Background

Pulmonary hemorrhage as a manifestation of amyloidosis is an infrequent phenomenon (Ogo et al. 2021). Furthermore, pulmonary hemosiderosis is characterized by recurrent episodes of interalveolar hemorrhage, leading to abnormal iron accumulation in the form of hemosiderin within alveolar macrophages (Levy and Wilmott 1986). Systemic amyloidosis can affect the pulmonary parenchyma diffusely, tracheobronchial, or parenchymatous (García et al. 2009). Although the lungs are frequently involved in amyloidosis, pulmonary manifestations seldom present symptomatically, posing challenges to diagnosis (Riehani and Soubani 2023; Milani et al. 2017). Unusual cases of systemic AL amyloidosis with pulmonary involvement have been documented (Milani et al. 2017), and in exceptional instances, vascular involvement can trigger arterial dissection with bronchial hemorrhage, presenting pulmonary hemorrhage as an infrequent manifestation of this amyloid involvement (Road et al. 1985).

In the specific context of AL amyloidosis, a clone of plasma cells or, less commonly, a clone of lymphoplasmacytes or B cells, produces monoclonal immunoglobulins. In approximately 80% of cases, these monoclonal immunoglobulins belong to the lambda (L) light chain, as opposed to the kappa (K) chain (Lacouture-Fierro et al. 2022). This phenomenon can develop within the framework of a plasma cell dyscrasia, such as in the case of multiple myeloma (Milani et al. 2017). We present here the case of a male patient whose pulmonary hemorrhage was the initial manifestation of AL pulmonary amyloidosis with kappa light chain involvement. Confirmation of the presence of multiple myeloma was obtained through a bone marrow biopsy. This case underscores the complexity of the clinical presentation of amyloidosis and its association with multiple myeloma.

Case presentation

The clinical case presents a 60-year-old male patient who requires an emergency care due to a symptomatic presentation that has developed over 6 months. The patient does not disclose any pathological personal history, prior medication use before admission, nor any family medical history. Symptoms include hemoptoic cough associated with dyspnea, a Modified Medical Research Council score of 3, and an approximate weight loss of 8 kg. Over the past two months, there has been a symptomatic worsening with a significant increase in hemoptysis and dyspnea. Upon admission, oxygen saturation is at 85%, with no significant findings on pulmonary auscultation, no cardiac auscultation abnormalities were detected. The abdomen is soft and depressible, with no palpable hepatomegaly or splenomegaly. There is no edema in the lower extremities, and the neurological examination is normal. No lymphadenopathy was palpated. Hemogram results are normal, but biochemistry reveals mild hypercalcemia and an elevated pro-brain natriuretic peptide level. The patient is human immunodeficiency virus-negative.

Chest X-ray shows cardiomegaly and extensive parenchymal involvement characterized by diffuse fine reticular opacities in both lung fields, more pronounced in the lower lobes (Fig. 1). A Chest Angiotomography reveals bilateral multilobar ground-glass opacities, diffusely infiltrating the pulmonary parenchyma. Areas of consolidation in the lower lobes, centrilobular and subpleural hypo-densities converging in the middle lobe, with evidence of pulmonary parenchymal destruction, are observed. The interpretation suggests the possibility of small vessel vasculitis with alveolar hemorrhage and emphysematous changes (Fig. 2).

Fig. 1
figure 1

Chest X-ray

Full size image
Fig. 2
figure 2

Chest Angiotomography

Full size image

In the chest X-ray, fine reticular infiltrates are observed in both fields, with a basal predominance as indicated by the white arrow.

In the chest angiotomography, ground-glass opacities are observed (white arrow), areas of parenchymal destruction (blue arrow), and basal consolidation areas (orange arrow).

Transthoracic echocardiography shows non-obstructive concentric remodeling of the left ventricle, a dilated right ventricle with reduced function, a dilated right atrium, and mild to moderate tricuspid regurgitation. A high probability of pulmonary hypertension is suggested, with a pulmonary artery systolic pressure of 50 mmHg and an ejection fraction of 57%. This constellation of findings points toward a complex medical condition that necessitates thorough evaluation and a multidisciplinary approach for clinical management.

Autoimmune studies were conducted in response to the clinical and radiological findings, including slightly positive antinuclear antibodies and Russell's viper venom. Additional results showed negative extractable nuclear antigens, negative antineutrophil cytoplasmic antibodies, negative anticardiolipins, and normal complement levels. Tumor markers, prostate-specific antigen, alpha-fetoprotein, and carcinoembryonic antigen, returned negative results, providing additional information in the patient's assessment.

Given the complexity of the clinical picture, a fibrobronchoscopy with bronchoalveolar lavage (BAL) was performed. Macroscopic findings during this procedure suggested the presence of alveolar hemorrhage, which was confirmed by BAL analysis (Fig. 3). A total of 100 cells were observed, with 96% being inflammatory, notably dominated by histiocytes (80%) and hemosiderophages (70%). Staining with Periodic Acid–Schif (PAS), Ziehl–Neelsen, (ZN) and Gomori's stain were negative, excluding the presence of certain pathogens and specific conditions (Fig. 3A), the cellular block is depicted in Fig. 3B.

Fig. 3
figure 3

Shows Papanicolaou staining and the cellular block from BAL. A Papanicolaou at 10× magnification. BAL. Hemosiderophages containing hemosiderin pigments in their cytoplasm are observed in red circles. B Cell block at 40 × magnification, Hematoxylin and Eosin stain reveals histiocytes and hemosiderophages accompanied by an amorphous eosinophilic background interspersed with erythrocytes in blue circles

Full size image

Due to the persistence of constitutional symptoms and extensive involvement of alveolar hemorrhage, with the imminent risk of ventilatory failure, the decision was made to transfer the patient to the Intensive Care Unit. Given the low probability of autoimmune disease, a pulmonary biopsy by thoracoscopy was chosen as the consecutive course of action.

The macroscopic findings of the pulmonary biopsy revealed an anthracotic lung with grayish lines and a nodular sensation in the lingula. The pathological report indicated an atypical lymphoplasmacytoid proliferation with deposits of eosinophilic amorphous material suggestive of amyloidosis (Fig. 4). Additionally, amyloid nodules were observed (Fig. 5).

Fig. 4
figure 4

Overview at 5 × magnification, Hematoxylin and Eosin stain, revealing widened alveolar septa due to deposits of amorphous eosinophilic material indicated by a red arrow, amyloid nodules marked by a blue arrow, and amyloid deposits in vessel walls indicated by a yellow arrow

Full size image
Fig. 5
figure 5

Overview at 5× magnification, Hematoxylin and Eosin stain show Amyloid nodule marked with a blue arrow

Full size image

The immunohistochemistry results provided additional details about the cellular composition, highlighting a mixed phenotype of lymphocytes with a slight predominance of CD3, CD5, and BCL2-positive T lymphocytes. A minimal population of CD20-positive B lymphocytes was identified, with no expression of CD23 and cyclin D1. The presence of plasma cells was less than 5% of hematolymphoid cellularity, expressing CD38 (Fig. 6) and CD138 but being negative for CD 56 (Fig. 7). No kappa-lambda restriction was observed. The cellular proliferative activity, measured by Ki67, was 10%.

Fig. 6
figure 6

Photomicrograph at 40× magnification. Immunohistochemistry with CD38 reveals membrane reactivity in plasma cells, indicated by red circles

Full size image
Fig. 7
figure 7

Photomicrograph at 40× magnification. Immunohistochemistry with CD56 reveals reactivity in neoplastic plasma cells, highlighted by red circles

Full size image

The positive Congo red staining in both interstitial and nodular acellular material (Fig. 8), coupled with the negativity of PAS staining for fungi, led to the diagnosis of diffuse interstitial amyloidosis. Given the amyloid involvement in both the lung and the heart, ATTR amyloid infiltration was ruled out through pyrophosphate scintigraphy and cardiac magnetic resonance imaging.

Fig. 8
figure 8

Polarized Red Congo at 5× magnification. Amyloid deposits are observed with apple-green birefringence in vessel walls indicated by a red arrow, and amyloid nodules indicated by a blue arrow

Full size image

The investigation to rule out systemic AL amyloidosis revealed normal protein electrophoresis (Fig. 9) and immunofixation (Fig. 10). However, Kappa light chains were found to be elevated in both serum and urine (Figs. 11, 12), with an increased K/L ratio. Additionally, a decrease in immunoglobulins G and M was observed. In light of these findings, a bone marrow biopsy was conducted, confirming the presence of multiple myeloma.

Fig. 9
figure 9

Protein electrophoresis in blood sample indicates hypoalbuminemia, decreased beta-1 fraction, and hypogammaglobulinemia

Full size image
Fig. 10
figure 10

The immunofixation in serum was normal

Full size image
Fig. 11
figure 11

The urine protein electrophoresis shows a monoclonal kappa peak

Full size image
Fig. 12
figure 12

In urine immunofixation, a monoclonal kappa band is evident

Full size image

The bone marrow biopsy report indicated a plasma cell population of 10%, with a pathological phenotype monotypic for Kappa light chains, consistent with plasma cell neoplasia involvement. Flow cytometry (Fig. 13) revealed 2.72% plasma cells, of which 0.03% were polyclonal with a normal phenotype, and the remaining 2.69% were monoclonal for Kappa. Additionally, the cells were positive for CD38, CD138, and beta-2 microglobulin.

Fig. 13
figure 13

Flow cytometry performed on bone marrow. The blue population represents the myeloid granulocytic lineage. The pink population represents the erythroid lineage. The violet-colored population denotes the B lymphoid lineage, while the light blue population refers to the monocytic lineage. The red population corresponds to plasma cells with a tumoral phenotype, exhibiting intermediate SSC/FSC expression, negative for CD45 and CD19, and positive for CD138, CD38, and monoclonality for KAPPA. The final result of the flow cytometry analysis concluded the presence of neoplastic plasma cells

Full size image

Upon the diagnosis of multiple myeloma and evidence of systemic amyloidosis, no leukemic karyotypes were identified. Treatment for multiple myeloma was initiated with Bortezomib (1.3 mg/m2) 2.3 mg SC on days 1, 4, 8, and 11, Lenalidomide 25 mg orally on days 1 to 14 of the cycle, Dexamethasone 40 mg orally on days 1 and 2, 4 and 5, 8 and 9, 11 and 12 of the cycle, and zoledronic acid 4 mg IV monthly, six to nine cycles were defined based on the patient's response and progression. Antiviral prophylaxis included acyclovir, and calcium plus vitamin D supplementation was administered. Underscoring the complexity and the need for comprehensive management to address both medical conditions effectively.

The patient was evaluated by the Hematology Service both in the chemotherapy room and through an external consultation. The informed consent for the start of chemotherapy was signed.

Discussion

In the specific case of AL amyloidosis, light chains can infiltrate virtually any organ, excluding the central nervous system. This leads to variable clinical manifestations, resulting in nonspecific symptoms that hinder early disease recognition. The average time from symptom onset to diagnosis ranges from 6 to 12 months, often requiring multiple assessments by different specialists before reaching a definitive diagnosis (Milani et al. 2017). The most common symptoms include fatigue (80%), dyspnea (70%), peripheral edema (60%), constipation or diarrhea (60%), paresthesias (50%), and weight loss (30%) (Lacouture-Fierro et al. 2022). Within the most common manifestations, hemoptysis or pulmonary hemorrhage are not evident, making the diagnosis even more challenging.

In Japan, a survey conducted on AL amyloidosis patients between 2012 and 2014 included 741 participants with reported primary manifestations, such as proteinuria, renal dysfunction, congestive heart failure, orthostatic hypotension, diarrhea, arrhythmia, hepatomegaly, peripheral neuropathy, and splenomegaly. It is noteworthy that the mentioned manifestations were not present in the case under study. From the entirety of patients, only 12 reported the presence of amyloid in the pulmonary biopsy. Therefore, it is possible that amyloidosis may not be promptly considered in the differential diagnoses of a patient presenting with hemoptysis. (Shimazaki et al. 2018).

This case underscores the importance of considering pulmonary amyloidosis as a potential cause of hemoptysis, especially in patients with multiple myeloma risk factors. The patient presented with pulmonary symptoms, including dyspnea and hemoptoic expectoration, for the six months preceding admission. Initial evaluation suggested the possibility of small-vessel vasculitis with alveolar hemorrhage and emphysematous changes. The confirmation of hemosiderophages through bronchoalveolar lavage (BAL) supported the diagnosis of pulmonary hemorrhage. However, the biopsy indicated the presence of amyloid material. Given the constitutional symptoms, systemic involvement was suspected, leading to an extended investigation with protein electrophoresis, which yielded normal results. Additionally, with elevated levels of Kappa light chains in blood and urine, the diagnosis of multiple myeloma was established, subsequently confirmed through bone marrow biopsy.

In the medical literature, cases of patients with pulmonary amyloidosis associated with multiple myeloma have been documented. These cases have revealed the presence of amyloid deposits in pulmonary biopsies, concomitantly accompanied by hemosiderosis, and have presented symptoms, such as cough and dyspnea. However, hemoptysis and pleuritic pain have been less common in these situations. In our case, the predominant symptoms were hemoptysis and dyspnea, which complicated the diagnosis from the outset (Ogo et al. 2021; Kronen et al. 2022).

Despite the diversity of histopathological forms of pulmonary amyloidosis, diffuse presentations in the lungs tend to be more common in the context of systemic amyloidosis, such as multiple myeloma. This pattern suggests the possibility that pulmonary amyloidosis in our patient may be a manifestation of a systemic pathology (Liu et al. 2018).

In cases of AL amyloidosis, light chains can infiltrate nearly any organ, excluding the central nervous system. This leads to variable clinical manifestations, resulting in nonspecific symptoms that complicate the early recognition of the disease. Generally, the average time from the onset of symptoms to diagnosis ranges from 6 to 12 months, often requiring multiple assessments (Milani et al. 2017).

Given a median survival of 13 months in cases of diffuse pulmonary amyloidosis, it is crucial to achieve a timely diagnosis and promptly initiate treatment to enhance life expectancy. In the case of our patient, treatment commenced immediately under the supervision of the Hematology department (Poletti et al. 2004).

Conclusions

The case presented underscores the importance of including pulmonary amyloidosis in the differential diagnosis of patients with pulmonary hemorrhage and constitutional symptoms, particularly when associated with a plasma cell neoplasm. The complexity of the clinical presentation emphasizes the need for comprehensive evaluation and interdisciplinary collaboration to achieve an early diagnosis and appropriate treatment.