A young female with multiple cavitary lung lesions

Abstract

A 21-year-old female with a history of HPV and recurrent laryngeal papillomatosis has required frequent removal of laryngeal papilloma through direct laryngoscopy and has been treated with interferon alpha since she was 7 months old. She now presented with worsening dyspnea, hemoptysis, night sweats and significant weight loss. Infectious work up was negative. CT thorax showed significantly increasing right lower lobe mass with thick septation, debris and fluid concerning for malignant transformation. CT-guided biopsy of the mass showed features concerning for necrotic squamous cell carcinoma (SCC). Multidisciplinary tumor board classified this as malignant transformation due to bilateral lungs involvement and aggressive nature of the disease and recommended treatment with combination of chemotherapy and immunotherapy. Unfortunately, she continued to have declining performance status with multiple hospitalizations for hypoxic respiratory failure. Repeat CT scan of the chest showed progression of the lung lesions with extensive mediastinal involvement. She was unable to tolerate any additional therapy and decided with her family to pursue inpatient hospice. Malignant transformation into squamous cell carcinoma in recurrent respiratory papillomatosis is rare and is associated with worse outcomes.

1. Case presentation

A 21-year-old woman presented with a one-month history of exertional dyspnea, cough, and hemoptysis. She also endorsed dysphagia to solids, fevers, chills, night sweats and unintentional weight loss of 20 lbs. in the last 6 months. The review of systems was otherwise negative. Her medical history was notable for recurrent laryngeal and respiratory papillomatosis diagnosed since she was 7 months old.

Her vital signs were notable for hypoxia on admission that required 2 L supplemental oxygen via nasal prongs. Physical examination revealed a thin-built lady with unremarkable findings. Laboratory tests were significant for WBCs of 15.2 K/CUMM, hemoglobin of 8.5 gm/dL, and platelets of 705 K/CUMM. The chest radiograph showed multiple enlarging solid and cavitary lesions [Fig. 1]. The patient was empirically started on antibiotics due to the concerns of superimposed infectious process. However, the infectious work up, including sputum gram stain & culture, respiratory viral panel, AFB stain & culture, and fungal serology, were negative and therefore, antibiotics were discontinued.

Fig. 1.

Chest radiograph with a posteroanterior projection showing large right lower lobe mass (blue arrow) and multiple bilateral cavitary lesions (orange arrow).

Of note, she had undergone multiple interventions via direct laryngoscopy and bronchoscopy with micro debridement and CO2 laser for the removal of papillomas since the time of diagnosis [Bronchoscopic images]. She was also started on interferon alpha for the disease progression and involvement of lung parenchyma but it was later discontinued due to significant fatigue. She was noted to have lung involvement with multiple cavitary lesions and nodules. She had undergone CT-guided biopsy of the largest cavitary lesion in the right lower lobe, which was negative for malignant transformation.

During this hospitalization flexible laryngoscopy was performed that revealed evidence of a post-resection scar band at the superior aspect of the epiglottis and the posterior aspect of the left true vocal cord with otherwise widely patent glottic opening with good movement of bilateral true vocal cords without upper airway obstruction. A CT scan of the chest showed significantly increasing bilateral multiple nodules and cavitating masses as compared to the previous CT scan. The largest mass in the right lower lobe with thick septation, debris and fluid, was concerning for malignant transformation [Fig. 2]. Therefore, CT-guided biopsy of the growing right lower lobe mass was done that showed necrotic squamous cells without atypia. The image-guided biopsy consisted of four tan white tissue cores measuring up to 0.5 cm. Microscopic examination showed the pulmonary parenchyma to be replaced by a squamous proliferation forming solid nests with bland cytologic features. Patchy necrosis was present, but no cytologic atypia or prominent desmoplastic reaction was seen.

Fig. 2.

A-B CT thorax lung window, axial sections showing bilateral cavitary lesion (orange arrow) with largest cavitary mass in the right lower lobe (green arrow), solid nodule in the right upper lobe (blue arrow) and tracheal papilloma (red arrow)

C- Sagittal and D & E coronal sections showing similar bilateral thick-walled cavitary lesions of different sizes (orange arrows) and large mass (green arrows)

F- Mediastinal window showing cavitary lesion (orange arrow) and large mass with areas of necrosis and debris (green arrow).

Question: What is the diagnosis?

Juvenile-onset recurrent respiratory papillomatosis with extensive pulmonary involvement.

2. Clinical discussion

This patient's clinical and radiological presentation was exertional dyspnea, hemoptysis, significant weight loss, and multiple bilateral enlarging cavitating necrotic lesions in the lungs. The initial differential diagnosis included superimposed acute infection such as pneumonia, tuberculosis, fungal disease, lung abscess and pulmonary papillomatosis with malignant transformation into squamous cell carcinoma of lung. The presence of enlarging cavitating lung lesions with negative infectious work up in a patient with history of recurrent respiratory papillomatosis (RRP) were highly concerning for the possibility of malignant transformation.

RRP is the most common benign laryngeal tumor caused by human papillomavirus (HPV). The incidence of infantile RRP is 4.5 per 100,000 children, likely due to HPV (most commonly types 6 and 11) acquired during vaginal delivery from the infected mother [[1], [2], [3]]. Our patient was positive for HPV subtypes 8, 11, 16, 18, 31, 33 and 51. Patients may present with varying severity of respiratory symptoms. Hoarseness and stridor are the common presentations requiring multiple tumor resections. HPV mutation may cause the progression of RRP to involve lower airways beyond vocal cords in 3–5 % cases, lung parenchyma in 3.3 %, and rarely, lung SCC in <1 % of cases (p53 genetic mutation). Infection with HPV-11, young age (<3 years), and previous surgical intervention are other risk factors in lower respiratory tract involvement.

CT scan is the standard imaging modality to characterize tracheobronchial and pulmonary lesions and follow disease progression [4]. Risk factors for malignant transformation include multiple recurrences along with exposure to immunosuppressants, radiation, chemotherapeutics, and smoking; the first two factors were present in our patient [3]. Given the possibility of malignant transformation, patients should be regularly followed up with serial CT scan of chest at a pulmonologist discretion [4].

There is no definitive curative treatment for RRP. Surgical excision for debulking of papilloma remains the mainstay of treatment. However, surgical complications such as respiratory tract burns, airway scarring and stenosis, and tracheoesophageal fistula have led to the use of other modalities such as CO2 laser resection or precise debridement with microdebrider [5]. Lesion recurrence after surgical procedures is common despite the adoption of new techniques and modern equipment. Tracheostomy is often required for extensive disease with the risk of laryngeal airway obstruction.

Several adjuvant therapies have been administered with little consensus on which treatments are most effective and the timing of their administration. These therapies include antiviral agents such as acyclovir, ribavirin or cidofovir. Systemic and intralesional interferon has also been used with some positive results in the reduction of lesion growth. However, interferon is not usually well tolerated because of systemic toxicity. It was discontinued in our patient secondary to severe fatigue. There is evolving data regarding the use of intralesional and systemic bevacizumab early in the RRP disease process to decrease disease progression and surgical/endoscopic interventions [6]. Prophylactic quadrivalent vaccine against HPV subtypes 6, 11, 16, and 18 can be a preventative option to decrease the incidence of RRP and should be considered in all patients [1,7,8]. Extensive RRP with pulmonary involvement is more aggressive and has poor outcomes as compared to the laryngeal lesions most commonly due to acute airway obstruction, respiratory infection, and malignant transformation [1,3].

The case was discussed in the multidisciplinary tumor board and the decision was made to treat it as malignant transformation into squamous cell carcinoma with a combination of chemotherapy and immunotherapy. This decision was clinically justified despite the negative pathology for malignancy due to the extensive lung involvement and the possibility of false negative biopsy. The patient was then started on Carboplatin/Abraxane/Pembrolizumab. She required multiple chemotherapy regimens including enrollment in a clinical trial over the course of sixteen months. Unfortunately, she continued to have declining performance status with multiple hospitalizations for hypoxic respiratory failure. Repeat CT scan of the chest showed enlargement of the lung lesions with extensive mediastinal involvement. She was unable to tolerate any additional therapy and decided with her family to pursue inpatient hospice and eventually passed away.

3. Radiological discussion

A systematic approach to cavitary lesions with specific clinical presentation, duration of symptoms, laboratory and radiological features can help establish the diagnosis in most cases [Table 1]. Acute or subacute cavitary lesions have been defined based on the duration of symptoms being ≤12 weeks [9].

Table 1.

Differential diagnosis of cavitary lesions of the lung based on the clinical and radiologic features.

Etiology	Clinical features	Radiological features	Differential diagnosis
Infection (Acute/subacute/chronic)	Fevers, chills, cough, risk factors for aspiration, history of IV drug use or infected invasive devices	Unilateral, thick walled, irregularly shaped, air fluid level Necrotic tissue surrounding the cavitation Multiple peripheral, small nodules with cyst Solitary or multiple thick wall cavitary lesion, apical or fibro cavitary lesion Multiple nodules with Halo sign which may cavitate leading to Air crescent sign Multiple, bilateral cavitary/nodular/consolidative changes Mucus plugging (Finger in glove appearance), atelectasis, Bronchiectasis, thin walled cavities with adjacent nodules	Lung abscess Necrotizing pneumonia Septic emboli Mycobacterium Tuberculosis (TB) Non-Tuberculous Mycobacterium (NTM) Invasive Pulmonary Aspergillosis (IPA) Fungal Parasitic Tracheobronchial Papillomatosis (HPV)
Rheumatologic lung diseases	Extrapulmonary manifestations of rheumatologic conditions with positive serology.	Multiple, bilateral, well defined nodules with central cavitation	Rheumatoid Arthritis (RA) Granulomatosis with polyangiitis (GPA)
Malignancy	Alarming features like chronic cough, hemoptysis, significant weight loss, smoking history, personal/family history of malignancy.	Solitary, upper lobe predominance, irregular walled cavity Multiple pulmonary nodules which can cavitate	Primary lung cancer (Squamous cell carcinoma) Pulmonary metastasis
Congenital	Usually asymptomatic, incidental findings on the imaging	Cystic or solid lung masses restricted to one part of the lung	Congenital cystic adenomatoid malformation Bronchogenic cyst Pulmonary sequestration

Our patient with known recurrent respiratory papillomatosis presented with multiple enlarging bilateral cavitary lung masses with consolidative changes and areas of necrosis. There was no air-fluid level, halo sign or air cresent sign evident on CT thorax. All of these findings were highly concerning for recurrent respiratory papillomatosis with malignant transformation into squmoaus cell carcinoma especially after the superimposed acute infectious process was ruled out.

RRP usually presents as laryngeal papillomas. It can disseminate to the tracheobronchial tree and lungs. There is evidence of ∼5 % of cases with laryngeal involvement and only 1 % of the cases can have pulmonary involvement [10]. CT scan findings include focal or diffuse airway narrowing or obstruction caused by nodular mucosal lesions projecting into the lumen.

The radigrphic patterns of pulmonary involvement from papillomatosis can vary. They can present as single or multiple multilobulated, well-defined, solid nodular or polypoid lesions. These lesions can be of various sizes, have a centrilobular distribution, and are scattered throughout the lungs. These lesions have a predilection for basal and posterior portions of the lungs. As the nodules grow they can become confluent. They can also transform into air-filled cysts or thick-walled cavities with or without central necrosis. In case of superimposed infections, air-fluid level, atelactasis, mucus plugging (finger-in-glove appearance), consolidative changes, air trapping, and bronchiectasis can be seen. Malignant transformation into squamous cell carcinoma can be seen in about 1 % of the cases [11]. It is suspected when there is an interval increase in the size of the mass or nodules along with mediastinal or hilar lymphadenopathy.

4. Pathologic discussion

Squamous papillomas grossly present as white or pink cauliflower-like lesions, and microscopically, they exhibit papillary fronds with loose fibrovascular cores covered by stratified squamous epithelium [12]. Cytologic features typical of HPV viral cytopathic effect are frequent findings, including wrinkled nuclei and perinuclear halos. Dysplasia is graded according to WHO classification as mild dysplasia, moderate dysplasia, severe dysplasia or carcinoma in situ based on features including maturation/orientation, nuclear pleomorphism, and the nuclear-cytoplasmic ratio [12]. Squamous cell papillomas/papillomatosis can infiltrate pulmonary parenchyma, resulting in cytologically bland squamous cells forming solid nests or lining cystic spaces [12]. Malignant transformation in lung involvement has been described, but is rare [13,14].

Multiple excision and biopsy specimens from this patient were examined at this institution from the time she was an infant to the age of 21. The earliest lesions lacked dysplasia, but at age 17 mild dysplasia was first diagnosed. At no time was moderate or severe dysplasia identified in the RRP. Pulmonary involvement by RRP was first diagnosed at age 14. She was biopsied again at age 21 (when she had multiple cavitary lung lesions). That lung biopsy showed replacement of normal pulmonary parenchyma by bland squamous epithelium without dysplasia [Fig. 3a]. The squamous epithelium surrounded small spaces lined by TTF-1 positive respiratory epithelium [Fig. 3b]. A repeat lung biopsy taken 6 months later at age 21 showed similar features, but in addition showed patchy necrosis [Fig. 3c]. Immunohistochemical staining for p16 was negative and immunohistochemical staining for p53 was wild-type in the lung involvement. Malignant transformation was not identified.

Fig. 3a.

A lung biopsy at age 21 showed RPP involving lung parenchyma, and characterized by replacement of normal parenchyma by bland-appearing squamous epithelium (asterisk) surrounding small spaces lined by respiratory epithelium (arrow). No dysplasia is present. (Hematoxylin and eosin, x100).

Fig. 3b.

Immunohistochemical staining for TTF-1 highlights the respiratory epithelium (arrow). (TTF-1 immunohistochemistry, x100)

Fig. 3c.

A lung biopsy taken 6 months after that illustrated in Fig. 1a and b shows patchy necrosis (asterisk), but no significant cytologic atypia or invasion. (Hematoxylin and eosin, x100).

An important differential diagnosis of lung involvement in RRP includes transformation to squamous cell carcinoma, which has been reported in HPV 11 positive cases of RRP [14]. p16 is usually expressed strongly and diffusely by HPV-dependent squamous cells carcinoma; however, p16 has been reported as negative in reports of malignant transformation, suggesting another pathway for tumor progression [14], and indicating that p16 is not a reliable marker for malignant transformation in this setting. The diagnosis of malignant transformation requires histologic features characteristic of squamous cell carcinoma, including significant cytologic atypia, destructive invasion, and desmoplastic response. Unfortunately, needle core biopsies provide limited tissue for evaluation, and because foci of malignancy are geographically limited, there exists the possibility of sampling error leading to a false negative diagnosis. The differential diagnosis in this setting also includes florid squamous metaplasia, the latter sometimes resulting from pulmonary injury, including diffuse alveolar damage.

5. Conclusion

RRP is the most common benign neoplasm of the larynx caused by human papilloma virus (HPV) infection types 6 and 11. Pulmonary invasion is reported to occur in 3 % of the patients with RRP. Malignant transformation to squamous carcinoma is seen in 0.5 % of the cases. Radiographic presentations include single or multiple pulmonary nodules, cysts or cavitary lesions. There should be a low threshold and high index of suspicion to biopsy these lesions when a malignant transformation is suspected. Moreover, multidisciplinary discussion with pulmonary, thoracic oncology, and thoracic surgery should be considered to guide the treatment plan if there is a high degree of suspicion for malignant transformation to squamous cell carcinoma even if the biopsy results are negative given the aggressive nature of the disease.

CRediT authorship contribution statement

Amina Pervaiz: Writing – review & editing, Writing – original draft, Resources. Sharad Oli: Resources. Waed Alkaram: Writing – original draft. Shefali Godara: Resources. Suzanne M. Jacques: Writing – review & editing, Supervision. Khaled Alshabani: Supervision.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Handling Editor: DR AC Amit Chopra