. Since October 2019, the patient had experienced white sputum production and chest distress several days before her menstrual period and hemoptysis on days 1 and 2 of her menstrual period. The blood was bright red in color, and the volume was approximately 1 to 2 mL. The patient visited another hospital from October to November 2020. Chest computed tomography (CT) showed patchy ground-glass opacity in the apicoposterior segment of the left upper lobe and a small solid nodule in the lateral segment of the right middle lobe, which was a benign lesion. Bronchoscopy revealed active bleeding in the posterior segment of the left upper lobe accompanied by local coarsening of the middle tracheal mucosa. Gynecological sonography revealed (1) abnormal intrauterine echo and the possibility of an endometrial polyp, which remained to be excluded; (2) uterine hypertrophy, inhomogeneous muscular layer echo, and the possibility of uterus adenomyosis, which remained to be excluded; and (3) no obvious abnormality in the bilateral uterine appendage areas. Information regarding other examination findings was unavailable. Based on these examination results, adenomyosis was suspected by the doctors at the other hospital. The patient reported treatment with drug therapies including antibiotics and oral GnRH antagonists, but no details concerning the treatments were available. After treatment, the patient continued to experience hemoptysis during menstruation. She experienced white sputum production and chest distress several days prior to menstruation and bright red hemoptysis (volume of 1–2 mL each time) on days 1 and 2 of menstruation. The patient reported no intolerance to cold, fever, night sweats, chest pain, palpitations, breathing difficulties, abdominal pain, diarrhea, nausea, or vomiting.

Almost 1 year later, the patient continued to experience repeated attacks of hemoptysis once a month consistent with her menstrual cycle. The attacks started on day 1 of her menstrual period and ended on the last day, and she experienced no discomfort in the intermenstrual period. Repeated chest CT examinations revealed exudative lesions in the lungs during the patient’s menstrual period. However, no abnormality was observed on chest CT during her intermenstrual period (the patient provided examination reports but no CT imaging data). Because of the poor therapeutic effect in the other hospital, the patient developed hemoptysis again when her menstrual period started one night before admission to our department. The patient was clinically healthy, and she denied any history of hypertension, diabetes, or pulmonary tuberculosis; any relevant family history; and any history of smoking, surgery, or drug use. She had not recently consumed any alcohol. She had gotten married at the age of 26 years. Her spouse was in good health, and the couple had two daughters. Her age at menarche was 13 years, and her menstrual period lasted for 4 days with a cycle of 28 days. Her last menstrual period had started on 23 December 2020, and she had regular menstrual cycles with scant menstrual flow.

Physical examination after admission revealed rough breathing sounds in the bilateral lungs and mild moist rales in the left upper lung. The rest of the physical examination findings were normal.

After admission, the patient underwent chest CT in our hospital on 23 December 2020, which revealed focal punctiform or patchy, slightly hyperdense opacities in the left upper lung (Figure 1(a)). Blood tests revealed no obvious abnormality (Table 1), a sputum acid-fast bacillus smear revealed no acid-fast bacillus, and a sputum mycobacterial culture (liquid culture method) was negative.

Figure 1.

Chest computed tomography was performed during menstruation. (a) Preoperative chest computed tomography. The thorax was symmetric. Focal punctiform or lamellar, ill-defined, slightly hyperdense opacities were found in the left upper lung. No calcified opacity was found in the mediastinal window. (b) One month postoperatively, the exudative lesions in the left upper lobe had been significantly absorbed and reduced, with only a small patch-like, ill-defined opacity remaining. The remaining lung lobes appeared clear with no abnormalities and (c) At 10 months postoperatively, the exudative lesions in the left upper lobe had been completely absorbed and resolved, and the remaining lung lobes exhibited clear radiographic findings with no abnormal density or opacity.

Table 1.

Blood test results.

Parameter	Value	Parameter	Value
White blood cell count	5.51 × 109/L	C-reactive protein concentration	1.0 mg/L
Hemoglobin concentration	135 g/L	Procalcitonin concentration	<0.05 ng/mL
Platelet count	182 × 109/L	Uric acid concentration	266 μmol/L
Neutrophil percentage	64.0%	Serum creatinine concentration	63 μmol/L
Neutrophil count	3.53 × 109/L	Alanine aminotransferase concentration	13 U/L
Lymphocyte count	1.56 × 109/L	Prothrombin time activity	93.80%
Monocyte count	0.32 × 109/L	Prothrombin time	11.1 s
Red blood cell count	4.48 × 1012/L	Activated partial thromboplastin time	31.2 s
Erythrocyte sedimentation rate	6 mm/h	Thrombin time	18.6 s
Myocardial creatine kinase concentration	15 U/L	Fibrinogen concentration	1.99 g/L
D-dimer concentration	0.26 mg/L	Prothrombin time–international normalized ratio	0.98

Based on the presence of catamenial hemoptysis, CT findings appearing concurrently with the menstrual cycle, and the other clinical findings mentioned above, the patient was diagnosed with (1) PEM accompanied by hemoptysis and (2) adenomyosis. Given the ineffectiveness of the previous drug therapy and the recurrent hemoptysis, PDT was proposed for the patient. Hematoporphyrin injection, 50 mg (Huading Modern Biological Pharmaceutical Co., Ltd., Chongqing, China) was administered as a photosensitizer on 23 December 2020, and bronchoscopic PDT was performed on 24 December 2020. After oral endotracheal intubation, an electronic bronchoscope (Olympus BF-260; Olympus Corporation, Tokyo, Japan) was inserted. Bronchoscopic examination revealed that the trachea had a smooth lumen with a sharp tracheal carina. Bronchoalveolar lavage was conducted in the proper branch of the left upper lobe, and a large amount of white secretion was eliminated. All segments of the proper branch of the left upper lobe were then explored using a superfine bronchoscope (Seesheen QG3032; Zhuhai Seesheen Medical Technology Co., Ltd., Zhuhai, China), revealing a small amount of bloody exudate in the subsegmental bronchial lumen and a slightly coarsened luminal mucosa. PDT was performed in the apical, posterior, and anterior segments of the left upper lobe using a PDT630-A semiconductor laser photodynamic therapeutic apparatus with a wavelength of 630 nm and power of 2 W (Leimai Science and Technology Co., Ltd., Shenzhen, China). Each segment was irradiated for 45 minutes (Figure 2). The PDT was successful, and the patient was safely returned to the ward after treatment. She was administered moxifloxacin for antibiotic prophylaxis.

Figure 2.

Images of bronchoscopic examination. (a) The bronchus of the left upper lobe as seen by bronchoscopy. (b) Superfine bronchoscopic exploration (outer diameter: 2.8 mm). Under bronchoscopy, a small amount of dark red exudate was observed in the bronchial opening of the left upper lobe, accompanied by coarse mucosal changes in the bronchial wall and (c) The optical fiber was inserted into the target airway.

After PDT, the patient’s clinical status was good, and she developed no symptoms such as hemoptysis, cough, expectoration, chest distress, or dyspnea. In the first month postoperatively, she experienced an extremely low amount of hemoptysis during her menstrual cycle, which disappeared after 1 day and was untreated. Chest CT revealed apparent absorption and reduction of the exudative lesions in the left upper lobe compared with preoperatively, leaving a small spot-like or patchy opacity. The remaining lung lobes were clear, with no abnormal opacity (Figure 1(b)).

No hemoptysis was observed throughout the following month. The patient was followed up for 2 years, and repeated chest CT examinations 1 year after PDT during her menstrual periods indicated that the exudative lesions in the left upper lobe had been completely absorbed; no abnormal opacity remained (Figure 1(c)). No bronchoscopic re-examination was performed. In the second year after PDT, the patient refused to return for a re-examination visit at the hospital, and she was therefore followed up via telephone for 1 year. She reported no hemoptysis and no drug use or other treatment measures, and she recovered smoothly.

All the patient’s details have been de-identified, and the patient provided written informed consent for participation in this study and publication of her case and all accompanying images. The patient also provided written informed consent for treatment after acquiring a full understanding of the treatment options. The case report was conducted in line with the principles of the Declaration of Helsinki by following the CARE guidelines and methodology. ⁷ Publication of this case report was authorized by the Scientific Research Review Ethics Committee of the University of Chinese Academy of Sciences Shenzhen Hospital (Ethics Approval No. LL-KT-2020140).

Discussion

EM is a condition in which endometrial tissues with growth function (glands and stroma) develop outside of the uterus. It is currently considered a systemic disease rather than a disease predominantly affecting the pelvis. EM can affect any part of the body, and its manifestations outside the female reproductive tract remain poorly understood. ⁵ PEM may occur because endometrial particles enter the lung parenchyma via the filtering function of the pulmonary vascular network, similar to the process of pulmonary embolism formation. ⁸ However, PEM may not be accompanied by pelvic EM. ² The etiology and diagnostic criteria of PEM, particularly the optimal therapeutic approach, remain controversial. ¹

The diagnosis of PEM is generally confirmed by a clinical history of catamenial hemoptysis, active bleeding observed through bronchoscopy, and imaging changes of lung lesions concurrent with the menstrual cycle; pathologically, PEM does not show significant histologic findings.^9,10 In our case, periodic hemoptysis was the major manifestation. Its pathogenesis might have been associated with vascular morphological changes due to the periodic changes in the estrogen concentration, inducing intrapulmonary hemorrhage and pulmonary exudative changes on CT. As mentioned before, CT examination in our case revealed patch-like exudation similar to lobar pneumonia, its distribution conformed to segmental change, and it occurred concurrently with the menstrual cycle. The clinical manifestations of our case were consistent with the diagnosis of PEM.

Multiple drugs have been used for the treatment of PEM, among which danazol for induction of pseudomenopause and GnRH agonist therapy for induction of ovarian castration have achieved significant therapeutic effects. Nevertheless, drug therapies are associated with major side effects and high cost because they must be taken for the long term. In addition, they only relieve symptoms. They neither treat the disease nor thoroughly remove the lesions, leading to a high relapse rate after treatment; moreover, they may induce infertility. ¹⁰ Therefore, some patients choose surgical treatment, especially those with fertility requirements. Pulmonary resection can be considered when a single point of bleeding has been definitively located. Surgery has a lower relapse rate than drug therapy. ¹¹ However, surgical resection is invasive and causes severe bodily trauma. Neither drug therapy nor surgery completely addresses the systemic effects of PEM. ⁶ Some scholars have reported that Nd-YAG laser therapy can be considered when drug therapy is ineffective or when patients cannot tolerate the drug-related side effects, especially patients with intratracheal EM. Endoscopic Nd-YAG laser therapy is a minimally invasive procedure that can eliminate mucosal and submucosal lesions. ¹² PDT treats target tissues based on the cytotoxic effect produced through the photodynamic reaction of a photosensitizer, and it can damage or kill cells with high proliferating activity, such as tumor cells and virus-infected cells. PDT has been used in the treatment of diseases including tumors and periodontitis. Some research has suggested that the ectopic endometrium comprises stroma of different stages, hyperplastic glands, and malformed blood vessels. It has relatively high proliferating activity and exhibits tumor-like biological behaviors such as invasion, colonization, and distant metastasis.^13,14 Ido et al. ¹⁵ described a patient with esophageal cancer whose coexisting esophageal varices were incidentally resolved during PDT. PDT is frequently employed in dermatology for the treatment of vascular malformations represented by the presence of a port wine stain.^16,17 In ophthalmology, PDT is used to treat new blood vessels in the iris.^18,19 The aforementioned studies suggest that apart from the ability to directly eliminate the proliferative tumor cells, PDT can also disrupt the vascular endothelium and induce occlusion of the hyperplastic blood vessels, demonstrating a favorable response of capillaries to PDT. These findings prompt us to consider whether PDT can be applied in the treatment of hemoptysis in patients with PEM.

Treatment of EM aims at suppressing lesion growth, treating pain, and ideally treating the systemic effects of the disease. ²⁰ However, therapy for PEM should be chosen according to the patient’s clinical symptoms, disease severity, and individual requirements. ²¹ In our patient, the changes in hormone levels led to failure of the ectopic endometrium and leakage from the malformed blood vessels, thereby inducing hemoptysis. ²² The photosensitizer hematoporphyrin can bind to the stroma of deformed blood vessels. As a result, it accumulates in abnormal tissues and the surrounding deformed blood vessels. Irradiation at a specific wavelength excites the hematoporphyrin, generating singlet oxygen and other free radicals. These released substances can damage the abnormal tissues and cells, lead to cell apoptosis, destroy the vascular endothelial cells, and block the blood vessels, thus achieving the purpose of destroying the ectopic endometrium, promoting hemostasis, and suppressing lesion growth. Considering the fixed, limited, and relatively superficial location of bleeding in our patient, we decided to proceed with PDT because the lesion was precisely restricted to a bronchus, which was easily reachable by the bronchoscope. To the best of our knowledge, PDT has not been previously applied in the treatment of PEM. Therefore, we referred to previous reports of PDT in the treatment of port wine stains and benign lung tumors. It is encouraging that a favorable effect was acquired after PDT in our case. After one cycle of PDT, the hemoptysis immediately disappeared with no obvious side effects. Moreover, no additional symptoms, including hemoptysis, were reported during the 2-year follow-up period.

Extrapelvic EM, including PEM, has been reported in a large number of patients; however, it was traditionally considered rare. ²³ No comparative study on the optimal diagnostic method, therapeutic strategy, or outcomes of extrapelvic EM has yet been performed. Therefore, the understanding and clinical suspicion of this disease should be improved, and multidisciplinary methods must be adopted for treating patients in a timely manner and optimizing their prognosis. However, drug therapy is associated with several drawbacks, including the necessity of long-term maintenance administration, a high recurrence rate after drug withdrawal, and serious adverse reactions. Notably, it is extremely difficult to clearly locate and display intrabronchial lesions by bronchoscopy, and this limitation has hindered the application of Nd-YAG laser therapy in PEM. In addition, Nd-YAG laser therapy may induce severe adverse reactions, including arrhythmia. ²⁴ Therefore, compared with the two above-mentioned treatments, PDT has the advantages of relatively few side effects and high patient tolerance. It also allows for lesion-targeted treatment. Our patient was still asymptomatic after a follow-up period of almost 2 years, which is a good long-term outcome. In PDT, it is not essential to accurately locate the position of the lesion within the bronchus. Instead, the clinician must only determine the segmental bronchus containing the lesion with a source of bleeding. In other words, all potential lesions within the radiation range of PDT can be treated. Accordingly, PDT can be considered as a treatment option for definite, relatively limited, and superficial bleeding sites in the lungs when drug therapy is ineffective or when its adverse effects are intolerable. Under such circumstances, this approach may achieve favorable therapeutic efficacy.

Conclusion

PDT can be a feasible option for treatment of multiple recurrent hemoptysis that relapses after drug withdrawal or that cannot be effectively controlled by drugs in patients with PEM who present with definite, superficial, and relatively limited lung lesions and no contraindications.