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March, 2021
Case of the Month

Clinical History: A 64-year-old woman with worsening exertional dyspnea underwent a chest CT without contrast, which was described as showing moderate pulmonary fibrosis with probable centrilobular and paraseptal emphysema, and multiple, bilateral noncalcified lung nodules, measuring up to 1 cm. Her past medical history was most significant for severe developmental delay. She was a never smoker. A wedge biopsy of the lung was performed for evaluation of interstitial lung disease. H&E-stained sections are shown in Figures 1-5. AFB and GMS were negative (not shown). Immunostains for smooth muscle actin (SMA), estrogen receptor (ER) and HMB-45 are shown in Figure 6.

Quiz:

Q1. Which immunohistochemical stain, when positive, is the most helpful in evaluating the smooth muscle-like spindle cells and establishing the diagnosis?

  1. HMB-45
  2. Estrogen receptor
  3. Progesterpone receptor
  4. Smooth muscle actin

Q2. In the lung, the characteristic distribution of the granulomas in this entity is

  1. Random
  2. Lymphangitic
  3. Air-space centered
  4. Bronchiolocentric with cavitation

Q3. Which of the following would best explain the histologic findings?

  1. An atypical mycobacterial infection.
  2. Surreptitious smoking.
  3. A history of uterine leiomyoma
  4. Tuberous sclerosis complex

Answers to Quiz

Q1. A
Q2. B
Q3. D

Diagnosis

1) Lymphangioleiomyomatosis; 2) Non-necrotizing granulomatous inflammation, consistent with sarcoidosis

Discussion

Histologic sections show well-formed, non-necrotizing granulomas confined to the interstitial compartment that aggregate to form macroscopic nodules with a characteristic pattern of lamellar fibrosis. This combination of features is typical of sarcoidosis, which tends to show a lymphangitic distribution, tracking along bronchovascular bundles, interlobular septa, and the visceral pleura. Granulomatous infection typically shows either randomly distributed or bronchiolocentric granulomas with or without necrosis that can involve both the interstitial compartment and distal airspaces. Pulmonary Langerhans cell histiocytosis, which radiographically presents as nodules and cysts, is an interstitial lesion seen almost exclusively in smokers that shows a bronchiolocentric distribution of fibroinflammatory nodules and stellate scars, and is characterized by the presence of CD1a-positive Langerhans cell sheets.

In the current case, in addition to the granulomas, there are scattered cysts, some of which show subtle, focal collections of abnormal smooth-muscle like spindle cells within the cyst walls focally infiltrating the perivascular interstitium. Upon closer inspection, the spindle cells show centrally-located, oval nuclei and variably abundant, slightly vacuolated pale eosinophilic cytoplasm. This combination of features is diagnostic of lymphangioleiomyomatosis, a diagnosis supported by the presence of immunoreactivity for HMB-45. The differential diagnosis includes benign metastasizing leiomyoma. When cystic, BML tends to show a circumferential population of atypical spindle cells, in contrast to the localized aggregates in LAM. Additionally, benign metastasizing leiomyoma is positive for SMA and ER/PR, but negative for HMB-45.

Lymphangioleiomyomatosis is a rare disorder almost exclusively affecting women and frequently occurring in the setting of tuberous sclerosis complex. Other manifestations of tuberous sclerosis include neuropsychiatric symptoms and renal angiomyolipomas. Given the history of developmental delay in this patient, the possibility of tuberous sclerosis was raised, leading to subsequent discovery of a renal angiomyolipoma. Rare case reports describe coexistent sarcoidosis and lymphangioleiomyomatosis; however, the association is likely random.

Take home message: Immunohistochemistry for HMB-45 can be helpful in establishing a diagnosis of lymphangioleiomyomatosis, particularly when the diagnosis is unexpected.

References

Cullivan S, De La Harpe Golden P, Doyle D, et al. Coexistent sarcoidosis and lymphangioleiomyomatosis in a patient with cystic lung disease. Respirol Case Rep 2018;7:e00389.

Di Marco F, Palumbo G, Terraneo S, et al. Lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia, and sarcoidosis: more pathological findings in the same chest CT, or a single pathological pathway? BMC Pulm Med 2017;17:107.

Johnson SR, Taveira-DaSilva AM, Moss J. Lymphangioleiomyomatosis. Clin Chest Med 2016;37:389-403.

Mukhopadhyay S, Gal AA. Granulomatous lung disease: an approach to the differential diagnosis. Arch Pathol Lab Med 2010;134:667-90.

Contributors

Kristine E. Konopka, MD
Assistant Professor of Thoracic Pathology
University of Michigan Ann Arbor, MI

Jeffrey L. Myers, MD
A. James French Professor of Diagnostic Pathology
University of Michigan Ann Arbor, MI
2022 PPS Lifetime Achievement Award
Kevin Leslie, MD
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